November 2021
Assessment of serum prolidase levels in patients with coronary artery in-stent restenosis
Tolga Memioğlu, Selim Ayhan, Ibrahim Dönmez
Department of Cardiology, Abant Izzet Baysal University Medical Faculty, Bolu, Turkey
DOI: 10.4328/ACAM.20689 Received: 2021-05-05 Accepted: 2021-07-17 Published Online: 2021-08-09 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1198-1202
Corresponding Author: Tolga Memioglu, Izzet Baysal State Hospital, Department of Cardiology, Saglik Mahallesi, Sehitler Cd., No: 20, 14300, Bolu, Turkey. E-mail: tolgaptca@hotmail.com GSM: +90 5531193323 P: +90 374 270 45 75 F: +90 374 270 45 85 Corresponding Author ORCID ID: https://orcid.org/0000-0002-3183-5815
Aim: Prolidase is an enzyme, which plays a role in the formation of a new matrix, collagen metabolism and cell development. It is known that the most important mechanism underlying in-stent restenosis is neointimal hyperplasia. Neointimal hyperplasia is associated with collagen synthesis and matrix proteins. The objective of our study was to reveal the relationship between serum prolidase levels and in-stent restenosis.
Material and Methods: This study included a total of 70 patients who were identified to be at a moderate and high risk as a result of clinical or non-invasive tests in the cardiology and emergency clinics of the Abant Izzet Baysal University training and Research Hospital and who underwent angiography. In-stent restenosis was identified in 40 patients. In the remaining 30 patients, there was no angiographically determined critical lesion. Serum prolidase levels were measured in all patients.
Results: The mean serum level of prolidase was found to be statistically significantly higher in the in-stent restenosis group compared to the restenosis-free group (p=0.02). The mean serum level of prolidase level was significantly higher in smokers compared to the non-smoker patients (p=0.04). It was observed that serum prolidase levels statistically significantly increased proportionally to the in-stent restenosis percentage (p=0.04).
Discussion: The results of this study indicate that prolidase enzyme levels may enable timely and correct assessment of in-stent restenosis, and may contribute to the decision for changing the treatment or timing to increase the intensity of the treatment in patients undergoing percutaneous coronary intervention (PCI) with coronary stenting.
Keywords: Percutaneous Intervention, Coronary Stent, In-Stent Restenosis, Prolidase
Introduction
In the world, cardiovascular diseases are the most frequent cause of mortality [1]. Despite novel modern treatment methods and the use of complex interventional and surgical techniques, mortality rates from these diseases remain high [2]. CVDs involve coronary arterial diseases (CAD), peripheral vascular diseases, hypertension (HT), cerebrovascular diseases, congestive heart failure (CHF), and congenital and valvular heart diseases; whereas, CADs include angina, myocardial infarction (MI), coronary failure, and coronary death [3]. The known most important risk factors of CAD are age, diabetes mellitus (DM), HT, smoking, dyslipidemia, obesity and sedentary lifestyle [4]. CADs more than 1.2 million myocardial infarction (MI) cases and more than 500.000 deaths every year in the USA [5].
In the treatment of CAD, the most commonly used interventional techniques include percutaneous transluminal coronary angioplasty (PTCA), coronary stent implantation and some therapeutic coronary devices. These methods are collected under the umbrella of percutaneous coronary intervention (PCI) [6]. Today, approximately 1.000.000 PCI procedures are performed annually in the USA [7].
A coronary stent implantation is now more widely used since it leads to fewer complications and provides better long-term clinical outcomes compared to PTCA.
One of the most important problems encountered following coronary stent implantation is restenosis of the coronary arterial stent. Coronary artery stent restenosis can be defined as a decrease in the artery diameter caused by the damage occurring during coronary revascularization and the resultant negative response against this condition [8].
Coronary artery restenosis often occurs in the form of in-stent restenosis (ISR). ISR has always been considered the “enemy” for interventional cardiologists, thus many technical advancements (bare metal, drug-eluting stents, drug-coated balloons) aimed at preventing ISR [9]. ISR has been shown to be an independent predictor for mortality during follow-up together with the other clinical risk factors including age, sex, DM, smoking, previous by-pass operation, and left ventricular ejection fraction [10]. Today, the rate of ISR may be as high as 60% to 80%. This rate may rise to 70% in patients with risk factors such as diabetes mellitus [11]. Coronary stent implantation has decreased the incidence of ISR compared to PTCA. Today, coronary stent implantation is the most frequently used method in the treatment of obstructive CAD to reduce ISR and is a better option than surgical revascularization. Despite advancements in medical and technological fields, ISR is a still not fully resolved problem. Smooth muscle cell proliferation and neointimal hyperplasia are the most important causes of ISR. This study was planned considering that serum prolidase enzyme, which plays a role in collagen formation, may be effective in ISR as well.
Prolidase is an enzyme that breaks peptide bonds in proline- containing dipeptides (X-Pro) and is found in many tissues such as bone, connective tissue, kidney, heart, intestinal mucosa, liver, brain, uterus, thymus, erythrocytes, leukocytes, fibroblasts and plasma. It contributes to the formation of new matrix and cellular growth in collagen metabolism.
Prolidase plays a role in the catabolism of proteins containing procollagen, collagen, proline and hydroxyproline inside the cell [12]. Proline and hydroxyproline amino acids, released by the prolidase enzyme, make up about 25% of the collagen tissue and help maintain the continuity of connective tissue. The increased destruction of collagen causes an increase in serum prolidase activity [13]. In a study about prolidase, it was aimed to determine the relationship between serum prolidase activity and ischemia time in different ischemia types. In conclusion, it was found that serum prolidase enzyme activity may be an important biomarker in predicting ischemia time [14].
To our knowledge, so far there have been no studies investigating the value of serum prolidase in patients with in- stent restenosis. Therefore, the objective of this study is to reveal the relationship between ISR and serum prolidase levels.
Material and Methods
This study included a total of 70 patients who were identified to be at a moderate and high risk as a result of clinical or non- invasive tests in the cardiology and emergency clinics of the Abant Izzet Baysal University training and Research Hospital, and who underwent angiography between 2013 through 2014. Forty patients with in-stent restenosis were assigned to the study group and the remaining 30 patients without ISR to the control group, and the results were compared between both groups.
Before the beginning of the study, the necessary approval was received from the local ethics committee of our hospital dated 23/12/2013 and 2013/08-249 numbered decision, in accordance with the Patient Rights Regulation and ethical principles. This study was supported by the Abant Izzet Baysal University, Scientific Research Projects Unit with the Project No: BAP – 2014.08.31.731. All participants signed written informed consent forms.
Patients with acute coronary syndrome, serious valvular diseases, severe coronary artery disease that may affect serum prolidase level, collagen tissue disease, chronic kidney and liver failure and rheumatological disease were excluded from the study.
Patients’ age, gender, presence of DM, HT, cholesterol levels, smoking status, history of PCI, ejection fraction (%EF), biochemical and hematologic parameters, drugs used, angiography outcomes, ISR stenosis rates, stent types (bare- metal stent/drug-eluting stent) and serum prolidase levels were investigated in details and recorded.
All angiography and PCI procedures were performed by cardiologists experienced in interventional procedures using the Siemens Axiom Artis angiography device with standard methods. A narrowing of ≥50% in the lumen diameter in the stent area was considered restenosis. A venous blood sample of 8 cc was drawn to a biochemical tube, centrifuged at 4000 ppm for 10 minutes, and the obtained serum sample was stored at -72oC until the analysis. Serum prolidase level was then studied in this sample in the laboratory of AIBU Medical Faculty Biochemistry Department. Measurements were done with the ELISA method using the Cusabio kit.
Statistical Analysis:
Data obtained in this study were statistically analyzed using SPSS (15.0, Inc, Chicago, IL, USA) statistical software.
Categorical variables were expressed as frequency and percentage. Continuous variables were expressed as mean ± standard deviation or median values. The Student’s t-test was used to compare continuous variables between the groups, while the Chi-square test was used to compared categorical variables. To calculate the correlations between continuous variables, Pearson’s analysis was used in parametric data and Spearman’s method in non-parametric data. Linear regression analysis was performed to determine independent predictors of stent restenosis. P values <0.05 were considered statistically significant.
Results
A total of 70 patients who had stents in their coronary arteries within the last year and underwent coronary angiography due to any indication other than acute coronary syndrome were included in this study. ISR was found in 40 patients.
The mean age was 63.3±10.3 years in the patient and 61.7±11.1 years in the control group (p=0.5). In the patient group, 9 patients were female and 31 were male, whereas in the control group, 11 were female and 19 male (p=0.19). The incidence of ISR was significantly higher in smokers compared to nonsmoker patients (Figure 1) (p=0.04). No statistically significant difference was found between ISR and control groups in terms of DM and HT (for all; p>0.05).
Again, no statistically significant difference was found between the ISR and control groups in age, echocardiographic parameters (left ventricular diastolic diameter, left ventricular systolic diameter, ejection fraction), urea, creatinine, hemoglobin, MCV, WBC, PLT, LDL, and NON- HDL cholesterol levels (for all; p>0.05).
Table 1 shows demographic features and Table 2 echocardiographic and laboratory parameters in patients with and without ISR.
When the drugs used were evaluated between the groups, no statistically significant difference was found between the ISR and control groups in terms of using beta blockers, statins, ACE inhibitors and/or angiotensin receptor blockers (ARB) (fol all; p>0.05).
There was no significant difference between the ISR and control groups in terms of stent types and coronary arteries where the stent was inserted (for all; p>0.05) (Table 3). Coronary arteries with ISR are seen in Figure 2.
In the comparison between the increase of restenotic stent rate and serum levels of prolidase, it was observed that serum prolidase level increased as the rate of restenotic stents increased, and this relationship was statistically significant (p=0.04).
The GENSINI angiographic score was statistically significantly higher in the ISR group compared to the control group (35.7±26.8 vs 19.8±17) (p=0.002).
The serum level of prolidase was found to be statistically significantly higher in the ISR group than in the control group (993.18 ± 609.99 mU/mL vs 468.53 ± 258.92 mU/mL) (p=0.02). A comparison of serum prolidase levels between ISR and control groups is shown in Figure 3.
In the multivariate linear regression analysis, independent predictors of stent restenosis were determined as prolidase, age, LDL and Gensini score.
When correlations between the parameters were evaluated, there was a moderate correlation between prolidase level and restenotic stent rate according to Pearson’s correlation analysis (r: 0.44, p: 0.03). In the linear regression analysis, including serum prolidase level, age, LDL and Gensini’s score; serum prolidase level (β: 0.45, p: 0.02) and Gensini’s score (β: 0.56, p: 0.02) were found to be independent predictors of in-stent restenosis.
Discussion
In our study, serum prolidase level was found to be significantly higher in the ISR group compared to the control group. In the correlation analysis, prolidase level was correlated with the rate of restenosis. In the linear regression analysis, we found that serum prolidase level and Gensini’s score were independent predictors of stent restenosis.
In-stent restenosis is defined as the gradual re-narrowing of the lesion in the stent in the coronary artery as a result of arterial damage and subsequent neointimal tissue proliferation [15]. It has been shown that coronary artery stent restenosis is a negative response caused by a decrease in vascular diameter due to damage occurring during coronary revascularization [8]. Neointimal hyperplasia is known to be the most important mechanism underlying ISR [16].
Neointimal hyperplasia is associated with collagen synthesis and matrix proteins. Previous studies have shown that, because of the wide tissue distribution, changes in serum prolidase enzyme levels may play a role in the development and outcome of many diseases and is directly associated with the synthesis of collagen, which is abundantly found in the body [14, 17, 18]. ’Rabus et al. compared 26 patients who underwent valve replacement due to rheumatic etiology, 24 patients who underwent valve replacement due to degenerative etiology and 20 healthy volunteers in terms of prolidase enzyme levels. Serum level of prolidase enzyme was statistically significantly higher in the control group than in the patient group (p<0.001). No significant difference was observed between rheumatic and degenerative valve replacement groups in terms of prolidase enzyme levels. There was no significant correlation between serum prolidase level and severity of valvular disease (p>0.05). The authors stated that rheumatic and degenerative valvular diseases were associated with decreased serum prolidase enzyme level [19].
In a study by Akturk et al. evaluating serum prolidase levels in 40 patients with coronary artery ectasia (CEA) and 40 control subjects with angiographically normal coronary arteries, serum prolidase level was found to be significantly higher in CEA patients and was an independent predictor of CEA [20].
In another study, serum level of prolidase enzyme was compared between the patients with ischemic and idiopathic dilated cardiomyopathy (DCM) and healthy individuals, and prolidase enzyme levels were found to be significantly lower in patients with ischemic DCM compared to the other two groups. The authors stated that the results obtained from this study were the opposite of those predicted. Normally, serum prolidase level is expected to be higher in patients with ischemic etiology, and the authors proposed that lower serum prolidase levels found in patients with ischemic etiology may be caused by decreased collagen cycle in heart tissue and decreased physical activity in these patients [21].
Demirbag et al. compared hypertensive patients with and without left ventricular hypertrophy and healthy individuals. In that study, serum prolidase level was significantly higher in the hypertensive patient groups and was associated with the duration of hypertension. [22].
In a study evaluating CAD patients, Yildiz et al. Compared 199 patients with severe CAD and 122 healthy individuals. Serum prolidase activity was found to be significantly higher in the CAD group (52.5±5.6 U/L vs 46.7± 5.1 U/L, p<0.001). On the other hand, the authors stated that serum prolidase level was an independent predictor of CAD [23].
In a study by Suner et al., the authors stated that increased prolidase activity may contribute to the development of slow coronary flow [24].
As we mentioned so far, prolidase enzyme levels have been evaluated in various cardiac conditions such as valvular diseases, hypertension and dilated cardiomyopathy, although there are no sufficient studies about the value of prolidase in patient groups with CAD and stent restenosis. Therefore, in the present study, we found significantly higher serum levels of prolidase in the patient group than in the control group (993.18± 609.99 mU/mL vs 468,53± 258,92 mU/mL, p= 0.02). In the current study, we demonstrated that serum prolidase levels were moderately correlated with the severity of stent restenosis. On the other hand, we found that serum prolidase level was an independent factor in predicting the severity of in- stent restenosis (β: 0.45, p: 0.02).
We think that the underlying reason for the high serum prolidase level in patients with stent restenosis was associated with the prolidase’s direct role in collagen synthesis and thus, its indirect role in the development of neointimal proliferation.
Study Limitations
Relatively small number of patients, lack of sufficient data about PCI procedures performed in patients (diameters and sizes of stents, duration and pressure of balloon inflation etc.) and the lack of evaluation of other biomarkers that play a role in the collagen mechanism are the main limitations of this study. Conclusion:
The data obtained in this study indicate that serum prolidase enzyme level is closely related with in-stent restenosis and is an independent factor in predicting the severity of in-stent restenosis.
Our results suggest that serum prolidase enzyme levels will enable early and correct evaluation of stent restenosis in patients undergoing PCI with coronary stents and will contribute to determining the time of altering or intensifying the existing treatment. Further comprehensive clinical studies with a large number of patients are needed to support our results.
Acknowledgment
We would like to thank Mehmet Tosun, MD from Abant Izzet Baysal University Medical Faculty, Department of Biochemistry for his valuable support in biochemical analyses.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. WHO. World Health Organization Cardiovascular Diseases. (https://www. who.int/health-topics/cardiovascular-diseases#tab=tab_1. Date of Access: 05.08.2021)
2. Mensah GA, Goff DC, Gibbons GH. Cardiovascular Mortality Differences-Place Matters. JAMA. 2017; 317(19):1955-7.
3. Buijtendijk MFJ, Barnett P, van den Hoff MJB. Development of the human heart. Am J Med Genet C Semin Med Genet. 2020; 184(1):7-22.
4. Joseph P, Leong D, McKee M, Anand SS, Schwalm J-D, Teo K, et al. Reducing the Global Burden of Cardiovascular Disease, Part 1: The Epidemiology and Risk Factors. Circ Res. 2017; 121(6):677-94.
5. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, et al. Heart disease and stroke statistics-2009 uptade: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009; 119(3):480-6.
6. Bhatt DL. Percutaneous Coronary Intervention in 2018. JAMA. 2018; 319(20):2127-8.
7. ’Trends in Characteristics and Outcomes of Hospital Inpatients Undergoing Coronary Revascularization in the United States, 2003-2016. Alkhouli M., Alqahtani F., Kalra A., Gafoor S., Alhajji M., Alreshidan M.,Holmes D.R., Lerman A. JAMA Network Open. 2020;3(2):e1921326. Corrected on April 28, 2020.
8. Kokkinidis DG, Waldo SW, Armstrong EJ. Treatment of coronary artery in-stent restenosis. Expert Rev Cardiovasc Ther. 2017; 15(3):191-202.
9. Cortese B, Berti S, Biondi-Zoccai G, Colombo A, Limbruno U, Bedogni F, et al. Drug-coated balloon treatment of coronary artery disease: a position paper of the Italian Society of Interventional Cardiology. Catheter Cardiovasc Interv. 2014; 83(3):427-35.
10. Cassese S, Byrne RA, Schulz S, Hoppman P, Kreutzer J, Feuchtenberger A, et al. Prognostic role of restenosis in 10 004 patients undergoing routine control angiography after coronary stenting. Eur Heart J. 2015; 36(2):94-9.
11. Glovaci D, Fan W, Wong ND. Epidemiology of Diabetes Mellitus and Cardiovascular Disease. Curr Cardiol Rep. 2019; 21(4):21.
12. Karna E, Szoka L, Huynh TYL, Palka JA. Proline-dependent regulation of collagen metabolism. Cell Mol Life Sci. 2020; 77(10):1911-18.
13. Kayadibi H, Gultepe M, Yasar B, Ince AT, Ozcan O, Ipcioglu OM, et al. Diagnostic value of serum prolidase enzyme activity to predict the liver histological lesions in non-alcoholic fatty liver disease: a surrogate marker to distinguish steatohepatitis from simple steatosis. Dig Dis Sci. 2009; 54(8):1764–71.
14. Aciksari G, Demir B, Uygun T, Gedikbasi A, Kutlu O, Atici A, et al. Serum prolidase activity in patients with cardiac syndrome X. North Clin Istanb. 2020; 7(5):471-7.
15. Nicolais C, Lakhter V, Virk HUH, Sardar P, Bavishi C, O’Murchu B, et al. Therapeutic Options for In-Stent Restenosis. Curr Cardiol Rep. 2018; 20(2):7.
16. Zhou W, Lin PH, Bush RL, Peden EK, Guerrero MA, Kougias P, et al. Management of in-sent restenosis after carotid artery stenting in high-risk patients. J Vasc Surg. 2006; 43(2):305-12.
17. Ekinci A, Kamasak K. Evaluation of serum prolidase enzyme activity and oxidative stress in patients with tinnitus. Braz J Otorhinolaryngol. 2020; 86(4):405-10.
18. Aslan M, Duzenli U, Esen R, Soyoral YU. Serum prolidase enzyme activity in obese subjects and its relationship with oxidative stress markers. Clin Chim Acta. 2017; 473:186-90.
19. Rabuş MB, Demirbağ, Sezen Y, Tasar M, Taşkın A, Aksoy N, et al. Serum prolidase activity in patients with degenerative and rheumatic heart valve diseases. Turk J Med Sci. 2010; 40(5):687-92.
20. Aktürk E, Aşkın L, Nacar H, Taşolar MH, Türkmen S, Çetin M, et al. Association of serum prolidase activity in patients with isolated coronary artery ectasia. Anatol J Cardiol. 2018; 19(2):110-16.
21. Sezen Y, Bas M, Altiparmak H, Yildiz A, Buyukhatipoglu H, Dag OF, et al. Serum prolidase activity in idiopathic and ischemic cardiomyopathy patients. J Clin Lab Anal. 2010; 24(4):213-8. DOI: 10.1002/jcla.20388.
22. Demirbag R, Yıldız A, Gur M, Yilmaz R, Elçi K, Aksoy N. Serum prolidase activity in patients with hypertension and its relation with left ventricular hypertrophy. Clin Biochem. 2007; 40(13-14):1020–5.
23. Yildiz A, Demirbag R, Yilmaz R, Gur M, Altiparmak IH, Akyol S. The association of serum prolidase activity with the presence and severity of coronary artery disease. Coron Artery Dis. 2008; 19(5):319-25. DOI: 10.1097/ MCA.0b013e32830042ba.
24. Suner A, Nurdag A, Polat M, Kaya H, Koroglu S, Acar G, et al. Evaluation of serum prolidase activity in patients with slow coronary flow. Postepy Kardiol Interwencyjnej. 2015; 11(3):206-11.
Download attachments: 10.4328:ACAM.20689
Tolga Memioğlu, Selim Ayhan, Ibrahim Dönmez. Assessment of serum prolidase levels in patients with coronary artery in-stent restenosis. Ann Clin Anal Med 2021;12(11):1198-1202
Citations in Google Scholar: Google Scholar
This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of the license, visit https://creativecommons.org/licenses/by-nc/4.0/
Diagnostic agreement of pediatricians and radiologists on chest x-rays in pediatric emergency department
Nilüfer Aylanç 1, Fatih Battal 2, Yusuf Güzel 2, Koray Öz 1
1 Department of Radiology, 2 Department of Pediatrics, Çanakkale Onsekiz Mart University, Faculty of Medicine, Çanakkale, Turkey
DOI: 10.4328/ACAM.20690 Received: 2021-05-05 Accepted: 2021-07-01 Published Online: 2021-07-17 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1203-1207
Corresponding Author: Nilüfer Aylanç, Çanakkale 18 Mart University, School of Medicine, Department of Radiology, 17100 Çanakkale, Turkey. E-mail: niluferaylanc@gmail.com P: +90 286 218 00 18 GSM: +90 5058569606 F: +90 286 218 37 38 Corresponding Author ORCID ID: https://orcid.org/0000-0002-5889-9763
Aim: In this study, we aimed to investigate the diagnostic agreement on chest x-rays between pediatrician and radiologist in anatomical and pathological evaluation.
Material and Methods: Chest radiographs of 700 cases from the pediatric emergency clinic were included in the study. The radiographs were evaluated by the pediatrician and radiologist as double-blind from a technical point of view (posture-position, inspiration adequacy, X-ray dose) and interpretation (hilar, mediastinal, parenchymal pathologies and cardiothoracic ratio). For results, Kappa analysis was used.
Results: The mean age of the patients was 4.5 ± 4.5 (min 0-max 18) years, 335 (47.9%) were females and 365 (52.1%) were males. The diagnostic agreement was found as moderate level with adequate inspiration, optimal position, mediastinal width, and left hilar fullness; low level of disagreement was found in optimal dose, pleural fluid, consolidation, mediastinal fullness, right hilar fullness, infiltration, peribronchial thickening, reticular signs and very good agreement was found in CTR. It was statistically significant in terms of all parameters (p <0.001).
Discussion: There may be differences, especially between interpretations of radiological examinations. To minimize these differences and to establish an accu- rate and precise diagnosis, the clinician and radiologist should have close contact. Compliance and consensus in the evaluation in the radiological assessment will help to manage the treatment process precisely and correctly.
Keywords: Chest Radiography, Radiologist, Pediatrician, Pediatric Emergency
Introduction
A chest x-ray is an important and initial diagnostic tool for evaluating the airways, pulmonary parenchyma, mediastinum, heart, pleura and chest wall. It is an imaging technique frequently used in the diagnosis and treatment of pediatric patients, including term and preterm neonates (1). Laboratory tests and radiological evaluations are at least as important as clinical findings (2). Accurate and rapid interpretation of chest radiography can provide early diagnosis, especially in emergency departments. Conditions such as the presence of thymus, some diseases special to children, organs in the developmental stage may make it difficult to interpret the chest radiography in childhood (3, 4). For these reasons, we think that the ability to read chest radiographs is important for radiologists or pediatricians. In the literature, we did not find any study comparing chest radiography evaluations between a radiologist and a pediatrician. In this study, we aimed to investigate the diagnostic agreement between those two observers.
Material and Methods
This study included chest x-rays of children aged 1 month to 18-year who were evaluated at our pediatric emergency clinic, between 01.2017 and 04.2018. After the study approval with the decision of the Clinical Research Ethics Committee dated 18/04/2018 and numbered 08-04, we retrospectively scanned chest radiographs. Children with chronic lung disease (tuberculosis, immune deficiency, ciliary dyskinesia, cystic fibrosis, etc.), congenital heart disease, trauma history and at the age of 0-28-days were not included in the study. The images were evaluated independently by each observer; one radiologist and one pediatrician, both with 15 years of experience. On radiographs, adequate inspiration, patient position, X-ray dose, presence of pleural fluid, consolidation, infiltration, peribronchial thickening, reticular signs, mediastinal fullness, right and left hilar fullness and CTR were evaluated. Mediastinal width was measured in cm with the lateral mediastinal borders at the upper mediastinum by drawing a linear measurement line. CTR was calculated as the ratio of the transverse diameter where the heart is widest to the transverse diameter where the thorax is widest.
Statistical Analysis
The data obtained were analyzed with the statistical package program SPSS 20.0 version (IBM SPSS Statistics 20; Chicago, IL, USA). Spearman’s correlation analysis was used according to the results of the normal distribution compatibility test. Correlation coefficient r: 0-0,24 as weak; r: 0.25-0.49 as moderate; r: 0.50-0.74 as strong; r: 0.75-1.0 as very strong. Kappa analysis (5) was used in categorical data evaluated by two observers. Agreement level in interpretation by Cohen’s kappa coefficient (κ) was <0: worse than chance-related, 0.01- 0.20: unimportant, 0.21-0.40: low, 0.41-0.60: moderate, 0, 61- 0.80: good, 0.81-1.00: very good (5). A p-value less than 0.05’ was considered statistically significant.
Results
While the mean age of 700 patients was 4.5 ± 4.5 (min 0-max 18) years; 335 (47.9%) were females and 365 (52.1%) were males.
In terms of adequate inspiration, diagnosis disagreement was experienced in 25.8% of cases, while the agreement was found in 16.4%. A moderate level of diagnostic compliance was found between observers (p <0.001, κ: 0.409). In the evaluation of the optimal position, both observers noted the absence of an optimal position in 34% of cases, while present in 40.6%. However, in 178 cases (25.4%), the diagnoses were discordant with moderate level but were statistically significant (p <0.001, κ: 0.501). In terms of optimal dose, it was present in 56% of cases, while not in 16%. In 196 (28%) cases, the diagnoses were incompatible. Statistically significant agreement was observed among the observers (p <0.001, κ: 0.343). In the evaluation of pleural fluid, both experts commented positively in 668 (98.9%) and negatively in 2 (1.1%) of the cases. The diagnosis was different only in 10 (1.4%) cases, and the compatibility between the observers was statistically significant. (p <0.001, r: 0.28). There was a statistically significant agreement in the consolidation (p <0.001, κ: 0.223). (Table 1)
Both observers stated that there was consolidation in a total of 664 (94.9%) cases, while not in 5 (0.7%) cases. Diagnosis mismatch was present in 31 (4.4%) cases (Figure 1). In the evaluation of infiltration, a very low level of disagreement was found, but it was statistically significant (p <0.001, κ: 0.118). In 414 (59.1%) patients, both observers stated that there was no infiltration, while 38 (5.4%) had it. In 248 patients (35.4%), the diagnoses were incompatible (Figure 2). In terms of peribronchial thickening, a statistically significant but unimportant- very low diagnostic disagreement was found (p <0.001, κ: 0.115). In 39% of cases (n = 273), the diagnoses were discordant (Table 1). Prominence in reticular signs was also evaluated. While both observers agreed in 101 (14.4%) cases that reticular signs were evident, in 351 (50.1%) cases, the findings were negative for both physicians. There was a diagnostic mismatch in 248 cases (35.4%), and it was statistically significant but at an unimportant-very low level. (p <0.001, κ: 0.202). In terms of mediastinal fullness, a weak but statistically significant diagnostic disagreement was detected (p <0.001, κ: 0.267). In 185 (26.4%) cases, the diagnoses were incompatible, and both physicians reported that there was no mediastinal fullness in 444 (63.3%) cases, and it was present in 71 (10.1%) cases. Hilar fullness was evaluated separately for both sides. In the evaluation of right hilar fullness, a statistically significant but weak diagnostic disagreement was achieved (p <0.001, κ: 0.36). In 204 cases (29.1%), the diagnoses of the observers differed. In the evaluation of left hilar fullness, a moderate and statistically significant diagnostic agreement was found (p <0.001, κ: 0.525). Only 153 (21.8%) patients had left hilar fullness (Table 1).
Mediastinal width was measured in cm. Statistically significant and moderate agreement was found (p <0.001, r: 0.375). Cardiothoracic ratio values were calculated. There was a statistically significant and very good agreement between observers (p <0.001, r: 0.865) (Figure 3) (Table 2).
Discussion
In our study, chest x-rays of child patients admitted to the pediatric emergency were evaluated and different levels of diagnostic disagreement were obtained among the radiologist and the pediatrician. In radiological examinations, interpretive differences due to observers are inevitable, both between the same or different clinicians [6,7]. Many factors, such as the physician’s education, experience and information about the patient’s clinic, may play a role in this difference [8]. However, every clinician aims to provide the most appropriate treatment or contribute to this process by making rapid and accurate diagnosis. In order to minimize possible interpretation differences or to standardize the approach to diagnosis, studies on especially artificial intelligence models are conducted [9].
In our study, a moderate agreement was found between observers in terms of adequate inspiration, optimal position, mediastinal width and left hilar fullness. For inspiration adequacy, the result may be related to the clinician’s knowledge and experience in chest X-ray. Mediastinal width was determined at the level of the upper mediastinum with both mediastinal lines bordered. Although using numerical data, moderate level agreement may be due to the fact that measurements were made from the upper mediastinum, from different levels, such as a bit upper or a bit lower. In the presence of left hilar fullness, the diagnostic mismatch may be due to asymmetries in posture positions. The situations in which the disagreement was found to be statistically significant but weak were optimal dose, pleural fluid, consolidation, mediastinal fullness, and right hilar fullness. Disagreement regarding optimal dose may be related to technical knowledge and experience in radiographic evaluation. Although adequate dosage is one of the points to consider at the beginning of the evaluation, in clinical practice, this can often be ignored or forced to be ignored, especially in busy centers. For the presence of pleural fluid, diagnostic disagreement was in only 1.4% of cases, and for the consolidation in only 4.4% of cases. The fact that observers agree in most cases is actually quite meaningful in clinical practice, and this will contribute patient’s treatment management
In mediastinal fullness, diagnostic mismatch was detected in almost 1⁄4 of the cases. Mediastinal fullness was interpreted visually and subjectively, rather than by measurement with numerical data. Some cases also have radiographs taken in the supine position, causing the appearance of the mediastinum fuller than normal, which may be a reason for the interpretive difference. Or, the fact that the mediastinum is physiologically seen full due to thymus, especially in the first 1-2 years of age may be a result of the differences. In right hilar fullness, in which the diagnostic agreement was statistically significant but weak, we think that anatomical factors may play a role here as well. The right hilus seems to be fuller compared to the left, because thebronchusreachingthelowerlobeismoreperpendicularand there are 3 main bronchi for the 3 lobes in right hemithorax. Considering the anatomical changes of the cases with age, this interpretative difference is an expected result.
In infiltration, peribronchial thickening and reticular signs, the disagreement level was very low, but statistically significant. In terms of infiltration, disagreement was in 35.4% of patients. Althoughtheinfiltrationprocesscanoccurinvariousforms,it is already more difficult to evaluate on radiographs than on computed tomography (CT) until it progresses. However, in daily practice, the first method of imaging is radiography. Also, it may be difficult to differentiate infiltration especially in the presence of insufficient inspiration and dose. Similarly, there was diagnostic disagreement of 35.4% in reticular signs and 39% in peribronchial thickening. Prominence in reticular signs is one of the early findings of interstitial pathologies and can sometimes be confused with opacities of vascular traces. Thus, in this process, CT would be more useful. However, since the cases are pediatric and the first-step imaging is a chest X-ray, the observers’ knowledge and experience play an important role here. In peribronchial thickening, the main bronchi may be prominent under 2 years, or when there is suboptimal posture, or anphase appearance of bronchi, then compliance decreases. There was a very good level of agreement in the CTR evaluation and the level was statistically significant. It was thought that, apart from the experience of the observer, the reason is the information obtained by calculating numerical data and therefore, a quantitative evaluation.
There are many studies on the diagnostic agreement in the literature and controversial results can still be obtained. In a review by Usubütün, it is pointed out that this situation is due to the uncertainty areas in medicine [8]. According to Fox [10], the existence of up-to-date scientific information in medicine and situations exceeding the physician’s knowledge, constitute the source of these uncertainties. Also, in that review, it was emphasized that physicians’ awareness of the uncertainties and learning to overcome problems, will contribute to their professional success. In one study, dentists examined periapical radiographs and investigated the main causes of diagnostic incompatibility. They emphasized that morphological differences in the anatomy and differences in peripheral bone density make evaluation difficult, and uncertainty occurs in radiologic interpretations in difficult cases [11].
In our study, moderate or low compliance in some parameters also depends on the limitation of chest radiographs. For example, superposition of tissues or postural disturbances make evaluation difficult and decreases diagnostic compliance. In another study, diagnostic compliance between observers was investigated using the fluorescent insitu hybridization method used in the diagnosis of helicobacter pylori, and it was found that the compliance was quite good in cases with high bacterial count, but decreased where the bacterial load was low. This result also shows that in cases where there is a high level of data, the diagnostic compliance is higher, since there are no gaps open to interpretation [12].
In a study by Erdogan et al. [13], humerus proximal fractures were evaluated by orthopaedists. Radiography and tomography findings of patients were evaluated by an experienced upper extremity surgeon and general orthopaedist. The diagnostic agreement was found to be higher in tomography than radiography, since the cross-sectional imaging gave detailed information and did not leave much clarification on interpretation. In another study, mammography examinations were evaluated by radiologists, in terms of diagnostic compatibility based on BIRADS system. Although this system provides diagnostic standardization to a large extent, diagnostic compliance is high for benign and malignant lesions, whereas diagnostic compliance is found to be moderate in the class defined as possible benign, which we call ‘category 3’. Therefore, in order to increase diagnostic compliance, it was emphasized that this system should be updated at certain time intervals in accordance with literature studies and scientific opinions [6]. In another study, radiologists evaluated the carotid system with Doppler ultrasound at different time intervals and advocated that the use of the same applicator and same device can increase compliance in cases requiring follow-up [7]; because there may be different interpretations in different times, although by the same observer.
Limitations
This paper attempts to measure diagnostic agreement between radiologists and pediatricians regarding interpretation of chest x rays. We did not aim to determine the accuracy of the diagnosis. The first limitation of our study is that no comparisons were made intra-observers. Another limitation is that only one pediatrician and one radiologist were involved in the study. We think that studies in which researching compliance of interpretations of more than one radiologist and pediatrician would be more valuable.
The strength of our study is that it is the first study in the literature comparing the evaluations of a pediatrician and radiologist over the same chest radiographs.
Radiologists can be expected to have more accurate interpretations, but in daily practice, clinicians have to examine and interpret more chest radiographs than radiologists during the treatment process. Although clinicians do not receive radiology training as much as radiologists, they can be more experienced in terms of radiographs compared to radiologists because they have to examine and interpret graphs in their clinical practice. In addition, because they know patients’ clinic, their evaluation on radiographs can be easier and more effective. In conclusion, in radiographic evaluation, there are still areas of disagreements in diagnostic interpretations with the same or different specialties or physicians with different levels of experience in the same specialty. Clinicians have to make radiological evaluations rapidly during the diagnostic phase and may not always be able to communicate with an experienced radiologist. Ideally, patient’s images should be evaluated in detail by different specialists, but this is not possible in practice. However, since diagnostic differences significantly affect the patient’s management, they should be minimized as much as possible and eliminated if possible.
Due to the rapid advances in radiologic methods, the variety of imaging modalities is also increasing. As in all diseases, it is necessary to request imaging methods with an appropriate algorithm in the diagnosis, follow-up and evaluation of the treatment response of pediatric respiratory system diseases. It is important to choose the most appropriate exam according to the disease or symptom, with the lowest ionizing radiation, easy accessibility and low cost. In our study, we showed that the clinician and the radiologist can interpret differently chest radiographs in the emergency department. For this reason, we think that clinician-radiologist cooperation is important as well as knowing the general characteristics of imaging examinations. If the chest radiography in children is seen as normal, but cannot not lighten the patient’s clinic, then the clinician may act a little more boldly when preferring chest CT. Thus, a good interpretation of radiography findings can prevent many unnecessary CT examinations. Therefore, radiologic examinations should be evaluated systematically using algorithms step by step. During this specialization training, data and parameters should be updated frequently, especially regarding the evaluation of the radiologic images, training seminars should be organized for remembering new data, and the training proficiency should be checked with exams. We strongly recommend that clinicians should contact the radiologist, especially on suspected radiologic findings. Likewise, the radiologist should contact the clinician and try to strengthen his/her diagnosis by obtaining information about patient’s clinic. A strong communication between different disciplines will confirm and facilitate patient management. In addition, all these processes will increase the experience of the specialists and keep their level of diagnostic agreement high by enabling them to update their knowledge.
Acknowledgment
We would like to thank Dr. Özgür Özerdoğan for their contribution to the article.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Walsh BK, Daigle B, Diblasi RM, Restrepo RD. AARC Clinical Practice Guideline. Surfactant Replacement Therapy. Respir Care. 2013; 58(2):367– 75.
2. Lange CD. Radiology in Pediatric Non-Traumatic Thoracic Emergencies. Insights Imaging. 2011; 2(5):585–98.
3. Aslan A, Yıkılmaz A. Normal and Pathological Pediatric Lung and Thorax Radiography. TRD Sem. 2017; 5:98-128.
4. Breysem L, Loyen S, Boets A, Proesmans M, Boeck KD, Smet MH. Pediatric Emergencies: Thoracic Emergencies. Eur Radiol. 2002; 12(12):2849–65.
5. Kılıç S. Kappa test. Journal of Mood Disorders. 2015; 5(3):142-4.
6. Parlak E, Gürses C, Yıldırım M, Alikanoğlu AS, Özan E, Kargı A, et al. Is Interpretation Differences of Radiologists an Important Issue in Breast Imaging Reporting And Data System? J Clin Anal Med. 2013; 4(4):307-9.
7. Adapınar B, Akcar N, Kebapcı M, Aslan Kb, Kaya T. Inter-Observer Correlation and Variability in Measurements and Doppler Parameters of Normal Carotis Communis-Interna and Vertebral Arteries. Turkish Journal of Cerebrovascular Diseases. 2003; 9(2):51-6.
8. Usubütün A. Are the Pathologic Diagnosis Reproducible? J Curr Pathol. 2017; 1:8-11.
9. Caobelli F. Artificial Intelligence in Medical Imaging: Game Over for Radiologists? Eur J Radiol. 2020; 126:108940.
10. Anderson RE, Fox RC, Hill RB. Medical Uncertainty And The Autopsy: Occult Benefits For Students. Hum Pathol. 1990; 21(2):128–35.
11. Keçeci AD, Kaya BÜ, Ünal GÇ, Taç G. Disagreement cases caused interobserver variations during evaluation of periapical status. SDÜ Medical Journal. 2006; 13(4):16-21.
12. Çiftci İH, Dilek FH, Şafak B, Aşık G, Acartürk G. Is There A Difference Between Observers In The Diagnosis Of Helicobacter Pylori With Fluorescent In Situ Hybridization Method? Turkish Microbiological Society Association. 2012; 42(2):61-5.
13. Erdoğan Ö, Canbora MK, Uzer G, Demiröz S, Köse Ö. Interobserver agreement in Proximal Humeral Fractures. Harran University Medical Journal. 2019; 16(3):417-20
Download attachments: 10.4328:ACAM.20690
Nilüfer Aylanç, Fatih Battal, Yusuf Güzel, Koray Öz. Diagnostic agreement of pediatricians and radiologists on chest x-rays in pediatric emergency department. Ann Clin Anal Med 2021;12(11):1203-1207
Citations in Google Scholar: Google Scholar
The evaluation of telemedicine-online health services during Covid-19 in Turkey private hospitals: Thematic analysis
Zeynep Merve Uçar 1, Eda Yılmaz Alarçin 2
1 Department of Medical Documentation and Secretarial, Istanbul Arel University, 2 Department of Health Management, Faculty of Health Sciences, Istanbul University-Cerrahpaşa, Istanbul, Turkey
DOI: 10.4328/ACAM.20694 Received: 2021-05-07 Accepted: 2021-07-26 Published Online: 2021-08-13 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1208-1211
Corresponding Author: Zeynep Merve Uçar, Department of Medical Services and Techniques, Vocational School of Arel University, 34295, Istanbul, Turkey. E-mail: zeynepucar@arel.edu.tr P: +90 0850 850 2735 / +90 0850 850 2114 F: +90 850 850 2735 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1862-2361
Aim: With the Covid-19 outbreak, it has been observed that people wanted to receive healthcare services remotely. In other words, people wanted to reach healthcare services or healthcare professionals from their homes without going to the hospital. Thus, this study aimed to determine how telemedicine-online health services of private hospitals are handled on websites and social media channels.
Material and Methods: Data was collected by conducting qualitative content analysis to the websites and corporate social media of hospitals in Istanbul, the city where the most private hospitals in Turkey are located. Overall, 608 data from 76 hospitals were analysed using the thematic analysis method.
Results: When the analysis of the information was received a total of 8 themes emerged. These were divided into thematic codes as the telemedicine-online health service status, including the number of hospital beds, the content of written, visuals etc. posts, features of the branches of the application and details of other online health services.
Discussion: The use of telemedicine-online health services in private hospitals is found to be at the initial stage and written and visual posts are insufficient. The information collected can help determine the current situation and contribute to private hospitals when determining new strategies.
Keywords: Telemedicine, Online health services, Private hospitals, COVID-19
Introduction
The widespread use of internet services and smartphones, as well as the emergence of fifth generation (5G) mobile networks, are facilitating online healthcare provision by health authorities [1]. The eHealth report, which includes online service delivery data, stated that the number of online health service users reached 9.3 million in 2017 and the income earned from online health services reached 47.60 billion dollars in 2018. This rate is expected to reach 132.35 million dollars by 2023 [2]. Especially in connection with the COVID-19 pandemic, health service delivery in online environments has increased rapidly [3]. Forecasts for Turkey’s future investment in online health services will increase by 25% in the next five years [3]. The reason for the increased interest in the use of online health services is that healthcare providers see that the cost of remote disease diagnosis and patient care is low, and individuals with various diseases think that remote access to health services is easy [4].
Individuals with various diseases can make video calls with medical specialists through online health services, diseases can be diagnosed during the interviews, medication related to the disease can be prescribed or the necessary personnel can be sent to provide home care services to the patient. All of these applications are described as telemedicine applications in the literature [5]. Patients with different illnesses can use online health services, including telemedicine, to learn more about the illnesses, seek emotional support after treatment, or access healthy lifestyle choices [6]. Increasing healthcare use in online environments expands and diversifies the channels for patient-physician interaction [7]. Considering limited medical resources, online healthcare communities aim to provide better treatment by lowering medical costs, making full use of available resources, and providing more diverse channels for patients [8]. But the lack or inaccuracy of hospitals’ marketing strategies insufficient publicity on corporate social media and websites [9], the approach of hospitals to the issue emerges as problems related to the use of online health services [10]. The authors missed reporting one of the most important advantages of telemedicine during the Covid-19 outbreak, namely the decreased risk of transmission of Covid-19, while providing continuous care to the community as reported by a recent systematic review [11]. This situation is affected by the increase in disadvantages in addition to its advantages with the emergence of telemedicine-online health services [4], [12]. This study aimed to determine how private hospitals in Istanbul, the city where most hospitals are located in Turkey, handle telemedicine-online health services on websites and social media channels.
Material and Methods
This study was carried out to determine how private hospitals in Istanbul, the city where most hospitals in Turkey are located, handle telemedicine online-health services on corporate social media accounts and websites. The study aimed to contribute to the literature by examining whether hospitals use telemedicine- online health services and on what subjects they focus on the most.
Data Collection Method
In the study, information obtained from hospitals’ websites and their corporate social media accounts were recorded into an Excel table in the form of a code-definition-sample to facilitate the data collection process. The recorded code files were combined under 8 main headings, including the characteristics of the hospitals. Within the scope of the study, information about 608 general and telemedicine-online health services of 76 private hospitals in Istanbul was analysed using the content analysis method.
Data Analysis Method
First of all, the websites and social media of all private hospitals in Istanbul were examined in detail and the necessary data were collected for the study. Later, the authorized persons of private hospitals were contacted one by one, and the information on their websites was confirmed. If there was a missing part that is not included on the websites, the information obtained from the interviews was added to the study. Afterwards, the basic contents of photographs, videos, and explanatory information about telemedicine-online health services of each hospital were examined separately and recorded into the Excel table. Thus, the preliminary preparation of the study was completed. In this step, 648 properties of 81 hospitals were recorded. In the first analysis, 92% of consistency between coders was obtained. Branches of hospitals under the same name in other regions were excluded from the study for the reliability of the study. Similar features were analysed in Excel by dividing them into sub-themes. Finally, eight themes divided into sub-headings, were examined in detail using the content analysis method. The criteria that Nowell et al. (2017) [13] stated as the criteria to be applied in qualitative research such as ‘‘ reliability ‘‘, ‘‘ verifiability ‘‘, ‘‘ transferability ‘‘ were checked for their presence in the collected data.
Results
Data on the number of beds in the hospitals included in the research, whether they have telemedicine applications, whether there is information about telemedicine on the hospital websites, and whether there is information about telemedicine on corporate social media are given in Table 1.
The content analysis of telemedicine online health services within the scope of the study is shown in Table 2.
Some of the visuals related to telemedicine on the websites and corporate social media of the hospitals within the scope of the study are shown in Figure 1.
Discussion
This study aimed to determine how private hospitals in Istanbul, the city where most hospitals are located in Turkey, handle telemedicine online-health services on corporate social media accounts and websites.
The study revealed that having more or less bed capacities in hospitals did not change the importance they place on telemedicine-online health services, but when it comes to telemedicine, a single branch (psychology) or several branches (gynaecology, etc.) focused on diseases that can be treated remotely. Allen et al. [14] pointed out that telemedicine application is complementary to the treatments performed in hospitals at the point of individual therapy, psychological counselling and clinical treatment and that the application should be expanded.
According to the findings of this study, the telemedicine-online health services used by hospitals were found to be based on asking questions to the specialist doctors at the point of diagnosing, and when necessary, inviting patients to the hospital to initiate the treatment. Al-Barazanchi et al. [15], examining telemedicine applications on diagnosis and treatment, declared that dermatological diseases such as malaria were diagnosed remotely, and their treatment was also performed remotely by prescribing necessary medications. Apart from this, the treatment of diseases requiring multidisciplinary expertise have been performed in hospitals [15]. However, the study by Machado et al. [16] has shown that even oral and dental health problems that are difficult to treat via telemedicine can be diagnosed and treated remotely, but when a vital problem is encountered, the process can be supported with the hospital. According to another finding of the study, it was observed that even if hospitals do not use telemedicine application, they use online health services applications such as e-appointment, e-pulse, e-result. A study examining telemedicine and its current clinical applications stated that telemedicine and e-health applications are different from each other. The points where these applications differ are explained as follows: while telemedicine covers a remote clinical service, e-health is expressed as a broader term that includes remote non-clinical services [5]. It has been stated that e-health applications are more comprehensive, including understanding the health index (e-result, e-laboratory), providing preventive health support (e-baby, e-critical) and appointment services [5]. From this point on, the telemedicine application can be included in online health services.
The examination of the visuals and written texts used by hospitals with telemedicine applications showed that visuals were designed to include technology, physician-technology, physician-patient and technologies. The study by Wang et al. [17] that suggests the application of telemedicine, stated that the visuality alone is not enough, audio effects should be added to written and visual posts for disabled people. There are no studies in the literature on hospitals using telemedicine-online health services.
Conclusion
The study found that, the number of hospitals using telemedicine- online health services is limited. Marketing strategies on telemedicine-online health services play a significant role in the success of health service delivery process of hospitals. Corporate brand managers have an important responsibility for patient’ understanding and actively participating in healthcare delivery process. It will be beneficial for the managers working in these institutions to closely follow new applications and technologies to provide the most appropriate integration to the process. In today’s conditions when the use of online services is widespread, explaining new applications to patients in a transparent and reliable way can cause consequences that significantly affect the health system, while creating a small additional workload for the hospital.
In order to increase the use of telemedicine-online health services in healthcare institutions, an increase in the number of tools, which describe the process, such as videos, pictures, photographs that appeal to people’s senses, may be beneficial in informing patients. Based on the findings of this study, it can be stated that hospitals with telemedicine applications have started to share the details of the application on their corporate social media by improving the processes. In addition, the remote operation of the process in a transparent and reliable way may change the patient’s attitude towards the hospital. It will help encourage patients to use the application and prevent some of the costs caused by physical transportation. This situation can both improve the service quality perception of the patient and support the increase in corporate efficiency.
Since this study is limited to private hospitals operating in Istanbul, it is thought that studies to be conducted by adding more inclusive and additional variables will contribute to the literature. Since the study is limited to the province of Istanbul, the city where most private hospitals in Turkey are located, there are limitations on the spot to include other countries and cities. Considering the limited number of studies examining the use of telemedicine-online health services in hospitals, the number of studies examining the use of telemedicine-online health services in hospitals may be increased. In addition to the efficiency of the application used, measurements such as the opinions of the patients about the applications, their usage status and satisfaction can be made. Thus, it can contribute to the literature by revealing the opportunities or threats to the use of telemedicine-online health services.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Liu S. Online mental health services in China during the COVID-19 outbreak. The Lancet Psychiatry. 2020; 7(4): e17–e18. DOI: 10.1016/S2215-0366(20)30077-8.
2. Chang YW, Hsu PY, Wang Y, Chang PY. Integration of online and offline health services: The role of doctor-patient online interaction. Patient Educ Couns. 2019; 102(10):1905–10. DOI: 10.1016/j.pec.2019.04.018.
3. Govil N, Raol N, Tey CS, Goudy SL, Alfonso KP. Rapid telemedicine implementation in the context of the COVID-19 pandemic in an academic pediatric otolaryngology practice. Int J Pediatr Otorhinolaryngol. 2020; 139:110447. DOI: 10.1016/j.ijporl.2020.110447.
4. Klonoff DC. Using telemedicine to improve outcomes in diabetes – An emerging technology. J Diabetes Sci Technol. 2009; 3(4):624–8. DOI: 10.1177/193229680900300401.
5. Lupton D, Maslen S. Telemedicine and the senses: a review. Sociol. Heal. Illn. 2017; 39(8):1557–71. DOI:10.1111/1467-9566.12617.
6. Zhang X, Guo X, Wu Y, Hung Lai K, Vogel D. Exploring the inhibitors of online health service use intention: A status quo bias perspective. Inf Manag. 2017; 54(8):987–97. DOI: 10.1016/j.im.2017.02.001.
7. Purcarea VL, Gheorghe IR, Gheorghe CM. Uncovering the Online Marketing Mix Communication for Health Care Services. Procedia Econ Financ. 2015; 26(15):1020–5. DOI: 10.1016/s2212-5671(15)00925-9.
8. Wu H, Lu N. Online written consultation, telephone consultation and offline appointment: An examination of the channel effect in online health communities. Int J Med Inform. 2017; 107:107–19. DOI: 10.1016/j.ijmedinf.2017.08.009.
9. Mano RS. Social media and online health services: A health empowerment perspective to online health information. Comput Human Behav. 2014; 39:404– 12. DOI:10.1016/j.chb.2014.07.032.
10. Liu S, Wang H, Gao B, Deng Z. Doctors Provision of Online Health Consultation Service and Patient Review Valence: Evidence from a Quasi-Experiment. Inf Manag. 2020; 13:103360. DOI: 10.1016/j.im.2020.103360.
11. Monaghesh E, Hajizadeh A. The role of telehealth during COVID-19 outbreak: a systematic review based on current evidence. BMC Public Health. 2020; 20(1):1193. DOI: 10.1186/s12889-020-09301-4.
12. Mills EC, Savage E, Lieder J, Chiu ES. Telemedicine and the COVID-19 Pandemic: Are We Ready to Go Live? Adv. Skin Wound Care. 2020; 33(8):410–17. DOI: 10.1097/01.ASW.0000669916.01793.93.
13. Nowell LS, Norris JM, White DE, Moules NJ. Thematic Analysis: Striving to Meet the Trustworthiness Criteria. Int J Qual Methods. 2017; 16(1):1–13. DOI: 10.1177/1609406917733847.
14. Van Allen J, Davis AM, Lassen S. The Use of Telemedicine in Pediatric Psychology: Research Review and Current Applications. Child Adolesc. Psychiatr Clin N Am. 2011; 20(1):55–66. DOI: 10.1016/j.chc.2010.09.003.
15. Al-Barazanchi I, Hamid S A, Abdulrahman RA, Abdulshaheed HR. Automated telemedicine and diagnosis system (ATDS) in diagnosing ailments and prescribing drugs. Period Eng Nat Sci. 2019; 7(2):888–94. DOI: 10.21533/pen.v7i2.486.
16. Machado RA, Souza NL, Oliveira RM, Martelli Júnior H, Bonan PR. Social media and telemedicine for oral diagnosis and counselling in the COVID-19 era. Oral Oncol. 2020; 105:104685. DOI: 10.1016/j.oraloncology.2020.104685.
17. Wang S Parsons M. Augmented reality as a telemedicine platform for remote procedural training. Sensors (Switzerland). 2017; 17(10):1–21. DOI: 10.3390/ s17102294.
Download attachments: 10.4328:ACAM.20694
Zeynep Merve Dinler , Eda Yılmaz Alarçin. The evaluation of telemedicine-online health services during covid-19 in Turkey private hospitals: Thematic analysis. Ann Clin Anal Med 2021;12(11):1208-1211
Citations in Google Scholar: Google Scholar
Can tooth color be used as part of caries risk assessment? A cross-sectional study
Ömer Hatipoğlu 1, Edanur Maraş 2, Katibe Tuğçe Temur 3
1 Department of Restorative Dentistry, Niğde Ömer Halisdemir University, Niğde, 2 Department of Endodontics, Recep Tayyip Erdogan University, Rize, 3 Department of Oral and maxillofacial radiology, Niğde Ömer Halisdemir University, Niğde, Turkey
DOI: 10.4328/ACAM.20697 Received: 2021-05-08 Accepted: 2021-08-20 Published Online: 2021-09-06 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1212-1217
Corresponding Author: Ömer Hatipoğlu, Restorative Dentistry, Niğde Ömer Halisdemir University, Niğde, Turkey. E-mail: ohatipoglu@ohu.edu.tr P: +90 507 882 2249 Corresponding Author ORCID ID: https://orcid.org/0000-0002-4628-8551
Aim: This study aimed to investigate whether the colors of the maxillary central incisor (MC1) and the maxillary first premolar (MP1) can serve as indicators to estimate dental caries risk.
Material and Methods: A total of 140 healthy dentistry students aged 18-25 years participated in this cross-sectional study. The MC1 and MP1 were polished with a polishing brush for 20 seconds. After polishing, in room light, L*, a*, b*, chroma, and hue values were measured from three different regions of the teeth with the VITA Easyshade spectrophotometer device. After color evaluation, dental caries burden was determined according to the Decayed, Missing, and Filled Teeth (DMFT) index. A questionnaire addressing demographic features, dietary habits, and smoking habits was also administered. Spearman’s correlation tests and multiple linear regression analyses were conducted.
Result: No significant correlation was found between DMFT scores and L* values. The DMFT index was positively correlated with the a*, b*, and chroma of the MC1 but was negatively correlated with hue. In terms of the MP1, no significant correlation was detected between DMFT and color parameters. Smoking and tooth-brushing had significant effects on MC1 b* and chroma and on MC1 a*, b*, and chroma, respectively. No significant effect of confounding factors was observed on MP1 L*, a*, b*, chroma, or hue.
Discussion: This study concludes that dental caries risk may be predicted with color values of the MC1. However, the same does not apply for the MP1. The ability to predict dental caries by evaluating the color of the MC1 shows the potential for color to be used as a part of caries risk assessment.
Keywords: Color, Correlation of Data, Dental Caries, Operative Dentistry
Introduction
Dental caries are affected by many environmental factors and constitute one of the most common chronic diseases in the world [1]. The quality and quantity of saliva, amount of consumed carbohydrates, fluoride intake, and hygiene habits of the patients are some of the relevant environmental factors [2]. In addition, differences in the enamel and dentin structure may affect one’s susceptibility to dental caries [3, 4].
One of the most important factors affecting the aesthetic appearance of teeth is color. Color can be defined by dimensions such as hue, light value, and chroma. Value is the amount of light reflected from an object. Chroma, on the other hand, expresses the saturation and intensity of the hue. In other words, there is an inversely proportional relationship between chroma and light values [5]. The absorption of light reduces the amount of light reflected on the human eye, resulting in a low light value and high chroma. While the enamel is capable of reflecting light in high amounts due to its highly inorganic structure, the dentine absorbs light more due to its highly organic structure and therefore it has high chroma [6]. Changes in the tooth surface that affect both color and dental caries susceptibility may be associated with the accumulation of bacterial biofilm [7].
The fact that the composition and thickness of the tooth structure can affect both dental caries and color may indicate the existence of a relationship between these two factors. However, to our knowledge, no study in the literature has examined this relationship to date, and it is therefore necessary to conduct research in this regard. The present study aims to determine the association between the color of the maxillary central incisor (MC1), the color of the maxillary first premolar (MP1), and caries burden as measured by the Decayed, Missing, and Filled Teeth (DMFT) index. The null hypotheses of the study were as follows:
(1) Color of the MC1 is not a predictor of caries burden. (2)Color of the MP1 is not a predictor of caries burden.
Material and Methods
Setting and Design
This health center-based cross-sectional study was conducted among dentistry students at Sütçü İmam University in Kahramanmaraş, Turkey, in June and July 2020. The sample size was calculated with the statistical program G*power 3.0.10 (http://www.gpower.hhu.de/). With 80% power, 0.05 alpha error, and 0.24 effect size (effect size predetermined based on a study group of 20 individuals), the necessity for 133 samples was determined. Inclusion criteria for baseline screening included being a healthy dentistry student between the ages of 18 and 25 years and having at least one non-restored MC1 and one non-restored MP1. Individuals meeting any of the following exclusion criteria were not considered for initial screening: (1) individuals treated with bleaching, (2) individuals with any health problems that could be an obstacle to dental hygiene, (3) individuals with internal staining (for reasons such as fluorosis, tetracycline, etc.) in both of their MC1 or MP1 teeth, and (4) individuals with a hereditary disease that may affect the structure of the teeth.
Blinding Procedures
To prevent measurement bias, the researchers were blinded to each other (each researcher individually examined each participant). Color and dental caries evaluations were carried out by Ö.H. and K.T.T. separately. The data obtained by these researchers were recorded in different Excel files (Microsoft Excel, Office 2013, USA) and sent to another researcher (E.M). Color and Dental Caries Examinations
Before the examinations, all examiners were initially trained and calibrated according to the WHO Basic Surveys Calibration Protocol for caries detection, coding findings, and recording, consisting of a theoretical training session followed by oral examination of five subjects (not part of the study sample) at Sütçü İmam University. Adequate standardization with a kappa value of 0.82 for caries and kappa value of 0.80 for color was obtained; 10% of examinations were duplicated and the percentage of agreement was 79% and 83% for caries and color, respectively.
Three different dimensions of color were measured objectively: L*, a*, and b*. L* indicates the light value, taking a numerical value between 0 (black) and 100 (white). As chromatic coordinates, a* and b* indicate the green-red axis and blue- yellow axis, respectively. In this respect, the formula C = [(a*)2 + (b*)2]0.5 is used in calculating chroma [5].
Color evaluation was carried out by Ö.H. The right MC1 and right MP1 (the left ones were used in the absence of right teeth or when there was a restoration in the right tooth) were polished with a polishing brush (Stoddart, Germany) for 20 seconds. After polishing, the teeth were dried with cotton pellets. In room light, the L*, a*, b*, chroma, and hue values were measured from three different regions of the teeth using the VITA Easyshade spectrophotometer device (VITA Zahnfabrik, Bad Säckingen, Germany).
An intraoral dental examination was performed for each subject by the same researcher (K.T.T.) using a sterile dental shepherd’s hook explorer and mirror. Caries evaluation was performed by visual exploration and digital panoramic radiography. In cases in which caries detection was challenging, the bitewing radiography technique was used to support the panoramic radiography. After the tooth was dried, each tooth was recorded as decayed (D), missing (M), or filled (F) and caries burden was then determined according to the DMFT index. Teeth filled or missing for a non-carious reason were not recorded and were checked according to the individual’s history. Additionally, third molar teeth were not recorded.
Questionnaire
A structured questionnaire was formulated by Ö.H. The language of the questionnaire was Turkish and it was translated into English. The questionnaire had adequate reliability with a Cronbach alpha coefficient of 0.716. Demographic features [age, gender (male OR female), family income (none OR 0-300 US$ OR 300-700 US$ OR 700-1400 US$ OR 1400 US$ and more], hygiene habits [such as tooth-brushing (once weekly OR once daily OR twice daily and more) and tongue-brushing (yes OR no), flossing (none OR once weekly OR once daily OR twice daily and more), and use of a mouthwash (none OR once weekly OR once daily OR twice daily and more)], and dietary habits [drinks (juice OR buttermilk OR cola OR coffee OR tea OR water) and foods (protein OR carbohydrates OR vegetables OR fruit) usually consumed] as well as amounts of sugar used in tea (none OR 1 teaspoon OR 2 teaspoons OR 3 teaspoons and more per serving) and smoking habits (yes OR no) were asked and recorded.
Statistical Analysis
The jamovi program (version 1.0.4; accessed at https://www. jamovi.org) was used for statistical analysis. The normality of data distribution was checked using the Shapiro-Wilk test. The correlation between dental caries and color parameters was calculated by Spearman test. Multivariate linear regression models were applied for all parameters, adjusting for any confounders. The omnibus ANOVA test was conducted to calculate the equality/inequality of the regression coefficients in multiple regression. Significance was set at p≤0.05.
Results
A total of 145 dentistry students were included in the initial screening and five were excluded from the analysis because of previously restored MC1 and MP1 teeth. In total, 140 dentistry students, including 50 men and 90 women with a mean age of 19.6±1.47 years, met the eligibility criteria and were included in this study.
Descriptive analyses of caries and color parameters for all survey questions are shown in Table 1. No significant effect was observed on DMFT or MC1 L* in the linear regression analysis (p>0.05). It was observed that smoking had a significant effect on MC1 b* and chroma (p<0.05), with values being higher among students who smoked. Tooth-brushing had a significant effect on MC1 a*, b*, and chroma, with these values being lower among those who brushed their teeth more frequently. Beverage habits had a significant effect on MC1 hue, with this value being highest among those who consumed coffee. However, no significant effect was observed on MP1 L*, a*, b*, chroma, or hue in the linear regression analysis (p>0.05) (Tables 1 and 2).
The DMFT index was positively significantly correlated with MC1 a*, b*, and chroma values and negatively significantly correlated with hue values (p<0.05). No significant correlation was found between L* values and DMFT scores (p>0.05). For the MP1, no significant correlation was detected between DMFT scores and other parameters (p>0.05) (Figures 1 and 2).
Discussion
Several studies have shown that permanent anterior teeth correlate with each other in terms of color [8, 9]. Based on these findings, Lee [8] stated that the color of other teeth can be estimated by referring to the color of a single tooth. As a carious lesion will create a demineralized area in the tooth resulting in an inaccurate shade measurement, only caries-free teeth were used in the present study. Since the presence of multiple carious teeth in the oral cavity will restrict the shade measurement of all of the teeth, the MC1 and MP1 were selected as references for the anterior and posterior teeth, respectively. This was the major limitation of the present study.
The first null hypothesis of this work, which was that the color of the MC1 is not a predictor of caries burden, was rejected. A positive correlation was found between dental caries and MC1 a*, b*, and chroma values. Enamel, due to its highly inorganic content, is capable of reflecting light in high amounts and this high optical density increases the light value; dentine, in contrast, contains more organic components and thus absorbs more light and increases the chroma value [6]. Alterations in the absorption amount of light due to differences in the inorganic structure and thickness of the enamel cause differences in the chroma values of teeth [10]. When the enamel rods and the surrounding interprismatic material are parallel to the dentin layer, light can easily reach the dentine, which increases the chroma value [11]. Higher amounts of organic matter in the tooth structure can also increase both hypomineralization and the chroma value [12]. Various studies have found an association between hypomineralization and dental caries [13]. However, no significant correlation was found between the L* value of the MC1 and total number of dental caries. Eimar et al. [14] stated that hydroxyapatite crystal size is a major predictor of light values. They found that the differences in hydroxyapatite crystal size do not change the light values while causing a change in chroma. They also stated that the main factors causing differences in chroma are the lattice parameters of hydroxyapatites, such as the a-axis and c-axis, and the lengths of these parameters are inversely related to chroma [14].
The second null hypothesis was accepted; there was no statistical difference between the MP1 chroma and light values and the total dental caries burden. Enamel thicknesses and crystal structures of the MC1 and MP1 differ from each other [15, 16]. Oguro et al. [10] found that variations in enamel thickness cause differences in tooth color. Differences in both enamel thickness and crystal structures may limit the ability of the MP1 to predict total dental caries burden [17, 18].
In the present study, it was shown that tooth-brushing and smoking habits affected the chroma values of the MC1. Some previous studies found that cigarette smoke can decrease L* and increase a* and b* values, consistent with the findings of the present study [19]. Tooth-brushing can also provide beneficial outcomes in terms of reducing cigarette stains, although not as much as tooth whitening [20]. In addition, in many studies, associations between habits of brushing and beverages and dental caries have been shown [21, 22]. The probable reason for the lack of an association between dental caries and any confounding factor in the present study may be that the subject group was narrow and restricted, which was a serious limitation of this study. The fact that the age range of the subjects was narrow and that their socioeconomic statuses and habits were similar may have raised the threshold of the occurrence of statistical difference.
Vieira-Junior et al. [23] found that as the roughness of the tooth surface increased, L* decreased and a* increased. Accumulation of plaque on dental tissues can increase the roughness of the tooth surface and disrupt the ideal crystal structure in the enamel over a long period of time [24]. In the present study, although polishing of the tooth surface was performed before measuring the color, any plaque that remained on the tooth surface for a long time may have impaired the optical properties of the tooth. The same is true for smoking habits. Polishing may not be sufficient to remove the deep discoloration of teeth caused by cigarettes and additional treatments such as whitening may be required to completely eliminate the discoloration of the teeth [25].
This study indicated that some color factors of the MC1 correlated with dental caries burden, and clinicians can use the color parameters of the MC1 as indicators to predict total dental caries burden. However, a common confounding factor affecting both dental caries and tooth color was not observed in this study. There may be different factors not evaluated in this study that affect both dental caries and tooth color, such as enamel and dentin thickness and composition. In this context, in future studies, it should be investigated whether the structural factors of the tooth have a common effect on the correlation of dental caries and tooth color.
Conclusion
Both tooth color and dental caries have multifactorial etiologies, and brushing, dietary habits, and morphological characteristics of the teeth can also have an influence. Dental caries burden may be predicted based on the chroma, a*, and b* values of the MC1. However, light value alone is insufficient to predict the dental caries burden. This study found no significant association between color and caries burden when evaluating the MP1. The ability to predict dental caries by evaluating the color of the MC1 shows the potential for color to be used as a part of caries risk assessment. However, further studies with wider demographics are required to support these hypotheses.
Acknowledgment
We thank the participants, clinicians, examiners, and all supporting staff involved in this study.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Watt RG (2005) Strategies and approaches in oral disease prevention and health promotion. Bull World Health Organ 83:711-718.
2. Anderson M (2002) Risk assessment and epidemiology of dental caries: review of the literature. Pediatr Dent 24:377-385.
3. Mortimer K (1970) The relationship of deciduous enamel structure to dental disease. Caries Res 4:206-223.
4. Shellis R (1984) Relationship between human enamel structure and the formation of caries-like lesions in vitro. Arch Oral Biol 29:975-981.
5. Sikri VK (2010) Color: Implications in dentistry. J Conserv Dent 13:249.
6. Ten Bosch J and Coops J (1995) Tooth color and reflectance as related to light scattering and enamel hardness. J Dent Res 74:374-380.
7. Quirynen M and Bollen C (1995) The influence of surface roughness and surface-free energy on supra-and subgingival plaque formation in man: A review of the literature. Journal of clinical periodontology 22:1-14.
8. Lee YK (2016) Color correlations among six types of permanent anterior teeth. J Esthet Restor Dent 28:S5-S13.
9. Đozić A, Kleverlaan CJ, Aartman IH and Feilzer AJ (2005) Relation in color among maxillary incisors and canines. Dent Mater 21:187-191.
10. Oguro R, Nakajima M, Seki N, Sadr A, Tagami J and Sumi Y (2016) The role of enamel thickness and refractive index on human tooth colour. J Dent 51:36-44.
11. Spitzer D and Ten Bosch J (1975) The absorption and scattering of light in bovine and human dental enamel. Calcif Tissue Res 17:129-137.
12. Xie Z, Kilpatrick NM, Swain MV, Munroe PR and Hoffman M (2008) Transmission electron microscope characterisation of molar-incisor-hypomineralisation. J Mater Sci Mater Med 19:3187.
13. Americano GCA, Jacobsen PE, Soviero VM and Haubek D (2017) A systematic review on the association between molar incisor hypomineralization and dental caries. Int J Paediatr Dent 27:11-21.
14. Eimar H, Marelli B, Nazhat SN, Nader SA, Amin WM, Torres J, Rubens Jr F and Tamimi F (2011) The role of enamel crystallography on tooth shade. J Dent 39:e3-e10.
15. Al-Jawad M, Simmons L, Steuwer A, Kilcoyne SH, Shore R, Cywinski R and Wood DJ (2008) Three dimensional mapping of texture in dental enamel. Key Eng Mater 361:877-880.
16. Al-Mosawi M, Davis GR, Bushby A, Montgomery J, Beaumont J and Al-Jawad M (2018) Crystallographic texture and mineral concentration quantification of developing and mature human incisal enamel. Sci Rep 8:1-18.
17. Harris EF and Hicks JD (1998) A radiographic assessment of enamel thickness in human maxillary incisors. Arch Oral Biol 43:825-831.
18. Feeney RN, Zermeno JP, Reid DJ, Nakashima S, Sano H, Bahar A, Hublin J-J and Smith TM (2010) Enamel thickness in Asian human canines and premolars. Anthropol Sci 118:191-198.
19. Zanetti F, Zhao X, Pan J, Peitsch MC, Hoeng J and Ren Y (2019) Effects of cigarette smoke and tobacco heating aerosol on color stability of dental enamel, dentin and composite resin restorations. Quintessence Int 50:156-166.
20. Bazzi JZ, Bindo MJ, Rached RN, Mazur RF, Vieira S and de Souza EM (2012) The effect of at-home bleaching and toothbrushing on removal of coffee and cigarette smoke stains and color stability of enamel. J Am Dent Assoc 143:e1-7.
21. Guido JA, Martinez Mier EA, Soto A, Eggertsson H, Sanders BJ, Jones JE, Weddell JA, Villanueva Cruz I and Anton de la Concha JL (2011) Caries prevalence and its association with brushing habits, water availability, and the intake of sugared beverages. Int J Paediatr Dent 21:432-440.
22. ElSalhy M, Honkala S, Söderling E, Varghese A and Honkala E (2013) Relationship between daily habits, Streptococcus mutans, and caries among schoolboys. J Dent 41:1000-1006.
23. Vieira-Junior W-F, Vieira I, Glaucia-Maria-Bovi Ambrosano F-H and Aguiar B (2018) Correlation between alteration of enamel roughness and tooth color. J Clin Exp Dent 10:e815.
24. Frank R and Brendel A (1966) Ultrastructure of the approximal dental plaque and the underlying normal and carious enamel. Arch Oral Biol 11:883-IN15.
25. Nakamura T, Saito O, Ko T and Maruyama T (2001) The effects of polishing and bleaching on the colour of discoloured teeth in vivo. J Oral Rehabil 28:1080- 1084.
Download attachments: 10.4328:ACAM.20697
Ömer Hatipoğlu, Edanur Maraş, Katibe Tuğçe Temur. Can tooth color be used as part of caries risk assessment? A cross-sectional study. Ann Clin Anal Med 2021;12(11):1212-1217
Citations in Google Scholar: Google Scholar
Evaluation of thiol / disulfide homeostasis and ischemia modified albumin levels in the differential diagnosis of central and peripheral vertigo
Alp Şener 1, Özcan Erel 2
1 Department of Emergency Medicine, 2 Department of Biochemistry, Yıldırım Beyazıt University, Faculty of Medicine, Ministry of Health Ankara City Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.20709 Received: 2021-05-18 Accepted: 2021-08-04 Published Online: 2021-08-16 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1218-1222
Corresponding Author: Alp Şener, Yıldırım Beyazıt University, Faculty of Medicine, Ankara City Hospital, Department of Emergency Medicine, Bilkent, Ankara, Turkey. E-mail: alpsener@yahoo.com P: +90 505 6497437 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0583-2936
Aim: We evaluated the role of ischemia-modified albumin (IMA) levels and thiol/disulfide homeostasis (TDH) parameters in the differential diagnosis of central and peripheral vertigo. Thus, we aim to present a new approach to the differential diagnosis of vertigo, especially in centers where magnetic resonance imag- ing (MRI) cannot be performed.
Material and Methods: The study was conducted in the emergency department (ED) using a prospective, non-randomized method. Patients with complaints of acute onset vertigo over 18 years old who underwent brain MRI were included in the study. Patients with acute ischemia with MRI were included in the central vertigo and with normal MRI in the peripheral vertigo group. Blood samples for native thiol (NT), total thiol (TT), disulfide, and IMA were collected at admission. Statistical analyzes were performed with the SPSS for Windows 16.0 Package Program.
Results: Age medians were found to be significantly higher in the central vertigo group compared to the peripheral vertigo group (65 vs 46; p<0.001). NT and TT levels were significantly lower in the central vertigo (n=29; 19.0%) group compared to the peripheral vertigo (n=124; 81.0%) group; Index-1 (D/NT) and IMA were significantly higher (p<0.05). In multiple regression analysis, age, Index-1 and IMA were found to be independent predictors in the differential diagnosis of central and peripheral vertigo (Odds: 1.061 [1.030-1.093], 2.423 [1.196-4.906], 1.060 [1.003-1.121]; respectively).
Discussion: It is possible to say that IMA and TDH parameters can be used in the differential diagnosis of vertigo when evaluated with the age of the patient.
Keywords: Age, Central Vertigo, Ischemia Modified Albumin, Peripheral Vertigo, Thiol/Disulfide Homeostasis
Introduction
Vertigo is a common complaint in the emergency department (ED) and is mentioned in 10% of all admissions [1]. The differential diagnosis of vertigo is difficult and critical in ED. There are many serious causes of vertigo with poor outcomes [1]. The rate of central etiology is approximately 3% [2]. In patients with isolated acute vertigo, peripheral vestibular system-related etiology is usually the first consideration. However, approximately 20-30% of vertebrobasilar or posterior system-originated stroke patients present with isolated vertigo without neurological deficit [3]. This leads to misdiagnosis of central vertigo [3].
Magnetic resonance imaging (MRI) is important in the differential diagnosis of vertigo [1,4]. However, MRI is not available in many EDs. In addition, false-negative results can be obtained using MRI in the first 48 hours, especially for the ischemic lesions of the posterior fossa [5]. In previous studies of stroke cases, many biomarkers have been evaluated for diagnostic or prognostic purposes [6-11]. However, not a single parameter has yet been established that can determine the indication of MRI in stroke patients and contribute to the clinical approach in practice [1].
Thiols in the plasma thiol pool form disulfide bridges as a result of oxidant stress. These disulfide bridges can also be reduced back to thiol groups. In this way, the thiol/disulfide balance works. It can be said that as the thiol/disulfide ratio increases, the status shifts to the antioxidant side; so, index-1 can give better information about antioxidant status [12]. In many diseases, it is known that this balance is collapsed in various ways. Bektaş et al expressed significant changes in stroke cases in terms of TDH parameters [9]. Şahin et al also showed that oxidative stress is on duty in benign paroxysmal positional vertigo cases [13].
The N-terminal of human serum albumin is an unstable segment; although this segment deteriorates when exposed to oxidative stress, its predisposition to bind some heavy metals such as cobalt increases. This is expressed as IMA. With ischemia and oxidative stress in stroke cases, this binding is increased and this reaction can be measured quantitatively [10,11].
In this study, we aimed to determine the value of TDH and IMA parameters in terms of the differential diagnosis of vertigo. A different approach can be provided using these biomarkers, especially in centers without MRI. It may be possible to avoid the cost of MRI through these biomarkers.
Material and Methods
Study Design
The study was carried out in the ED using a prospective, observational method from 01.07.2018 to 31.12.2018. The study was approved by the local ethics committee of Ankara Yıldırım Beyazıt University Faculty of Medicine (25.06.2018/137). Informed consent was obtained from each participant.
Study Setting and Population
Patients who were admitted to the ED with acute onset (within the last 24 hours) of vertigo and who underwent brain MRI for the differential diagnosis of peripheral/central vertigo were included in the study. Patients for whom MRI was contraindicated, under 18 years of age, pregnant and/ or tobacco users were excluded from the study. Patients with significant neurological symptoms and/or signs such as motor/ sensory neurologic deficits, speech disorder, unconsciousness and seizure, with all types of lesions (hematoma, mass, cyst, aneurysm, arteriovenous malformation, etc.) other than ischemic infarcts on MRI, acute ischemic lesions other than posterior fossa lesions, and with all infections and previous diagnosis of peripheral vertigo were excluded. The causes of lightheadedness other than central and peripheral vertigo, such as traumatic emergencies, acute crisis of cardiovascular and metabolic diseases, were also excluded.
Study Protocol
When patients who met the criteria were admitted to the ED, blood samples were collected for TDH parameters and IMA within the first hour. MRI was performed in patients without contraindications. Patients without any pathology on MRI were included in the peripheral vertigo group. Patients compatible with acute ischemic infarct in the posterior fossa on MRI were included in the central vertigo group.
The TDH and IMA parameters were integrated into routine biochemical tests and were studied simultaneously. The TDH parameters consisting of native thiol (NT), total thiol (TT) and disulfide (D), were measured by an automatic spectrophotometric measurement method developed and defined by Erel and Neşelioğlu [12]. In this method, reducible disulfide bridges are reduced to thiol groups, and then the total thiol level, consisting of native and reduced thiols, is measured. Half of the difference between total and native thiol forms the amount of dynamic disulfide. The ratios of these parameters (Index 1: D/NT; Index 2: D/TT; Index 3: NT/TT) were also analyzed. Samples for IMA were analyzed using the Albumin Cobalt Binding test mentioned in the study of Bar-Or et al [14]. This test measures the capacity of human serum albumin to absorb reduced cobalt ions. Sample Size
The sample size was calculated using the stroke group data from the study by Bektaş et al [9]; it was found that at least 19 patients should be included in each group for NT and TT parameters with 80% power and 5% Type-1 error. For IMA, the sample size was calculated using the data from the study by Jena et al [15]. In this calculation, the minimum required number of samples was calculated even lower. Based on these results, at least 20 patients were included in each group.
Data Analysis
Data were analyzed with the SPSS for Windows 16.0 Package Program. Comparisons of proportions for independent samples were made by the Chi-Square test. The normality analysis of continuous data was performed by the Shapiro-Wilk test. Independent Samples t-test was used for data showing normal distribution, and the Mann Whitney-U test was used for non- normal distribution of data; median, interquartile range (IQR) and minimum/maximum values were expressed. ROC analysis was performed for the parameters, which were statistically significantly different between the two groups. Multiple regression analysis was performed to evaluate the independent predictors in the differential diagnosis of vertigo. P <0.05 level was used for statistical significance.
Results
One hundred and fifty-three patients were included in the study, and 29 of them were diagnosed with acute ischemic stroke (19.0%; all had cerebellar infarct), and 124 of them were evaluated as peripheral vertigo (81.0%). While the age was found to be significantly higher in the central vertigo group, the gender distribution was homogeneous (Table 1).
NT, TT and index-3 levels were significantly lower in the central vertigo group compared to the peripheral vertigo group, and the IMA, index-1 and index-2 were significantly higher. Although D was higher in stroke group, this difference was not statistically significant (Table 1).
We performed logistic regression analysis for the differential diagnosis of vertigo. According to the multicollinearity analysis, a significant relationship was detected between NT, D, TT and indices. In this regard, age, native thiol, Index-1 and IMA were included in the analysis in Step-1. The backward method and Wald statistics were used for the elimination of the variables. As a result, age, Index-1 and IMA were found to be independent predictors (Table 2).
ROC analysis is performed for the differential diagnosis of central and peripheral vertigo; AUC values for age, Index-1 and IMA are shown in Table-3; ROC curves were presented in Figure 1. As it can be seen from Table 3, there is no common coordinate with both high sensitivity and high specificity rates. For the age variable, the maximum Youden index on the ROC analysis was calculated at the level of ≥52 years old. We repeated the analysis for the subgroup aged ≥52 (Tables 1 and 2). In this analysis, while IMA, index-1 and index-2 were found to be significantly higher in the central vertigo group, the index-3 was found to be lower in the peripheral vertigo group. There was no significant difference in other variables (Table 1). Among these age-homogeneous groups, no parameters were found valuable in the differential diagnosis of vertigo in multivariate logistic regression analysis (Table 2).
Discussion
Differential diagnosis of central and peripheral vertigo can be challenging when patients present with isolated acute vertigo in ED. MRI is the most commonly used diagnostic tool. No useful biomarker suitable for clinical practice has been found for this differentiation. In this study, we found that there was a significant difference in IMA and TDH parameters between these two patient groups. According to the results of this study, it is possible to say that IMA and TDH parameters can be used in the differential diagnosis of vertigo, if evaluated with the age of the patient. However, it is not possible to declare clearly that these parameters can be used instead of MRI in the differential diagnosis of central and peripheral vertigo.
Vertigo and dizziness are complaints that affect more than 90 million people in the United States only [1,16]. The differential diagnosis of vertigo is very important because of the effects on morbidity, mortality, and of course, financial costs [1,17]. Central nervous system pathologies that present with isolated acute vertigo can cause permanent neurological deficits, as well as death [1]. Patients with central vertigo etiologies present with imbalance and ataxia rather than acute vertigo. In contrast to peripheral lesions, in central pathologies, nystagmus is not affected by fixed gaze, changes direction with gaze, and may be completely torsional or vertical [16]. But often central pathologies are misdiagnosed as peripheral vertigo [3]. Central etiology may mimic peripheral vertigo, and peripheral lesions may mimic central etiology [16].
Nowadays, MRI is the preferred diagnostic tool for the differential diagnosis of patients with acute vertigo [17,18]. In recent years, the frequency of using MRI and CT in this regard has increased significantly. However, there was no significant increase in the rate of central pathologies diagnosed with this increased use [1]. This fact reminds the issue of the financial cost. In this manner, patient selection for MRI is important in the differential diagnosis of vertigo.
In the literature, we identified two biomarker studies on the differential diagnosis of central and peripheral vertigo. Akıncı et al reported that C-reactive protein, fibrinogen and D-dimer levels did not show a statistically significant difference in patients with central and peripheral vertigo [19]. Kartal et al also studied s100B protein for the same purpose and found that s100B level was significantly higher in the central group; however, the authors finally stated that it was not possible to conclude that s100B could be used instead of MRI [1].
It has been shown a decrease in thiol levels is due to oxidative stress in a wide spectrum of diseases such as a cerebrovascular event, benign paroxysmal positional vertigo, pneumonia, and myocardial infarction [9,13,20-23]. Additionally, IMA levels were found to be higher in many diseases in which ischemic processes were more prominent [11,15,24,25]. Based on these data, it can be predicted that central vertigo cases can be differentiated from peripheral vertigo cases by using TDH and IMA parameters. Thus, in this study, for the first time in the literature, TDH parameters and IMA were investigated in the differential diagnosis of vertigo.
Bektaş et al stated that oxidative stress plays an important role in ischemic stroke [9]. In this study, NT and TT levels were found to be lower in the stroke group than in the control group. In our study, similar results were found. In a study of Şahin et al on benign paroxysmal positional vertigo (BPPV), the mean values of NT and TT were statistically significantly lower than in the control group; the authors stated that oxidative stress was important in the pathogenesis of BPPV in light of these results [13]. In our study, while determining the peripheral vertigo patient group, all central causes were excluded using MRI; also, all other ischemic and metabolic causes were excluded by laboratory analysis. Additionally, in this study, contrary to the study by Şahin et al, TDH and IMA blood samples were analyzed simultaneously with all routine laboratory analyzes. These differences in methodology may have affected the results. In our study, significant differences in TDH parameters between central and peripheral vertigo groups showed a more severe oxidative stress pathogenesis in stroke (central vertigo) group. However, in order to make a comment based on the specificity and sensitivity values in Table 3, no clear data are available in this study that all TDH parameters can be used instead of MRI in the differential diagnosis of vertigo.
It is known that the risk of stroke increases with age [1,2]. Therefore, higher age in the stroke group is expected in this study. When interpreting the results of the analysis, it should be considered that this situation (although it disrupts the homogenization of the groups) is in accordance with the usual distribution in the population. However, according to the level determined in the ROC analysis for age, the analyzes were repeated in the age group of 52 years and above (Tables 1 and 2). In the analyzes performed in this subgroup, it was observed that age and gender were homogeneously distributed, and there was no difference between the central and peripheral vertigo groups in terms of NT and TT parameters (Table 1); but Index-1 and Index-2 were found to be higher in the central vertigo group. However, it is clear that this subgroup analysis does not reflect the universe. The results of the logistic regression analysis show that it would be reasonable to include the age parameter in the analysis anyway.
In the literature, studies on ischemic stroke, hemorrhagic stroke and subarachnoid hemorrhage have shown that IMA levels are increased in patients compared to healthy volunteers [10,11,15]. To the best of our knowledge, this study is the first to analyze the IMA parameter in the differential diagnosis of central and peripheral vertigo; in addition, IMA has not been analyzed previously in the peripheral vertigo patients. The results of this study on stroke disease are consistent with the fact of ischemic pathogenesis of stroke and the literature. IMA levels were significantly higher in the central vertigo group compared to the peripheral vertigo group.
Limitations
Being a single-center study and the small number of patients in the study groups are important limitations. However, the fact that the inclusion criteria were quite strict was effective in a small number of subjects. Since this is the first study on this subject in the literature, sample size analysis should have been conducted using similar studies as much as possible. Whether the difference in age distribution between groups is a limitation is an issue open to interpretation. False negative results may occur in the first 48 hours with MRI; in this respect, the lack of a new MRI for follow-up should be considered as another limitation.
Conclusions
Although the value of many biomarkers has been studied in both central and peripheral vertigo, there is no marker included in clinical practice. In this study, it was observed that TDH indices and IMA were higher in the central vertigo group compared with the peripheral vertigo group. However, with these results, it is not correct to say that adequate sensitivity and specificity rates have been reached in terms of differential diagnosis of vertigo and using these markers instead of MRI. Nevertheless, we can say that these parameters can be useful in the differential diagnosis of vertigo when considering the age of the patient.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Kartal AG, Yılmaz S, Yaka E, Pekdemir M, Sarısoy HT, Çekmen MB, et al. Diagnostic value of S100B protein in the differential diagnosis of acute vertigo in the emergency department. Acad Emerg Med. 2014; 21(7):736-41.
2. Mármol-Szombathy I, Domínguez-Durán E, Calero-Ramos L, Sánchez-Gómez S. Identification of dizzy patients who will develop an acute cerebrovascular syndrome: a descriptive study among emergency department patients. Eur Arch Otorhinolaryngol. 2018; 275(7):1709-13.
3. Venhovens J, Meulstee J, Verhagen WI. Acute vestibular syndrome: a critical review and diagnostic algorithm concerning the clinical differentiation of peripheral versus central aetiologies in the emergency department. J Neurol. 2016; 263(11):2151-7.
4. Marzo SJ, Leonetti JP. The importance of magnetic resonance imaging in the evaluation of vertigo and imbalance. Skull Base Surg. 2000; 10(4):171-2.
5. Edlow JA, Newman-Toker D. Using the Physical Examination to Diagnose Patients with Acute Dizziness and Vertigo. J Emerg Med. 2016; 50(4):617-28.
6. Reynolds MA, Kirchick HJ, Dahlen JR, Anderberg JM, McPherson PH, Nakamura KK, et al. Early biomarkers of stroke. Clin Chem. 2003; 49:1733–9.
7. Sharma R, Macy S, Richardson K, Lokhnygina Y, Laskowitz DT. A-blood-based biomarker panel to detect acute stroke. J Stroke Cerebrovasc Dis. 2014; 23:910–8.
8. Laskowitz DT, Kasner SE, Saver J, Remmel KS, Jauch EC, BRAINStudy Group. Clinical usefulness of a biomarkerbased diagnostic test for acute stroke: the Biomarker Rapid Assessment in Ischemic Injury (BRAIN) study. Stroke. 2009; 40(1):77-85.
9. Bektas H, Vural G, Gumusyayla S, Deniz O, Alisik M, Erel O. Dynamic thioldisulfide homeostasis in acute ischemic stroke patients. Acta Neurol Belg. 2016; 116(4):489–94.
10. Menon B, Ramalingam K, Krishna V. Study of Ischemia Modified Albumin as a Biomarker in Acute Ischaemic Stroke. Ann Neurosci. 2018; 25(4):187-90.
11. Gunduz A, Turedi S, Mentese A, Altunayoglu V, Turan I, Karahan SC, et al. Ischemia-modified albumin levels in cerebrovascular accidents. Am J Emerg Med. 2008; 26(8):874-8.
12. Erel Ö and Neşelioğlu S. A novel and automated assay for thiol/disulphide homeostasis. Clin Biochem. 2014; 47(18):326–32.
13. Şahin E, Deveci İ, Dinç ME, Özker BY, Biçer C, Erel Ö. Oxidative Status in Patients with Benign Paroxysmal Positional Vertigo. J Int Adv Otol. 2018; 14(2):299-303.
14. Bar-Or D, Lau E, Winkler JV. A novel assay for cobalt-albumin binding and its potential as a marker for myocardial ischemia-a preliminary report. J Emerg Med. 2000; 19(4):311-5. DOI: 10.1016/s0736-4679(00)00255-9.
15. Jena I, Nayak SR, Behera S, Singh B, Ray S, Jena D, et al. Evaluation of ischemia-modified albumin, oxidative stress, and antioxidant status in acute ischemic stroke patients. J Nat Sci Biol Med. 2017; 8(1):110-13.
16. Thompson TL, Amedee R. Vertigo: a review of common peripheral and central vestibular disorders. Ochsner J. 2009; 9(1):20-6.
17. Saber Tehrani AS, Kattah JC, Kerber KA, Gold DR, Zee DS, Urrutia VC, et al. Diagnosing Stroke in Acute Dizziness and Vertigo: Pitfalls and Pearls. Stroke. 2018; 49(3):788-95.
18. Lawhn-Heath C, Buckle C, Christoforidis G, Straus C. Utility of head CT in the evaluation of vertigo/dizziness in the emergency department. Emerg Radiol. 2013; 20(1):45-9.
19. Akinci E, Aygencel G, Keles A, Demircan A, Bildik F. Role of C-reactive protein, D-dimer, and fibrinogen levels in the differential diagnosis of central and peripheral vertigo. Adv Ther. 2007; 24(5):1068-77.
20. Şener A, Kurtoğlu Çelik G, Özhasenekler A, Gökhan Ş, Tanrıverdi F, Kocaoğlu S, et al. Evaluation of dynamic thiol/disulfide homeostasis in adult patients with community-acquired pneumonia. Hong Kong Journal of Emergency Medicine. 2019; 26(6):343-50.
21. Sivri S, Kasapkara HA, Polat M, Alsancak Y, Durmaz T, Erel Ö, et al. Dynamic thiol/disulphide homeostasis and its prognostic value in patients with non-ST elevation-acute coronary syndromes. Kardiol Pol. 2018; 76(2):426-32.
22. Sengoren Dikis O, Acat M, Casim H, Haskul I, Neselioglu S, Simsek A, et al. The relationship of thiol/disulfide homeostasis in the etiology of patients with obstructive sleep apnea: a case-control study. Aging Male. 2019; 3:1-8.
23. Köseoğlu H, Alışık M, Başaran M, Tayfur Yürekli Ö, Solakoğlu T, et al. Dynamic thiol/disulphide homeostasis in acute pancreatitis. Turk J Gastroenterol. 2018; 29(3):348-53.
24. Turedi S, Yilmaz SE, Mentese A, Turkmen S, Karaca Y, Sen O, et al. The diagnostic value of serum ischemia-modified albumin levels in experimentally induced carbon monoxide poisoning and their correlation with poisoning severity. Acad Emerg Med. 2013; 20(7):652-8.
25. Charpentier S, Ducassé JL, Cournot M, Maupas-Schwalm F, Elbaz M, Baixas C, et al. Clinical assessment of ischemia-modified albumin and heart fatty acid-binding protein in the early diagnosis of non-ST-elevation acute coronary syndrome in the emergency department. Acad Emerg Med. 2010; 17(1):27-35.
Download attachments: 10.4328:ACAM.20709
Alp Şener, Özcan Erel. Evaluation of thiol / disulfide homeostasis and ischemia modified albumin levels in the differential diagnosis of central and peripheral vertigo. Ann Clin Anal Med 2021;12(11):1218-1222
Citations in Google Scholar: Google Scholar
Tp-E interval, Tp-E/QT ratio and fragmented QRS parameters in patients with panic disorder
Aslı Kazgan 1, Sevler Yıldız 2, Denizhan Danacı Keleş 3, Fikret Keleş 4, Osman Kurt 5
1 Department of Psychiatry, Siverek State Hospital, Şanlıurfa, 2 Department of Psychiatry, University of Binali Yıldırım, Erzincan, 3 Department of Psychiatry, Mental Health And Illness Hospital, Elazığ, 4 Department of Cardiology, Fethi Sekin City Hospital, Elazığ, 5 Department of Public Health, Fırat University, Medical Faculty, Elazığ, Turkey
DOI: 10.4328/ACAM.20710 Received: 2021-05-19 Accepted: 2021-07-23 Published Online: 2021-08-09 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1223-1228
Corresponding Author: Aslı Kazgan, Siverek State Hospital, Department of Psychiatry, 63600, Şanlıurfa, Turkey. E-mail: dr.kazgan@hotmail.com P: +90 505 740 33 68 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0312-0476
Aim: In the presented research, we intended to appraise ventricular repolarization and factors of myocardial change in patients diagnosed with panic disorder (PD).
Material and Methods: Fifty patients with newly diagnosed panic disorder and 50 healthy individuals as a control group were included in the research. All par- ticipants were administered Sociodemographic Data Form, Panic Disorder Severity Scale (PDSS), followed by electrocardiography (ECG).
Results: Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio were found to be remarkably higher in PD patients than in the control group (p<0,001). The incidence of fragmented QRS in PD patients (72%) was significantly higher than the rate of fragmented QRS in the control group (36%) (p<0,001). The median PDSS score of PD patients with fragmented QRS on their ECG was 16.0 (13.5-18.5), and the median PDSS score of those without fragmented QRS on their ECG was 13.0 (9.0-16.0), thus there was a statistically remarkable difference between them (p=0.0.05). In PD patients, a moderately positive relationship has been found between PDSS scale score and Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio, respectively (p=0.000 r=0.496) (p=0.002 r=0.436) (p=0.008 r=0.369).
Discussion: The study suggests that untreated PD patients may be at high risk in terms of arrhythmic events due to abnormal ventricular conduction and myocardial damage. Tp-e interval, Tp-e/QT ratio and fragmented QRS factors may allow evaluation of subclinical heart disease before the clinical presenta- tion becomes apparent in PD.
Keywords: Panic Disorder, Tp-e Interval, Tp-e/QT, Tp-e/QTc, Fragmented QRS
Introduction
Panic disorder (PD) is a chronic psychiatric disorder with recurrent panic attacks during which a person presents symptoms associated with the autonomic nervous system such as palpitations, chest pain, shortness of breath, sweating, tremors. These physical symptoms accompanying the attacks indicate increased sympathetic activity and therefore abnormally functioning autonomic nervous system [1]. In addition to the limited information available on a causal relationship between panic disorder and cardiovascular disease (CVD) [2], PD is related with an increased risk of CVD and mortality [3]. In PD patients, PD was found to be associated with CVD, cardiomyopathies [4], arrhythmia and decreases in heart rate variability [2, 5]. Among the arrhythmia markers, Tp-e/QTc ratio, Tp-e/QT ratio and fQRS parameters attract attention as predictors of mortality and morbidity [6, 7].
Fragmented QRS (fQRS) is a finding for the ventricular depolarization disorder that can show damage associated with myocardial fibrosis and can be readily determined in electrocardiography (ECG). It shows a conduction delay caused by myocardial fibrotic tissue. Fibrotic tissue decelerates the electrical conduction rate, causing non-homogeneous ventricular activation. This condition is displayed in the form of a kerf in QRS complex on the ECG and is considered superior to the Q wave in the determination of myocardial scar, and was associated with a short survey after acute myocardial infarction [8, 9]. In a study conducted on patients diagnosed with depressive disorder, the presence of fQRS was associated with the disease period, and it was reported that it could be used to detect subclinical cardiac damage [10].
One way to indicate myocardial repolarization is to measure the T wave. Transmural dispersion (TDR) of Tp-e, the spacing among the top and end of the T wave, is known to be a predictor of ventricular repolarization. The presence of TDR shows us that ventricular repolarization does not take place synchronously throughout the overall ventricle [11]. An increased Tp-e spacing and a high Tp-e/QT ratio in electrocardiography are remarkable indicators for the development of ventricular arrhythmia in electrocardiography [12]. Tp-e interval, Tp-e/QT ratio were investigated in schizophrenia sufferers, and ventricular arrhythmia has been shown to be predetermined in this patient group [13].
Some clinical studies have shown an increased risk of demise from cardiovascular illnesses or cardiovascular causes in patients diagnosed with panic disorders [14]. Therefore, we intended to assist the early diagnosis of subclinical patients by evaluating ventricular activation factors such as Tp-e interval, Tp-e/QT ratio and fQRS in PD patients.
Material and Methods
This study was approved by Fırat University, Medical Faculty Ethics Committee. (Date: 04.02.2021, Number: 2021/02-01). Informed consent was obtained from the individuals who participated in this study.
The research was planned as case-control. Local ethics board approval has been obtained for the study. Fifty patients with newly diagnosed panic disorder according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental
Disorders-5 (DSM-5) were included in the study, while 50 healthy individuals with socio-demographic characteristics similar to the patient group were recruited as control groups. After completing the diagnostic and treatment phases with regard to the patient’s complaint, a face-to-face interview was conducted with the participants for about 15 minutes. After the participants were informed about the goal of the research prior to the survey, their written and verbal informed consent was obtained. A socio-demographic Data Form and the Panic Disorder Severity Scale were applied to all participants. After applying the scales, all participants underwent non- interventional electrocardiography (ECG).
Criteria for inclusion in the patient group
The containment conditions for the case group were as follows: diagnosis with panic disorder according to DSM-5 criteria for the first time, age range of the patients between 18-65 years, literacy requirement, signing an informed consent form, no another accompanying psychiatric disorder, no known drug treatment, no systemic and metabolic disease, no dementia, mental retardation, cognitive impairment or neurological disease history, not current psychiatric treatment and no use of alcohol and substance abuse in the last 6 months, no known cardiovascular disease (no history of cardiac failure, valvular heart disease, cardiomyopathy, myocardial infarction, and cardiovascular diseases such as bundle branch block and arrhythmia, no history of bypass surgery, stent implantation, pacemaker implantation and hypertension) and the nonexistence of pathology in ordinary blood and biochemical tests.
Criteria for inclusion in the control group
The containment conditions for the control group were as follows: age 18-65 years, no history of another psychiatric disorder, no history of medical treatment, no serious neurological diseases and systemic diseases, nonexistence of pathology in ordinary blood and biochemical tests, absence of any heart diseases. Measurement of Tp-e/QT, Tp-e/QTc and fQRS on ECG
Regular 12-lead ECG monitoring was applied in outpatient ECG rooms for all patients and controls. The room was isolated from noise, so the ECG records were not influenced by the exterior determinants. Recordings were carried out when the participant achieved sufficient natural breathing (after a waiting time of 5-10 minutes), when the participant was in a supine situation and was not permitted to talk during the ECG recording. All participants were applied a regular 12-lead body surface ECG (Nihon Kohden, Tokyo, Japan) at a paper speed of 50 mm/s. The Tp-e interval, QT and QTc interval, Tp-e/QT and Tp-e/QTc ratio, and the presence of fragmented QRS were manually appraised by 2 cardiologists. Special ECG reading rulers were used to obtain a precise measurement. The QT interval was appraised in milliseconds from the first deviation of the QRS complex up to the T wave reached isoelectric line. The QTc interval was computed using the Bazett technique (QTc = QT/VRR). The Tp-e interval was calculated by measuring the time in milliseconds from the top of the T wave to the point where the deflection line intersects the isoelectric line. These assessments were made from precordial leads, which are most suitable for measurement. Cases with significant U-wave or negative or biphasic T wave in surface ECG were excluded from the study.
Detection of Fragmented QRS in ECG
Fragmented QRS was described as an extra R wave (R’), or notch in the R or S wave in at least 2 successive leads that do not display typical branch block characteristics and match a coronary blood supply area [15]. Cases showing a typical branch block pattern were excluded from the study.
Scales used in the study:
1) Sociodemographic Data Form: It is prepared by researchers for the purposes of the study. It is a form that includes demographic data such as age, marital status, educational status, place of residence, working status and economic situation, as well as clinical evaluation questions such as how many years has the patient suffered from psychiatric disorders, presence of psychosocial stress factor, history of inpatient treatment, and use of tobacco or alcohol.
2) Panic Disorder Severity Scale: The purpose of the panic disorder severity scale is to detect symptom severity in panic disorder with or without agoraphobia, the frequency of panic attacks, to measure limited symptom attacks, the severity of anticipatory anxiety, phobic avoidance, and functional impairment. The evaluation is made by taking the last month into account. It consists of seven items. The lowest score that can be obtained from the scale is 0 and the highest score is 28 [16].
Statistical analysis
The analysis is evaluated using the SPSS 22 package program (Statistical Package for Social Sciences; SPSS Inc., Chicago, IL). Descriptive data were shown with n, % values in categorical data and mean ±standard deviation, median, interquartile range values (25-75 percentile values) in continuous data. The Chi-square analysis (Pearson’s Chi-square) was administered to compare categorical factors between groups. The suitability of continuous variables for normal distribution was assessed using the Kolmogorov-Smirnov test. The independent Samples t-test was used to compare factors that matched normal distribution between the two groups, and the Mann-Whitney U test was administered to compare variables that were not normally distributed between the two groups. Spearman’s correlation test was used to investigate the link of continual factors. In the evaluation, the level of statistical importance was taken as p<0.05.
Results
The research consisted of 100 people in total, 50 patients with panic disorders and 50 healthy individuals as a control group. The mean age of the case group was 35.9±9.4 (min=20- max=60) years and the mean age in the control group was 34.5±9.3 (min=18-max=60) years, and there was no statistically significant difference between the groups (p=0.469). It was observed that 56% of the participants in the case group were male, and 40% of the participants in the control group were male. There was no significant difference in gender between the groups (p=0.109). It was observed that the educational status of the patient group was notably higher than that of the control group (p=0.03). The probability of being a housewife in the control group (50%) was significantly higher than in the case group (20%) (p=0.007). There were no significant differences between the groups in terms of marital status (p=0.224), place of residence (p=0.061), economic status (p=0.811), family history of heart disease (p=0.817) and smoking (p=0.509) (Table 1).
The PDSS score of the patient group was significantly higher than that of the control group (p<0,001). The Tp-e interval, Tp-e/ QT ratio and Tp-e/QTc ratio in the case group were significantly higher than in the control group (p<0,001). The incidence of fragmented QRS in the case group (72%) was significantly higher than the incidence of fragmented QRS (36%) in the control group (p<0,001) (Table 2) (Figures 1, 2).
In the case group, the median PDSS score of those who displayed fragmented QRS on the ECG was 16.0 (13.5-18.5), and the median PDSS score of those whose ECG did not present a fragmented QRS on the ECG was 13.0 (9.0-16.0), thus there was a statistically remarkable difference between them (p=0.0.015).
It was established that there was a moderate positive relationship between PDSS scale score and Tp-e interval, Tp-e/ QT ratio and the Tp-e/QTc ratio in the case group (p=0.000 r=0.496), (p=0.002 r=0.436), (p=0.008 r=0.369) (Table 3) (Figure 3).
Discussion
One of the most important findings of our research is that the Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio, which are TDR markers in the PD patient group, are significantly higher and there is a moderate positive relationship between these parameters and symptom severity. Another finding is that the incidence of fQRS in PD patients was 72%, which is higher than in the control group, and the symptom severity in PD patients with fQRS was higher than in those without fQRS. As far as we know, our research is the first in this field to show the variability in fQRS among patients with PD. All these findings may demonstrate an increased risk of cardiac arrhythmia in PD patients. While a high risk of cardiovascular mortality was mentioned in anxiety disorders in general [17], PD was specifically related to an increased risk of CVD and mortality [3]. In a research involving 35 patients with panic disorders, higher rates of myocardial alterations were detected in patients, including left ventricular hypertrophy, and it was mentioned that care should be taken in terms of subclinical myocardial alterations in these patients [4]. In a prospective study conducted on 5,303 people in 2010, it was found that non-fatal CVD developed among patients with anxiety disorders, including PD, during 3 years of follow-up [18]. Fleet et al. [19] reported that panic attack can induce myocardial perfusion defects in patients with CVD and PD, despite the use of cardiac medication, by using the panic-inducing effect of carbon dioxide.
Tp-e interval and high Tp-e/QT ratio are cited as crucial factors in electrocardiography to forecast the development of ventricular arrhythmia in clinical trials, and their increased values have been related with cardiovascular mortality [12]. The same parameters were studied in schizophrenia patients, and it was demonstrated that Tp-e interval, Tp-e/QT could predetermine ventricular arrhythmia in this patient group [13]. In a recent study conducted on 40 PD patients, it was found that Tp-e interval, Tp-e/QT and Tp-e/QTc rates increased significantly compared to the control group, but fQRS was not evaluated in this patient group [20]. In our study, these parameters with ventricular arrhythmia markers in patients with PD were found to be significantly higher than in a healthy individual in the control group, which is consistent with previous findings. In light of these findings, it may be necessary to refer to the heart rate connection between panic disorder and the autonomic nervous system. Increased sympathetic activity and decreased vagal tonus changes may explain our findings in PD patients.
QTc and Tp-e interval is directly related to heart rate. Evidence for a strong association between PD and cardiomyopathies, arrhythmia and reduced heart rate variability (HRV) has been presented in previous studies [2, 4-5]. Ventricular repolarization, which plays a considerable role in the occurring of ventricular arrhythmia, is controlled by the autonomic nervous system. It has been shown that patients with PD have a higher rate of autonomic nervous system disorders such as decreased vagal tonus and increased sympathetic system activation [1]. Heart rate variability is a vagal tonus marker and an indicator of autonomic nervous system activity. The reduction in HRV is a predictor of cardiac events. In the study conducted by Hovland et al., decreased heart rate changeability has been found in patients with PD, and they also reported that this was related with symptom intensity of panic disorder [21]. In our study, a moderately positive relationship was found between symptom severity of PD patients and the Tp-e interval, the Tp-e/QT ratio, and the Tp-e/QTc ratio. Although the Tp-e interval and QT are affected by heart rate, the Tp-e/QT ratio and the Tp-e/QTc ratio are not affected. This suggests that PD patients may be at increased risk of ventricular arrhythmia in proportion to the severity of the disorder.
Another arrhythmia predictor, fQRS, represents myocardial ischemic areas [6]. In a study devoted to depressive disorder, the presence of fQRS was associated with the disease, and fQRS was thought to be a useful tool for detecting subclinical cardiac damage in these patients [10]. In our study, patients with fQRS in PD patients had a higher symptom load. In their research, Esler et al. identified various cardiac arrhythmia, including atrial fibrillation, in emergency room admissions in PD patients, and reported that patients with severe chest pain were at cardiac risk.
During a panic attack, an intense sympathetic discharge occurs, as well as strong bodily sensations such as anxiety, shortness of breath, palpitations and chest pain. Thus, it is seen that panic attack causes real ischemia, which may be associated with adrenaline-mediated coronary vasospasm in CVD patients. Due to increased ventricular contractions, the increase in the need for myocardial O2 can lead to a possible myocardial ischemia. It was also determined that there was a 7-fold increase in serotonin cycle in patients when there were no panic attacks during rest [22]. These findings are likely related to the neurochemical infrastructure of the relationship between FQRS and PD.
The strength of our study is that the sampling consists of patients who had been diagnosed with PD for the first time and who did not have additional drug use. Antipsychotics cause anticholinergic effects with some substances that induce myocardial fibrosis and cause prolongation of QTc [23].
According to the TILDA study, one of the largest studies ever on antidepressants, autonomic imbalance antidepressants were found to be more associated with antidepressant medications [24]. In this research, the fact that the incidence of fQRS in PD patients who were treated with drugs was as high as 72%, and other ventricular arrhythmia parameters were significantly higher, suggests that these patients may be at risk of ventricular arrhythmia regardless of medication factor.
The main limitations of our study are the low number of cases, which is cross-sectional, and the inability to quantify myocardial fibrosis.
Conclusion
The findings of our study suggest that untreated PD patients may be at high risk for arrhythmic events due to abnormal ventricular conduction and myocardial damage. The Tp-e interval, Tp-e/QT ratio, and fragmented QRS parameters pose significant potential for noninvasive easy measurements that can evaluate subclinical heart disease without clinical clarification in PD.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Cohen H, Benjamin J. Power spectrum analysis and cardiovascular morbidity in anxiety disorders. Auton Neurosci. 2006; 128(1-2):1-8. DOI: 10.1016/j. autneu.2005.06.007.
2. Machado S, Sancassiani F, Paes F, Rocha N, Murillo-Rodriguez E, Nardi AE. Panic disorder and cardiovascular diseases: An overview. Int Rev Psychiatry. 2017; 29(5):436–44. DOI: 10.1080/09540261.2017.1357540.
3. Katerndahl DA. The association between panic disorder and coronary artery disease among primary care patients presenting with chest pain: An updated literature review. Prim Care Companion J Clin Psychiatry. 2008; 10(4):276–85. DOI: 10.4088/pcc.v10n0402.
4. Caldirola D, Schruers KR, Nardi AE, De Berardis D, Fornaro M, Perna G. Is there cardiac risk in panic disorder? An updated systematic review. J Affect Disord. 2016; 194:38–49. DOI:10.1016/j.jad.2016.01.003.
5. Chalmers J A, Quintana DS, Abbott MJ, Kemp AH. Anxiety disorders are associated with reduced heart rate variability: A meta-analysis. Front Psychiatry. 2014; 5:80. DOI:10.3389/fpsyt.2014.00080.
6. Jain R, Singh R, Yamini S, K Das M. Fragmented ECG as a risk marker in cardiovascular diseases. Curr Cardiol Rev. 2014; 10(3): 277-86. DOI: 10.2174/15 73403X10666140514103451.
7. Kilicaslan F, Tokatli A, Ozdag F, Uzun M, Uz O, Isilak Z, et al. Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio are prolonged in patients with moderate and severe obstructive sleep apnea. Pacing Clin Electrophysiol. 2012; 35(8):966−72. DOI: 10.1111/j.1540-8159.2012.03439.x.
8. Das MK, Zipes DP. Fragmented QRS: a predictor of mortality and sudden cardiac death. Heart Rhythm. 2009; 6(Suppl. 3):8-14. DOI: 10.1016/j.hrthm.2008.10.019.
9. Lorgis L, Jourda F, Hachet O, Zeller M, Gudjoncik A, Dentan G. Prognostic value of fragmented QRS on a 12-lead ECG in patients with acute myocardial infarction. Heart Lung. 2013; 42(5):326-31. DOI: 10.1016/j.hrtlng.2013.05.005.
10. Ilter A, Aslan M, Caliskan IZ, Besli F, Tusun E. Major depressive disorder is associated with fragmented QRS. Acta Cardiol. 2017; 72(2):156-60. DOI: 10.1080/00015385.2017.1291138.
11. Sauer A, Wilcox JE, Andrei AC, Passman R, Goldberger JJ, Shah SJ. Diastolic electromechanical coupling: association of the ECG T-peak to T-end interval with echocardiographic markers of diastolic dysfunction. Circ Arrhythm Electrophysiol. 2012; 5(3): 537–43. DOI: 10.1161/CIRCEP.111.969717.
12. Zhao X, Xie Z, Chu Y, Yang L, Xu W, Yang X, et al. Association Between Tp-e/ QT Ratio and Prognosis in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction. Clinical Cardiology. 2012; 35(9):559–64. DOI:10.1002/clc.22022.
13. Özsoy F, Zorlu Ç, Kaya Ş. Electrocardiographic evaluation of the ventricular arrhythmia risk in patients with schizophrenia. Anatolian Journal of Psychiatry. 2020; 22:85-9. DOI: 10.5455/apd.7015.
14. Tully PJ, Turnbull DA, Beltrame J, Horowitz J, Cosh S, Baumeister H, et al. Panic disorder and incident coronary heart disease: a systematic review and meta-regression in 1131612 persons and 58111 cardiac events. Psychol Med. 2015; 45(14):2909–20. DOI:10.1017/S0033291715000963.
15. Das MK, Michael MA, Suradi H, Peng J, Sinha A, Shen C, et al. Usefulness of fragmented QRS on a 12-lead electrocardiogram in acute coronary syndrome for predicting mortality. Am J Cardiol. 2009; 104(12):1631-7. DOI: 10.1016/j. amjcard.2009.07.046.
16. Shear MK, Brown TA, Barlow DH. Multi-center, collaborative Panic Disorder Severity Scale. Am J Psychiatry. 1997; 154(11):571-5. DOI: 10.1176/ ajp.154.11.1571.
17. Emdin CA, Odutayo A, Wong CX, Tran J, Hsiao AJ, Hunn BH. Meta-analysis of anxiety as a risk factor for cardiovascular disease. Ame J Cardiol. 2016; 118(4):511–9. DOI:10.1016/ j.amjcard.2016.05.041.
18. Batelaan NM, Have MT, Van Balkom AJ, Tuithof M, de Graaf R. Anxiety disorders and onset of cardiovascular disease: the differential impact of panic, phobias and worry. J Anxiety Disord. 2014; 28(2):252–8. DOI: 10.1016/j. janxdis.2013.12.003.
19. Fleet R, Lespérance F, Arsenault A, Grégoire J, Lavoie K, Laurin C, et al. Myocardial perfusion study of panic attacks in patients with coronary artery disease. Am J Cardiol. 2005; 96(8):1064-8. DOI: 10.1016/j.amjcard.2005.06.035.
20. Afsin A, Asoğlu R, Orum MH, Cicekci E. Evaluation of TP-E Interval and TP-E/QT Ratio in Panic Disorder. Medicina. 2020; 56(5):215. DOI:10.3390/ medicina56050215.
21. Hovland A, Pallesen S, Hammar Å, Hansen AL, Thayer JF, Tarvainen MP, et al. The relationships among heart rate variability, executive functions, and clinical variables in patients with panic disorder. Int J Psychophysiol. 2012; 86(3): 269– 75. DOI: 10.1016/j.ijpsycho.2012.10.004.
22. Esler M, Alvarenga M, Lambert G, Kaye D, Hastings J, Jennings G, et al. Cardiac sympathetic nerve biology and brain monoamine turnover in panic disorder. Annals of the New York Academy of Sciences. 2004; 1018:505–14. DOI:10.1196/ annals.1296.062.
23. Beach SR, Celano CM, Noseworthy PA, Januzzi JL, Huffman JC. QTc prolongation, torsades de pointes, and psychotropic medications. Psychosomatics. 2013; 54(1):1–13.
24. O’Regan C, Kenny RA, Cronin H, Finucane C, Kearney PM. Antidepressants strongly influence the relationship between depression and heart rate variability: findings from The Irish Longitudinal Study on Ageing (TILDA). Psychol Med. 2015; 45(3):623–36. DOI: 10.1017/S0033291714001767.
Download attachments: 10.4328:ACAM.20710
Aslı Kazgan, Sevler Yıldız, Denizhan Danacı Keleş, Fikret Keleş, Osman Kurt. Tp-E interval, Tp-E/QT ratio and fragmented QRS parameters in patients with panic disorder. Ann Clin Anal Med 2021;12(11):1223-1228
Citations in Google Scholar: Google Scholar
Effect of less affected grip strength training on grip strength in both hands in unilateral cerebral palsy
Aya T’Allah Y. Kandeel, Asma O. Sayed, Mohamed I. Elassal
Department of Pediatric, Faculty of Physical Therapy, Cairo University, Cairo, Egypt
DOI: 10.4328/ACAM.20711 Received: 2021-05-21 Accepted: 2021-07-09 Published Online: 2021-07-24 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1229-1232
Corresponding Author: Aya T’Allah Yasser Kandeel, Department of Pediatric, Faculty of Physical Therapy, Cairo University, 48 Sakr Kourish Buildings, El Maadi, Cairo, Egypt. E-mail: drayayasser92@gmail.com P: +20 01116177812 Corresponding Author ORCID ID: https://orcid.org/0000-0002-4893-6030
Aim: This study was performed to show the effect of less affected grip strength training on grip strength on both upper limbs and its impact on functional manual ability in children with unilateral cerebral palsy/hemiplegia.
Material and Methods: This study involved twenty-four children aged 7-12 years from both sexes with unilateral cerebral palsy or hemiplegia, whose degree of spasticity was 1 and +1 according to the modified Ashworth scale. Assessment of grip strength of both hands and functional manual ability were performed using a Camry Hand Held Dynamometer, a Manual Abilities Classification System, and a Pediatric Upper Extremity Motor Activity Log for pre- and post-training test. The Camry Hand Held Dynamometer was used for grip strength training of the less affected hand.
Results: This study revealed that less affected grip strength training showed a significant increase in grip strength on both upper limbs, with the mean strength gain on the more affected side being 58.06 ± 27.88%, while that of the less affected side was 42.36 ± 28.53% compared with pre-training with improvement in functional manual abilities.
Discussion: This study showed a positive role of less affected grip strength training not only on ipsilateral but also on contralateral grip strength in improving functional manual abilities in children with unilateral cerebral palsy or hemiplegia, so this procedure may be used clinically in hand rehabilitation for them.
Keywords: Cerebral Palsy, Hemiplegia, Cross Education, Grip Strength
Introduction
Cerebral Palsy (CP) is one of the most frequent neurological causes of motor disability in children that occurred in the developing fetal or infant brain leading to permanent disorders [1]. Unilateral Cerebral Palsy (UCP), also called Hemiplegic CP, upper-limb dysfunction can range from mild to profoundly impaired, depending on the timing, site, extent and nature of the brain lesion [2]. Deficits in timed motor performance and grip strength were noted in the less-affected (LA) hands of children with UCP compared to their typically-developing peers. Therefore, considering LA hand in intervention may be useful when considering the scope of clinical assessments and goal setting during rehabilitation [3].
Unilateral handgrip training program using the selected protocol increased handgrip strength bilaterally due to the cross-education of strength [4]. The cross-education of strength and skill learning was first discovered in 1894 by Scripture et al. who determined that muscular strength in contralateral limb could be improved following unilateral training. The mechanism behind the cross-education of the strength includes cortical and spinal adaptation, which alter the neural drive to the contralateral, untrained limb [5] and there is evidence for plasticity of interhemispheric connections to mediate cross- education produced by a simple motor task [6].
The Manual Ability Classification System (MACS) provides a new perspective for classifying manual ability in children and adolescents with CP. Parents and therapists have perceived the classification as meaningful description of variations in manual ability. Inter-rater reliability between parents and therapist, as well as between therapists was excellent; inter-rater reliability for different age groups was equally good [7].
The Pediatric Upper Extremity Motor Activity Log (PMAL) had high internal consistency and test-retest reliability. Convergent validity was supported by a strong correlation between changes in PMAL scores and the use of MA arm during playing [8].
Grip strength measurement is a well-known method to investigate hand function, providing insight into the combined action of a number of extrinsic and intrinsic muscles, and in several patient groups, grip strength measurement with a dynamometer is known to have excellent reliability [9].
Material and Methods
The study involved 24 children of both sexes with hemiplegia, aged 7-12 years from the outpatient clinic of Faculty of Physical Therapy, Cairo University Hospital and Modern University for Technology & Information. The local medical ethics committee at the University approved all study procedures. Written informed consent was obtained from all childrens’ parents before participation in the study. This study involved children with grade 1 and 1+ spasticity according to the Modified Ashworth Scale who were able to sit independently and follow instructions. Children with a history of recent nonunion fracture, poor perception or cognition, and any contracture or deformity affecting hand mobility were excluded from this study.
The Modified Ashworth Scale (MAS) was used for the evaluation of spasticity. A Camry Dynamometer was used for the assessment of grip strength. The Manual Ability Classification System (MACS) and Pediatric Upper Extremity Motor Activity
Log (PMAL) were used for the functional manual ability assessment.
Before training, three baseline pre-tests were performed at intervals of 4-7 days. After training, one post-test was performed within 1 week. Maximal grip strength was performed in pre- and post- tests.
The Camry Dynamometer was used for grip strength training inform of 5 sets × 5 repetitions × 5 seconds of maximal grip contractions in the LA hand with a 3-second break between contractions and a 2- minute break between sets [4]. Before training, a warm-up session with 3 sets × 5 repetitions × 5 seconds 50% maximal grip contraction was completed. The training was performed in a comfortable sitting position, a less affected shoulder was adducted, 90 degrees elbow flexed forearm neutral with 0-15 degrees of ulnar deviation. The arm was not supported and the dynamometer was placed vertically and in line with the forearm.
Results
This study was performed to investigate the effect of LA grip strength training on grip strength in both hands in UCP, showing its impact on a child’s functional ability quantitatively and qualitatively. Twenty-four children with hemiplegia participated in this study. The data obtained from the study groups pre- and post- training regarding grip strength of MA, grip strength of LA, PMAL and MACS were statistically analyzed and compared. The mean ± SD age of the study group was 9.29 ± 1.62 years and the number of girls was 11 (46%), while the number of boys was 13 (54%). The distribution of the affected side in the study group revealed that 16 (67%) subjects had the right side affected and 8 (33%) subjects had the left side affected as shown in (Table 1).
The mean ± SD grip strength of MA pre-training in the study group was 5.39 ± 1.95 kg, while post- training it was 8.22 ± 2.62 kg. The mean difference was -2.83 kg, so there was a significant increase in the grip strength of MA in the study group post- training compared to that pre- training (p = 0.0001), as shown in (Table 2) and (Figure 1).
The mean ± SD grip strength of LA pre- training in the study group was 11.29 ± 3.25 kg, while post- training it was 15.78 ± 4.59 kg. The mean difference was -4.49 kg. There was a significant increase in the grip strength of LA in the study group post- training compared to that pre- training (p = 0.0001) as shown in (Table 3) and (Figure 2).
The mean ± SD grip strength gain of MA in the study group was 58.06 ± 27.88%, while that of the LA was 42.36 ± 28.53%. The meandifferencewas15.7%.Therewasasignificantincreasein the grip strength gain of MA compared to that of LA (p = 0.02) as shown in Figure 3.
The median (IQR) value of HO pre-training in the study group was 1.9 (2.45-1.3), while post-training it was 2.5 (3.27-2.22). There was a significant increase in the median value of HO in the study group post-training compared to that pre- training (p= 0.0001).
The median (IQR) value of HW pre-training in the study group was2.1(2.57-1.67),whileposttrainingitwas2.6(3.3-2.5).There was a significant increase in the median value of HW in the study group post-training compared to that pre-training (p = 0.0001).
The median (IQR) grade of MACS pre-training of the study group was 2 (3-2), while post-training it was 2 (2-2). There was a significant change in MACS of the study group post-training compared to that pre- training (p = 0.001).
Discussion
The main aim of this study was to determine the effect of training of grip strength of LA side on grip strength bilaterally and functional manual ability in children with hemiplegia, regardless of etiological causes.
This study involved twenty-four participants aged from seven to twelve years, with hemiplegia with a degree of spasticity of 1 and +1 according to MAS. Three baseline pre-tests, separated by 4-7 days, and one post-test within 1 week after training were performed for assessment. Although this design required more time and labor, it has been validated as a replacement of the control group. MACS and PMAL were used for manual functional ability assessment, while the Camry dynamometer was used for grip strength assessment.
The MACS can be reliably used for children between 4 and 18 years of age [10]. Despite its advantages, MACS was not designed to classify UCP children in an objective way [11].
A handgrip dynamometer is a reliable measurement when standardized methods and calibrated equipment are used, even when there are different assessors or different brands of dynamometers [12]. Grip strength training was performed for 5 weeks inform of 3 sessions per week [4].
This study included 24 children with hemiplegia of both sexes: 11 girls (46%) and 13 boys (54%); their mean age was 9.29 ± 1.62 years. The result showed that grip strength training of LA increased the voluntary grip strength for both the LA and MA sides with a significant increase in the grip strength gain for MA compared to that of LA (p = 0.02) and significantly changed manual functional ability, which may be induced by cross- education phenomena.
Cross-education phenomenon was used in patients with unilateral injuries, such as knee osteoarthritis, tendinopathy, fracture, stroke, and cerebral palsy, which are extremely common [13], and it was observed that unilateral training induced contralateral gains in strength with a moderate to large magnitude [14], but it was reported that there were only modest effects and limited clinical relevance for this phenomenon [15]. Thus, this study was performed to show the efficacy of this training in pediatric hand rehabilitation specifically in children with hemiplegia, and this study results showed a more significant increase in strength gain in both trained and untrained sides (LA and MA). A recent meta-analysis showed that a cross- education strength gain was 18% in young adults, 15% in older adults and 29% in a patient population [16], and our study strength gain of MA was 58.06 ± 27.88%. Thus, cross- education impact may be greater in children than in adults and the elderly, which will need more research.
This study showed that the median grade of MACS pre- training was 2 (3-2), while post- training it was 2 (2-2), the median value of HO pre- training was 1.9 (2.45-1.3), while post- training it was 2.5 (3.27-2.22), and the median value of HW pre- training was 2.1 (2.57-1.67), while post-training it was 2.6 (3.3-2.5). It can be concluded that there was a significant change in MACS post-training compared to that pre- training (p = 0.001), a significant increase in the median value of HO post- training compared to that – training (p = 0.0001), and a significant increase in the median value of HW post- training compared to that pre- training (p = 0.0001).
There were many positive comments from some caregivers that the child started using the MA side much better in some activities of daily living, one of these comments was that MA hand movements started to be more precise and tremor-like movements were less than before training, which may be related to the increased activation found within the cerebellum due to cross-education training that may lead to improved timing and activation of agonists, antagonists and synergist muscle groups, which improve the coordination of a movement task [17]. There are some limitations in our research. Many of the participants apologized that they unable to come three times per week, so instead of taking only five weeks for treatment they take more weeks to complete 15 sessions and some of them were unable to complete the entire protocol due to pandemic COVID-19.
Conclusion
It can be concluded that grip strength training on less affected side can be clinically used in the future as a new procedure for pediatric rehabilitation specifically for children with hemiplegia to increase not only their grip strength bilaterally, but also to improve their functional manual ability, making their life better.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Sadowska M, Sarecka-Hujar B, Kopyta I. Cerebral Palsy: Current Opinions on Definition, Epidemiology, Risk Factors, Classification and Treatment Options. Neuropsychiatr Dis Treat. 2020; 16:1505-18.
2. Holmefur M, Kits A, Bergström J, Krumlinde-Sundholm L, Flodmark O, Forssberg H, et al. Neuroradiology can predict the development of hand function in children with unilateral cerebral palsy. Neurorehabil Neural Repair. 2013; 27(1):72-8.
3. Rich TL, Menk JS, Rudser KD, Feyma T, Gillick BT. Less-affected hand function in children with hemiparetic unilateral cerebral palsy: a comparison study with typically developing peers. Neurorehabil Neural Repair. 2017; 31(10-11):965-76.
4. Barss TS, Klarner T, Pearcey GE, Sun Y, Zehr EP. Time course of interlimb strength transfer after unilateral handgrip training. J Appl Physiol. 2018; 125(5):1594-608.
5. Lee M, Hinder MR, Gandevia SC, Carroll TJ. The ipsilateral motor cortex contributes to cross‐limb transfer of performance gains after ballistic motor practice. J Physiol. 2010; 588(1):201-12.
6. Hortobágyi T, Richardson SP, Lomarev M, Shamim E, Meunier S, Russman H, et al. Interhemispheric plasticity in humans. Med Sci Sports Exerc. 2011; 43(7):1188-99.
7. Eliasson AC, Krumlinde‐Sundholm L, Rösblad B, Beckung E, Arner M, Öhrvall AM, et al. The Manual Ability Classification System (MACS) for children with cerebral palsy: scale development and evidence of validity and reliability. Dev Med Child Neurol. 2006; 48(7):549-54.
8. Uswatte G, Taub E, Griffin A, Vogtle L, Rowe J, Barman J. The pediatric motor activity log-revised: assessing real-world arm use in children with cerebral palsy. Rehabil Psychol. 2012; 57(2):149-58.
9. Schreuders TA, Roebroeck ME, Goumans J, van Nieuwenhuijzen JF, Stijnen TH. Stam HJ. Measurement error in grip and pinch force measurements in patients with hand injuries. Phys Ther. 2003; 83(9):806-15.
10. Jeevanantham D, Dyszuk E, Bartlett D. The manual ability classification system: a scoping review. Pediatr Phys Ther. 2015; 27(3):236-41.
11. Gajewska E, Sobieska M, Samborski W. Manual ability classification system for children with cerebral palsy. Chir Narzadow Ruchu Ortop Pol. 2006; 71(4):317- 19.
12. Smidt N, van der Windt DA, Assendelft WJ, Mourits AJ, Devillé WL, de Winter, AF, et al. Interobserver reproducibility of the assessment of severity of complaints, grip strength, and pressure pain threshold in patients with lateral epicondylitis. Arch Phys Med Rehabil. 2002; 83(8):1145-50.
13. Frazer AK, Pearce AJ, Howatson G, Thomas K, Goodall S, Kidgell DJ. Determining the potential sites of neural adaptation to cross-education: implications for the cross-education of muscle strength. Eur J Appl Physiol. 2018; 118(9):1751-72.
14. Manca A, Hortobágyi T, Rothwell J, Deriu F. Neurophysiological adaptations in the untrained side in conjunction with cross-education of muscle strength: a systematic review and meta-analysis. J Appl Physiol. 2018; 124(6):1502-18.
15. Carroll TJ, Herbert RD, Munn J, Lee M, Gandevia SC. Contralateral effects of unilateral strength training: evidence and possible mechanisms. J Appl Physiol. 2006; 101(5):1514-22.
16. Green LA, Gabriel DA. The effect of unilateral training on contralateral limb strength in young, older, and patient populations: a meta-analysis of cross education. Physical Therapy Reviews. 2018; 23(4-5):238-49.
17. Mason J, Frazer AK, Horvath DM, Pearce AJ, Avela J, Howatson G, et al. Ipsilateral corticomotor responses are confined to the homologous muscle following cross-education of muscular strength. Appl Physiol Nutr Metab. 2018; 43(1):11-22.
Download attachments: 10.4328:ACAM.20711
Aya T’Allah Y. Kandeel, Asma O. Sayed, Mohamed I. Elassal. Effect of less affected grip strength training on grip strength in both hands in unilateral cerebral palsy. Ann Clin Anal Med 2021;12(11):1229-1232
Citations in Google Scholar: Google Scholar
Comparison of hemodynamic effects of magnesium and esmolol in spinal surgery
Dilek Kutanıs, Hulya Ulusoy
Department of Anesthesiology and Critical Care, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey
DOI: 10.4328/ACAM.20713 Received: 2021-05-22 Accepted: 2021-08-04 Published Online: 2021-08-13 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1233-1238
Corresponding Author: Dilek Kutanis, Karadeniz Technical University Faculty of Medicine, Deparpment of Anesthesiology and Intensive Care Medicine, Trabzon, Turkey. E-mail: dilekkutanis@gmail.com P: +90 +90 505 622 50 22 F: +90 462 325 3205 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1919-9614
Aim: Little is known about whether one of these agents has superiority over the other in attenuating hemodynamic responses associated with tracheal in- tubation. This paper aims to compare the effects of intravenous injection of low-dose esmolol, magnesium sulfate, and placebo on hemodynamic responses associated with endotracheal intubation.
Material and Methods: Sixty patients receiving elective spine surgery were randomized into three groups: esmolol group (E; 0.2 mg/kg bolus, 3 mg/kg/h infu- sion thereafter), magnesium sulfate group (M; 30 mg/kg bolus, 10 mg/kg/h infusion thereafter), or control (placebo) group (C). Heart rate (HR), mean arterial pressure (MAP), and systolic (SBP), and diastolic blood pressure (DBP) were recorded at baseline, after induction, intubation, prone positioning, skin incision, supine positioning, and at recovery. Differences in HR, MAP, SBP, and DBP in the three groups during anesthesia and recovery were the most important result of this work.
Results: HR, MAP, SBP, and DBP were similar in all groups following endotracheal intubation. Hypotension occurred in three patients in group M at the end of anesthesia when they were repositioned to the supine position. On the other hand, neither group E nor group C experienced hypotension (p=0.043). Bradycardia (HR < 50 bets/min) was observed in six patients in group M, in four patients in group E, and one patient in group C when the patients were placed in the prone position (p=0.043).
Discussion: Our findings show that 30 mg/kg magnesium sulfate and 0.2 mg/kg esmolol boluses and infusions (30 mg/kg bolus and 10 mg/kg/h, respectively) were not more effective than placebo in the prevention of the hemodynamic variations after endotracheal intubation. Higher magnesium sulfate and esmolol doses may blunt elevated heart rate and blood pressure following endotracheal intubation.
Keywords: Laryngoscopy, Endotracheal Intubation, Esmolol, Magnesium Sulfate
Introduction
Spine surgery is increasingly being performed for the management of symptomatic nerve stem and cord compression. Although congenital, oncologic, traumatic, degenerative, and infectious causes may be associated with nerve stem and spinal cord compression, the most common indication for spinal surgery is lumbar disc herniation [1].
Anesthesia aims to maintain adequate oxygenation of the brain and spinal cord while ensuring a stable hemodynamic profile during the surgical procedure. Controlling pain and muscle relaxation may complicate hemodynamic stability during induction, laryngoscopy, endotracheal intubation, prone positioning, skin incision, supine positioning, and extubation [2]. However, tachycardia, rise in blood pressure, and premature ventricular systole may further deteriorate heart rhythm and blood pressure, particularly in heart failure and ischemic heart disease, which may be encountered due to the sympathetic hyperactivity occurring during laryngoscopy, endotracheal intubation [3]. Blockage of sensory receptors and afferent nerves by local anesthetic agents, inhibition of central effects of the pain through opioids, suppression of efferent pathways by local anesthetic agents such as (e.g., lidocaine) beta- blockers, sympathetic ganglion blockers, and calcium channel blockers are utilized to prevent the development of unfavorable hemodynamic variations induced by the sympathetic hyperactivity occurring during endotracheal intubation [4, 5]. Esmolol, a short-acting beta-blocker, has been shown to attenuate hemodynamic variations after tracheal intubation in hypertensive patients [6]. Magnesium sulfate is another agent used to prevent the adrenal medulla and adrenergic nerve endings secreting catecholamines to inhibit blood pressure changes during tracheal intubation [7]. Magnesium sulfate also has vasodilator properties through blocking the calcium ion in vascular smooth muscle [8]. Although both agents have been reported to have mechanisms that attenuate the hemodynamic responses occurring during tracheal intubation, little is known about whether one of these agents has superiority over the other in minimizing the hemodynamic responses occurring during tracheal intubation.
This work aimed to compare the effects of intravenous administration of low-dose esmolol, magnesium sulfate, and placebo on hemodynamic responses associated with endotracheal intubation.
Material and Methods
Patient selection
This randomized, prospective, placebo-controlled study enrolled all consecutive patients planned to undergo elective spine surgery. The inclusion criteria included patients aged 18 years or older, and class I and II patients according to the American Society of Anesthesiologists (ASA). The exclusion criteria were as follows: administration of beta-blocker agents within the last week, Glasgow Coma Scale score of <14, body mass index of > 30 kg/m2, 2nd or 3rd-degree atrioventricular block, advanced cardiac failure, coronary heart disease, chronic lung disease, systolic and diastolic blood pressure of >180/100 mmHg or < 90/60 mmHg, advanced liver or kidney disease, and pregnancy. Eighty subjects were eligible for the study. Twenty subjects were excluded since they met at least one of the exclusion criteria. Remaining 60 patients were randomized into three groups as follows: Esmolol group (E) (n=20), Magnesium sulfate group (M) (n=20), Control group (C) (n=20). All participants gave their written informed consent. Before the study, approval was obtained from the local ethics committee. The study was carried out in compliance with the ethical principles specified in the Declaration of Helsinki.
Anesthesia
All patients arrived to the operating room following eight hours of fasting. A standardized general anesthesia procedure was applied to all patients. Midazolam (0.03 mg/kg) and 0.01mg/ kg of atropine sulfate were administered intravenously as a premedication. Electrocardiogram, non-invasive BP measurements, and monitoring of peripheral oxygen saturation (SaO2) were performed with pulse oximetry throughout the surgery. End-tidal CO2 (EtCO2) was recorded following the induction of anesthesia. The numeric Rating Scale (NRS) (where 0 indicates no pain and 10 indicates worst possible pain) was used to monitor pain. A modified Ramsey Sedation Scale (mRSS) was used to monitor the degree of sedation. Loading doses of the study drugs were administered before the induction of anesthesia by an anesthesia team blinded to the study subject (For group E: esmolol 0.2 mg/kg, diluted with 20 ml saline applied in one minute; for group M: MgSO4 30 mg/ kg, diluted with 20 ml saline applied in one minute; for group C: 20 ml of saline applied in one minute). Study drugs were then infused throughout the surgery (3 mg/kg/h of esmolol for group E, 10 mg/kg/h of MgSO4 for group M, and 20 ml/h of saline for group C).
Midazolam (0.01 mg/kg), 1 mcg/kg fentanyl, 5 mg/kg iv sodium thiopental and 0.15 mg/kg cisatracurium were administered intravenously for general anesthesia. Maintenance of anesthesia was provided using 4% desflurane, 40% nitrous oxide and 60% oxygen. Patients received ventilation at a tidal volume of 7–9 ml/kg. Also, all patients received diclofenac sodium at a dose of 75 mg intramuscularly 30 minutes before the completion of the surgery.
Primary outcome
HR, MAP, SBP,DBP and SaO2 were monitored at the following time points:
T0: Baseline value before drug administration
T1: in the fifth minute after bolus drug administration
T2-1: in the first minute after induction, T2-3: in the third minute after induction, T2-5: in the fifth minute after induction
T3-1: in the first minute after endotracheal intubation, T3-3: in the third minute after endotracheal intubation
T4-1: Prone position in the first minute, T4-3: Prone position in the third minute
T5-1: in the first minute following skin incision, T5-5: in the fifth minute following skin incision
T6-30: 30 minutes following skin incision, T6-60: 60 minutes following skin incision, T6-90: in the 90th minute following skin incision, T 6-120: in the 120th minute following skin incision
T7: End of operation
T8: In supine position and when anesthesia ends
T9-1: in the first minute after extubation, T9-5: in the fifth minute after extubation
T10: Exit from the room
T11: Leaving the recovery unit (when the Aldrete Recovery Score is ≥ 9 points)
Differences in HR, MAP, SBP, and DBP in groups throughout the anesthesia and recovery were the primary outcome measure of this study.
Statistical analysis
The IBM SPSS 20.0 software (SPSS Inc., Armonk, NY, USA) was used for statistical analyses. The Shapiro-Wilk test was used to check the normality. Continuous variables are described using means (±) and standard deviations (SD), while categorical variables are described using numbers and percentages. Continuous variables were compared using the ANOVA test (Tukey’s Honest Significant Difference [HSD] was performed for post-hoc analyses). Variance analysis was used to compare intra-group variances (a paired samples t-test was used for posthoc analyses). Pearson’s chi-squared test was performed to compare categorical variables. Statistical significance was set at p<0.05.
Results
A total of 60 subjects (mean age 42.9 ± 11.6 years, 43.3% males) were included in the study. A comparison of the demographic characteristics of the study groups is presented in Table 1. Age, distribution of genders, body mass index, anesthesia time, operation time, and ASA class were similar.
The variations in SBP from T0 to T11 are listed in Figure 1. SBP was lower in patients receiving MgSO4 than in those receiving esmolol five minutes after induction (T2-5) and before leaving the recovery room (p=0.021, p=0.016, respectively).
The variations in DBP from T0 to T11 are listed in Figure 2. DBP was lower in patients receiving MgSO4 than in control subjects one minute after induction (T2-1)(p=0.019). DBP was lower in patients receiving MgSO4 and subjects receiving esmolol than in control subjects when the patients were repositioned to the supine position (T8)(p=0.035).
The variations in MAP from T0 to T11 are listed in Figure 3. MAP was lower in patients receiving MgSO4 than in control subjects one minute after induction (T2-1)(p=0.028) and when the patients were repositioned to the supine position (T8) (p=0.028). The MAP of the patients receiving MgSO4 was also lower than that of the subjects receiving esmolol five minutes after induction (T2-5) (p=0.046).
The variations in HR from T0 to T11 are listed in Figure 4.
Patients receiving esmolol had considerably lower HR than those receiving MgSO4 and controls five minutes after the loading dose (p<0.001 and p=0.002, respectively) and one minute following the induction of anesthesia (p=0.001 and p=0.003, respectively).
SaO2 was significantly higher in subjects receiving MgSO4 than in those receiving esmolol (p=0.014). EtCO2 was significantly higher in subjects receiving MgSO4 than in controls one minute after endotracheal intubation (p=0.033).
Hypotension (drop in SBP < 90 mmHg or > 30 mmHg reduction in SBP compared to baseline) occurred in three patients in group M at the end of the anesthesia when the patients were repositioned to the supine position. On the other hand, neither group E nor group C patients experienced hypotension (p=0.043). Bradycardia (HR < 50 bets/min) was observed in six patients in group M, in four patients in group E, and one patient in group C when the patients were placed in the prone position (p=0.043).
Discussion
This work was undertaken to compare esmolol and magnesium sulfate effects on hemodynamic responses during endotracheal intubation. We found that endotracheal intubation was associated with an increase in HR, SBP, DBP, and MAP. In the study, subjects receiving esmolol or magnesium sulfate gave hemodynamic responses to endotracheal intubation similar to those of control group subjects. However, SBP, DBP, and MAP were lower in subjects receiving magnesium sulfate than in those receiving esmolol during the induction phase. On the other hand, esmolol was associated with a lower heart rate during the induction phase than magnesium sulfate. Besides those receiving esmolol or control subjects, patients receiving magnesium sulfate were increasingly vulnerable to hypotension when repositioned to the supine position.
It has been shown that airway manipulation during laryngoscopy and endotracheal intubation leads to reflex sympathetic activity, characterized primarily by systemic arterial hypertension and tachycardia [9, 10]. Manipulations of the pharynx and larynx have been shown to correlate with an increase in plasma epinephrine and norepinephrine concentrations [11]. Hemodynamic variations during laryngoscopy and endotracheal intubation are transient and do not significantly affect healthy individuals. However, they may induce ischemia in patients with coronary artery disease (CAD), peripheral artery disease (PAD), and cerebrovascular disease, and may induce intracranial hemorrhage [7]. Therefore, inhibition of this transient increase in arterial pressure and pulse rate may prevent further complications in hypertension, CAD, and PAD patients, as well as in those with a history of intracranial hemorrhage.
Several agents have been administered to blunt the hemodynamic reactions occurring during laryngoscopy and endotracheal intubation. Beta-blockers, calcium channel blockers, Na nitroprusside, nitroglycerine, alpha agonists, vasodilators, fentanyl, and lidocaine have traditionally been used to prevent unfavorable hemodynamic responses occurring during endotracheal intubation [12]. Esmolol and magnesium sulfate have also been used at varying doses to inhibit hypertension and tachycardia during intubation.
Esmolol is a short-acting, cardio-selective beta-blocker used to manage hypertensive emergencies and supraventricular tachyarrhythmias [13]. Extensive data indicate that esmolol can blunt hemodynamic responses associated with endotracheal intubation. One of the earliest trials with esmolol was a Canadian multicentre trial, which found that 100 and 200 mg of esmolol effectively suppressed the increase in SBP during intubation [14]. Levitt et al., in their study, examined the effects of esmolol 2 mg/kg and lidocaine 2 mg/kg on intubated patients with isolated head injury, and reported that esmolol and lidocaine had similar efficacy in blunting the hemodynamic response to intubation in this patient population [15]. Another study by Ugur et al. compared esmolol 1.5 mg/kg, lidocaine 1.5 mg/kg, and fentanyl 1 μg/kg boluses in 120 ASA class I- and II patients [16]. The authors reported that hemodynamic responses occurring during endotracheal intubation were more effectively prevented with esmolol bolus than with lidocaine and fentanyl. Gogus et al. aimed to compare the effects of 1 μg/ kg dexmedetomidine (infusion in 10 min) and 2 μg/kg fentanyl and 2 mg/kg esmolol boluses on attenuating the hemodynamic response to endotracheal intubation. The authors found that dexmedetomidine was superior to fentanyl and esmolol in preventing tachycardia and that esmolol prevented the increase in SBP, DBP, and MAP following intubation [17]. Selvaraj et al. compared dexmedetomidine 1 μg/kg (infusion in 10 min) and esmolol 0.5 mg/kg iv. bolus to prevent the hemodynamic response to laryngoscopy and endotracheal intubation. The authors reported that dexmedetomidine infusion was superior to esmolol bolus in preventing the increase in HR, SBP, and MAP following intubation [18]. More recently, Sharma et al. reported that dexmedetomidine 1 μg/kg (infusion in 10 min) was superior to esmolol 1.5 mg/kg (infusion in 10 min) in maintaining hemodynamic stability following endotracheal intubation [19]. Magnesium sulfate, another agent, used to blunt hemodynamic responses occurring during endotracheal intubation, blocks the release of catecholamines by the adrenal medulla and has a systemic and coronary vasodilator effect by antagonizing calcium ion in vascular smooth muscle [20]. Magnesium has also been shown to cause central nervous system depression by acting as an antagonist of N-methyl-D-aspartate (NMDA) receptors [21]. Panda et al. reported that 30 mg/kg bolus of magnesium sulfate could optimally control BP during intubation in hypertensive patients [7]. Nooraei et al. showed that 60 mg/ kg of magnesium sulfate bolus was more effective than 60 mg/ kg of lidocaine bolus in controlling blood pressure following endotracheal intubation [22]. In a study on patients undergoing elective coronary artery bypass grafting surgery, Kiaee et al. used lidocaine (1.5 mg/kg) and magnesium sulfate (50 mg/kg within five minutes) to explore their impact on hemodynamic responses during endotracheal intubation. The authors found that lidocaine produced a more considerable decrease in blood pressure than magnesium sulfate [23]. Recently, Mendonca et al. reported that lidocaine 2 mg/kg and magnesium sulfate 30 mg/kg (both infused over 10 minutes) yielded similar results in preventing the hemodynamic responses occurring during endotracheal intubation [21].
Although both esmolol and magnesium sulfate have shown favorable outcomes in preventing the hemodynamic variations following endotracheal intubation, few data have been reported regarding the superiority of one agent over the other. Kumar et al. compared magnesium sulfate 60 mg/kg bolus, esmolol 2 mg/ kg bolus, and diltiazem 0.2mg/kg bolus and found that esmolol was the most effective of the three agents in preventing the rise in HR and BP following endotracheal intubation [24]. David et al. administered magnesium sulfate 50 mg/kg bolus and esmolol 1.5 mg/kg bolus to subjects undergoing elective ENT surgeries. The authors reported that esmolol was superior to magnesium sulfate in reducing HR, MAP, SBP, and DBP following endotracheal intubation [25]. Kumar et al. compared magnesium sulfate 60 mg/kg bolus, esmolol 2 mg/kg bolus, and diltiazem 0.2mg/kg bolus and found that esmolol was the most effective of the three agents in preventing increases in HR and BP following endotracheal intubation. Verma et al. compared magnesium sulfate and esmolol in patients undergoing valvular heart surgery. The authors reported that esmolol 1.5 mg/kg was superior to magnesium sulfate 50 mg/ kg iv. (both infused over five minutes) in minimizing hemodynamic responses occurring during endotracheal intubation. Recently, Machado et al. studied the efficacy of esmolol 1.5 mg/kg and magnesium sulfate 30 mg/kg and found that esmolol was more effective than magnesium sulfate in blunting the hypertensive response to intubation, but with more frequent hypotension [8].
Our findings show that 30 mg/kg magnesium sulfate and 0.2 mg/kg esmolol boluses and infusions (30 mg/kg bolus and 10 mg/kg/h, respectively) were not more effective than placebo in preventing hemodynamic variations after endotracheal intubation. Esmolol and magnesium sulfate doses used in our study were much lower than those used in previous studies. With this in mind, we believe that magnesium sulfate 30 mg/ kg and esmolol 0.2 mg/kg do not significantly impact HR and BP following endotracheal intubation compared to placebo. Considering the previous evidence of the favorable effect of the two drugs on hemodynamic responses after intubation, we suggest that the administration of magnesium sulfate and esmolol at higher doses is necessary to attenuate the increase in BP HR following endotracheal intubation.
Conclusion
Magnesium sulfate (30 mg/kg) and esmolol (0.2 mg/kg) boluses do not significantly impact HR and BP following endotracheal intubation compared to placebo. Administration of magnesium sulfate and esmolol at higher doses may blunt the increase in BP and HR following endotracheal intubation.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Pierce JT, Kositratna G, Attiah MA, Kallan MJ, Koenigsberg R, Syre P, et al. Efficiency of spinal anesthesia versus general anesthesia for lumbar spinal surgery: a retrospective analysis of 544 patients. Local Reg Anesth. 2017; 10:91- 8. DOI: 10.2147/LRA.S141233.
2. Marulasiddappa V, Nethra HN. A Comparative Study of Clonidine and Lignocaine for Attenuating Pressor Responses to Laryngoscopy and Endotracheal Intubation in Neurosurgical Cases. Anesth Essays Res. 2017; 11(2):401-5. DOI: 10.4103/0259-1162.194557.
3. Çukurova Z, Çetingök H. Kalsiyum Kanal Blokerlerinin Laringoskopi ve Trakeal Entubasyona Bağlı Kardiyovasküler Değişikliklere Etkilerinin Karşılaştırılması (Comparison of the Effects of Calcium Channel Blockers on Cardiovascular Changes Due to Laryngoscopy and Tracheal Intubation). Med J Bakirkoy. 2018; 14(2):236-41.
4. Kord Valeshabad A, Nabavian O, Nourijelyani K, Kord H, Vafainejad H, Kord Valeshabad R, et al. Attenuation of Hemodynamic Responses to Laryngoscopy and Tracheal Intubation: Propacetamol versus Lidocaine-A Randomized Clinical Trial. Anesthesiol Res Pract. 2014; 2014:170247. DOI: 10.1155/2014/170247.
5. Bostan H, Eroglu A. Comparison of the clinical efficacies of fentanyl, esmolol and lidocaine in preventing the hemodynamic responses to endotracheal intubation and extubation. Journal of Current Surgery. 2012; 2(1):24-8.
6. Sharma S, Mitra S, Grover VK, Kalra R. Esmolol blunts the haemodynamic responses to tracheal intubation in treated hypertensive patients. Can J Anaesth. 1996; 43(8):778-82. DOI: 10.1007/BF03013028.
7. Panda NB, Bharti N, Prasad S. Minimal effective dose of magnesium sulfate for attenuation of intubation response in hypertensive patients. J Clin Anesth. 2013; 25(2):92-7. DOI: 10.1016/j.jclinane.2012.06.016.
8. Machado LS, Silva AS, Fonseca EV, Rezende RV, Oliveira BH, Fabris DB, et al. Comparative Study of the Efficacy of Esmolol and Magnesium Sulfate in Attenuating Hemodynamic Response to Laryngoscopy and Endotracheal Intubation. J Anes Perio Manag. 2020; 4: 006.
9. Balasubramaniam S, Jeevarathnam R. Comparison of fentanyl and butorphanol in attenuating the haemodynamic responses to laryngoscopy and endotracheal intubation. Journal of Evolution of Medical and Dental Sciences. 2016; 5(99):7288-94.
10. Dashti M, Amini S, Azarfarin R, Totonchi Z, Hatami M. Hemodynamic changes following endotracheal intubation with glidescope(®) video-laryngoscope in patients with untreated hypertension. Res Cardiovasc Med. 2014; 3(2):e17598. DOI: 10.5812/cardiovascmed.17598.
11. Prys-Roberts C, Greene LT, Meloche R, Foëx P. Studies of anaesthesia in relation to hypertension. II: Hemodynamic consequences of induction and endotracheal intubation. 1971. Br J Anaesth. 1998; 80(1):106-22; discussion 104- 5. DOI: 10.1093/bja/80.1.106.
12. Kovac AL. Controlling the hemodynamic response to laryngoscopy and endotracheal intubation. J Clin Anesth. 1996; 8(1):63-79. DOI: 10.1016/0952- 8180(95)00147-6.
13. Abrams J, Allen J, Allin D, Anderson J, Anderson S, Blanski L, et al. Efficacy and safety of esmolol vs propranolol in the treatment of supraventricular tachyarrhythmias: a multicenter double-blind clinical trial. Am Heart J. 1985; 110(5):913-22. DOI:10.1016/0002-8703(85)90185-1.
14. Miller DR, Martineau RJ, Wynands JE, Hill J. Bolus administration of esmolol for controlling the haemodynamic response to tracheal intubation: the Canadian Multicentre Trial. Can J Anaesth. 1991; 38(7):849-58. DOI: 10.1007/BF03036959.
15. Levitt MA, Dresden GM. The efficacy of esmolol versus lidocaine to attenuate the hemodynamic response to intubation in isolated head trauma patients. Acad Emerg Med. 2001; 8(1):19-24. DOI: 10.1111/j.1553-2712.2001.tb00541.x.
16. Ugur B, Ogurlu M, Gezer E, Nuri Aydin O, Gürsoy F. Effects of esmolol, lidocaine and fentanyl on haemodynamic responses to endotracheal intubation: a comparative study. Clin Drug Investig. 2007; 27(4):269-77. DOI: 10.2165/00044011-200727040-00006.
17. Gogus N, Akan B, Serger N, Baydar M. The comparison of the effects of dexmedetomidine, fentanyl and esmolol on prevention of hemodynamic response to intubation. Rev Bras Anestesiol. 2014; 64(5):314-9. DOI: 10.1016/j. bjan.2013.10.010.
18. Selvaraj V, Manoharan KR. Prospective randomized study to compare between intravenous dexmedetomidine and esmolol for attenuation of hemodynamic response to endotracheal intubation. Anesth Essays Res. 2016; 10(2):343-8. DOI:10.4103/0259-1162.181226.
19. Sharma S, Suthar OP, Tak ML, Thanvi A, Paliwal N, Karnawat R. Comparison of Esmolol and Dexmedetomidine for Suppression of Hemodynamic Response to Laryngoscopy and Endotracheal Intubation in Adult Patients Undergoing Elective General Surgery: A Prospective, Randomized Controlled Double-blinded Study. Anesth Essays Res. 2018; 12(1):262-6. DOI: 10.4103/aer.AER_226_17.
20. Herroeder S, Schönherr ME, De Hert SG, Hollmann MW. Magnesium– essentials for anesthesiologists. Anesthesiology. 2011; 114(4):971-93. DOI: 10.1097/ALN.0b013e318210483d.
21. Mendonça FT, de Queiroz LM, Guimarães CC, Xavier AC. Effects of lidocaine and magnesium sulfate in attenuating hemodynamic response to tracheal intubation: single-center, prospective, double-blind, randomized study. Rev Bras Anestesiol. 2017; 67(1):50-6.. DOI: 10.1016/j.bjan.2016.02.001.
22. Nooraei N, Dehkordi ME, Radpay B, Teimoorian H, Mohajerani SA. Effects of intravenous magnesium sulfate and lidocaine on hemodynamic variables following direct laryngoscopy and intubation in elective surgery patients. Tanaffos. 2013; 12(1):57-63.
23. Mesbah Kiaee M, Safari S, Movaseghi GR, Mohaghegh Dolatabadi MR, Ghorbanlo M, Etemadi M, et al. The effect of intravenous magnesium sulfate and lidocaine in hemodynamic responses to endotracheal intubation in elective coronary artery bypass grafting: a randomized controlled clinical trial. Anesth Pain Med. 2014; 4(3):e15905. DOI: 10.5812/aapm.15905.
24. Kumar S, Mishra M, Mishra L, Bathla S. Comparative Study Of The Efficacy Of IV Esmolol, Diltiazem And Magnesium Sulphate In Attenuating Haemodynamic Response To Laryngoscopy And Tracheal Intubation. Indian Journal of Anaesthesia. 2003;47(1):41.
25. David D, Shanmugapriya V, Anuradha N, Anandhakumar G. Comparison of Esmolol and Magnesium Sulphate for Attenuation of Hemodynamic Stress Response to Laryngoscopy and Intubation in Elective ENT Surgeries. Indian Journal of Anaesthesia and Analgesia. 2018; 5 (2):186-91
Download attachments: 10.4328:ACAM.20713
Dilek Kutanıs, Hulya Ulusoy. Comparison of hemodynamic effects of magnesium and esmolol in spinal surgery. Ann Clin Anal Med 2021;12(11):1233-1238
Citations in Google Scholar: Google Scholar
The relationship between urinary bisphenol A levels and body weight in children
Ayşe Kılıç 1, Sevinç Gümüş Pekacar 1, Aylin Yetim 1, Gonca Keskindemirci 1, Mustafa Özçetin 2, Muhammet Ali Varkal 1, Firdevs Baş 3 Şükran Poyrazoğlu 3, Feyza Darendeliler 3, Dilek Battal 4, Ayça Aktaş 5, İsmet Çok 5
1 Department of Pediatrics, İstanbul University, Medical Faculty, Istanbul, 2 Department of Family Health, Istanbul University, Institute of Child Health, Istanbul, 3 Department of Pediatric Endocrinology, İstanbul University, Medical Faculty, Istanbul, 4 Department of Pharmaceutical Toxicology, Mersin University, Faculty of Pharmacy, Mersin, 5 Department of Pharmaceutical Toxicology, Gazi University, Ankara, Turkey
DOI: 10.4328/ACAM.20715 Received: 2021-05-25 Accepted: 2021-08-14 Published Online: 2021-08-19 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1239-1243
Corresponding Author: Mustafa Özçetin, Turgut Özal Street, No:118, 34093, Fatih, İstanbul, Turkey. E-mail: mozcetin@gmail.com P: +90 212 414 20 00 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0697-4271
Aim: Bisphenol A (BPA), one of the most commonly produced and used endocrine disruptors in the world, is a chemical employed in the production of polycar- bonate and epoxy resins. A significant relationship between urinary BPA levels and obesity has been shown in clinical trials. This study aimed to investigate the relationship between urinary BPA levels and obesity in childhood.
Material and Methods: The study was performed with a total of 172 children: 75 participants with a weight status of obesity, 33 participants with a weight sta- tus of overweight, and 64 participants with a weight status of normal. Sociodemographic data, family history of chronic diseases, preferred water/beverage/ food containers, prepared water/beverage/food consumption, screen-based behavior time, and regular physical activity rates of children data were gathered from parents via questionnaire.
Results: Among 172 children, 47.7% (n = 82) were males and 52.3% (n = 90) were females. The mean age was 11.7 ±3.3 (4-18) years. The age and gender distribution was similar between the body mass index groups. The total screen-based sedentary behavior time was higher in the obese group than in the normal weight group; 85.6% (n = 143) of all participants drank water from plastic bottles. Socio-demographic and anthropometric features, total time of screen-based sedentary behaviors, usage of plastic water/beverage/food containers, pre-packaged water/beverage/food consumption, and IR detection rates were similar between the BPAmcg/kreat percentile groups.
Discussion: BPA was detectable in all urine specimens. As the urinary BPA level increased, BMI SDS increased. Urinary BPA levels were not associated with IR.
Keywords: Bisphenol A, Childhood, Insulin Resistance, Obesity
Introduction
Obesity became an epidemic in the first decade of the 21st century. In 2010, forty-two million children below the age of five were overweight worldwide. Thirty-five million of these children were living in developed countries (available at: http:// www.who.int/dietphysicalactivity/childhood/en/). Globally, the prevalence of overweight and obesity combined has risen by 47.1% for children between 1980 and 2013. [1]. Various industrial products, such as polymers known for their durability, are ubiquitous in the products of modern, developed countries. Unfortunately, it has been recognized in recent years that these products can be harmful. The effects of widely-used chemicals on the endocrine systems of humans have been increasingly investigated and understood.
Bisphenol A (BPA) is found in polycarbonate plastics and epoxy resins. Polycarbonate plastics are often used in containers that store food and beverages, such as water bottles. They are also used in many consumer goods [2]. Though BPA has been used since the 1970s, its effects have only recently been understood, with the first clinical studies published in the last decade. Until this research, no study investigating the relationship between BPA exposure and obesity in Turkish children had been published. The present study aimed to investigate the relationship between childhood obesity and urinary BPA levels.
Material and Methods
Study and control groups: Study participants included children diagnosed with overweight or obesity who were followed up between March 2014 and October 2014 at the Istanbul Faculty of Medicine, Pediatric Endocrinology outpatient clinic. The age-and gender-matched control group included children who presented to Istanbul Faculty of Medicine, General Pediatrics outpatient clinic with normal weight and no chronic disease or history of drug usage. All parents of the participants were informed of the study objectives. Written consent was obtained from all parents, and written or verbal consent was obtained from all children included in the study. The study was approved by the Ethics Committee of Istanbul University Faculty of Medicine (no. 1795). This study was funded by the Scientific Research Projects Coordination Unit of Istanbul University (project number: 41594).
Clinical evaluation: Height and weight of all subjects were measured by an experienced physician using a wall-mounted, calibrated Harpenden Stadiometer (Holtain Ltd., Crymych, UK) and an electronic scale (sensitivity at 0.1 kg level). Body mass index (BMI) was calculated using the following formula: BMI = weight (kg)/height (m2). Height and weight measurements of the parents who were present during outpatient follow-up visits were performed as well. Standard deviation scores (SDS) of these measurements were calculated using national data [3, 4]. The group classified as obese consisted of the children with BMI SDS >2. The group classified as overweight consisted of children with BMI SDS 1-2. The normal weight group consisted of the children with BMI SDS <1. The BMI values of the parents who were absent during outpatient follow-up were calculated with height and weight data based on parent declaration. BMI values between 25 and 30 classified subjects as overweight, while BMI values >30 classified subjects as obese.
A total of 178 patients were initially accepted to participate in the study. Two children in the normal weight group were later excluded from the study due to malnutrition, and two children in the obese group were excluded from the study because their urine samples became unusable either some other time during the study. The study continued with a total of 172 patients, including 75 patients with obesity, 33 patients with overweight, and 64 patients with normal weight.
Laboratory evaluation and biochemical assays: Fasting glucose, fasting insulin, and blood lipid profile values of the participants were obtained from the laboratory result system. Insulin resistance was evaluated with the homeostasis model assessment for the insulin resistance index (HOMA-IR), which was calculated as insulin (mU/l) × (glucose [mg/dl] × 0.055)/22.5 (HOMA-IR). HOMA-IR limit values in the prepubertal period were 2.67 in boys and 2.22 in girls. In the puberty period, these limit values were 5.22 in boys and 3.82 in girls. When evaluating blood lipid levels, total cholesterol levels of >213 mg/dl, HDL cholesterol levels of <33 mg/dl, LDL cholesterol levels of >135 mg/dl, and triglyceride cholesterol levels of >195 mg/dl were considered abnormal [5,6].
Fresh spot urine samples were obtained from all children and placed in glass urine containers. The urine samples were kept at -20 Co until the time of the study. BPA, bisphenol A glucuronide (BPAG), and creatinine levels were measured in urine samples using high-performance liquid chromatography/ mass spectrometer method. Since spot urine was obtained, the results were corrected by dividing them by urinary creatinine value. The total numbers of corrected and uncorrected BPA and BPAG values were evaluated [7]. Percentile ranges were determined by BPA levels, and the patients were divided into four groups accordingly.
The laboratory method used in this study, reported in the research conducted by Battal et al., is a newly developed method. This method has been standardized and its sensitivity and validity have been proven. It was developed to obtain a more sensitive measurement for BPA and BPA glucuronide (lower limit for detection BPA:0.03 μg /L, BPA glucronide:0.10 μg /L) [9]. The high percentage of BPA detection may also be explained by the difference in the laboratory method. Statistical analysis
The Number Cruncher Statistical System (NCSS) 2007 (Kaysville, Utah, USA) was used for statistical analysis. When evaluating the study data, the Welch ANOVA test was used for comparison between three or more groups in terms of variables that showed a normal distribution in comparison of quantitative data, and the Games-Howell test was used to determine the group that caused the difference. Descriptive statistical methods (mean, standard deviation, median, frequency, ratio, minimum, maximum) were also used. The Kruskal-Wallis test was used to compare three or more groups that did not show a normal distribution, and the Mann-Whitney U test was used to determine the group that caused the difference. Pearson’s chi-square test and the Fisher-Freeman-Halton exact test were used in the comparison of qualitative data. A p-value of < 0.05 was considered significant.
Results
Among 172 children, 47.7% (n = 82) were males and 52.3% (n = 90) were females. The mean age was 11.68 ±3.25 years (4-18 years). The age and gender distribution between the groups was statistically similar. Familial obesity rates were lower in the subjects with normal weight than in the subjects with overweight or obesity. Comparison of gender, age, height, weight, and parental obesity history in the groups is shown in Table 1.
Evaluation of insulin resistance and dyslipidemia: Fasting blood glucose (FBG) levels were significantly higher in subjects with normal weight compared to subjects with obesity and overweight. Besides, fasting insulin values were higher in the subjects with obesity compared to the subjects with normal weight. HOMA-IR values were higher in the obesity group compared to the normal weight group. Comparison of glucose and lipid metabolism parameters between the groups is shown in Table 2.
Evaluation of the total of the urine creatinine-corrected BPA and BPAG measurements: The mean values of urine creatinine- corrected BPA and BPAG measurements increased in proportion with BMI, but no difference was observed between the median values that were used in statistical assessment, since there was no normal distribution (Table 3).
Discussion
Obesity occurs due to a combination of genetic, behavioral, and environmental factors [9]. Industrialization in the food sector, a reduction in physical activity, and increased calorie intake as a result of rapidly developing technology are the main causes of obesity. BPA is an endocrine disrupter chemical, and is widely used to produce polycarbonate and epoxy resin all over the world [9]. BPA is frequently used in packages of water, beverages, and food. Consumption of these products is thought to be the main reason for BPA exposure. BPA exposure is determined by measuring BPA levels in urine. A few multiparticipant research indicated that BPA had been found at rates in urine samples in the range from 83% to 98% [10-12].
In this study, BPA was detected in all urine samples. The study group consisted of a limited number of subjects, including individuals with obesity and overweight, and a control group, which is likely the main reason for the increased rate of BPA detection. Another potential cause of high BPA rates is that spring water throughout Turkey, and particularly Istanbul, is commonly kept, sold, and consumed in bottles and carboys containing BPA.
The results of this study were also compared with data from clinical studies conducted with children in the literature. In the study conducted by Becker et al., the 50th percentile value for urinary BPA was 2.81 μg /L for the 6-8 year age group, 2.13 μg /L for the 9-11 year age group and 2.6 μg /L for the 12- 14 year age group [12]. In the study conducted by Calafat et al., the percentile distributions of urinary BPA values by age were examined according to the NHANES 2003-2004 data. In the 6-11 year age group, the 50th percentile value for urinary BPA was 3.7 μg /L, and the 95th percentile value was 16 μg /L. In the 12-19 year age group, the 50th percentile value for urinary BPA was 4.2 μg /L, and the 95th percentile value was 16.5 μg /L. In the 6-11 year age group, the 50th percentile value for urine creatinine corrected BPA was calculated as 4.2 μg/g creatinine, and the 95th percentile value was calculated as 15.7 μg/g creatinine. In the 12-19 year age group, the 50th percentile value was calculated as 2.7 μg/g creatinine, and the 95th percentile value was calculated as 11.4 μg/g creatinine [11]. The results of these two studies, conducted at the national level, were higher than those found in this study. In this study, in which the subjects were between the ages of 4 and 18, the 50th percentile value for creatinine-corrected urinary BPA was 0.056 μg/g creatinine. The difference in age ranges and number of subjects between the studies might have caused the difference in results.
In the studies conducted by Transande and Wells, an increase in the prevalence of obesity was found with increasing BPA percentile [13, 14]. In our study, a gradually increasing percentage in the total prevalence of obesity and overweight with increasing BPA percentile in the groups established by the percentile ranges of urine creatinine-corrected BPA values. When the prevalence of obesity was examined alone, an uptrend was noted in the 1st, 2nd, and 3rd groups (59.5% in the first group, 67.4% in the 2nd group, 69.8% in the 3rd group). Again, a gradually increasing percentage in the prevalence of overweight and obesity corresponded with increasing BPA percentile in the groups established by non-urine creatinine- corrected BPA values percentile range (36.4% in the 2nd group, 40.5% in the 3rd group, 53.5% in the 4th group). These findings suggest that increased urinary BPA values are associated with an increased prevalence of overweight and obesity.
In a study conducted in China by Wang et al., an increase in the prevalence of obesity was found with increasing BPA percentile in the 8-11 year age group and in girls [10]. In another study conducted in China by Li et al., 2 ng/ml was considered the limit value, and increased BPA value was associated with obesity in prepubertal girls (9-12 years). This association was not observed in boys or in the total population, however [15]. In this study, a no correlation was found between BPA levels and prevalence of obesity in comparisons made with age and gender.
Eng et al. considered the consumption of instant drinks at least once a day a risk factor for increasing BPA due to BPA in the packages, as well as a risk factor for obesity because of increased calories intake [16]. However, in their study, they did not find a significant correlation between BPA levels and consumption of instant drinks. No correlation was found between BPA percentile and the variables for insulin resistance and fasting blood glucose [16]. In our study, the number of subjects with insulin resistance increased with increasing BPA presence, though it was not statistically significant. In a study conducted by Khalil et al., fasting insulin and increased HOMA- IR were correlated with an increased presence of BPA in men [17]. These findings may be explained by the effects of BPA on insulin release.
Some methodological differences render comparison of the studies difficult. Urinary BPA level has been corrected with urine creatinine in most studies. However, in some studies, such as in a study conducted by Wang et al., urinary BPA has been corrected with urine density. Creatinine level varies with the amount of muscle mass and by gender, such that corrections made with urine creatinine may further decrease the values in men. Urinary density is a highly variable parameter. Assessment considering the urinary creatinine ratio is a commonly used method in drug studies. There is no consensus on the ideal method for BPA correction. This makes it difficult to compare values. Since BPA level has been corrected with urine creatinine in most studies conducted with children, this study used that method. Another methodological difference is related to the BPA measurement technique. Although the method used in this study is similar, it is thought to be more sensitive [7]. However, this method does not create a difference which could affect the results, because the standardization studies of the method are compatible with the global literature, and the minimum detectable concentration corresponds to the other studies. This sensitivity might have caused the detection of BPA in all samples, a result, which has not previously been found in the literature. Nevertheless, environmental contamination cannot be excluded.
The possibility that BPA, a lipophilic chemical, may accumulate in the adipose tissue is an unclear assumption. The relationship of BPA with BMI may be due to the accumulation of BPA at higher levels in individuals with obesity given excess adipose tissue. Thus, this finding may not be a cause, but rather an outcome [18]. The effect assigned to BPA may be the cumulative effect of many chemical substances. There are more than a thousand commercial chemicals that may have similar effects. These include bisphenol F and bisphenol S, which are being used with increasing frequency, and phenols and phytates, which have been introduced previously [19]. Products containing BPA may also contain other endocrine disrupters, and the effects attributed to BPA may be the effects of these chemicals or a cumulative effect. However, cell and animal studies that have observed the effects of BPA alone given in repeated doses, provide evidence supporting the effects of BPA.
Conclusion
This study found that screen-based behavior time increased the frequency of obesity and overweight. Physical activity rate was also higher in normal weight children than in children with obesity, which supports the association of physical activity with BMI. Obesity is a risk factor for IR and lipid profile abnormalities. Since urine creatinine-corrected BPA and BPGA increased in proportion with BMI, exposure to BPA and obesity were thus correlated. In addition, BPA was correlated with IR. The contribution of BPA to obesity and IR was presented in this study, but more comprehensive research is needed in this area.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: This study was funded by the Scientific Research Projects Coordination Unit of Istanbul University (project no. 41594).
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014; 384(9945):766-81.
2. Artacho-Cordon F, Arrebola JP, Nielsen O, Hernandez P, Skakkebaek NE, Fernandez MF, et al. Assumed non-persistent environmental chemicals in human adipose tissue; matrix stability and correlation with levels measured in urine and serum. Environ Res. 2017; 156:120-7.
3. Neyzi O, Bundak R, Gökçay G, Günöz H, Furman A, Darendeliler F, et al. Reference Values for Weight, Height, Head Circumference, and Body Mass Index in Turkish Children. J Clin Res Pediatr Endocrinol. 2015; 7(4):280–93.
4. Unalan D, Senol V, Bayat M, Mazicioğlu MM, Öztürk A, Kurtoğlu S, et al. Change in waist circumference over 3 years in Turkish children and adolescents. Ann Hum Biol. 2013; 40:419-25
5. National Cholesterol Education Program Highlights of the report of the expert panel on blood cholesterol levels in children and adolescents. Pediatrics. 1992; 89(3):495–501.
6. Can M, Piskin E, Guven B, Acikgoz S, Mungan G. Evaluation of Serum Lipid Levels in Children. Pediatr Cardiol. 2013; 34(3):566–9.
7. Battal D, Cok I, Unlusayinc I, Tunctan B. Development and validation of an LC-MS/MS method for simultaneous quantitative analysis of free and conjugated bisphenol A in human urine. Biomed Chromatogr. 2014; 28(5):686-93.
8. Shen SW, Lu Y, Li F, Yang CJ, Feng YB, Li HW, et al. Atherogenic index of plasma is an effective index for estimating abdominal obesity. Lipids Health Dis. 2018; 17: 11.
9. Shelby MD. NTP-CERHR monograph on the potential human reproductive and developmental effects of bisphenol A. Ntp Cerhr Mon. 2008; 22:1-64
10. Wang HX, Zhou Y, Tang CX, Wu JG, Chen Y, Jiang QW. Association between bisphenol a exposure and body mass index in Chinese school children: a cross- sectional study. Environ Health. 2012; 11:79.
11. Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL. Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003-2004. Environ Health Perspect. 2008; 116:39–44.
12. Becker K, Göen T, Seiwert M, Conrad A, Pick-Fuss H, Müller J, et al. GerES IV: Phthalate metabolites and bisphenol A in urine of German children. Int J Hyg Environ Health. 2009; 212(6):685–92.
13. Trasande L, Attina TM, Blustein J. Association between urinary bisphenol A concentration and obesity prevalence in children and adolescents. JAMA. 2012; 308:1113–21.
14. Wells EM, Jackson LW, Koontz MB. Association between bisphenol A and waist-to-height ratio among children: National Health and Nutrition Examination Survey 2003-2010. Ann Epidemiol. 2014; 24(2):165-7.
15. Li DK, Miao M, Zhou Z, Wu C, Shi H, Liu X, et al. Urine Bisphenol-A Level in Relation to Obesity and Overweight in School-Age Children. PLoS One. 2013; 8(6):e65399.
16. Eng DS, Lee JM, Gebremariam A, Meeker JD, Peterson K, Padmanabhan V. Bisphenol A and Chronic Disease Risk Factors in US Children. Pediatrics. 2013; 132(3):e637–45.
17. Khalil N, Ebert JR, Wang L, Belcher S, Lee M, Czerwinski SA, et al. Bisphenol A and cardiometabolic risk factors in obese children. Sci Total Environ. 2014; 470-1:726-32.
18. Fernandez MF, Arrebola JP, Taoufiki J, Navalon A, Ballesteros O, Pulgar R, et al. Bisphenol-A and chlorinated derivatives in adipose tissue of women. Reprod Toxicol. 2007; 24:259–64.
19. Geens T, Aerts D, Berthot C, Bourguignon J-P, Goeyens L, Lecomte P, et al. A review of dietary and non-dietary exposure to bisphenol-A. Food Chem Toxicol. 2012; 50(10):3725-40.
Download attachments: 10.4328:ACAM.20715
Ayşe Kılıç, Sevinç Gümüş Pekacar, Aylin Yetim, Gonca Keskindemirci, Mustafa Özçetin, Muhammet Ali Varkal, Firdevs Baş, Şükran Poyrazoğlu, Feyza Darendeliler, Dilek Battal, Ayça Aktaş, İsmet Çok. The relationship between urinary bisphenol A levels and body weight in children. Ann Clin Anal Med 2021;12(11):1239-1243
Citations in Google Scholar: Google Scholar
Parents’ knowledge and attitudes about adenovirus enteritis of children
Zeynep Yılmaz Öztorun
Department of Pediatrics, Faculty of Medicine, Niğde Ömer Halisdemir University, Niğde, Turkey
DOI: 10.4328/ACAM.20717 Received: 2021-05-28 Accepted: 2021-08-22 Published Online: 2021-08-24 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1244-1247
Corresponding Author: Zeynep Yilmaz Öztorun, İnönü mahallesi, Hande Sitesi, No: 31, Niğde, Turkey. E-mail: drzeynoyilmaz@gmail.com P: +90 533 725 78 45 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8017-3048
Aim: This study aimed to examine the effect of the sociodemographic characteristics of the parents of children hospitalized for adenovirus enteritis and child care attitudes of parents on the course of adenovirus enteritis.
Material and Methods: A total of 57 patients aged <6 years who were hospitalized for adenovirus enteritis were included in the study. A questionnaire was administered to the parents to gather data on the patients’ birth history, chronic diseases, and breastfeeding times, and parents’ level of education and knowledge about adenovirus enteritis and dehydration. The questionnaire also included items about hygiene measures for dehydration. Kidney function tests, electrolyte values, and blood gas analysis were performed to evaluate the dehydration status of the patients objectively.
Results: Of 57 patients, their mean age was 19.84 ± 14.97 months. The mean number of patients’ siblings was 1.76 ± 0.76. 10.5% of parents had knowledge about adenovirus-related diarrhea. Parents believed that adenoviruses were transmitted through contaminated water (45.6%), food (17.5%), and surface (19.3%) and through human-to-human contact (17.5%). A significant relationship was found between parental education level and knowledge of diarrhea caused by an adenovirus (p = 0.032). In addition, a significant relationship was noted between parental education level and hand washing after each diaper change (p = 0.016). Moreover, no significant difference was found between the duration of breastfeeding and the time to initiation of oral intake after diarrhea (p = 0.501).
Discussion: It was thought that having a large family, education level, working status of parents were factors that influence the course of adenovirus and the development of dehydration that would require hospitalization. We believe that families’ knowledge of adenovirus infection and possible complications will help in preventing irreversible morbidities. Therefore, adenovirus infections need to be included in informative speeches in the field of preventive medicine.
Keywords: Adenovirus, Gastroenteritis, Child
Introduction
Human adenoviruses are a group of double-stranded membraneless deoxyribonucleic acid viruses belonging to the Adenoviridia family [1]. Known transmission routes are aerosol particulate or droplets, hand–ocular, fecal-oral, and fecal (fomites) [2]. More than 80% of adenovirus infections occur in children aged <4 years because of humoral immunity deficiency[3,4].
Different adenovirus genotypes may cause diverse clinical findings and various diseases such as acute respiratory disease, acute gastroenteritis, keratoconjunctivitis, hemorrhagic cystitis, hepatitis, hemorrhagic colitis, pancreatitis, nephritis, and meningoencephalitis [5]. Human adenovirus, which includes serotypes 40 and 41, is associated with F gastroenteritis and is therefore called enteric adenovirus [6,7]. Vomiting and diarrhea- related fluid loss that develops in enteritis can increase the circulating blood volume and then lead to dehydration and electrolyte imbalance [7]. Poor hygienic conditions, inadequate access to clean drinking water, and insufficient sanitation increase the risk of disease transmission [8, 9]. Studies examining the parents’ knowledge of children with adenovirus enteritis about the disease and what families should do in approaching the disease are limited in the literature.
This study aimed to examine the effect of the knowledge level of the parents about the disease of their young children hospitalized for adenovirus enteritis, sociodemographic characteristics of the patients and parents, and child care attitudes of the parents on the course of adenovirus enteritis.
Material and Methods
This cross-sectional study included 57 children aged <6 years who were hospitalized in the pediatric ward of our hospital with the diagnosis of adenovirus gastroenteritis between April 2020 and October 2020. The patients aged 0-6 years who had adenovirus gastroenteritis and who developed nutritional intolerance due to enteritis were included in the study. Those aged >6 years old, those who used antibiotics in the last 15 days, and those with chronic gastrointestinal system disease were excluded from the study.
A questionnaire was administered to the parents to collect data about their children’s birth history, chronic diseases, and breastfeeding times, and parents’ level of education and level of knowledge about adenovirus enteritis and dehydration. This questionnaire also included items about hygiene measures for dehydration. Parents’ education level, profession, and working status were recorded. Symptoms such as upper respiratory tract infection or keratoconjunctivitis accompanying adenovirus enteritis were recorded, if any. Children with adenovirus enteritis were evaluated for the presence of clinical and physical examination findings of dehydration. Kidney function tests, electrolyte values (sodium, potassium), and blood gas analysis were performed to evaluate the dehydration status of the patients objectively. The data has been collected systematic and comprehensive manner.
Voluntary informed consent was obtained from the parents. Approval was obtained from Niğde Ömer Halisdemir University Clinical Research Ethics Committee (approval number. 38497978-645-E.13951, dated March 10, 2020).
The student’s t-test was used for the analysis of data that showed normal distribution among independent groups. The Mann–Whitney U test was used for variables that did not show a normal distribution. The chi-square test was used to analyze categorical variables. Analysis of the data was carried out with the SPSS (version 24) software package. P <0.05 was considered significant.
Results
In total, 57 pediatric patients were included in the study. Of these patients, 17 were girls and 40 were boys. The mean age of the patients was 19.84 ± 14.97 months. The mean number of patients’ siblings was 1.76 ± 0.76. In addition, 41.5% of the patients had one sibling, 43.9% had two siblings, 12.2% had three siblings, and 2.4% had four or more siblings. The mean birth weight of the patients was 3040 ± 550.94 grams. Other sociodemographic characteristics of the patient and parents are shown in Table 1.
In this study, 66.7% of the parents had the habit of washing their hands before preparing complementary food for the child and 33.3% did not. In addition, 63.2% of the parents used to wash their hands after every diaper change, 10.5% had knowledge about adenovirus-related diarrhea, and 89.5% did not have knowledge about it. Parents believed that adenoviruses were transmitted through contaminated water (45.6%), food (17.5%), and surface (19.3%) and through human-to-human contact (17.5%). Moreover, 17 children were previously hospitalized for diarrhea; 35.1% of the patients were brought to the hospital because of vomiting, 45.6% of diarrhea, 14% of fever, and 5.3% of being unable to feed. Dehydration symptoms developed in 70.2% of the patients before hospitalization, and 22.8% received treatment for bicarbonate deficit, 26.3% had impaired renal function tests, and 31.6% had upper respiratory tract infection and diarrhea. Keratoconjunctivitis and diarrhea were found in 24.6% of the patients.
Of the parents, 71.9% thought that probiotic supplementation reduced the number and frequency of diarrhea, and 42.1% thought that zinc treatment improved the patient’s diet. After the onset of diarrhea, 12.3% of the patients started oral intake on the first day, 36.8% started on the second day, 36.8% started on the third day, and 19.3% started on the fourth day and beyond.
In this study, a significant relationship was found between parents’ education level and their knowledge of diarrhea due to adenovirus (p = 0.032). Moreover, parents who were secondary school graduates (50%), high school graduates (33.3%), and university graduates (16.7%) had knowledge about adenovirus diarrhea, and none of the parents who were primary school graduates had heard of adenovirus-related diarrhea. As regards the relationship of parental education level and profession with hand hygiene, no relationship was found between parental profession and hand washing after each diaper change (p = 0.148). However, a significant relationship was noted between parental education level and hand washing after each diaper change (p = 0.016). 71.4% of those who did not wash their hands after changing diapers were primary school graduates, 19% were high school graduates, and 9.5% were secondary school graduates. A significant relationship was found between parental education level and hand washing before preparing complementary food (p = 0.049). 68.2% of those who did not wash hands are primary school graduates, 19.8% are secondary school graduates, 11% are high school graduates, and 12% was a university graduate. No significant difference was found between children with employed parents and those with unemployed parents with respect to time to initiation of oral intake (p = 0.412). In this study, no significant relationship was found between the duration of breastfeeding and the development of signs of dehydration (p = 0.715) and measuring bicarbonate deficit (p = 0.348). No significant relationship was observed between the duration of breastfeeding and the development of upper respiratory tract infection symptoms and diarrhea (p = 0.174). In addition, no significant difference was found between the duration of breastfeeding (<6 months, 6–12 months, and >12 months) with respect to the initiation of oral intake after diarrhea (p = 0.501). The effects of various situations on time to initiation of oral intake after diarrhea are shown in Table 2.
Discussion
Knowledge of parents about hand disinfection, hand washing, diaper change, and disease transmission significantly was found to remarkably reduce the transmission rates of organism- causing diarrhea. These measures should be continued for a long time because the pathogen continues to be excreted even after the disappearance of symptoms [10]. In the present study, the higher the parents’ education level, the higher the rate of hand washing before complementary food preparation and after the diaper change. The rate of those who did not wash their hands before preparing complementary food was also high among those with a low education level.
John Moyo et al. stated that parent’s education level is 75% primary education, 16.7% secondary education, 8.2% higher education respectively in their study [11]. They detected that the majority of adenovirus-infected diarrhoeic children were dehydrated [11]. Dey et al. stated that adenovirus infection causes severe gastroenteritis and dehydration [12]. In this present study, the parent of children with adenovirus enteritis has higher school graduates, and 70.2% of the patients had dehydration symptoms. The findings concur with the results from the literature.
Motamedifar et al. stated that diarrhea is the most common symptom in adenovirus enteritis, and fever is the second common symptom [13]. In the present study, diarrhea (45.6 %) and vomiting (35.1 %), respectively, are the most common causes of hospital admission in children with adenovirus enteritis. The fact that the frequency of enteritis symptoms in our study was not similar to the study of Motamedifar et al. was thought to be related to the low number of patients. Awareness of the modes of transmission of adenovirus enteritis may affect the parents’ approach to the disease and the precautions they should take. Napolitano et al. found that less than half of the parents knew about enteritis. Of these parents, 60.8% believed that the pathogen is transmitted through contaminated water, 56% through contaminated foods, 38% through contaminated surfaces, and 36% through human-to- human contact [14]. In the present study, parents know that adenovirus enteritis is most often transmitted by contaminated water, followed by contaminated surface, contaminated food, and human-to-human contact, in this order. In the present study, the knowledge levels of the parents about the transmission routes were similar to those in the literature.
A study conducted in Australia revealed that viral enteritis was among the most common causes of diarrhea in children aged <5 years in developing countries [15]. Moreover, household economic status is significantly associated with the prevalence of diarrhea, especially in low-income countries [16]. In the present study, 70.2% of the parents were unemployed, 47.4% of the patients lived in the village, and 53.6% lived in the city, and the percentage of those with ≥2 siblings was higher than those with one sibling. These findings suggest that the low economic situation in the family and living in a crowded home may increase the incidence of enteritis.
In a study conducted in Italy, family physicians increased the awareness of families by informing them about rotavirus enteritis or by recommending rotavirus vaccination. With the influence of social media and other information sources on vaccination, parents have better understood the importance of both rotavirus enteritis and vaccination [17]. The lack of vaccine against adenovirus is the reason why this issue is not included in child informative speeches of health professionals in preventive medicine and in written and visual communication channels. Adenovirus infections may cause keratoconjunctivitis during their course [18]. Keratoconjunctivitis has an epidemic course and causes permanent scar formation in the cornea and morbidity in the form of decreased visual acuity [19]. In our study, 10.5% of the parents had knowledge about adenovirus enteritis. If parents are informed about adenovirus infection, they may recognize clinical findings early and prevent dehydration. In this way, keratoconjunctivitis will be prevented, and early admission to eye clinics will be arranged, if necessary. In addition, early and effective measures will be taken to prevent intrafamilial spread of adenoviral conjunctivitis, which is highly contagious by contact.
Not breastfeeding affects the incidence and prevalence of acute infectious gastroenteritis in developed or developing countries [20]. In the present study, no significant relationship was observed between the duration of breastfeeding and the development of signs of dehydration, and the time to initiation of oral intake after diarrhea. The finding that the duration of breastfeeding did not affect the symptoms and response time to treatment may be due to the low number of patients included in the study. This situation constitutes the limitation of the study.
Conclusion
It was thought that the education level and the working status of the parents and having a large family are factors that effectively affect the course of adenovirus infection and the development of dehydration that would require hospitalization. We believe that families’ knowledge about adenovirus infection and possible complications will be helpful in preventing irreversible morbidities. It is important to include adenovirus infections in informative speeches in the field of preventive medicine.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Lu X, Erdman DD. Molecular typing of human adenoviruses by PCR and sequencing of a partial region of the hexon gene. Arch Virol. 2006;151(8):1587- 1602.
2. Garnett CT, Talekar G, Mahr JA, Huang W, Zhang Y, Ornelles DA, et al. Latent species C adenoviruses in human tonsil tissues. J Virol. 2009;83(6):2417-2428. 3. Ison MG. Adenovirus infections in transplant recipients. Clin Infect Dis. 2006;43(3):331-9.
4. Chang SY, Lee CN, Lin PH, Huang HH, Chang LY, Ko W, et al. A community- derived adenovirus type 3 in children in Taiwan between 2004 and 2005. J Med Virol. 2008;80(1):102-112.
5. Lynch 3rd JP, Fishbein M, Echavarria M. Adenovirus. Semin Respir Crit Care Med. 2011;32(4):494–511.
6. Chiba S, Nakata S, Nakamura I, Taniguchi K, Urasawa S, Fujinaga K, et al. Outbreak of infantile gastroenteritis due to type 40 adenovirus. Lancet. 1983;2(8356):954–7.
7. Dey RS, Ghosh S, Chawla-Sarkar M, Panchalingam S, Nataro JP, Sur D, et al. Circulation of a novel pattern of infections by enteric adenovirus serotype 41 among children below 5 years of age in Kolkata, India. J Clin Microbiol. 2011;49(2):500–5.
8. Powers KS. Dehydration: Isonatremic, hyponatremic, and hypernatremic recognition and management. Pediatr Rev. 2015;36(7):274-283.
9. Prüss-Ustün A, Bartram J, Clasen T, Colford Jr JM, Cumming O, Curtis V, et al. Burden of disease from inadequate water, sanitation and hygiene in low- and middle-income settings: a retrospective analysis of data from 145 countries. Trop Med Int Health. 2014;19(8):894-905.
10. Ejemot-Nwadiaro RI, Ehiri JE, Arikpo D, Meremikwu MM, Critchley JA: Hand washing promotion for preventing diarrhoea. Cochrane Database Syst Rev. 2015; 9:CD004265. doi: 10.1002/14651858.CD004265.pub3.
11. Moyo SJ, Hanevik K, Blomberg B, Kommedal O, Nordbø SA, Maselle S, et al. Prevalence and molecular characterisation of human adenovirus in diarrhoeic children in Tanzania; a case control study. BMC Infect Dis. 2014;14:666.
12. Dey SK, Shimizu H, Phan TG, Hayakawa Y, Islam A, Salim AF, et al. Molecular epidemiology of adenovirus infection among infants and children with acute gastroenteritis in Dhaka City, Bangladesh. Infect Genet Evol. 2009; 9(4):518–522.
13. Motamedifar M, Amini E, Shirazi PT. Frequency of Rotavirus and Adenovirus Gastroenteritis Among Children in Shiraz, Iran. Iranian Red Crescent Medical Journal. 2013; 15(8): 729-33
14. Napolitano F, Adou AA, Vastola A, Angelillo IF. Rotavirus Infection and Vaccination: Knowledge, Beliefs, and Behaviors among Parents in Italy. Int J Environ Res Public Health. 2019;16(10):1807.
15. Fletcher S, Van Hal S, Andresen D, McLaws ML, Stark D, Harkness J, et al. Gastrointestinal pathogen distribution in symptomatic children in Sydney, Australia. J Epidemiol Glob Health. 2013;3(1):11-21.
16. Woldemicael G. Diarrhoeal morbidity among young children in Eritrea: environmental and socioeconomic determinants. J Health Popul Nutr. 2001;19(2):83-90.
17. Marchettia F, Vetterb V, Confortic G, Espositod S, Bonanni P. Parents insights after pediatric hospitalization due to rotavirus gastroenteritis in Italy. Hum Vaccin Immunother. 2017;13(9):2155-9.
18. Lee CS, Lee AY, Akileswaran L, Stroman D, Najafi-Tagol K, Kleiboeker S, et al. Determinants of Outcomes of Adenoviral Keratoconjunctivitis. Ophthalmology. 2018;125(9): 1344–1353.
19. Muller MP, Siddiqui N, Ivancic R, Wong D. Adenovirus-related epidemic keratoconjunctivitis outbreak at a hospital-affiliated ophthalmology clinic. Am J Infect Control. 2018;46(5):581-3.
20. Posovszky C, Buderus S, Classen M, Lawrenz B, Keller KM, Koletzko S. Acute Infectious Gastroenteritis in Infancy and Childhood. Dtsch Arztebl Int. 2020;117(37):615-624.
Download attachments: 10.4328:ACAM.20717
Zeynep Yılmaz Öztorun. Parents’ knowledge and attitudes about adenovirus enteritis of children. Ann Clin Anal Med 2021;12(11):1244-1247
Citations in Google Scholar: Google Scholar
The relationship between blood nitric oxide levels and brain infarct volume in patients with ischemic stroke
Arife Erdogan 1, Ahmet Çağdaş Acara 1, Yaprak Özüm Ünsal 2, Özge Yılmaz Küsbeci 2, Sibel Bilgili 3, Mumin Alper Erdogan 4, Aykut Gokturk Uner 5, 6, Huriye Akay 1, İsmet Parlak 1
1 Department of Emergency Medicine, Izmir Bozyaka Research and Training Hospital, Izmir, Turkey, 2 Department of Neurology, Izmir Bozyaka Research and Training Hospital, Izmir, Turkey, 3 Department of Biochemistry, Izmir Bozyaka Research and Training Hospital, Izmir, Turkey, 4 Department of Physiology, Izmir Katip Celebi University Faculty of Medicine, Izmir, Turkey, 5 Department of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, USA, 6 Department of Physiology, Adnan Menderes University Faculty of Veterinary Medicine, Aydın, Turkey
DOI: 10.4328/ACAM.20718 Received: 2021-05-27 Accepted: 2021-07-28 Published Online: 2021-08-10 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1248-1252
Corresponding Author: Arife Erdogan, Izmir Cigli Regional Training Hospital, Department of Emergency Medicine, Izmir, Turkey. E-mail: arife.erdogan@yahoo.com P: +90 531 343 97 31 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2488-2012
Aim: Cerebrovascular disease (CVD) is the third leading cause of morbidity and mortality. Most risk factors disrupt the contraction and enlargement of the cerebrovascular endothelium. One of the main players in the maintenance of cerebrovascular homeostasis is nitric oxide (NO). In this study, we aimed to in- vestigate the level of NO in patients with ischemic stroke and to determine the role of NO by comparing the infarct volumes of patients’ brain as measured by computed tomography (CT) with the levels of NO.
Material and Methods: This is a prospective observational study. Blood samples and brain computed tomography images were taken at 0 and 24 hours from the ischemic stroke patients. Serum NO levels and the volumes of ischemic brain lesions were measured using CT imaging.
Results: In our study, we had 60 patients who are diagnosed with acute ischemic stroke and 37 healthy individuals. Mean NO levels in stroke patients were significantly lower compared with the control group. Patients were classified into 3 groups as 0-7, 8-14, 15≤ according to their NIHSS scores to compare their NO levels and infarct volumes. When the infarct volume of the group, which had an NIHSS score of 15≤ at 0 hours was compared with the other groups, it was found to be significantly higher (p<0.001). NO levels in the same group at 0 hours were significantly lower than in the other groups.
Discussion: The relationship between serum NO levels and brain infarct volume in ischemic stroke patients was clearly demonstrated in our study.
Keywords: Cerebrovascular Disease, Ischemic Stroke, Nitric Oxide, Infarct Volume
Introduction
Stroke is a clinical case occurring after sudden cerebral functional failure due to pathology of the vessels in the brain, and it is the third leading cause of death following cardiovascular diseases and cancer [1]. The most common type of stroke is ischemic stroke [2]. Ischemic stroke is caused by several risk factors such as herodofamilial predisposition, hypertension, diabetes mellitus, obesity, and elevated blood lipids, all of which might be independently associated with each other [3]. These risk factors may cause failure in cerebrovascular endothelin function, which plays a critical role in the regulation of cerebral blood flow [4]. Microvascular endothelial cells in the brain can produce and release many vasoactive substances, including nitric oxide (NO) and endothelin-1 that play a major role in the maintenance of cerebrovascular homeostasis [5,6].
NO is an inorganic gas that plays important roles in the control of cerebral blood flow, thrombogenesis, and the modulation of neuronal activity [7,8]. NO is produced in the endothelial cells, glial cells, neurons and macrophages by 3 different isoforms of the enzyme nitric oxide synthase (NOS) [9]. The identified functions of NO in the vascular system are regulation of vasomotor tonus, inhibition of thrombocyte adhesion and aggregation, suppression of cell proliferation and platelet activation, and the modulation of myocardial contraction [10]. Endothelial NO derived from endothelial nitric oxide synthase (eNOS) is the most important determinant of basal vascular tone, which regulates systemic circulation. NO is also involved in the regulation of local circulation of some organs (e.g., in the heart and brain) [11,12]. Studies have shown that both inactivation of eNOS genes by neural nitric oxide synthase (nNOS) inhibitors and eNOS deficiency cause hypertension in rats [11]. Risk factors predisposing to atherosclerosis are associated with a reduction in bioactive NO levels, and abnormal endothelial function. This depends on whether NO is truly deficient or inactivated by entering the reaction with oxygen-derived radicals. In addition, platelets also contribute to the control of platelet activation by synthesizing NO [13,14]. A growing number of studies were conducted on the relationship between stroke and NO levels in order to understand whether NO production and its levels are important in terms of the diagnosis, prognosis and prevention of cerebrovascular diseases. Therefore, this study aims to investigate the relationship between blood NO levels and infarct volumes of the brain measured by computed tomography in patients with ischemic stroke.
Material and Methods
Study design and patients
This is a prospective observational study conducted between November 2017 and January 2018 on ischemic stroke patients who were admitted to the emergency room and were diagnosed with ischemic stroke. We received ethical approval from Clinical Research Ethics Committee of Izmir Bozyaka Training and Research Hospital (No:8.11.2017/4). The study population consisted of 60 patients with a first episode of hemispheric ischemic stroke within 24-hour after the onset of symptoms. Thirty-seven healthy subjects served as controls. Systemic and neurological examinations were performed following a detailed anamnesis of each patient.
Assessments and analyses
The severity of the neurological deficit was determined by the National Institute of Health Stroke Scale (NIHSS) score. The NIHSS is widely used to assess the severity of acute ischemic stroke. For a more detailed study of the patients, we divided them into 3 groups according to the NIHSS scale. Patients were grouped according to the NIHSS scoring system as mild (0-7), moderate (7-14), and severe (greater than 15, 15≤).
Routine blood tests and ECG were also done. Cerebral infarct location was detected using CT. The aforementioned assessments and tests were performed again together with neurological examination 24 hours after the first admission. Venous blood samples (8-mL vacuum and gel separator tubes, BD Vacutainer SSTTM II Advance) were collected and centrifuged for 10 minutes at 3,000 rpm after blood clotted. The sera were decanted and stored at -80 0C until the ELISA assay. Serum NO levels were determined using a commercial ELISA kit (Andy Gene Biotechnology, China) according to the manufacturer’s instructions. CT was used to find and measure the ischemic area of the brain at the time of the first admission and 24 hours after the first admission. The volume of the ischemic area of the brain was calculated according to the Cavalieri method by multiplying the surface area of the lesion with the imaging cross-sectional thickness (5mm) (Figure 1) [15].
Statistical analysis
All data were evaluated using the SPSS version 22.0 package program. Data were expressed as mean ± SD (Standard Deviation) values in the tables. The data were evaluated using Shapiro-Wilk for normal distribution. The Wilcoxon Sign Test was conducted for dependent variables and the Kruskal-Wallis Test was done for more than two independent groups when assumptions of normal distribution and/or homogeneity of variance were violated. The Mann-Whitney U test was performed between two independent groups that did not meet the normal distribution when necessary. In all patients, Spearman’s correlation analysis was used to examine correlations between NO levels and infarct volumes. Since the data between the groups separated according to the NIHSS score were not normally distributed, Logarithmic transformation was performed followed by a one- way ANOVA test on these data. Duncan’s Post-Hoc analysis was performed to determine which groups were different because the relationship between infarct volume and NO levels was significant among these groups. The Mann-Whitney U test was performed because the data were not normally distributed when comparing NO levels in the control group and the patient group at 0 hours. The effects of group and gender on NO levels in the NIHSS groups were evaluated by a two-way analysis of variance. Among the NIHSS score groups, a two-way ANOVA test was used for repeated measurements to compare NO levels at 0 and 24 hours. Statistical significance level was taken p < 0.05 in all tests.
Results
Baseline characteristics of patients with stroke are shown in Table 1; 84.4% of patients were diagnosed with at least one comorbid disease, while 16.6% of them had no comorbid disease. For control subjects (n=37), the mean age of males (n=20) and females (n=17) was 51.08 ± 8.37 (Table 1).
The mean NO level in the control group was 37.965 ± 7.269 μmol/L (male / female 39.315 ± 7.223 / 36.376 ± 6.824 μmol/L). In the patient group, it was 21.184 ± 7.2847 at 0 hours and 25.955 ± 9.372 μmol/L at 24 hours. According to gender, the male/female ratio at 0 hours was 21.56 ± 6.860/20.715 ± 7.646 μmol/L. At the 24th hour, it was 26.16 ± 8.814/25.701 ± 9.830 μmol/L. We found that gender had no effect on NO levels (p>0.05). The mean NO levels for the entire patient group at 0 and 24 hours were significantly lower when compared to the control group (p<0.001). We also found that the mean NO level in the patient group at 24 hours increased compared to the 0- hour level.
The mean NIHSS score of the patients at the time of admission (0 hours) was calculated as 8.016 ± 4.335. NIHSS score was 0-7 in 33 patients (53.3%), NIHSS score was 8-14 in 19 patients (33.3%) and NIHSS score was 15 and over in 8 patients (13.3%). Additionally, the mean NIHSS score of the patients at 24 hours was calculated as 7.6 ± 4.603. NIHSS score at 24 hours was between 0-7 in 37 patients (61.6%), between 8-14 in 16 patients (26.6%), and 15 and over in 7 patients (11.6%).
When the patients were grouped according to their NIHSS scores at 0 hours, mean NO levels of the patients with NIHSS score 15 and over were significantly lower than NO levels in the other score groups (p<0.001), although a significant increase was observed in infarct volume of patients NIHSS score 15≤ (p<0.001). Likewise, mean NO levels of the patients with NIHSS score of 15≤ at 24 hours were significantly lower than in other groups at 24 hours (p<0.001). In the same manner, there was a significant increase in infarct volume of patients’ NIHSS score 15≤ at 24 hour (p<0.001) (Table 2).
Patients were divided into 3 groups according to their altered NIHSS scores when comparing the difference between 0 and 24 hours, as increased NIHSS score, decreased NIHSS score, and unchanged NIHSS score. NIHSS scores were increased in 7 patients, decreased in 18 of them, and no changes were found in 35 of them. It was found that the NO levels measured at 24 hours in patients with increased NIHSS score group were not statistically significant, but were lower than the NO levels at 0 hours (p>0.05). In addition, it was observed that the mean infarct volume was significantly higher in the increased NIHSS score group compared to the other groups (p<0.001). Likewise, in the group with increased NIHSS score, it was observed that NO levels at 24 hours were lower than the 0-hour levels, although it is not statistically significant, while the opposite situation was also observed in the group with a decreased NIHSS score (Table 3).
Regarding the results of comparison between altered NIHSS score groups in Table 3, we further analyzed the relationship among these groups, and used Spearman’s correlation analysis for this purpose. We found statistically significant negative correlations between both infarct volume-NO levels and NIHSS scores-NO levels at 0 and 24 hours (p<0.01 and p<0.001) (Figure 2).
Discussion
Studies have shown that early diagnosis and treatment of patients who come to emergency services with CVD can reduce the effects of this disease on mortality and morbidity. Thus, for use in the early diagnosis and treatment of patients with ischemic stroke, studies with many molecules that are effective in pathogenesis are being made. Chemerin, basic fibroblast growth factor (bFGF), Adropine, Pentraxin 3 and NO are some of them [14,16].
One of the most important factors affecting the pathogenesis of ischemic stroke is the deterioration of endothelial function. In patients exposed to vascular risk factors, endothelium- dependent relaxation dysfunction is detected prior to morphological changes in the cell wall [17,18]. According to a study, such as hypertension, hyperlipidemia, smoking and diabetes, abnormal endothelial functions have been shown to be associated with a decrease in NO levels [19].
NO is a potent vasodilator synthesized by the nitric oxide synthase enzyme from L-arginine. NO inhibits platelet aggregation, leukocyte chemotaxis and their adhesion, as well as downregulates chemokine expression, reduces smooth muscle cell proliferation, migration and LDL oxidation, and thus it has anti-atherogenic and anti-thromboembolic effects [11,19]. In studies conducted by Drake and colleagues, it has been shown that the most important signaling molecule that plays a role in the autoregulation of cerebral blood flow and in cerebrovascular endothelium is endothelial NO [11].
In general, according to some studies, loss of endothelial NO is considered to be the central mechanism in the pathogenesis of endothelin dysfunction [19,20]. In both cerebral and peripheral vasculature, a decrease in endothelial NO results in impaired vascular function and processes such as vasoconstriction, increase in arterial blood pressure, proliferation of vascular smooth muscle cells, platelet aggregation, adhesion of white blood cells, and inflammation. For this reason, it has been found that the preservation of endothelial NO production is important for the prevention of cerebrovascular diseases [14].
Many animal experiments have been carried out in order to understand the mechanism of NO action at the molecular level. In animal studies performed, the infarct area due to middle cerebral artery occlusion was found to be larger in the eNOS Knock-out mice than the control group. Activation of eNOS has been shown to provide protection against stroke by preventing inflammation, platelet aggregation, thrombosis, and apoptosis. According to these studies, it has been demonstrated that NO is an important mediator in the regulation of cerebral blood flow [10,21].
In a study by Rashid and colleagues, plasma levels of NO in 38 controls, 228 ischemic stroke, and 49 hemorrhagic stroke patients were examined, and as a result, levels of NO in control group was 64.0 ± 36.3 μmol/L, 49.9 ± 26.1 μmol/L in the group of ischemic stroke and 41.7 ± 19.5 μmol/L in the group of hemorrhagic stroke [22]. Nandhagopal found that serum NO levels were lower in stroke patients (40.9 ± 3.9 μmol / L) than in the control group (59.9 ± 7.3 μmol / L) in a study of 40 stroke patients (Nandhagopal R, Krishnamoorhy SG, Vengamma B. Circulating Levels of Nitric Oxide in Stroke, Poster Abstracts, Sri Venkateswara Institute of Medical Sciences. 2005, Tirupati, India). In another study, the NO levels in 81 patients with acute ischemic stroke were 58.46 ± 1.92 μmol and were 61.22 ± 0.95 μmol in 50 healthy controls (Bengü Ş. Evaluation of asymmetric dimethylarginine, endothelial nitric oxide synthase and nitric oxide as a risk factor for early-onset ischemic stroke cases in Eastern Anatolia Region, (PhD Thesis), Erzurum, 2014.). In contrast to all of these data, Moro et al. found that NO levels in cerebrospinal fluid and in serum were higher in stroke patients than in the control group [23].
In our study, similar to other studies in the literature, mean NO levels in stroke patients were significantly lower (p<0.001). In addition, although the NO levels of patients measured at 24 hours were significantly increased compared to the 0-hour level, they were significantly lower than in the control group (p<0.001).
The infarct volumes were significantly higher in the group of NIHSS 15≤ at 0 hours when compared with the other groups (p<0.001). NO levels at 0 hours were significantly lower in the group with NIHSS score 15 and over compared with the groups of NIHSS score 0-7 and 8-14 (p<0.001).
According to the investigation among these groups, NO levels at 0 hours were significantly lower in the group of NIHSS score 15 and over when compared with the other groups, additionally, NO levels for the same group at the 24 hours were also lower (p<0.001). When we compared NO levels at 0 hours and 24 hours, the increase in NO levels for the NIHSS score 0-7 and 8-14 groups was significant (p<0.001). Nevertheless, there was no change in the levels of NO in the group of NIHSS score 15 and over. According to these results, it can be said that the infarct volume may be lowered due to the protective effect of NO that occurs as a result of its increase.
To examine our data from another perspective, patients were divided into 3 groups according to the NIHSS score at 24 hours as increased, decreased and unchanged. In patients with an increased NIHSS score, NO levels decreased at 24 hours compared to 0 hours, and the infarct volumes were significantly higher than in the other groups (p<0.001). NO levels of the patients in the groups of decreased and unchanged NIHSS score at 24 hours were increased compared to 0 hours. These results also support the association between NO levels and infarct volume.
Conclusion
Our study investigates the relationship between NO levels and infarct volume in stroke patients. In many experimental animal studies, NO activity and eNOS are associated with such disease models and their protective effects are known. This study highlights the protective effects of NO in ischemic stroke through demonstrating the significant relationship between infarct volumes and NO. However, the molecular mechanisms underlying this relationship need to be studied with more detailed animal studies, and should be strengthened by clinical studies involving even more patients.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Demaerschalk BM, Kleindorfer DO, Adeoye OM, Demchuk AM, Fugate JE, Grotta JC, et al. Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2016; 47(2) 581–641.
2. Perl II J, Samples SD. Thrombolytic Therapy for Acute Ischemic Stroke. Tech Vasc Interv Radiol. 2001; 4(2):115-21.
3. Saposnik G, Barinagarrementeria F, Brown Jr RD, Bushnell CD, Cucchiara B, Cushman M, et al. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke. 2011; 42(4):1158–92.
4. Katusic ZS, Austin SA. Endothelial nitric oxide: protector of a healthy mind. Eur Heart J. 2014; 35(14):888–94.
5. Vila N, Castillo J, Davalos A, Chamorro A. Proinflammotory Cytokines and Early Neurologycal Worsening in Ischemic Stroke. Stroke 2000; 31:2325-9.
6. Zhu J, Song W, Li L, Fan X. Endothelial nitric oxide synthase: a potential therapeutic target for cerebrovascular diseases. Molecular Brain. 2016; 9(1):1-8.
7. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991; 43:109-42.
8. Faraci FM, Brian JE Jr. Nitric oxide and the cerebral circulation. Stroke. 1994; 25: 692–703.
9. Iadecola C, Pelligrino DA, Moskowitz MA, Lassen NA. Nitric oxide synthase inhibition and cerebrovascular regulation. J Cereb Blood Flow Metab. 1994; 14:175–92.
10. Barbato JE, Tzeng E. Nitric oxide and arterial disease, J Vasc Surg. 2004; 40(1):187-93.
11. Drake CT, Iadecola C. The role of neuronal signaling in controlling cerebral blood flow. Brain Lang. 2007; 102(2):141–52.
12. Toda N, Ayajiki K, Okamura T. Cerebral blood flow regulation by nitric oxide: recent advances. Pharmacol Rev. 2009; 61(1):62–97.
13. Broos K, Feys HB, De Meyer SF, Vanhoorelbeke K, Deckmyn H. Platelets at work in primary hemostasis. Blood Rev. 2011; 25(4):155–67.
14. Atochin DN, Huang PL. Endothelial nitric oxide synthase transgenic models of endothelial dysfunction. Pflugers Arch. 2010; 460(6):965–74.
15. Clatterbuck RE, Sipos EP. The efficient calculation of neurosurgically relevant volumes from computed tomographic scans using Cavalieri’s direct estimator. Neurosurgery. 1997; 40:339–43.
16. Saenger AK, Christenson RH. Stroke Biomarkers: Progress and Challenges for Diagnosis, Prognosis, Differentiation and Treatment. Clinical Chemistry. 2010; 56:21–33.
17. Muscari A, Puddu GM, Serafini C, Fabbri E, Vizioli L, Zoli M. Predictors of short-term improvement of ischemic stroke. Neurol Res. 2013; 35(6):594–601.
18. Bora ES, Erdogan MA, Meral A, Karakaya Z, Erbas O. Protective effect of dapagliflozin on colistin-induced renal toxicity. Signa Vitae. 2021; 1:6.
19. Lloyd-Jones DM, Bloch KD. The Vascular Biology of Nitric Oxide and its Role in Atherogenesis. Annual Review of Medicine. 1996; 47:365-75.
20. Srivastava K, Bath PM, Bayraktutan U. Current therapeutic strategies to mitigate the eNOS dysfunction in ischaemic stroke. Cell Mol Neurobiol. 2012; 32(3):319–36.
21. Tan XL, Xue YQ, Ma T, Wang X, Li JJ, Lan L, et al. Partial eNOS deficiency causes spontaneous thrombotic cerebral infarction, amyloid angiopathy and cognitive impairment. Mol Neurodegener. 2015; 10(1):1-14.
22. Rashid PA, Whitehurst A, Lawson N, Bath PM. Plasma nitric oxide (nitrate/ nitrite) levels in acute stroke and their relationship with severity and outcome. J Stroke Cerebrovasc Dis. 2003; 12(2):82-7.
23. Moro MA, Cardenas A, Hurtado O, Leza JC, Lizasoain I. Role of Nitric Oxide after Brain Ischemia. Cell Calcium 2004; 36(3-4):265-75.
Download attachments: 10.4328:ACAM.20718
Arife Erdogan, Ahmet Çağdaş Acara, Yaprak Özüm Ünsal, Özge Yılmaz Küsbeci, Sibel Bilgili, Mumin Alper Erdogan, Aykut Gokturk Uner, Huriye Akay, İsmet Parlak. The relationship between blood nitric oxide levels and brain infarct volume in patients with ischemic stroke. Ann Clin Anal Med 2021;12(11):1248-1252
Citations in Google Scholar: Google Scholar
The correlation of vitamin D level with the disease etiology and disease level in patients with chronic liver disease
Ece Ulukal Karancı 1, Dinç Dinçer 2, Yusuf Karancı 3, Cihan Bedel 3
1 Department of Internal Medicine, Health Science University, Antalya Training and Research Hospital, 2 Division of Gastroenterology, Department of Internal Medicine, Akdeniz University Medical School, 3 Department of Emergency Medicine, Health Science University, Antalya Training and Research Hospital, Antalya, Turkey
DOI: 10.4328/ACAM.20721 Received: 2021-06-01 Accepted: 2021-08-07 Published Online: 2021-08-17 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1253-1257
Corresponding Author: Cihan Bedel, Health Science University Antalya Training And Research Hospital, Kazım Karabekir Street, postal zip code: 07100, Muratpaşa, Antalya, Turkey. E-mail: cihanbedel@hotmail.com P: +90 507 564 12 54 F: +90 242 249 44 87 Corresponding Author ORCID ID: https://orcid.org/0000-0002-3823-2929
Aim: Although vitamin D (VD) deficiency or insufficiency is demonstrated to exist in the majority of patients with chronic liver disease (CLD), there are also studies that prove otherwise or show that this may only be related to VD deficiency at severe levels. Therefore, we aimed to evaluate 25-(OH)VD (25-OHD) level in patients with various type of CLD and the clinical significance of its deficiency or insufficiency.
Material and Methods: The 25-OHD levels measured in patients diagnosed with CLD were retrospectively recorded. According to their VD levels, patients were categorized into four groups as normal (≥30 ng/ml), insufficient (20-29.9 ng/ml), deficient (10-19.9 mg/ml) and severely deficient (<10 ng/ml).
Results: One hundred seventy-eight (52.4%) of 340 patients were females, and the mean age of the patients was 52.8±13.77 years. The mean 25-OHD level of the patients was 19.43±9.71. Patients with Hepatitis C Virus had significantly higher 25-OHD levels than patients with cirrhosis, non-alcoholic fatty liver disease (NAFLD) and Hepatitis B Virus (p=0.014). When the patients were divided into groups according to their 25-OHD levels, 47 patients (13.8%) were found to have a sufficient level, 113 (33.2%) an insufficient level, 120 (35.3%) a deficient level, and 60 (17.6%) a severely deficient level. In regression analysis, albumin and direct bilirubin are independent predictors of the VD level severity (odds ratio [OR]: 0.477, 95% confidence interval [CI]: 0.234-0.720, p <0.001; OR: 0.74, 95% Cl: 0.135-1.609, p=0.021, respectively).
Discussion: High levels of VD deficiency can be seen in patients with CLD, especially in women. Awareness of VD level in patients with CLD, which can be detected through periodic screenings, may be beneficial
Keywords: Vitamin D, Chronic Liver Disease, Child-Pugh Score, MELD Score
Introduction
Vitamin D (VD) is among the fat-soluble vitamins and a group of sterols with hormones and hormone precursors, since they can also be synthesized endogenously in the appropriate biological medium. Its effect on calcium, phosphorus metabolism and bone mineralization is most important [1,2]. Over recent years, VD deficiency and insufficiency have been found to be correlated with many chronic and common diseases, including cancers, cardiovascular diseases, metabolic syndrome, infectious and autoimmune diseases. VD deficiency is currently considered a global pandemic [3,4].
VD synthesis in humans mainly results from the exposure of the skin to sunlight. For further activation, vitamin D is hydroxylated in liver to create 25-(OH) vitamin D (25-OHD) and transformed into 1,25 (OH)2 VD [1,25(OH)2 D], which is an active metabolite in the kidneys [5]. For this reason, severe VD deficiency can be foreseen in people with chronic liver disease (CLD). Studies have shown that VD deficiency or insufficiency is observed in most of the patients with CLD due to mainly alcohol, secondarily chronic hepatitis C (HCV) [6]. However, there are also studies suggesting that no significant correlation could be found between the VD level and CLD, or if there is a significant correlation, this may only be related to VD deficiency at severe levels [7,8]. Moreover, there are few studies that examine the correlation between cirrhosis and chronic hepatitis stages and VD level in the literature. The primary goal of this study was to document vitamin D deficiency in patients with CLD and find its association with the liver cirrhosis.
Therefore, in this study, it was aimed to compare the diseases leading to cirrhosis and chronic hepatitis, stage of cirrhosis, grade of hepatosteatosis, stage of chronic hepatitis, and activation level with 25-OHD that can be measured in blood.
Material and Methods
This study included 502 patients suffering from CLD, who applied to the gastroenterology department of a tertiary university hospital between August 2016 and February 2017. Primary inclusion criteria were as follows: (1) Patients with CLD; (2) patient’s age ≥18 years; Exclusion criteria were as follows: (1) Patients suffering from other comorbid conditions such as ischemic heart disease, malignity or other chronic conditions (n=48), (2) Patients still receiving VD treatment (n=12), (3) Patients with missing laboratory data (n=102). Consequently, 340 patients complying with these criteria were selected for this study.
The diagnosis history of CLD was based on physical examination, biochemical abnormalities suggestive of CLD, such as impaired liver function tests, ultrasonography (US) signs of CLD, chronic liver parenchymal changes in liver biopsy, medical records suggesting. The diagnosis of alcoholic liver disease was established as more than one positive response in the (CAGE (Cut down, Annoy, Guilt, Eye opener) questionnaire based on the medical history of the patients. In this scoring, item responses in CAGE questions receive 0 points for “no” and 1 point for “yes” answers. A high score is an indicator of alcohol-related problems. A total score of two or more is considered clinically significant. However, there was no single laboratory and imaging study to confirm the diagnosis, we had to use CAGE to diagnose alcoholic liver disease. The diagnosis of chronic hepatitis B (HBC) and HCV was based on serologic markers (HBV surface antigen with ELISA, anti-HCV antibody with third-generation ELISA, anti-HIV antibodies) and liver function tests, including assessment of alanine transaminase (ALT) and aspartate transaminase (AST) enzyme levels, alpha fetoprotein, platelet count, total and direct bilirubin, albumin and prothrombin were tested. Autoimmune hepatitis markers were also evaluated for the diagnosis of autoimmune hepatitis. The diagnosis of non-alcoholic fatty liver disease was based on the typical (US) findings of hepatosteatosis without the history of significant alcohol consumption. Cirrhosis patients without any reason were determined to have cryptogenic cirrhosis.
The demographic profile and history of the patients were examined in full. From the samples taken during the admission of the patients, serum bilirubin, serum albumin, international normalized ratio (INR) and blood platelet counts were recorded. Hepatitis serology and autoimmune markers were examined for the diagnosis of CLD. Blood samples were taken in a dark room for the prediction of 25 (OH) VD, and its levels were checked in the serum using the UV detector and immuChrom brand kit (ImmuChrom GmbH, Tiergartenstr 7, Heppenheim Germany) in high-performance liquid chromatography (HPLC) (LC 20AT, Shimadzu, Japan). VD levels were categorized into four groups as normal (≥30 ng / ml), insufficient (20-29.9 ng / ml), deficient (10-19.9 mg / ml) and severely deficient (<10 ng / ml). According to the Child-Pugh classification, the cirrhosis patients were divided into 3 stages as Group A, B and C. Five parameters were used to calculate these scores. The parameters were ascites, hepatic encephalopathy, serum bilirubin, INR, and serum albumin. Each parameter was scored as 1, 2 or 3. The total score was interpreted as Child-Pugh A if it was 5-6, Child-Pugh B if it was 7-9 and Child-Pugh C if it was 10-15. The model for end- stage liver disease (MELD) score of the patients was calculated with the logarithmic formula of the patients’ values of the INR, bilirubin and creatinine. The fibrosis score and HAI score were calculated according to the presence of fibrosis in CLD patients. Fibrosis was staged with the Ishak scale (ranging from 0=no fibrosis to 6=cirrhosis). Non-alcoholic fatty liver disease (NAFLD) is semi-quantitatively scored between 0-3 in US. The grading is as follows: 0-not available, 1-slight, 2-mild, 3-severe. All patients were informed about the details of the study and written consent was obtained. All procedures were performed in accordance with the ethical standards of the Declaration of Helsinki. Permission was obtained from the Akdeniz University clinical research ethics committee (2017-184).
Statistical analysis
Data analysis was performed using the IBM Statistical Package for Social Sciences-20 (SPSS-20) packaged software. Descriptive statistics were demonstrated as mean ± standard deviation for continuous variables. Chi-square test, Kruskal-Wallis test, and Mann-Whitney-Wilcoxon test were used to compare differences between groups for qualitative or quantitative variables, where appropriate. P <0.05 was accepted as statistical significance.
Results
Three hundred forty patients who met the inclusion criteria were analyzed in the study. Among these patients, 178 (52.4%) were females and 162 (47.6%) were males. The mean age of the patients was 52.8±.13.77 years. When the etiology of CLD patients and cirrhosis patients was examined in terms of CLD, 77 (22.6%) were determined as cirrhosis patients, 74 (21.8%) as NAFLD patients, 117 (34.4%) as HBV patients, 72 (21.2%) as HCV patients. In terms of the etiology of cirrhosis, the most frequently observed were 25 (32.5%) cases of HBV and 20 (26%) cases of HCV. According to the NAFLD staging, 42 patients (56.7%) were at Grade 2, 20 patients (27.1%) at Grade 1, and 12 (16.2%) were at Grade 3. When the Child-Pugh staging of the patients diagnosed with cirrhosis was examined, 58 of them were determined to be 75.3% A, 14 (18.2%) B, and 5 (6.5%) C. According to the fibrosis score, 71 patients (93.43%) of the patients had a score of ≤4, while only 5 (6.57%) had a score of 5 and above. The mean 25-OHD level of the patients was 19.43±9.71. In our study, a statistically significant correlation was found in terms of the CLD and VD classification. Patients with HCV had significantly higher 25-OHD levels than patients with cirrhosis, NAFLD and HBV (P=0.014). When 25-OHD levels were compared according to the NAFLD staging, a significant difference was observed. Grade 1 patients had significantly higher 25-OHD levels compared to Grade 2 and 3 (21.87±11.77, 18.26±9.09, 12.70±5.08; p=0.022). There was no significant difference between gender, etiology and stage of cirrhosis and fibrosis score groups in terms of 25-OHD levels. The correlation between demographic, etiologic characteristics and VD od CLD patients is shown in Table 1.
In our study, the mean fibrosis score of patients with HBV was 2.73±1.21, the mean HAI score was 8.53±2.70, whereas the mean fibrosis score of the patients with HCV was 2.20±1.30, and the mean HAI score was 5.20±2.77. The mean MELD score of the patients was 10.17±4.52. The mean albumin level was 4.37±2.17 g/dL, the total bilirubin level was 0.78±0.75 mg/dL, the direct bilirubin level was 0.25±0.42 and the platelet level was 224.94±91.61 x109/L. There was no significant difference between these parameters in terms of 25-OHD levels. The correlation between the demographic, laboratory results, fibrosis scores and the VD level are shown in Table 2.
Among the 178 female patients, 42 (23.6%) had VD levels at a severely deficient level (<10), 59 (33.1%) had VD levels at a deficient level (between 10-20), 52 (29.2%) had VD levels at an insufficient level (20-30) and 25 (14.0%) had VD levels at a sufficient level (>30). Among the 162 male patients, 18 (11.1%) had VD levels at a severely deficient level (<10), 61 (37.7%) had VD levels at a deficient level (between 10-20), 61 (37.7%) had VD levels at an insufficient level (20-30) and 22 (13.6%) had VD levels at a sufficient level (>30). In our study, a statistically significant correlation was found between gender and VD level classification (p=0.020; Figure 1). Accordingly, the VD level can be said to be lower in female patients with CLD than male patients.
When the patients were grouped according to their 25-OHD levels, 47 patients (13.8%) were found to have it at a sufficient level, 113 (33.2%) at an insufficient level, 120 (35.3%) at a deficient level, and 60 (17.6%) at a severely deficient level. The correlation between demographic, laboratory, and fibrosis scores and 25-OHD level classification of the CLD patients is presented in Table 3. There was no significant correlation between age, fibrosis scores of the patients with HBV and HBC, MELD score and 25-OHD level classification of the laboratory parameters (albumin, total-direct bilirubin, platelet). In multivariate analysis, albumin and direct bilirubin are the independent predictors of the VD level severity (odds ratio [OR]: 0.477, 95% confidence interval [CI]: 0.234-0.720, p<0.001; OR: 0.74, 95% Cl: 0.135-1.609, p=0.021, respectively).
Discussion
VD is a hormone that plays a significant role in the regulation of calcium metabolism and bone health. Recently, it has been shown to have significant effects on the immune system, insulin secretion, cell proliferation and cell differentiation by inhibiting matrix metalloproteinases, and several others [9,10]. Studies have reported that VD levels may be low in patients since those with a chronic disease spend their lives more at home and they are less exposed to sunlight [11]. Other causes of low VD levels in patients with CLD are a decrease in hepatic hydroxylation, an increase in extrahepatic involvement of VD together with adipose tissue, impairment of intestinal absorption and a decrease in its intake via the diet [12,13]. In our study, it was aimed to document the VD deficiency in patients with CLD. The mean 25-OHD level, which was found as 19.43±9.71 ng/mL in our patients, supports this purpose. When we grouped the patients according to their 25-OHD levels, more than half of the patients were found to have deficient or severely deficient levels of 25-OHD.
Obesity and insulin resistance have an inverse correlation with serum VD levels [14,15]. Current data suggest a correlation between VD insufficiency/deficiency and NAFLD, and this correlation can partially be explained with VD sequestration in the adipose tissue. VD sequestration in the body fat leads to a decrease in the hydroxylation possibility. Weight loss after the bariatric surgery had controversial effects on serum 25-OHD levels, and some studies reported increased levels whereas others put forward decreased levels [16-18]. In a study conducted byTargheretal.[19],patientswithNAFLDhadsignificantlylow 25-OHD levels compared to the control groups. Nakano et al. [20] discovered in a rat model that rats receiving phototherapy had higher VD metabolite levels, increased adiponectin levels, decreased transforming growth factor beta, and decreased α-smooth muscle actin than the control groups. Lee et al. [21] conducted a study that provided nutritional recommendations to help with weight loss and examined 82 patients with NAFLD for two months. The authors found out that weight loss increased serum VD levels and developed metabolic parameters in NAFLD [21]. These studies suggest that a low VD might be correlated with a higher suspected NAFLD prevalence and possibly higher disease severity. In our study, similar to the literature, patients with NAFLD were found to have low 25-OHD levels. Besides, in our study, a significant difference was observed when the 25- OHD levels were compared according to the NAFLD staging. Grade 1 patients were found to have significantly higher 25- OHD levels compared to Grade 2 and 3.
In a study by Malham et al. [22], VD deficiency was found to be more frequent in patients with alcoholic cirrhosis compared to patients with primary biliary cholangitis (PBC). These data were contrary to the assumption that VD deficiency might be more frequent in PBC than other cirrhosis etiologies, since the lipid metabolism is impaired. This is an important study showing that there are also other factors for VD metabolism apart from lipid metabolism regarding bile acid. According to our data, no significant correlation could be found between the etiology of cirrhosis and VD level.
The decompensation rate of the cirrhosis patients is about 10% per year. The most important objective parameter used in the determination of the prognosis in patients is the Child- Pugh classification. The Child-Pugh stage is correlated with the prognosis of the patient and is used clinically very often, but it is insufficient to evaluate some patients [23]. For this reason, MELD scores, which are created with the logarithmic transformation of some parameters, are used [24]. In a study, by Paternostro et al. [7], they observed a decrease in the VD level as the Child-Pugh score increased. Again, in the same study, VD deficiency was found to be a prediction factor in cirrhosis mortality. In a study conducted by Bankuti et al. [25], the correlation between MELD and Child-Pugh scores and VD deficiency was found to be significant. Studies indicated that the VD level was lower in the Child C, and this is an expected finding, since the liver is involved in the synthesis and storage in VD metabolism. As a result of these studies, it can be concluded that cirrhosis progresses more aggressively and quickly in the patient groups with low VD levels. In our study, similar to the literature, the lowest VD level was detected in the Child C, and although the MELD score decreased as VD deficiency increased, this was not statistically significant, unlike other studies.
This study has some limitations. The first limitation is the monocenter structure of the study, and that it was conducted on a partially low number of people. Secondly, treatment options may vary among the cases, even though the hospital where the study was carried out had standard clinic treatment protocols, and moreover, drugs and some patient-related factors may affect the VD level. Based on the results of our study, 25-OHD levels were found to be low in patients with CLD, and it seems to be associated with negative clinical outcomes in these patients. In this patient group, it can be thought that VD may provide potential benefit in addition to their treatment. Prospective and extensive studies are needed in order to better understand the mechanism of the correlation between the patients with CLD and VD.
Conclusion
High levels of VD deficiency can be seen in patients with CLD, especially in women. Awareness of VD level in patients with CLD, which can be detected with periodic screenings, may be beneficial. There was no significant correlation between age, fibrosis scores of the patients with HBV and HBC, MELD score and 25-OHD level classification
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Pacifico L, Osborn JF, Bonci E, Pierimarchi P, Chiesa C. Association between vitamin D levels and nonalcoholic fatty liver disease: potential confounding variables. Mini Rev Med Chem. 2019; 19(4):310-32.
2. Hoan NX, Van Tong H, Le Huu Song CGM, Velavan TP. Vitamin D deficiency and hepatitis viruses-associated liver diseases: A literature review. World J Gastroenterol. 2018; 24(4):445-60.
3. Manson JE, Brannon PM, Rosen CJ, Taylor CL. Vitamin D deficiency-is there really a pandemic. N Engl J Med. 2016; 375(19):1817-20.
4. Amrein K, Scherkl M, Hoffmann M, Neuwersch-Sommeregger S, Köstenberger M, Berisha AT, et al. Vitamin D deficiency 2.0: An update on the current status worldwide. Eur J Clin Nutr. 2020; 74(11):1498-513.
5. Jenkinson C. The vitamin D metabolome: An update on analysis and function. Cell biochemistry and function 2019; 37:408-23.
6. Arteh J, Narra S, Nair S. Prevalence of vitamin D deficiency in chronic liver disease. Dig Dis Sci. 2010; 55(9):2624-8.
7. Paternostro R, Wagner D, Reiberger T, Mandorfer M, Schwarzer R, Ferlitsch M, et al. Low 25-OH-vitamin D levels reflect hepatic dysfunction and are associated with mortality in patients with liver cirrhosis. Wien Klin Wochenschr. 2017; 129(1): 8-15.
8. Stokes CS, Krawczyk M, Reichel C, Lammert F, Grunhage F. Vitamin D deficiency is associated with mortality in patients with advanced liver cirrhosis. Eur J Clin Invest. 2014; 44(2):176-83.
9. Czaja AJ, Montano-Loza AJ. Evolving role of vitamin D in immune-mediated disease and its implications in autoimmune hepatitis. Dig Dis Sci. 2019; 64(2):324-44.
10. Bril F, Maximos M, Portillo-Sanchez P, Biernacki D, Lomonaco R, Subbarayan S, et al. Relationship of vitamin D with insulin resistance and disease severity in non-alcoholic steatohepatitis. J Hepatol. 2015; 62:405–11.
11. Holick, MF. The global D-Lemma: the vitamin D deficiency pandemic even in sun-drenched countries. J Clin Sci Res 2018; 7:101.
12. Williams CE, Williams EA, Corfe BM. Vitamin D status in irritable bowel syndrome and the impact of supplementation on symptoms: what do we know and what do we need to know?. Eur J Clin Nutr. 2018; 72:1358-63.
13. Bjelakovic G, Nikolova D, Bjelakovic M, Gluud C. Vitamin D supplementation for chronic liver diseases in adults. Cochrane Database Syst Rev. 2017; 11:CD011564.
14. Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab. 2007; 92:2017–29.
15. Hetta HF, Fahmy EM, Mohamed GA, Gaber MA, Elkady A, Elbadr MM, et al. Does vitamin D status correlate with insulin resistance in obese prediabetic patients? An Egyptian multicenter study. Diabetes Metab Syndr. 2019; 13:2813- 17.
16. DiGiorgi M, Daud A, Inabnet WB, Schrope B, Urban-Skuro M, Restuccia N, et al. Markers of bone and calcium metabolism following gastric bypass and laparoscopic adjustable gastric banding. Obes Surg. 2008; 18(9):1144–8.
17. Bruno C, Fulford AD, Potts JR, McClintock R, Jones RM, Cacucci BM, et al. Serum markers of bone turnover are increased at six and 18 months after Roux- en-Y bariatric surgery: correlation with the reduction in leptin. J Clin Endocrinol Metab. 2010; 95(1): 159–66.
18. Wang HY, She GT, Sun LZ, Lu H, Wang YP, Miao J, et al. Correlation of serum vitamin D, adipose tissue vitamin D receptor, and peroxisome proliferator- activated receptor γ inwomen with gestational diabetes mellitus. Chin Med J 2019; 132:2612.
19. Targher G, Bertolini L, Scala L, Cigolini M, Zenari L, Falezza G, et al. Associations between serum 25- hydroxyvitamin D3 concentrations and liver histology in patients with non- alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis. 2007; 17(7):517–24.
20. Nakano T, Cheng YF, Lai CY, Hsu LW, Chang YC, Deng JY, et al. Impact of artificial sunlight therapy on the progress of non-alcoholic fatty liver disease in rats. J Hepatol. 2011; 55(2):415-25.
21. Lee SM, Jun DW, Cho YK, Jang KS. Vitamin D deficiency in non-alcoholic fatty liver disease: The chicken or the egg? Clin Nutr. 2017; 36(1):191–7.
22. Malham M, Jørgensen SP, Ott P, Agnholt J, Vilstrup H, Borre M, et al. Vitamin D deficiency in cirrhosis relates to liver dysfunction rather than aetiology. World J Gastroenterol. 2011; 17(7):922-5.
23. Yang F, Ren H, Gao Y, Zhu Y, Huang W. The value of severe vitamin D deficiency in predicting the mortality risk of patients with liver cirrhosis: A meta-analysis. Clin Res Hepatol Gastroenterol. 2019; 43(6):722-9.
24. Kim TH, Yun SG, Choi J, Goh HG, Lee HA, Yim SY, et al. Differential Impact of Serum 25-Hydroxyvitamin D3 Levels on the Prognosis of Patients with Liver Cirrhosis According to MELD and Child-Pugh Scores. J Korean Med Sci. 2020; 35: e129.
25. Bankuti R, Wagner D, Reiberger T, Mandorfer M, Schwarzer R, Ferlitsch M, et al. Low 25-OH-vitamin D levels reflect hepatic dysfunction and are associated with mortality in patients with liver cirrhosis. Wien Klin Wochenschr. 2017; 129(1):8-15.
Download attachments: 10.4328:ACAM.20721
Ece Ulukal Karancı, Dinç Dinçer, Yusuf Karancı, Cihan Bedel. The correlation of vitamin D level with the disease etiology and disease level in patients with chronic liver disease. Ann Clin Anal Med 2021;12(11):1253-1257
Citations in Google Scholar: Google Scholar
For which non-muscle invasive bladder cancer is Re-Transurethral Resection more valuable?
Murat Akgül 1, Çağrı Doğan 1, Cenk Murat Yazıcı 1, Mehmet Fatih Şahin 1, Ayşegül İsal Arslan 2, Meltem Öznur 2
1 Department of Urology, 2 Department of Pathology, Tekirdağ Namık Kemal University, Faculty of Medicine, Tekirdağ, Turkey
DOI: 10.4328/ACAM.20722 Received: 2021-06-01 Accepted: 2021-08-02 Published Online: 2021-08-19 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1258-1262
Corresponding Author: Murat Akgül, MD, Tekirdag Namık Kemal University, Urology Department, Süleymanpaşa, 59020, Tekirdağ, Turkey. E-mail: drmuratakgul@gmail.com P: +90 505 339 96 02 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6187-1940
Aim: In this study, we aimed to evaluate the re-transurethral resection (re-TUR) pathologies and to compare the pathology results between transurethral re- section of the bladder (TUR-B) and re-TUR for non-muscle invasive bladder cancer (NMIBC). Additionally, we aimed to assess the factors affecting the re-TUR pathology and try to define more valuable re-TUR patient groups. We also aimed to evaluate the effect of re-TUR on recurrence and progression.
Material and Method: We performed re-TUR in intermediate/high-risk NMIBC patients, 4-6 weeks after the index TUR-B. Both TUR-B and re-TUR pathology characteristics, including tumor stage, grade, size, number, lymphovascular invasion (LVI), carcinoma in situ (CIS), variant pathology, and intermediate/high-risk status were analyzed retrospectively. The recurrence and progression rates were also evaluated according to re-TUR.
Results: A total of 78 patients with NMIBC were included in the study. The index TUR-B pathologies were Ta-Low: 6 (7,7%), Ta-High: 5 (6,4%), T1-Low: 14 (17,9%), T1-High: 53 (67,9%). Re-TUR positivity was n: 40 (51 %), and upstaging/upgrading at re-TUR was n: 11 (14 %) in all groups. Re-TUR positivity was significantly higher in high-risk compared to intermediate-risk NMIBC (p:0,026). Re-TUR positivity was higher in patients with hydronephrosis, CIS, LVI, dif- ferentiation, size (>3 cm), and multiple tumor presence (p<0,05). There was no significant relationship between recurrence/progression and re-TUR (p>0,05).
Discussion: Residual tumor was common after the index TUR-B, and upstaging after re-TUR was very important. Re-TUR is critically important in high-risk NMIBC, presence of hydronephrosis, CIS, LVI, variant pathology, size (>3 cm), and multiple number of tumors.
Keywords: Bladder Cancer, TUR-B, Re-TUR, Pathology
Introduction
Bladder cancer (BC) is 7th most common cancer in males and 13th most mortal cancer in both males and females [1]. Smoking, genetic factors, chemical agents, and many other factors are risk factors for the etiology of BC [2-4]. Approximately 75% of BC is non-muscle invasive bladder cancers (NMIBC) and 25% are muscle-invasive bladder cancers (MIBC) at the time of diagnosis [5]. Differentiating the NMIBC from MIBC is so important because the treatment protocol is totally different. If patients were misdiagnosed with NMIBC instead of MIBC, it would be catastrophic for the treatment strategy. To prevent this situation, re-TUR (re-transurethral resection) is performed 2-6 weeks after the index TUR-B (transurethral resection of the bladder) operation [6]. Complementary TUR-B should be performed if there is no muscle tissue at the pathology specimen or the index TUR-B is incomplete. However, re-TUR is a totally different procedure from complementary TUR-B. Re-TUR is performed after complete TUR-B to prevent misclassification or to resect undetected tumors after the index TUR-B [7].
The European Urology Association (EAU) guidelines defined Ta_ Low grade tumors as low-risk NMIBC category, which means that the risk of progression is low for this group. On the other hand, T1 tumors, high-grade tumors, carcinoma in situ (CIS) pathologies, and all features, including multiple, recurrent, and large (>3 cm) tumors are in the high-risk NMIBC group. The rate of progression in this group is significantly higher than low-risk group [8,9]. Pathologies between these two groups are considered intermediate-risk groups for NMIBC. Re-TUR is proposed to be unnecessary in low-risk NMIBC. On the other hand, in high-risk NMIBC, re-TUR is routinely recommended. However, there is no exact recommendation about the feasibility of re-TUR for intermediate-risk NMIBC [9].
In this study, we aimed to evaluate the re-TUR pathologies and to compare pathology results between TUR-B and re-TUR for intermediate and high-risk NMIBC. In addition, we aimed to evaluate the most valuable patient groups for re-TUR and factors affecting re-TUR pathology. We also aimed to assess the influence of re-TUR on recurrence and progression for intermediate and high-risk NMIBC patients.
Material and Methods
Study population and protocol
With the permission of the local ethics committee, the patients who underwent the re-TUR between 2013-2020 in our clinic were retrospectively included in the study. The patients underwent TUR-B operation under general or spinal anesthesia using a continuous flow 27 French 30° optical resectoscope instrument and a video camera system (Karl StorzTM, Tuttlingen, Germany).
The study included patients who were at intermediate and high-risk classification. Patients with Ta_Low grade pathology who present one of following parameters: multiple, recurrent, or >3 cm tumors, were considered intermediate risk NMIBC. Therefore, re-TUR was also applied for these Ta_Low grade patients who were classified as intermediate-risk group. On the other hand, patients who had low-risk NMIBC, patients with MIBC, patients with in-complete TUR-B, and patients who had no muscle tissue in the pathologic specimen, were excluded from the study.
The re-TUR operation was performed approximately 4-6 weeks after the index TUR-B for intermediate and high-risk NMIBC patients. During re-TUR operation, resection was performed from the same area of the primary tumor including the deep muscle layer, regardless of residual or recurrent tumor. The re-TUR specimen was checked for any residual tumor and for changes in tumor stage or grade. All patients who were not upstaged to MIBC received standard BCG immunotherapy. Both TUR-B and re-TUR pathology characteristics, including tumor stage, tumor grade, tumor size, tumor number, presence of lymphovascular invasion (LVI), presence of CIS, presence of variant pathology, and tumor risk status were analyzed. The Re- TUR positivity (residual tumor) of the patients was evaluated and analyzed according to these variables.
Statistical Analysis
In descriptive statistics of the data, frequency, ratio, mean, and standard deviation values were used. Continuous data were reported as means ± standard deviations (SD) or median values, as appropriate. Statistical analyses were performed using the SPSS 21.0 package program. The chi-square/Fisher’s Exact test in cross tables was used in statistical analyses. P <0.05 was considered statistically significant.
Results
A total of 78 patients with intermediate and high-risk NMIBC were included in the study. The mean age of the patients was 63.9±9.0 (38- 85 years). There were 72 (92,3 %) males and 6 (7,7 %) female patients. The mean follow-up time was 42,1±29,6 (min 10 – max 142) months. According to the EAU risk classification, 6 (7,7 %) patients were in the intermediate- risk group and 72 (92,3 %) patients were in the high-risk group. The index TUR-B and re-TUR pathologies of the patients were shown in Table 1.
Most of the re-TUR positivity was seen in high-grade patients. Three of (60 %) Ta_High grade patients (n:5) had re-TUR positivity and 1 of them upstaged to MIBC. T1_High grade patients (n:53) had the highest number of re-TUR positivity (n:31) (58,5 %). Eight of the T1_High grade patients upstaged to MIBC (15 %). The patients who were upstaged to T2 were treated with ‘radical cystectomy’ or ‘radiotherapy + chemotherapy’. On the other hand, none of the Ta_Low grade patients (n:6) had re-TUR positivity (Table 1).
Re-TUR positivity and up-stage/grade were demonstrated according to tumor stage, tumor grade, and intermediate/ high-risk NMIBC in Table 2. Re-TUR positivity was n: 40 (51 %), and upstaging/upgrading at re-TUR was n: 11 (14 %) in all groups. There was a statistically significant difference between Re-TUR positivity and T stage/grade (p:0.031). In addition, re- TUR positivity was significantly higher in high-risk compared to intermediate-risk NMIBC (p:0.026). Although the recurrence (n:18) and progression (n:11) were higher in the high-risk group (n:72), statistical analysis did not show any significant difference. The odds ratio of re-TUR positivity was 5,57 for recurrence (95% CI: 1,7-18,5) and 6,52 for progression (95% CI: 1,3-33,5).
Re-TUR positivity was significantly higher in patients with hydronephrosis, CIS, LVI, variant pathology, size (3 cm>), and multiple tumor presence (Table 3). In addition, different tumor variants such as sarcomatoid, neuroendocrine, micropapillary, plasmacytoid differentiation had a worse prognosis than others. In our study, there were 4 patients with different variants and 3 of them (75 %) had re-TUR positivity.
Discussion
Bladder cancer is an aggressive tumor with high morbidity and mortality rate. It is really important to choose the best treatment option for BC. The EAU guidelines recommend re-TUR for possible upstaging of NMIBC to invasive cancer and clearance of residual tumor after index TUR-B [9]. It was demonstrated that the presence of residue and tumor upstaging was high in the re-TUR series. Therefore, re-TUR is critically important for complete resection and re-staging after index TUR. Disease management and mortality of the patients may totally change with the help of re-TUR pathology. Although there are different recommendations on the timing of re-TUR, the most accepted time for the procedure is from 2 to 6 weeks after the index TUR-B [10].
The upstaging rates of T1 patients were found to be high in the literature. Fritsche et al analyzed the data of 1136 patients treated with radical cystectomy for the clinical T1 high stage group and demonstrated that nearly half of the pT1 patients (49,7 %) had MIBC pathology [11]. These rates supported the inadequacy of clinical decision-making based on current treatment paradigms and staging tools for T1_high stage tumors. Herr et al also stated that re-TUR revealed up to 43 % upstaging and up to 85 % of re-TUR positivity [12]. The re-TUR positivity was 51 %, and the upstaging rate was 14 % in our study. In recently published reviews, the residual tumor rates were approximately 51-58 % and T2 upstaging rates were 8-11 %, which were similar to our study results [13,14]. Subgroup analysis in the literature documented that re-TUR positivity was 17-67 % in Ta patients and 20-71% in T1 patients. Most residual tumors (36-86 %) were found at the original resection site [14]. In our study, the re-TUR positivity was found 27 % for Ta and 55 % for T1 patients, which was similar to the literature. The necessity of re-TUR was not uniformly accepted. Some authors did not recommend re-TUR due to the low percentage of upstaging, possible complications, and the cost of the surgery [15]. Gaya et al claimed that re-TUR is mandatory only if there was no muscle tissue in the initial resection specimen. They thought that the absence of muscle is the only risk factor for understaging [16]. However, their patient population was low, and the lack of muscle tissue is the reason for complementary TUR-B not for re-TUR. In our study, the re-TUR positivity of T1_high grade patients was 58 %, and the upstaging rate was 15 %. T1 high grade is the highest stage for NMIBC and these patients are at the edge of the border for MIBC. Therefore, it would be proper to undertake re-TUR for these patients. On the other hand, re-TUR is an invasive operation; the pros and cons of the procedure also should be considered. There are also questions about the necessity of re-TUR, especially in the COVID-19 pandemic period. Clinicians need to be more careful to make the surgical indications for their patients in terms of both patient and public health [17]. Any surgical procedure that does not have significant indication must be questioned. Shared decision-making would be the solution for this situation. In this way, clinicians should discuss the decision of re-TUR requirement collectively with patients in light of the evidence- based literature.
The impact of re-TUR on long-term outcomes for T1 patients was discussed in several studies in the literature [16-20]. Divrik et al revealed in their prospective randomized clinical trial that re-TUR had significantly decreased the recurrence and progression rates in patients with newly diagnosed T1 stage [18]. In addition to this Sfakianos et al claimed that the absence of re-TUR before initiating intravesical BCG therapy for high- risk NMIBC significantly increased the risk of recurrence [19]. On the other hand, some studies claimed that the recurrence and progression of T1_high grade patients treated with BCG without re-TUR were not as bad as previously thought [20]. They reported that oncological results and the rate of recurrence/ progression would not be affected after re-TUR for T1_high- grade. Moreover, re-TUR can cause patient distress and higher re-operation-related healthcare costs [21]. In our study, we could not find any statically significant relation between re- TUR and recurrence/progression. It might be due to appropriate intravesical BCG and other curative treatments plus close follow-up.
The presence of hydronephrosis, CIS, LVI, variant pathology, and tumor size >3cm in index TUR are generally associated with a poor prognosis of BC. Bishr et al reported that the adverse prognostic features related to re-TUR were as follows: the number of tumors (>3 lesions), tumor size (>3 cm), hydronephrosis, invasion of the lamina propria (T1), high-grade, concomitant CIS, different tumor variants and T1 stage [22]. We also analyzed these variables in terms of re-TUR positivity. We examined that the re-TUR positivity rate was significantly higher in patients with these variables. When these factors are present, it will no doubt be critically important to perform re- TUR.
Limitations
The retrospective study design was one of our limitations. However, according to our clinical policy, we performed a strict follow-up protocol for BC patients. The strict follow-up protocol of the patients might reduce potential bias associated with the retrospective nature of the study. The relatively low number of patients was another limitation of our study. This might be related to the exclusion criteria from our study population. To standardize our study population, patients with incomplete index TUR-B and patients with no muscle tissue at index TUR-B specimens were excluded from the study. Another limitation of our study was the absence of a control group to whom we did not perform re-TUR. However, the presence of a control group in the high-risk group is an ethical problem for this study design. In our clinical practice, we routinely perform re-TUR in high-risk NMIBC patients.
Conclusion
The residual tumor is common after index TUR-B. The re-TUR is definitely required to detect this residual tumor and to reveal cancer upstaging. It should be noted that re-TUR is critically important in high-risk NMIBC, presence of hydronephrosis, CIS, LVI, variant pathology, size (>3 cm), and multiple tumors. However, collaborative decision-making would be useful in determining the re-TUR indication for selected patients. The effect of re-TUR on recurrence and progression in NMIBC is still a dilemma.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder cancer incidence and mortality: A global overview and recent trends. Eur Urol. 2017; 71(1):96-108. DOI: 10.1016/j.eururo.2016.06.010
2. Miyazaki J, Nishiyama H. Epidemiology of urothelial carcinoma. Int J Urol. 2017; 24(10):730-4. DOI: 10.1111/iju.13376
3. Baykan O, Akgul M, Uren N, Yaman A, Tinay I, Ergul E, et al. The Relationship Between Urothelial Type Bladder Cancer, Plasma 25-Hydroxyvitamin D Levels, and Vitamin D Receptor ApaI BsmI FokI, and TaqI Polymorphisms. Clin Lab. 2019; 65(4). DOI: 10.7754/Clin.Lab.2018.180339
4. Cumberbatch MGK, Jubber I, Black PC, Esperto F, Figueroa JD, Kamat AM, et al. Epidemiology of Bladder Cancer: A Systematic Review and Contemporary Update of Risk Factors in. 2018. Eur Urol. 2018; 74(6):784-95. DOI: 10.1016/j. eururo.2018.09.001
5. Brierley JD, Gospodarowicz M, Wittekind C, editors. TNM classification of malignant tumors. UICC International Union Against Cancer. 8th edition. US: Wiley-Blackwell; 2017.
6. Mostafid AH. Time to re-evaluate and refine re-transurethral resection in bladder cancer? BJU Int. 2016; 118:9-10. DOI: 10.1111/bju.13385
7. Adiyat KT, Katkoori D, Soloway CT, De Los Santos R, Manoharan M, Soloway MS. “Complete transurethral resection of bladder tumor” are the guidelines being followed? Urology. 2010; 75(2):365-7. DOI: 10.1016/j.urology.2009.08.082
8. Witjes JA, Moonen PMJ, Van Der Heijden AG. Review pathology in a diagnostic bladder cancer trial: effect of patient risk category. Urology. 2006; 67:751-5. DOI: 10.1016/j.urology.2005.10.028
9. Babjuk M, Burger M, Compérat E, Gontero P, Mostafid AH, Palou J, et al. EAU guidelines on non-muscle-invasive (Ta, T1 and CIS) bladder cancer, in EAU guidelines. Arnhem, the Netherlands: European Association of Urology guidelines office; 2020.
10. Baltacı S, Bozlu M, Yıldırım A, Gökçe MI, Tinay I, Aslan G, et al. Significance of the interval between first and second transurethral resection on recurrence and progression rates in patients with high-risk non-muscle-invasive bladder cancer treated with maintenance intravesical Bacillus Calmette-Guérin. BJU Int. 116(5):721-6. DOI: 10.1111/bju.13102
11. Fritsche HM, Burger M, Svatek RS, Jeldres C, Karakiewicz PI, Novara G, et al. Characteristics and out- comes of patients with clinical T1 grade 3 urothelial carcinoma treated with radical cystectomy: results from an international cohort. Eur Urol. 2010; 57(2):300-9. DOI: 10.1016/j.eururo.2009.09.024
12. Herr HW, Donat SM. A re-staging transurethral resection predicts early progression of superficial bladder cancer. BJU Int. 2006; 97(6):1194:8. DOI: 10.1111/j.1464-410X.2006.06145.x
13. Naselli A, Hurle R, Paparella S, Buffi NM, Lughezzani G, Lista G, et al. Role of Restaging Transurethral Resection for T1 Non-muscle invasive Bladder Cancer: A Systematic Review and Meta-analysis. Eur Urol Focus. 2018; 4(4):558-67. DOI: 10.1016/j.euf.2016.12.011
14. Cumberbatch MGK, Foerster B, Catto JWF, Kamat AM, Kassouf W, Jubber I, et al. Repeat Transurethral Resection in Non-muscle-invasive Bladder Cancer: A Systematic Review. Eur Urol. 2018; 73(6):925-33. DOI: 10.1016/j. eururo.2018.02.014
15. Palou J, Pisano F, Sylvester R, Joniau S, Serretta V, Larré S, et al. Recurrence, progression and cancer-specific mortality according to stage at re-TUR in T1G3 bladder cancer patients treated with BCG: not as bad as previously thought. World J Urol. 2018; 36(10):1621-7. DOI: 10.1007/s00345-018-2299-2
16. Gaya JM, Palou J, Cosentino M, Patiño D, Rodríguez-Faba O, Villavicencio H. A second transurethral resection could be not necessary in all high-grade non- muscle-invasive bladder tumours. Actas Urológicas Españolas (English). 2012; 539-44. DOI: 10.1016/j.acuro.2012.03.011
17. Ho HC, Hughes T, Bozlu M, Kadıoğlu A, Somani BK. What do urologists need to know: Diagnosis, treatment, and follow-up during COVID-19 pandemic. Turk J Urol. 2020; 46(3):169-77. DOI: 10.5152/tud.2020.20119
18. Divrik RT, Sahin AF, Yildirim U, Altok M, Zorlu F. Impact of routine second transurethral resection on the long-term outcome of patients with newly diagnosed pT1 urothelial carcinoma with respect to recurrence, progression rate, and disease-specific survival: a prospective randomised clinical trial. Eur Urol. 2010; 58(2):185-90. DOI: 10.1016/j.eururo.2010.03.007
19. Sfakianos JP, Kim PH, Hakimi AA, Herr HW. The effect of restaging transurethral resection on recurrence and progression rates in patients with nonmuscle invasive bladder cancer treated with intravesical bacillus Calmette- Guerin. J Urol. 2014; 191(2):341-5. DOI: 10.1016/j.juro.2013.08.022
20. Gontero P, Sylvester R, Pisano F, Joniau S, Oderda M, Serretta V, et al. The impact of re-transurethral resection on clinical outcomes in a large multicentre cohort of patients with T1 high-grade/Grade 3 bladder cancer treated with bacille Calmette-Guérin. BJU Int. 2016; 118:44-52. DOI: 10.1111/bju.13354
21. Calò B, Chirico M, Fortunato F, Sanguedolce F, Carvalho-Dias E, Autorino R, et al. Is repeat transurethral resection always needed in high-grade T1 bladder cancer? Front Oncol. 2019; 9:465. DOI: 10.3389/fonc.2019.00465
22. Bishr M, Lattouf JB, Latour M, Saad F. Tumour stage on re-staging transurethral resection predicts recurrence and progression-free survival of patients with high-risk non-muscle invasive bladder cancer. Can Urol Assoc J. 2014; 8(5-6):306-10. DOI: 10.5489/cuaj.1514
Download attachments: 10.4328:ACAM.20722
Murat Akgül, Çağrı Doğan, Cenk Murat Yazıcı, Mehmet Fatih Şahin, Ayşegül İsal Arslan, Meltem Öznur. Which non-muscle invasive bladder cancer is more valuable for re-transurethral resection? Ann Clin Anal Med 2021;12(11):1258- 1262
Citations in Google Scholar: Google Scholar
Factors affecting mortality in neonatal pneumothorax
Unal Bakal 1, Tugay Tartar 1, Mehmet Sarac 1, Mustafa Aydın 2, Ercan Genc 1, Ahmet Kazez 1
1 Department of Pediatric Surgery, 2 Department of Neonatology, Fırat University, Medical Faculty, Elazig, Turkey
DOI: 10.4328/ACAM.20723 Received: 2021-06-04 Accepted: 2021-08-13 Published Online: 2021-08-29 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1263-1266
Corresponding Author: Ahmet Kazez, Firat University Medical Faculty, Depatment of Pediatric Surgery, 23119, Elazig, Turkey. E-mail: akazez@firat.edu.tr P: +90 532 608 32 32 F: +90 424 238 80 96 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0440-3555
Aim: We aimed to determine the prevalence, demographic and clinical features of neonatal pneumothorax (NP) and to investigate the effects of these variables on mortality.
Material and Methods: The medical records of patients with NP who were treated with tube thoracostomy method between 2004 and 2018 were examined. The causes, clinical features, additional anomalies, demographic data and mortality rate of NP patients were investigated. The results were compared with chi-square, Mann-Whitney U, ROC (receiver operating characteristic) analysis and Binary Logistic Regression test.
Results: NP prevalence in our setting was 1.56%. Sixty-six of the patients were girls and 54 were boys. Mortality was significantly higher in female newborns (p = 0.005), mechanical ventilator support (p = 0.005), cardiopulmonary resuscitation history (p = 0.001), birth-weight of < 1380 g (p = 0.001) and gestational age of < 30 weeks (p = 0.001) and diagnosis time of > 5 days (p = 0.001). Among congenital heart diseases, mortality was also significantly higher in patients with patent foramen ovale + patent ductus arteriosus and atrial septal defect + patent ductus arteriosus (p = 0.032). In addition, mortality was significantly higher in the patients with respiratory distress syndrome (p = 0.01). However, mode of delivery, pneumothorax side, presence of additional anomalies, Apgar score, age of diagnosis did not have significant effect on mortality (p > 0.005).
Discussion: The neonates with ≤ 1400 g birth-weight, 33 weeks gestational age, > 5 postnatal days, history of CPR and mechanical ventilator support, and female gender constitute a sensitive population for development of pneumothorax and therefore should be closely monitored.
Keywords: Respiratory Distress Syndrome, Neonate, Pneumothorax, Risk Factor, Mortality
Introduction
Pneumothorax is the presence of air in the space between the parietal and visceral pleura [1]. Symptomatic pneumothorax occurs in 0.05% of newborns [2]. Although there are many factors in the etiology of neonatal pneumothorax (NP), prematurity and mechanical ventilator therapies are among the most important factors. The prevalence of pneumothorax was reported to be higher in newborns treated by the mechanical ventilator (6-33%) [3]. NP is also increasing in the presence of some pulmonary diseases such as meconium aspiration syndrome (MAS), respiratory distress syndrome (RDS), pneumonia and pulmonary hypoplasia [1-3]. Although NP is one of the treatable respiratory problems, which usually occurs in the first days of life, its mortality rate is still high (30-36%) [4,5]. Though there are many studies in the literature on the etiology and frequency of NP, there are not enough studies on the prediction of mortality by affecting factors in these cases. In this study, it was aimed to determine the prevalence, demographic and clinical features of NP cases and to define the effect of these variables on mortality.
Material and Methods
Study Design
The medical records of 128 patients with pneumothorax who were treated with tube thoracostomy between January 1, 2004 and January 30, 2018 were analyzed retrospectively. Eight out of 128 patients were excluded from the study because of incomplete records. Patients’ gestational age, gender, mode of delivery, birth-weight, Apgar score at 5 minutes, diagnosis time, duration of tube thoracostomy drainage, history of mechanical ventilator treatment, accompanying diseases or anomalies, cardiopulmonary resuscitation history, pneumothorax side (right, left, or bilateral) and outcome were investigated. It is defined that preterm delivery < 37 completed weeks and full- term delivery ≥ completed 37 weeks.
The diagnosis was made clinically and radiologically on the basis of chest X-ray, and for selected cases, using computed tomography (CT). An 8-12 Fr thorax tube was used for the treatment of pneumothorax. All interventions were performed by a pediatric surgeon. Thoracal tubes were placed in the area where the pre-axillary line was connected with the 4th intercostal line. The control chest X-ray was checked for localization of the tube, and then, in the absence of accumulation of air on the radiograph taken, the tube was removed and the incision was closed for 3 days.
This study was conducted with the approval of the Non- Interventional Research Ethical Committee of Fırat University (approval date/no: 22.11.2018 / 19-7). This study was not supported by any foundation.
Statistical Analysis
Data were analyzed using SPSS statistics (SPSS statistics Inc., Chicago, USA) version 22, Java state and MS Excel Software. The Shapiro-Wilk test was used to determine the normal distribution of the data. Descriptive statistics are expressed as the median (minimum, maximum) for variables that do not show a normal distribution in continuous data, and as a percentage [% (n)] for categorical variables. The Mann-Whitney U test was used to compare two groups that were not normally distributed. The Chi-square test was used to analyze categorical data. The ROC (receiver operating characteristic) analysis was performed to determine the cut-off value of the variables to evaluate the mortality. The relevant values are given with area under the curve (AUC) and standard deviation, 95% confidence interval, sensitivity and specificity. The relevant cut-off values are calculated according to the Youden index. Binary logistic regression analysis was used to analyze the effect of independent variables on two outcome- dependent variables. The significance level was determined as p < 0.05.
Results
A total of 8161 newborn infants were admitted to the neonatal intensive care unit (NICU) during the study period. One hundred twenty-eight of them were diagnosed with NP. Eight patients were excluded from the study due to incomplete records. According to this, the NP prevalence was 1.56%. Fifty-four of patients were male (45%) and 66 were female (55%). The mortality rate for all patients was 56.7% (n: 68). The mortality rate was significantly higher in females (n: 45, 68.2%) than in males (n: 23, 42.6%) (p = 0.005).
The characteristics of the patients like birth-weight, gestational age, admission time, age of diagnosis, duration of tube thoracostomy drainage, Apgar score at 5 minutes, and mortality rates in relation to these variables are given in Table 1. In terms of accompanying diseases, the mortality rate was significantly higher in patients with RDS. This disease was followed by MAS, and hypoxic-ischemic encephalopathy (HIE) (p = 0.001). The mortality rates of the patients according to the accompanying diseases are given in Table 2. Mortality was significantly higher in patients required mechanical ventilation (p = 0.001) and in patients underwent cardio-pulmonary resuscitation (CPR) (p = 0.001). The mortality rates of the patients according to mechanical ventilator support, type of delivery, CPR history, side of pneumothorax, and presence of congenital heart disease (CHD) are given in Table 3. Sixty patients (50%) had congenital heart disease. Mortality occurred in 30 (50%) of these patients. Although the mortality rate was not significantly high in patients with CHD (p = 0.197). In 8 (30.8%) of 26 (43.3%) patients with patent foramen ovale (PFO) + patent ductus arteriosus (PDA) and in 7 (58.3%) of 12 (20%) patients with atrial septal defect (ASD) + PDA had developed mortality. Mortality was significantly higher in these patients (p = 0.032).
Five of 10 (16.7%) patients with atrial septal aneurysm (ASA) + PFO + PDA, 2 of 4 patients with ASD, 6 of 6 patients with ventricular septal defect (VSD) + PFO + PDA and 2 of 2 patients with Tetralogy of Fallot developed mortality.
ROC analysis of the patients’ birth weight, gestational age, age of diagnosis and duration of tube thoracostomy drainage was performed to determine the critical threshold for mortality. Binary logistic regression analysis demonstrated that gestational age, duration of tube thoracostomy drainage, and accompanying additional anomalies significantly increased mortality compared to other variables.
Discussion
In this study, the clinical and demographic characteristics of a sensitive population who developed pneumothorax, as well as risk factors that were affecting the mortality were demonstrated. NP is a common and life-threatening condition for NICU patients. NP prevalence is between 0.5-1% in term infants in NICU. In this study, the NP prevalence in NICU was found to be 1.56%. When the demographic data were analyzed, NP was reported to be more common in low birthweight infants [6,7]. It was reported as 13% in infants with a birth weight of 500-750 g and 2% in infants with a birth weight of 1251-1500 g [7].
It has been reported that mortality significantly increases, especially in < 2500 g infants [5-7]. In addition, Verma et al. [8] reported that the risk of bronchopulmonary dysplasia was 13-fold higher in the < 1500 g infants who developed pneumothorax. In our study, the median birthweight of the surviving patients was 2650 g, and the median birth-weight of deceased patients was 1380 g. A birth-weight of 1400 g was found as a critical limit for mortality. According to this, patients with low birthweight should be followed up closely for the development of pneumothorax and mortality in the event of a sudden deterioration.
Studies have shown that mortality is more common in preterm cases with NP [9,10]. On the contrary, another study reported that there was no difference in mortality between preterm and term babies with NP. In our study, the median gestational age was 30 weeks in the dead patients, and a < 33 gestational week was found to be a critical limit for mortality.
It was found that one of the effective parameters of mortality was female sex. However, although NP prevalence was found to be higher in boys, the effect of gender on mortality was not reported some studies [5,7,9,11,12]. In contrast to the previous studies, the present study found that the female gender significantly increased both the prevalence and mortality rate of NP.
Studies have reported that NP occurs more frequently in the first three days of life [9,13]. In our study, the median age of NP development was 4 days. However, it was found to be 5 days in dead patients. The mortality rate was significantly high in patients who developed NP after the postnatal fifth day.
In patients with NP, comorbidities of RDS, MAS, pneumonia, premature rupture of membranes (PROM), oligohydramnios, and perinatal asphyxia are frequently reported. Madansky et al. [14] reported that 41% of newborns diagnosed with MAS developed NP; likewise, Santos Silva et al. [15] reported that 3.8 % of patients with NP had MAS, 30 % had RDS. Apiliogullari et al [9] also reported that 43% of cases with NP had RDS and 17% had RDS and MAS. In studies, it was found that 89% of patients with NP had PROM with a 26% mortality rate, 38% had RDS, 22% had MAS, 14% had transient tachypnea of the newborn, and 12% had pneumonia [5,13]. Likewise, 35.7% of our patients had RDS, 12.5% had MAS, and 8.3% had HIE. Mortality was significantly higher in patients with comorbidities of RDS, MAS, HIE and mortality of these three diseases constituted 73.7% of the overall mortality. In the studies, it was reported that the pneumothorax developed more on the right side (73%), but it did not have any effect on mortality if it developed on the right, left or bilaterally [9,13]. In addition, the type of delivery (vaginal or C/S) and the Apgar score at 5 minutes have been reported to have no effect on the development of NP [5,13,16]. In our study, in accordance with the literature, pneumothorax was seen more on the right side; however, it was determined that the side of pneumothorax, the type of delivery and the Apgar score at 5 minutes did not differ in terms of mortality.
It has been described in the studies that mechanical ventilator treatment is a predisposing factor for NP development [10,17]. Zenciroğlu et al. [10] reported that 90.6% of deceased patients had received mechanical ventilation therapy. In our study, mechanical ventilation therapy was required in 93% of the cases. While there was no mortality in patients without mechanical ventilation requirement, the mortality rate was 60% of those who needed mechanical ventilation. Because this significantly increases mortality in patients with NP, NICU practitioners should develop their mechanical ventilation strategies to reduce pulmonary complications and improve long-term outcomes.
In the study of Apiliogullari et al. [9], 10 out of 30 patients with NP died, while 9 of them had CPR history. In addition, Zenciroğlu et al. [10] reported that CPR had increased mortality in NP cases. In our study, all patients who died had a CPR history, while no mortality was noticed in patients without CPR history. The increased mortality in patients undergoing CPR may be due to respiratory and circulatory collapse.
In a study, the number of CHD was significantly higher (55%) in patients with symptomatic NP compared to the control group [7]. In the present study, 50% of the cases had CHD. The most common CHDs were the associations of PFO + PDA and ASD + PDA. Mortality was significantly higher in these two associations. The addition of circulatory collapse to respiratory collapse in NP patients with CHD might have been effective in increasing the mortality in these patients.
Conclusion
Neonatal pneumothorax is a fatal respiratory disease which is more common in the first days of life with increased prevalence due to accompanying additional diseases and anomalies, and can be treated with early diagnosis. The cases with birth weight ≤ 1400 g, 33 weeks gestational age, > 5 postnatal days, history of CPR and mechanical ventilator support, and female gender constitute a sensitive population for development of pneumothorax and therefore should be closely monitored.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Ibrahim H, Ganesan K, Mann G, Shaw NJ. Causes and management of pulmonary air leak in newborns. Pediatr Child Health. 2009; 19:165-70.
2. Fanaroff AA, Stoll BJ, Wright LL, et al. Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol. 2007; 196: 147. e1-8.
3. Horbar JD, Badger GJ, Carpenter JH, et al. Trends in mortality and morbidity for very low birth weight infants, 1991-1999. Pediatrics. 2002; 110: 143-51.
4. Ramesh Bhat Y, Ramdas V. Predisposing factors, incidence and mortality of pneumothorax in neonates. Minerva Pediatr. 2013; 65: 383-8.
5. Al Matary A, Munshi HH, Abozaid S, Qaraqei M, Wani TA, Abu-Shaheen AK. Characteristics of neonatal pneumothorax in Saudi Arabia: three years’ experience. Oman Med J. 2017; 32: 135-9.
6. Litmanovitz I, Carlo WA. Expectant management of pneumothorax in ventilated neonates. Pediatrics. 2008; 122: 975-9.
7. Katar S, Devecioğlu C, Kervancioğlu M, Ülkü R: Symptomatic spontaneous pneumothorax in term newborns. Pediatr Surg Int. 2006; 22: 755-8.
8. Verma RP, Chandra S, Niwas R, Komaroff E. Risk factors and clinical outcomes of pulmonary interstitial emphysema in extremely low birth weight infants. J Perinatol. 2006; 26: 197-200.
9. Apiliogullari B, Sunam GS, Ceran S, Koc H. Evaluation of neonatal pneumothorax. J Int Med Res. 2011; 39: 2436-40.
10. Zenciroğlu A, Aydemir C, Baş AY, Demirel N. Evaluation of predisposing and prognostic factors in neonatal pneumothorax cases. Tuberk Toraks. 2006; 54: 152-6.
11. O’Keeffe FN, Swischuk LE, Stansberry SD. Mediastinal pseudomass caused by compression of the thymus in neonates with anterior pneumothorax. AJR Am J Roentgenol. 1991; 156: 145-8.
12. Ngerncham S, Kittiratsatcha P, Pacharn P. Risk factors of pneumothorax during the first 24 hours of life. J Med Assoc Thai. 2005; 88: 135-41.
13. Lim HS, Kim H, Jang Y, et al. Characteristics of pneumothorax in a neonatal intensive care unit. J Korean Soc Neonatol. 2011; 18: 257-64.
14. Madansky DL, Lawson EE, Chernick V, Taeusch HW. Pneumothorax and other forms of pulmonary air leak in newborns. Am Rev Respir Dis. 1979; 120: 729-37.
15. Santos Silva Í, Flôr-de-Lima F, Rocha G, Alves I, Guimarăes H. Pneumothorax in neonates: a level III Neonatal Intensive Care Unit experience. J Pediatr Neonat Individual Med. 2016; 5:e050220. doi: 10.7363/050220.
16. Bhatia R, Davis PG, Doyle LW, Wong C, Morley CJ. Identification of pneumothorax in very preterm infants. J Pediatr. 2011; 159: 115-20.
17. Seguier-Lipszyc E, Elizur A, Klin B, Vaiman M, Lotan G. Management of primary spontaneous pneumothorax in children. Clin Pediatr. 2011; 50: 797-802.
Download attachments: 10.4328:ACAM.20723
Unal Bakal, Tugay Tartar, Mehmet Sarac, Mustafa Aydın, Ercan Genc, Ahmet Kazez. Factors affecting mortality in neonatal pneumothorax. Ann Clin Anal Med 2021;12(11):1263-1266
Citations in Google Scholar: Google Scholar
Investigation of Risperidone’s anti-tumor activity on MCF-7 breast cancer cells
Utku Dönem Gündoğdu 1, Funda Karabağ Çoban 2, Recep Liman 2, Mehmet Emrah Şelli 2
1 Department Of Oncology, Private Parkhayat Hospital, Afyonkarahisar, 2 Department Of Molecular Biology And Genetics, Uşak University, Faculty Of Science And Literature, Usak, Turkey
DOI: 10.4328/ACAM.20724 Received: 2021-06-04 Accepted: 2021-08-19 Published Online: 2021-09-07 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1267-1271
Corresponding Author: Utku Dönem Gündoğdu, Department of Oncology, Private Parkhayat Hospital, 03200, Afyonkarahisar, Turkey. E-mail: dr.utkudonem@gmail.com P: +90 506 505 70 76 Corresponding Author ORCID ID: https://orcid.org/0000-002-3881-5075
Aim: Despite increasing survival rates, breast cancer is still the cause of most cancer-related deaths after lung cancer. Risperidone is a nonconventional antipsychotic drug approved by the US Food and Drug Administration in 1994 for clinical use. It is a strong dopamine receptor D2 (DRD2) antagonist. It is also a benzisoxazole derivative with high affinity for serotonin 5-hydroxytryptophan (5-HT2a and 5-HT2c) adrenergic receptors. The stimulation of DRD2 and 5-HT2a receptors has been found to be cancerogenic in several studies. The present study aims to investigate the antitumor activity of risperidone against MCF-7 breast cancer cells, which potentially takes effect via DRD2 and 5-HT2 antagonism.
Material and Methods: A commercially available CCK-8 cell counting assay kit was used to determine the effects of risperidone on MCF-7 proliferation. To evaluate its effect on cell migration, a two-dimensional cell scratch assay was utilized. Finally, single-cell gel electrophoresis (comet assay) was performed to determine DNA damage.
Results: Risperidone significantly suppressed proliferation and migration while triggering DNA damage in MCF-7 cells.
Discussion: The potential of risperidone as an antitumor agent in breast cancer was revealed and encouraging data were obtained for future studies aiming to elucidate its predicted mechanism. This study also provides encouraging preliminary data for the development of new drugs to effectively treat various cancer types via DRD2 and 5-HT2a blockage with minimal side effects.
Keywords: 5-HT2a, Breast Cancer, Dopamine, DRD2, Risperidone, Serotonin
Introduction
Currently, 1 out of every 8 women will fight breast cancer at some point in their lives. Although survival has been improved with newly developed treatment strategies and increased awareness of early diagnosis, treatment success has still not reached the desired level. It is clear that we need new treatment strategies.
Studies have shown that those exposed to chronic stress are predisposed to develop cancer. A relationship between various neurotransmitters and cancer progression has also been identified [1]. Many studies report that dopamine and serotonin stimulate angiogenesis in cancer [2-9].
Exogenous serotonin has been shown to induce tumor cell proliferation in vitro [10]. It also stimulates tumor angiogenesis via the activation of serotonin receptor 1b and serotonin receptor 2b [2-4]. Serotonin 5-hydroxytryptophan (5-HT2b) was detected at higher rates in the endothelial cells in cases of breast cancer, colon cancer, and pancreatic cancer [11]. It has been determined that ritanserin, a 5-HT2a receptor antagonist, induces apoptosis in colon cancer [12]. The serotonin 5-HT2a receptor has been shown to stimulate TGF-β1 expression through ERK proliferative and fibrotic signals in mesangial cells and has also been shown to increase cell proliferation [13]. Anticancer activity through an antagonistic effect on the dopamine DRD2 receptor has also been revealed by some studies [14, 15]. Increased expression of DRD2 in cancer cells was shown by Diakatou et al. [16]. It was reported that the DRD2 antagonist exerts its antitumor activity by partial activation of the cAMP/PKA pathway [17]. Studies in which thioridazine, a well-known antipsychotic agent, was used as a DRD2 antagonist revealed its proapoptotic, antiangiogenic, and antiproliferative activities against various tumor types [18-20]. Risperidone is a selective monoaminergic antagonist with unique properties. It is a benzisoxazole derivative and a second- generation antipsychotic drug with strong affinity to 5-HT2a, 5-HT2c, D2, and H1 α1 adrenergic receptors [21].
Developing new drugs in cancer research is both costly and time- consuming. However, the design of treatment modalities on the basis of drugs that are already in clinical use can potentially shorten the process and lower the research costs. Considering its antagonistic effect on 5-HT2 and DRD2 receptors, we thought that risperidone would be a good candidate for the exploration of potential anticancer activity against a well- established breast cancer cell line, MCF-7.
Material and Methods
This study was approved by the Scientific Projects Coordinatorship of Uşak University with Decision No: 2018/ ARGE002.
Maintenance of cell cultures
The MCF-7 cell line used in our experiments is a cell line originally isolated from the breast tissue of a 69-year-old Caucasian woman (ATCC HTB-22). Cells were grown and passaged in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS, Capricorn Scientific), 2 mM L-glutamine (Capricorn Scientific), 100 IU/mL penicillin (Capricorn Scientific), and 100 μg/mL streptomycin (Capricorn Scientific).
Measurement of cell proliferation
For the proliferation experiment, 10,000 cells were seeded per well in 90 μL of medium in a 96-well plate and incubated for 24 hours at 37 °C. By the end of this period, the cells had reached about 75% confluence. At that point, 10 μL of risperidone (Toronto Research Chemicals) solutions prepared by serial dilution in cRPMI were added to final concentrations of 800, 400, 200, 100, 50, 10, 1, 0.1, and 0.01 μM. Only methanol, the solvent of risperidone, was added as a negative control. As a positive control, cisplatin, a well-known chemotherapeutic agent, was added with a final concentration of 30 μM. Considering the possibility of not having an autocrine cycle with dopamine and serotonin synthesis in the MCF-7 cell line, 50 μM dopamine (Toronto Research Chemicals) and 10 μM serotonin (Toronto Research Chemicals) were added to some wells together with risperidone. Controls of only dopamine and only serotonin were used to investigate the risperidone-independent effects of those compounds. Cells were incubated for 12, 24, 48, and 72 hours after risperidone was added.
The Cell Counting Kit-8 (CCK-8; Sigma Aldrich) was used in accordance with the manufacturer’s instructions to metabolically measure cell viability. The CCK-8 kit determines cell viability by calorimetrically measuring the amount of soluble yellow formazin in the medium formed by the dehydrogenase enzyme as a result of metabolic activity in living cells with a principle similar to MTT assays. Briefly, 10 μL of CCK-8 solution was added to the wells and an amount of formazin proportional to the viable cells was measured at 450 nm after 2 hours of incubation at 37 °C using the Multiskan FC Microplate Photometer (Thermo Fischer Scientific). Experiments were repeated three times, each with technical duplicates, and the values were normalized to negative controls.
Measurement of cell migration
We investigated the effect of risperidone on MCF-7 cell migration at IC50/2 (80 μM), IC50 (160 μM), and IC50×2 (320 μM) concentrations by two-dimensional cell scratch assay. When MCF-7 cells reached 100% confluency on a 24-well plate, the cells were scraped with a P200 pipette tip. The scraped cells were then washed out twice with PBS to obtain a smooth, clean cut at the edges. Images were obtained at 0, 24, 48, and 72 hours from three separate points marked with a pen from each scratch using an inverted microscope (Nikon) with a camera attachment. These images were analyzed using open- source ImageJ software and the healing rate of the cuts was determined by normalizing to 0 hours. The assay was performed in triplicate and only methanol was used as a negative control. Determination of DNA damage
Various concentrations of risperidone (IC50/2, IC50, and IC50×2) were administered to MCF-7 cells in 24-well plates for 72 hours. Cisplatin (5 μM) was used as a positive control. Cells were first washed with PBS and then pelleted by centrifugation at 700×g for 10 minutes at 0 °C. A normal-boiling agarose gel solution (1%, 100 μL) was dripped onto a slide closed with a coverslip. The first layer of agarose was ready after holding at 4 °C for 5 minutes. The cell suspension (25 μL; 106 cells/mm3 in PBS) was mixed with 75 μL of 0.65% low-boiling agarose at 45 °C and then quickly spread over the first agarose layer. This was kept at 4 °C for 5 minutes for the slide to freeze. To lyse the cell and nucleus membrane and release the DNA in the agarose, the slides were placed in an ice-cold lysis buffer (2.5 M NaCl, 100 mM Na2EDTA, 10 mM Tris, 1% sarkosyl, 10% DMSO, and 1% Triton X-100, pH 10) and kept at 4 °C for 1 hour in the dark. Before the electrophoresis process, the slides were held in an alkaline electrophoresis buffer (300 mM NaOH and 1 mM Na2EDTA, pH 13) for 20 minutes at 4 °C in the dark to unwind the double-stranded DNA. Electrophoresis was performed in the same buffer for 20 minutes in the dark at 4 °C at 25 V (0.96 V/ cm; approximately 250 mA). After electrophoresis, slides were washed 3 times for 5 minutes with 5 mL of 0.4 M Tris HCl (pH 7.5) to neutralize the alkaline buffer. Slides were then stained with 60 μL of ethidium bromide (20 μg/mL) and evaluated within 4 hours.
DNA images were captured with a fluorescence microscope (Nikon). The evaluation of images was performed semi- quantitatively in the form of visual scoring. Undamaged cells were detected by the observation of a bright center with less intense edges (no migration). In the event of DNA damage, an irregularly edged appearance is observed depending on the number of fragments or chain breaks and the level of alkaline- labile regions. Depending on the severity of the damage, there is an extension from the center to the edge. This appearance is called stretch or low migration. As the damage increases, the cells will take the form of a comet (high migration). The final stage is apoptosis. DNA images were scored subjectively from 0 (no damage) to 4 (high damage) according to the degree of damage observed. The experiment was performed in triplicate and Duncan’s test was used for statistical analysis.
Results
Antiproliferative effect of risperidone on MCF-7 cells
The CCK-8 proliferation assay revealed that risperidone suppresses proliferation of MCF-7 cells in a dose-dependent manner without being affected by external serotonin and dopamine supplementation (Figure 1), suggesting that an autocrine cycle was most likely established by the synthesis of dopamine and serotonin by the MCF-7 cells. Hence, dopamine and serotonin were not added exogenously in the following migration and genotoxicity experiments.
It was observed that the proliferation of MCF-7 cells was suppressed at rates of up to 100% after 72 hours in the presence of risperidone above 400 μM, which was equivalent to the effect of cisplatin at 30 μM. A similar antiproliferative effect was observed after 48 hours, but not after 12 or 24 hours (data not shown), implying that risperidone requires about 48 hours to show its cytotoxic effects.
The IC50 value of risperidone, or the concentration at which 50% of cells lose their viability, was estimated to be about 160μM based on the trendline equation of the viability curve. The proliferation of MCF-7 cells was not affected by the addition of either dopamine or serotonin in the absence of risperidone, suggesting that the observed antiproliferative effect arose solely from risperidone.
Inhibitory effect of risperidone on MCF-7 cell migration
The effects of risperidone on the migration of MCF-7 cells after 24, 48, and 72 hours at IC50/2, IC50, and IC50×2 doses were examined by cell scratch assay. Risperidone was shown to inhibit migration at increased concentrations (Figure 1). Comparisons made with the control group containing only a solvent (methanol) showed that this difference was significant for IC50×2 (320 μM) at 48 and 72 hours (p=0.023 and p=0.008, respectively) and for IC50 at 72 hours only (p=0.039). The gap closure or migration percentage decreased from about 70% to 30% compared to the control group at the end of 72 hours in the presence of 320 μM risperidone (Figure 2).
Genotoxic effect of risperidone on MCF-7 cells
It was observed that risperidone at IC50/2 (80 μM), IC50 (160 μM), and IC50×2 (320 μM) concentrations caused DNA damage in MCF-7 cells in proportion to the applied concentration (Table 1). The effect was not as high as that of cisplatin at 5 μM (51±3.61 AU), but it was significant at all concentrations (5±1, 9.67±1.53, and 13.67±0.58 AU for increasing concentrations).
Discussion
Studies have shown that chronic stress may increase the predisposition to developing cancer, which is supported by the known associations of various neurotransmitters with cancer progression [1]. Drugs that cause DRD2 antagonism have been shown to have therapeutic effects for various cancer types. Antipsychotic agents that work as DRD2 antagonists, such as sulpiride, dexamethasone, and thioridazine, have been shown to have antitumor activities against breast cancer [23, 24]. In another study, tropisetron and ketanserin were found to suppress proliferation of the MCF-7 breast cancer cell line through 5-HT2a and 5-HT3 antagonism [25]. In the present study, risperidone, which is accepted as an antipsychotic drug in the global literature, was considered for use as an antitumor agent against breast cancer due to its well-known DRD2 and 5-HT2a antagonistic effects. Its antitumor effects on MCF-7 breast cancer cells were demonstrated in vitro by revealing its antiproliferative and genotoxic as well as migration-suppressing properties against MCF-7 cells.
Any contribution to revealing the mechanisms behind the antitumor activity of risperidone is crucial to enable more effective drug design for tumor growth intervention studies. Therefore, in future studies, the mechanistic background of risperidone’s antitumor activity needs to be elucidated by studying its effects on DRD2- and 5-HT2a-associated ERK and Akt signaling pathways. Once we have a better understanding of those underlying mechanisms, any drug currently in use or in the process of being developed that takes effect via DRD2 and/ or 5-HT2a antagonism may be considered for use in potential antitumor applications.
This study has provided encouraging preliminary data for the development of new drugs to effectively treat various cancer types via DRD2 and 5-HT2a blockage with minimal side effects.
Acknowledgment
Study concept and design: Gündoğdu, Karabağ Çoban, Liman, Şelli; Acquisition of data: Gündoğdu, Karabağ Çoban, Liman, Şelli; Analysis and interpretation: Gündoğdu, Şelli; Drafting of the manuscript: Gündoğdu, Karabağ Çoban, Şelli; Critical review of the manuscript: Gündoğdu, Karabağ Çoban, Liman, Şelli; Statistical analysis: Gündoğdu, Karabağ Çoban, Şelli; Administrative, technical, and material support: Gündoğdu, Karabağ Çoban, Liman, Şelli; Study supervision: Gündoğdu, Karabağ Çoban, Şelli. All authors have read and approved the final manuscript.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: This study was funded by the Uşak University Scientific Research Projects (UBAP) Coordinatorship.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Jiang SH, Hu LP, Wang X, Li J, Zhang ZG. Neurotransmitters: emerging targets in cancer. Oncogene. 2020 Jan; 39 [ 3]: 503-15.
2. Qin L, Zhao D, Xu J, Ren X, Terwilliger EF, Parangi S, et al. The vascular permeabilizing factors histamine and serotonin induce angiogenesis through TR3/Nur77 and subsequently truncate it through thrombospondin-1. Blood. 2013 Mar 14; 121 [ 11]: 2154-64.
3. Zamani A, Qu Z. Serotonin activates angiogenic phosphorylation signaling in human endothelial cells. FEBS letters. 2012 Jul 30; 586 [ 16]: 2360-5.
4. Asada M, Ebihara S, Yamanda S, Niu K, Okazaki T, Sora I, et al. Depletion of serotonin and selective inhibition of 2B receptor suppressed tumor angiogenesis by inhibiting endothelial nitricoxide synthase and extracellular signal-regulated kinase 1/2 phosphorylation. Neoplasia. 2009 Apr 1; 11 [ 4]: 408-IN10.
5. Basu S, Nagy JA, Pal S, Vasile E, Eckelhoefer IA, Bliss VS, Manseau EJ, Dasgupta PS, Dvorak HF, Mukhopadhyay D. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nature medicine. 2001 May; 7 [ 5]: 569-74.
6. Sarkar C, Chakroborty D, Chowdhury UR, Dasgupta PS, Basu S. Dopamine increases the efficacy of anticancer drugs in breast and colon cancer preclinical models. Clinical Cancer Research. 2008 Apr 15; 14 [ 8]: 2502-10.
7. Moreno-Smith M, Lee SJ, Lu C, Nagaraja AS, He G, Rupaimoole R, et al. Biologic effects of dopamine on tumor vasculature in ovarian carcinoma.Neoplasia. 2013 May 1; 15 [ 5]: 502-IN15.
8. Borcherding DC, Tong W, Hugo ER, Barnard DF, Fox S, LaSance K, et al. Expression and therapeutic targeting of dopamine receptor-1 [ D1R] in breastcancer. Oncogene. 2016 Jun; 35 [ 24]: 3103-13.
9. Peters MA, Walenkamp AM, Kema IP, Meijer C, de Vries EG, Oosting SF. Dopamine and serotonin regulate tumor behavior by affecting angiogenesis. Drug Resistance Updates. 2014 Oct 1; 17 [ 4-6]: 96-104.
10. Drozdov I, Kidd M, Gustafsson BI, Svejda B, Joseph R, Pfragner R, et al. Auto regulatory effects of serotonin on proliferation and signaling pathways in lung and smallin testine neuro endocrine tumor celllines. Cancer: Interdisciplinary International Journal of theAmerican Cancer Society. 2009 Nov 1; 115 [ 21]: 4934-45.
11. Peters MA, Meijer C, Fehrmann RS, Walenkamp AM, Kema IP, de Vries EG, et al. Serotonin and dopamine receptor expression in solid tumours including rare cancers. Pathology&Oncology Research. 2020 Jul; 26 [ 3]: 1539-47.
12. Ahmadi AA, Shadifar M, Ataee R, Vaillancourt C, Ataee A, Oufkir T, et al. The Serotonin 5-HT2A Receptor Antagonist Ritanserin Induces Apoptosis in Human Colorectal Cancer and Acts in Synergy with Curcumin. Int Biol Biomed J. 2015 Jun 10; 1: 56-65.
13. Grewal JS, Mukhin YV, Garnovskaya MN, Raymond JR, Greene EL. Serotonin 5-HT2A receptor induces TGF-β1 expression in mesangial cells via ERK: proliferative and fibrotic signals. American Journal of Physiology-Renal Physiology. 1999 Jun 1; 276 [ 6]: F922-30.
14. Sachlos E, Risueño RM, Laronde S, Shapovalova Z, Lee JH, Russell J, et al. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell. 2012 Jun 8; 149 [ 6]: 1284-97.
15. Li J, Zhu S, Kozono D, Ng K, Futalan D, Shen Y, et al. Genome-widesh RNA screen revealed integrated mitogenic signaling between dopamine receptor D2 [ DRD2] and epidermal growth factor receptor [ EGFR] in glioblastoma. Oncotarget. 2014 Feb; 5 [ 4]: 882.
16. Diakatou E, Alexandraki KI, Tsolakis AV, Kontogeorgos G, Chatzellis E, Leonti A, et al. Somatostatin and dopamine receptor expression in neuroendocrine neoplasms: correlation of immunohistochemical findings with somatostatin receptor scintigraphy visual scores. Clinical endocrinology. 2015 Sep; 83 [ 3]: 420-8.
17. Jandaghi P, Najafabadi HS, Bauer AS, Papadakis AI, Fassan M, Hall A, et al. Expression of DRD2 is increased in human pancreaticductal adeno carcinoma and inhibitors slow tumor growth in mice. Gastroenterology. 2016 Dec 1; 151 [ 6]: 1218-31.
18. Shen J, Ma B, Zhang X, Sun X, Han J, Wang Y, et al. Thioridazine has potent antitumor effects on lung cancer stem like cells. Oncology letters. 2017 Mar 1; 13 [ 3]: 1563-8.
19. Yong M, Yu T, Tian S, Liu S, Xu J, Hu J, et al. DR2 blocker thioridazine: A promising drug for ovarian cancer therapy Corrigendum in/10.3892/ol. 2020.11285. Oncology letters. 2017 Dec 1; 14 [ 6]: 8171-7.
20. Tegowski M, Fan C, Baldwin AS.Thioridazine inhibits self-renewal in breast cancer cells via DRD2-dependent STAT3 inhibition, but induces a G1 arrest independent of DRD2. Journal of Biological Chemistry. 2018 Oct 12; 293 [ 41]: 15977-90.
21. Janssen PA, Niemegeers CJ, Awouters F, Schellekens KH, Megens AA, Meert TF. Pharmacology of risperidone [ R 64 766], a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties.Journal of pharmacology and experimental therapeutics. 1988 Feb 1; 244 [ 2] :685-93.
22. Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science. 1976 Apr 30; 192 [ 4238]: 481-3.
23. Juan LI, Yi WA, Liu LI, Yuan YU, Yangyi BA.Thioridazine Sensitizes Apoptotic Effect of TRAIL in Human Lung Cancer PC9 Cells Through ER Stress Mediated Up-regulation of DR5. Zhongguo Fei AiZa Zhi. 2017 Feb 1; 20 [ 2].
24. Yao QY, Li J, Chen R, Yao Y, Xue JS, Chen WJ, et al.Preclinical PK/PD model for the combinatorial use of dexamethasone and sulpiride in the treatment of breast cancer. Acta Pharmacologica Sinica. 2019 Dec; 40 [ 12]: 1596-602.
25. Hejazi SH, Ahangari G, Deezagi A. Alternative view point against breast cancer based on selective serotonin receptors 5HTR3A and 5HTR2A antagonists that can mediate apoptosis in MCF-7 cell line. Current drug discovery technologies. 2015 Dec 1; 12 [ 4]: 240-9.
Download attachments: 10.4328:ACAM.20724
Utku Dönem Gündoğdu, FundaKarabağ Çoban, Recep Liman, Mehmet Emrah Şelli. Investigation of Risperidone’s anti-tumor activity on MCF-7 breast cancer cells. Ann Clin Anal Med 2021;12(11):1267-1271
Citations in Google Scholar: Google Scholar
Investigation of factors related to scapula position in young women with neck pain: A control group study
Sebahat Yaprak Cetin 1, Emine Aslan Telci 2, Cemre Karabay 2, Burak Karagöz 2, Rabia Uzun Öz 2, Suat Erel 2
1 Department of Physiotherapy and Rehabilitation, Akdeniz University, Faculty of Health Sciences, Antalya, 2 School of Physiotherapy and Rehabilitation, Pamukkale University, Denizli, Turkey
DOI: 10.4328/ACAM.20725 Received: 2021-06-02 Accepted: 2021-08-19 Published Online: 2021-09-06 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1272-1276
Corresponding Author: Sebahat Yaprak Cetin, Department of Physiotherapy and Rehabilitation, Akdeniz University, Faculty of Health Sciences, Antalya, Turkey. E-mail: fzt.ycetin@gmail.com P: +90 543 633 80 30 Corresponding Author ORCID ID: https://orcid.org/0000-0002-7467-1398
Aim: The primary aim of this study was to examine the relationships between scapular position and pain, muscle shortness, shoulder and neck stabilization, and disability in women with neck pain. We additionally aim to compare scapular position, muscle shortness, shoulder and neck stabilization, and disability in women with and without neck pain.
Material and Methods: The study included 42 women with a mean age of 21.53±2.33 years. For evaluation of scapula position, the protractor method and the Lennie test were used. In the neck pain group, the scapula position was measured by protractor method and right and left muscle shortness was tested for both dominant and non-dominant sides. In addition, a visual analog scale (VAS), the International Physical Activity Questionnaire (IPAQ), pectoralis minor muscle shortness, closed kinetic chain shoulder stabilization, neck flexor muscle endurance test, and the Neck Disability Index were used for evaluation.
Results: According to VAS scores, on a scale of 1-10, the pain level of the group with neck pain was recorded as 4.81±1.15. On the non-dominant side, a statistically negative and low-level significant correlation was found with the right-side shortness test (p<0.001, p<0.04). When the groups were compared, no significant difference was found between the studied parameters (p>0.05).
Discussion: As a result of this study, it was seen that scapular position as measured by protractor method was associated with muscle shortness. In addition, neck pain increases disability. The protractor method may be a viable measurement method for evaluation of scapula position.
Keywords: Neck Pain, Scapula Position, Muscle Strength, Women, Protractor Method
Introduction
Neck pain is a recurrent disorder characterized by periods of remission and exacerbation. Studies have shown that approximately 54% of adults experience neck pain in a 6-month period [1]. It is known that the surrounding structures are also affected by neck pain. These structures include sections such as the shoulder girdle and the scapula. The position of the scapula and the alignment of the neck vertebrae are indicators of changes in joint position and muscle length [2]. It is known that the vertebral edge of the standard position of the scapula is parallel to the spine, positioned approximately 7.5 cm from the midline of the rib cage and located between the 2nd and 7th thoracic vertebrae [2, 3]. Abnormal scapular position is also known to be associated with neck pain [4]. In addition, changes in the activation of the muscles surrounding the shoulder girdle and scapula and changes in the anatomical position of these structures are also observed with neck pain [3]. Studies have shown that restoration of normal scapular kinematics has positive effects on the cervical vertebrae, such as increased range of motion and pain reduction [5-7]. Clinical measurement of the scapular position enables us to examine the effects of disease states on scapular position [8].
There are a limited number of studies in the literature examining scapular position in people with neck pain, but these studies report that scapular position is associated with pain [9-12]. In addition, it has been suggested in the literature that women should be examined in terms of scapular asymmetry and neck pain because they have relatively weak muscles and are more prone to abnormal body alignment [10]. In one study, the position of the scapula and the cervical range of motion were examined in individuals without neck pain [6]. Increasing the number of these studies will provide more objective data with the determination of the changes that can be seen in the scapula in people with neck pain.
The normal scapular position is affected by the dominant side, and the scapula is positioned lower on the side of the dominant hand [3]. In the literature, methods such as radiography, Moire topography, infrared/visual spectrum motion analysis systems, electromagnetic tracking systems, electromechanical digitizers and palpation meters, goniometers, inclinometers, sliding calipers, string measurement, and measuring tapes have been used to measure the position of the scapula [8]. Another common method is the Lennie test. It has been stated that it is important to measure the position of the scapula in the vertical plane in order to measure and evaluate shoulder height asymmetry [8]. O’Shea et al. [13] emphasized that another important aspect of measuring scapular position is measuring the vertical distance between scapular and spinal landmarks. Therefore, they developed the protractor method, which measures the vertical position of the scapula. It was stated that studies to be carried out with this method would reveal the relationship between musculoskeletal pain and the vertical position of the scapula [8]. In the literature, no study has examined the factors affecting the scapula position as measured by the Lennie test and protractor method in individuals with neck pain. The primary aim of the present study was therefore to examine the relationships between scapular position and pain, muscle shortness, shoulder and neck stabilization, and disability in women with neck pain.
We also aimed to compare scapular position, muscle shortness, shoulder and neck stabilization, and disability in women with and without neck pain.
Material and Methods
Participants
This study was conducted with female students with and without neck pain studying in the Department of Physiotherapy and Rehabilitation of a university. All volunteering female students with and without neck pain were planned to be included in the study; therefore, this universe was accepted as the sample group. In the first part of the study, 59 people were included. Seventeen people who did not correctly mark the body diagram were excluded. Blinding was applied, paying attention to the fact that the researchers who would evaluate the data did not know whether the participants were experiencing neck pain or not. Approval was obtained from the ethics committee of the relevant medical faculty for the study (ethics approval number: 2018-10). Individuals who volunteered for the study and signed the voluntary consent form were included.
Since it was planned to include sedentary people in the study, the International Physical Activity Questionnaire (IPAQ) was applied to participants before evaluations were performed. Students determined to be inactive according to the IPAQ were included in the study. Participants with pain in any part of the body other than the neck were excluded from the study if their pain intensity was higher than 3.5 on a scale of 1-10 using a visual analog scale (VAS).
Inclusion criteria were as follows: Members of the determined sample group confirming voluntary consent to participate in the study; neck pain VAS score of 3.5 or above; inactivity according to the IPAQ score.
Exclusion criteria were as follows: Neck pain VAS score below 3.5 in the patient group; pain in any part of the body other than the neck with a VAS score of 3.5 or above; pain in the shoulder area due to conditions such as degeneration, impingement, or thoracic outlet syndrome due to any trauma; history of any surgical operations due to any musculoskeletal problems; any health problems that would prevent individuals from performing the tests; unwillingness to volunteer for the study; inability to complete any of the applied tests; the discovery of any of these exclusion criteria during the course of the application. Procedures
The evaluation protocols to be applied to the individuals by the researchers were explained and the study was begun. Our assessment consisted of four different parts. In the first part, the demographic information of the participants such as age, height, weight, and the presence of neck pain were recorded. In the second part, participants were asked to mark the areas with pain on a body diagram, and a VAS was used for pain severity assessment. In the third part, tests related to the neck and scapula were applied. In the final part, the Neck Disability Index questionnaire was used to evaluate the effects of neck pain on daily life. Evaluations were made by two physiotherapists. Assessments
International Physical Activity Questionnaire (IPAQ): This questionnaire was developed by Craig et al. [14]. The Turkish validity and reliability study of this test was conducted by
Saglam et al. [15]. In the evaluation of all activities, the criterion is that each activity is done for at least 10 minutes at a time. Standard MET values, whereby METs represent multiples of the resting metabolic rate, have been established for these activities. Scores are obtained as “MET minutes/week” by multiplying the minutes, days, and MET values. Physical activity levels are classified as physically inactive at 3000 MET minutes/ week [14].
Evaluation of scapula position: The protractor method and Lennie test were used for scapula evaluation. In the Lennie test, the distance between two points was measured with the help of a special ruler by marking C7 and the top of the medial edge of the scapula while the person was sitting in a neutral position; this value was recorded in centimeters. The C7 method was applied while using a protractor [8]. With this method, the distance between this point and the suture below C7 to the upper point of the medial edge of the scapula was measured and recorded in centimeters.
Evaluation of pectoralis minor muscle shortness: For this evaluation, subjects lay supine with knees in flexion, arms alongside the trunk, and elbows in extension. In this position, the distance between the acromion and the bed was measured and recorded in centimeters. Increases in length indicate the shortness of the minor pectoral muscle [16].
Closed kinetic chain shoulder stabilization test: This test was used for evaluation of shoulder stabilization. Two observers monitored the participants according to the protocol for the administration of the test. While one observer kept time, the other observer counted the repetitions of the participant’s movements, performed on the knees with a modified push-up position. Participants were positioned with a straight back and 91.4 cm of spacing between the hands. Paying attention to the parallelism of the hands, participants lifted one hand for 15 seconds, touching it to the other hand, and then returned to the starting position. The same process was then repeated for the other side. The maximum number of repetitions per 15 seconds was recorded. Rest periods of 45 seconds were given and the test was repeated three times [17].
Neck flexor muscle endurance test: For measurements of the endurance of the cervical muscles, individuals were asked to lie on a bed in supine position with hands next to the body and legs in a 45° hooked position. They were then asked to perform head retraction with their jaws slightly back. While performing this test, the participant placed her thumb and index finger under the most swollen part of the occiput. The participant was then asked to raise the upper part of her head so that the fingers were slightly removed from the occiput. The test was considered finished when the participant stated that she felt too much pain to continue, she reached the end of her endurance, she lost the chin retraction position, she flexed her head until contact between the head and the researcher’s fingers was completely lost, or superficial flexor muscles such as the sternocleidomastoid and anterior scalene muscles contracted. This time was recorded in seconds [18].
Neck Disability Index: This index consists of 10 items including pain intensity, personal care, lifting, reading, headache, concentration, working, driving, sleeping, and recreation. Individuals participating in this study were asked to score themselves between 0 (no disability) and 5 (complete disability) for each category. Total scores range from 0 (no disability) to 50 (complete disability) [19].
Statistical analysis
Data were analyzed with the SPSS 22 package program. Continuous variables were given as mean±standard deviation and categorical variables as numbers and percentages. When parametric test assumptions were met, the independent samples t-test was used to compare differences between independent groups. If parametric test assumptions were not met, the Mann- Whitney U test was used to compare independent groups’ differences. In addition, the relationships between continuous variables were analyzed using Spearman or Pearson correlation analysis, and differences between categorical variables were analyzed using chi-square analysis. Correlation coefficients are interpreted as follows: 0.00-0.19, very weak; 0.20-0.39, weak; 0.40-0.59, moderate; 0.60-0.79, strong; 0.80-1.0, very strong. Significance was accepted at p<0.05.
Results
This study included 42 women with a mean age of 21.53±2.33 years. The demographic data of these women are shown in Table 1. The pain level of the group with neck pain according to VAS scores was recorded as 4.81±1.15 cm.
In the group with neck pain, the scapula position was measured by the protractor method and both right and left shortness tests on the dominant side (p<0.000, p<0.03, Table 2), and a statistically negative and low-to-moderate significant correlation was found between the right and left shortness tests on the non-dominant side (p<0.02, p<0.04, Table 2). When the two groups were compared, no significant difference was found between the evaluated parameters (p>0.05, Table 3).
Discussion
The results of this study revealed a relationship between scapular position and shortness tests in women with neck pain. When women with and without neck pain were compared, no difference was found for any parameters.
The pectoralis minor is adaptively shortened in the kinematic changes of scapular position [16]. As a result of the present study, a relationship was found between scapula position measured by protractor method on the dominant and non- dominant sides and the shortness test of the pectoralis minor muscle. No difference was found between the results of the Lennie test and the measured scapular position for any parameter. This result may show that the protractor method is an effective evaluation tool.
Studies show that the neck flexor muscles are weak in women with neck pain. In addition, decreased cervical endurance is associated with neck pain [20-22]. Cervical flexor and extensor muscle groups also control the position of the scapula [20]. In this study, however, no relationship was found between scapular position and neck flexor endurance.
In the literature, there is no study examining the relationship between scapular position and shoulder stabilization in individuals with neck pain. In the present study, no relationship was found between scapular position and shoulder stabilization. This result may be due to the low number of individuals with neck pain, the inclusion of only one gender, and the young age of the participants.
In another study conducted with female students, no relationship was found between scapular position and the level of neck disability [10]. In the present study, as well, no correlation was found between scapular position and the level of neck disability. This may be due to the low level of disability in the group with neck pain in the present study. Higher levels of disability may change the scapular position.
In studies investigating the relationship between scapular position and pain, no relationship was found in drivers, but scapular position was associated with pain among computer professionals with neck pain [11, 12]. In the present study, there was no relationship between neck pain and scapular position as measured by protractor and by Lennie test. In those previous studies, it was thought that individuals may have neck pain due to work-related abnormal posture, with a resultant relationship between pain and scapula position. In the present study, participants were non-working students with neck pain. Students may not yet suffer from neck pain because they are not working.
In Dahiya and Ravindra’s study conducted with computer professionals, the scapular position of individuals with neck pain was found to be significantly different compared to the scapular position of those without neck pain. That result was thought to be due to individuals with neck pain working with abnormal postures for long periods [12]. In the present study, when women with and without neck pain were compared, no difference was found in terms of scapular position. The individuals included in this study consisted of only students, however. Therefore, similar results were found in both groups as participants had not developed abnormal postures related to their professions.
In the present study, no difference was found between the groups in terms of muscle shortness. In addition, pectoralis minor muscle shortening was more common in the group without neck pain. Shortness of the pectoralis minor muscle may be associated with chest and arm pain [21]. Therefore, there may be no difference between the groups in terms of muscle shortness.
Some studies found a difference in neck flexor endurance when comparing individuals with and without neck pain and concluded that individuals with neck pain had insufficient capacity in terms of endurance [22, 23]. In another study, no difference was found between groups in terms of endurance [24]. These studies reported that the forward position of the head may be related to the weakness of the deep flexor cervical musculature. In the study of Aimi et al. [24], in which the head position was almost the same as that observed in both groups in the study conducted by Oliveira and Silva [22], it was suggested that the head position is different in people with neck pain, so that may affect the results. In the present study, although the mean endurance was better in the control group without neck pain, no significant difference was found between the two groups in terms of endurance. No measurements were conducted regarding head position.
Individuals with work-related neck pain particularly try to modify the scapular position to reduce pain, and this is also associated with shoulder stabilization [25]. Although the control group of the present study had better shoulder stabilization, no significant difference was found between the two groups in terms of shoulder stabilization. This may be due to the fact that the group with neck pain consisted of students who are not yet professionally employed and therefore do not have severe work-related pain.
One limitation of this study was that the sample size was smaller than expected. Another limitation was that we could not measure head position. Further studies can be done by measuring different parameters (head position, etc.) related to scapular position with younger groups including both genders and greater numbers of participants with neck pain. Conclusion
This study was one of the first studies to use the protractor method to evaluate scapular position. As a result, it was seen that the scapular position as measured by the protractor method was associated with muscle shortness. In addition, neck pain increased disability scores. Accordingly, it may be said that the protractor method is a viable measurement method. However, more studies are needed in which both genders are included and more patients are compared with different age groups.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Cote P, Cassidy JD, Carroll LJ, Kristman V. The annual incidence and course of neck pain in the general population: a population-based cohort study. Pain 2004;112:267-273.
2. Sahrmann SA. Diagnosis and Treatment of Movement Impairment Syndromes. Mosby, Inc., St. Louis, 2002; MO.
3. Kendall FP, McCreary EK, Provance PG, Rodgers MM, Romani WA. Muscles: testing and function with posture and pain. Baltimore: Williams & Wilkins; 2005.
4. Cools AM, Struyf F, De Mey K, Maenhout A, Castelein B, Cagnie B. Rehabilitation of scapular dyskinesis: from the office worker to the elite overhead athlete. Br J Sports Med. 2014; 48(8): 692-697
5. Martínez-Merinero P, Lluch E, Gallezo-Izquierdo T, Pecos-Martín D, Plaza- Manzano G, Nuñez-Nagy S, et al.The influence of a depressed scapular alignment on upper limb neural tissue mechanosensitivity and local pressure pain sensitivity. Musculoskelet Sci Pract. 2017; 29:60-65.
6. Andrade GT, Azevedo DC, De Assis Lorentz I, Galo Neto RS, Sadala Do Pinho V, Ferraz Gonçalves RT, et al. Influence of scapular position on cervical rotation range of motion. J Orthop Sports Phys Ther. 2008;38 (11): 668-673
7. Ha SM, Kwon OY, Yi CH, Jeon HS, Lee WH. Effects of passive correction of scapular position on pain, proprioception, and range of motion in neck- painpatients with bilateral scapular downward-rotation syndrome. Man Ther. 2011; 16(6):585-589.
8. Sobush DC, SimoneauGG, Dietz KE, LeveneJA, GrossmanRE, SmithWB. The lennie test for measuring scapular position in healthy young adult females: a reliability and validity study J Orthop Sports Phys Ther. 1996;23(1):39-50.
9. Zabihhosseinian M, Holmes MWR, Howarth S, Ferguson B, Murphy B. Neck muscle fatigue differentially alters scapular and humeral kinematics during humeral elevation in subclinical neck pain participants versus healthy controls. J Electromyog Kinesiol 2017; 33: 73–82.
10. Kim SR, Kang MH, Bahng SY, An JK, Lee JY, Park SY, Kim SG.Correlation among scapular asymmetry, neck pain, and neck disability index (NDI) in young women with slight neck pain. J Phys Ther Sci. 2016; 28:1508–1510.
11. Vincent JD, Yamuna K. Correlation of the Scapular Position and Neck Pain in Auto Drivers. J Physiother Res. 2017; 2(1):2
12. Dahiya J, Ravindra S. Effect of Scapular Position in Computer Professionals with Neck pain. Internation J Sci Res. 2015; 4 (5):2075-2080.
13. O’shea A, Kelly R, Williams S, McKenna L. Reliability and validity of the measurement of scapular position using the protractor method. Phys ther, 2006; 96(4): 502-510.
14. CraigCL, Marshall AL, Sjöström M, Bauman AE, Booth ML, Ainsworth BE, et al. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc. 2003;35(8):1381-95.
15. SaglamM, Arikan H, Savci S, Inal-Ince D, Bosnak-Guclu M, Karabulut E, et al. International physical activity questionnaire: reliability and validity of the Turkish version Percept Mot Skills. 2010;111(1):278-84.
16. Borstad J, Ludewig PM. The Effect of Long Versus Short Pectoralis Minor Resting Length on Scapular Kinematics in Healthy Individuals.J Orthop Sports Phys Ther 2005; 35(4):227-38.
17. Tucci HT, Martins J, de Carvalho Sposito G, Camarini PMF, de Oliveira AS. Closed Kinetic Chain Upper Extremity Stability test (CKCUES test): a reliability study in persons with and without shoulder impingement syndrome. BMC Musculoskelet Disor.2014;15(1), 1.
18. HarrisKD, Heer DM, Roy TJ, Diane M Santos, Julie M Whitman, Robert S Wainner. Reliability of a measurement of neck flexor muscle endurance Phys Ther. 2005 Dec;85(12):1349-55.
19. Aslan E, Karaduman A, Yakut Y, et al. The cultural adaptation, reliability and validity of neck disability index in patients with neck pain: a Turkish version study. Spine. 2008;33:362- 365.
20. Guru K, Praveen N, Selvamani K. Isometric Endurance of Neck Muscles and Muscles for Scapular Positioning in Individuals With and Without Postural Neck Pain. J Allied Health Sci Pract. 2013;01:11(2).
21. SandersRJ, AnnestSJ. Thoracic outlet and pectoralis minor syndromes Semin Vasc Surg. 2014;27(2):86-117.
22. OliveiraAC, SilvaAG. Neck muscle endurance and head posture: A comparison between adolescents with and without neck pain. Man Ther. 2016;22:62-7.
23. PivaSR, Erhard RE, Childs JD, Browder DA. Inter-tester reliability of passive intervertebral and active movements of the cervical spine. Man Ther. 2006;11(4):321-30.
24. Aimi M, Schmit EFD, Ribeiro RP, Candotti CT. Posture, muscle endurance and ROM in individuals with and without neck pain. Fisioter Mov. 2019;32:e003220:1- 10.
25. Lee Y, Shin MMS, Lee W. Effects of shoulder stabilization exercise on pain and function in patients with neck pain. J Phys Ther Sci. 2015; 27(12): 3619–3622.
Download attachments: 10.4328:ACAM.20725
Sebahat Yaprak Cetin, Emine Aslan Telci, Cemre Karabay, Burak Karagöz, Rabia Uzun Öz, Suat Erel. Investigation of factors related to scapula position in young women with neck pain: A control group study. Ann Clin Anal Med 2021;12(11):1272-1276
Citations in Google Scholar: Google Scholar
A retrospective radiological analysis of impacted mandibular third molar teeth and associated pathologies in a group of adult patients
Katibe Tugce Temur 1, Ömer Hatipoğlu 2
1 Department of Oral and maxillofacial radiology, 2 Department of Restorative Dentistry, Niğde Ömer Halisdemir University, Niğde, Turkey
DOI: 10.4328/ACAM.20727 Received: 2021-06-02 Accepted: 2021-08-19 Published Online: 2021-09-04 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1277-1282
Corresponding Author: Katibe Tuğçe Temur, Department of Oral and Maxillofacial Radiology, Faculty of Dentistry, Omer Halisdemir University, Nigde, Turkey. E-mail: tugcetemur@ohu.edu.tr P: +90 553 161 67 32 Corresponding Author ORCID ID: https://orcid.org/0000-0001-9947-5679
Aim: Deciding on prophylactic extraction of impacted mandibular teeth can be challenging for clinicians. This study aimed to categorize the impacted mandibular teeth in a group of adult patients by two different classifications and determine their relationship with pathological changes.
Material and Methods: Preoperative panoramic radiographs of 1165 patients who had previously undergone removal of impacted mandibular third molar teeth were analyzed. Impacted teeth were categorized according to the Winter and Pell & Gregory classifications. Associated pathological findings included caries in adjacent molar teeth, pericoronal radiolucencies, possible cyst or tumor finding, and root resorption in adjacent molar teeth.
Results: The most common pathological findings associated with impacted mandibular third molars were pericoronal radiolucency (33.7%) and caries in second molars (24.9%), respectively. Distal decays were detected in second molars adjacent to those in mesioangular, Class I, and Level A positions. Radiolucency was found most frequently in those in vertical, Class II, and Level B positions (p<0.001). Cyst and tumor were found to be most common in those in horizontal, Class III, and Level C positions (p <0.001). Finally, resorption was found to be most common in impacted teeth in the horizontal and Class II positions (p<0.001).
Discussion:. Considering the positions of impacted mandibular third molars may provide an estimate of the possible future pathologies. This study may provide dentists and oral and maxillofacial surgeons with guiding findings in deciding on prophylactic removal of impacted teeth.
Keywords: Impacted Teeth, Retrospective, Pathological Changes, Mandibular Third Molars
Introduction
Impacted teeth are shown as those that do not erupt in the expected time, which is accepted as an anomaly. Impacted teeth can be located far from the expected eruption area, or they can be completely or partially covered with mucoperiosteum and bone [1, 2]. Mandibular third molar teeth are the most frequently impacted teeth among others [3]. Systemic or local factors may cause permanent teeth to remain impacted. Systemic causes include genetic causes, malnutrition, and specific syndromes, such as Cleidocranial dysostosis, Gardner syndrome, and Gorlin- Sedano syndrome, and Yunis-Varon syndrome, while local causes are characterized by insufficient dental arch, compact bone on the tooth, and sizes and positions of adjacent teeth [4- 6]. Impacted mandibular third molars are often asymptomatic unless irritating factors cause the development of symptoms [7]. However, impacted teeth may cause various odontogenic tumors and complaints such as pain, caries, pericoronitis, resorption of adjacent roots, tooth cysts, and caries in adjacent second molars [8, 9]. Besides, prophylactic removal of non- pathological impacted third molars is widely practiced, but it is controversial [10].
Dental panoramic imaging in dentistry is a two-dimensional imaging method based on the tomographic technique, which has been widely used since the 1950s. Its resolution is poorer and less detailed than intraoral radiographs. However, it is a useful diagnostic method for imaging the teeth, jawbone, and surrounding anatomical structures in the jaw-face region [11]. In the presence of impacted third molars, dental panoramic radiography, also known as orthopantomography (OPG), may help determine eruption patterns, positions, and inclinations of teeth and the relationship with their neighboring teeth and structures [12].
The Pell & Gregory classification, one of the methods used in the classification of impacted teeth, classifies wisdom teeth by the ramus plane and impaction depth [6,13]. Another classification, the Winter classification, considers the inclination of the impacted teeth to the long axis of second molars [6,14].
It was thought that the evaluation of teeth positions and associated pathologies in patients undergoing removal of impacted mandibular teeth would provide valuable contributions to dentists and oral and maxillofacial surgeons while deciding on prophylactic tooth extraction.
Ultimately, it was aimed in the present study to categorize the impacted mandibular teeth by two different classifications and investigate whether there was a relationship between them and pathological changes.
Material and Methods
In this retrospective study, preoperative panoramic radiographs of the patients who underwent tooth extraction were reviewed. The study was granted with the relevant ethical approval by Sütçü İmam University, School of Medicine, Clinical Research Ethics Committee (2019/11). The research was carried out on the radiographs of patients aged 20 years and over with partially or fully impacted mandibular third molas and with a second molar tooth. However, radiographs of wisdom teeth that did not complete root development, patients under 20 years of age, and radiographs with low image quality were excluded from the study.
All radiographs were taken by single personnel on the same device, considering the ideal shooting procedures, with an exposure time of 66 kV, 10.0 mA 16 sec. in the GENDEX GDP- 700 device.
Patient age and gender data were extracted from a digital patient automation. Impacted teeth on panoramic radiographs were categorized using the Winter and Pell & Gregory classifications. In the Pell and Gregory classification, impacted mandibular teeth are grouped into Class I, Class II, and Class III by the mandibular ramus plane and Level A, Level B, and Level C by the occlusal plane, respectively.
On the other hand, according to the Winter classification, impacted teeth are grouped as mesioangular, distoangular, vertical, horizontal, and other (buccal-lingual, transverse) [6, 13, 14].
In this study, radiographic lesions were categorized as follows:
1-Caries in adjacent teeth,
2-Pericoronal radiolucencies (>2.5mm.)
3-Possible cyst or tumor finding
4-Root resorption in adjacent teeth (Figure 1-3).
The radiographs were analyzed by an oral and maxillofacial radiologist with four years of experience.
Statistical Analyses
Jamovi (Version 1.0.4) software was used for all statistical analyses. Descriptive statistics with Pearson’s χ2 test were given to reveal associations between demographic characteristics, classifications of third molars and caries, radiolucency, cyst- tumor, and resorption. The probability level for statistical significance was set at p = 0.05.
Results
In this study, preoperative panoramic radiographs of 1165 (780 females, 385 males) patients with impacted mandibular teeth were reviewed. The age distribution of the patients is given in Table 1. A total of 1165 surgically removed teeth (516 no. 38 and 649 no. 48) were included in the study. In the study, impacted mandibular teeth were found to be most frequent in males and in the 30-40 age group. Besides, there were pathological findings in 67.1% of the removed impacted teeth (Table 1). The most common radiographic finding associated with impacted mandibular third molars was pericoronal radiolucency (33.7%), which was followed by adjacent tooth decay (24.9%) (Table 1). According to the Winter classification, there were 509 teeth (43.6%) in mesioangular position, while only ten teeth (0.85%) were in other positions (Table 1). By the depth of impaction in the Pell & Gregory classification, Level B was determined to be the most frequent impaction in the teeth (41.7%), and according to the relationship with the ramus plane, the teeth were most commonly in Class II position (38.5%) (Table 1).
A significant difference was found between age and cyst- tumor pathological findings (p<0.001). Patients aged 30-40 years had more cyst-tumor findings. The incidence of tooth decay and cyst-tumor in second molars was higher in males (p<0.001). Decays were observed to be most frequent in second molars when impacted teeth were in mesio-angular position (according to the Winter classification) and in Class II and Level A positions (according to the Pell & Gregory classification) (p<0.001). By the Winter classification, radiolucency was found to be most frequent in teeth in the vertical position, followed by the distoangular position. It was the most frequent in teeth in Class II and Level B positions according to the Pell & Gregory classification (p<0.001).
Cyst-tumor was the most prevalent finding in teeth in the horizontal position according to the Winter classification, while it was most common in teeth in Class III and Level C positions according to the Pell & Gregory classification (p<0.001). Horizontal (the Winter Classification) and Class II (the Pell & Gregory classification) were the most prevalent positions where root resorption in second molars was detected (p<0.001). Table 2 displays the comparisons of the pathological findings by demographic characteristics and impaction classifications for impacted mandibular third molars.
Discussion
Considering the age profile of the patients, it was found that the removal operation was done mostly between the ages of 30-40 years and 20-30 years, respectively. Supporting our findings, the relevant literature suggests that the most active years for the dental surgery on impacted third molars are between 20 and 40 years of age [15].
The preoperative radiographs of the patients showed that the most prevalent pathologies were pericoronal radiolucency (33.7%) and distal decays of adjacent second molars (24.9%). In a similar study, Polat et al. determined that the most common pathologies associated with impacted mandibular teeth were caries in adjacent teeth (12%) and distal radiolucency (9.7%) [16]. The high frequency of pathology in this study may be due to the fact that the sample consisted of patients who underwent tooth extraction.
In the study, it was concluded that impacted teeth were most frequent in mesio-angular position (43.6%) and vertical position (26.6%), according to the Winter classification. In a study conducted in Pakistan, Nazir et al. reported that impacted teeth were found mostly in a mesio-angular position followed by vertical, distoangular, and horizontal positions [17]. It was also found in the study by Mollaoğlu et al. that the mesioangular position was the most prevalent position for impacted mandibular third molars [18]. Again, Msagati et al. found 738 (76%) of the impacted mandibular third molars were in the mesioangular position, 87 (8.9%) were in the horizontal position, and 69 (7.1%) were in the distoangular position [4].
On the other hand, according to the impaction depth in the Pell & Gregory classification, the impacted teeth in the radiographs were mostly found in Level B (41.7%) position. By the relationship with the ramus, they appeared most frequently in Class II (38.5%) position. Nazir et al. also detected impacted teeth to be the most frequent in Class II position, followed by Class I and Class III positions. Unlike our study, their study found that the most common positions were Level A, followed by Level B and C, according to the impaction depth position [17]. In the study of Blondeau et al. in Canada, the most prevalent position for mandibular third molars was Level B [19].
Yılmaz et al. reported that the positional changes in impacted teeth might vary depending on genetic differences and the sample selection [9]. The sample of this study consisted of a group of patients who underwent an impacted tooth removal operation.
Much of the thinking in the literature agrees that a period of 2-13 years is required for the development of cysts associated with impacted mandibular third molars [20]. The longer a tooth is impacted, the higher the risk occurs for developing cysts and tumors [21]. In this study, it was determined that cyst-tumor findings were more common in patients aged 30-40 years. It was also detected that cyst-tumor finding was the most prevalent in teeth in the horizontal (the Winter classification), Class III, and Level C (the Pell & Gregory classification) positions (p <0.001). Moreover, males were at more risk of developing cyst-tumor (p <0.001). Similar to our study, Nazir et al. stated that cyst-tumor findings were most frequently associated with
Level C position [17]. Vigneswaran et al. examined the incidence of cyst-tumor associated with impacted mandibular third molars, and reported that the highest pathology incidence was in males. However, compared to our study, the incidence of cyst tumors increased at younger ages. Besides, it was stated that the tooth position associated with cyst-tumor was vertical and distoangular positions, according to the Winter classification [22].
It was discovered that the incidence of distal tooth decays in second molar teeth were most prevalent when impacted teeth were in the mesioangular (the Winter classification), Level A, and Class II (the Pell & Gregory classification) positions (p <0.001). This finding was followed by the Level B and Class-I positions (p <0.001). In a recent study, in parallel with this study, second molar decays were most prevalent when impacted molars were in Level A and Class II positions. This situation was explained by the fact that teeth in Level A and Class II positions are at the highest level in the mouth; therefore, they are exposed to the oral cavity. Also, why second molars are not decayed when impacted teeth in Level C position is because these teeth are not exposed to the oral cavity since they are fully impacted. On the other hand, partial eruption of the tooth in the mesioangular position is reported to cause distal caries in the mandibular second molar due to plaque accumulation [23]. The incidence of radiolucency was significantly higher in those in vertical (the Winter classification), Class II, and Level B (the Pell & Gregory classification) positions (p <0.001). Similar to this study, Polat et al. evaluated pathologies associated with impacted mandibular teeth and reported frequent radiolucency in the distal parts of impacted teeth in the disto-angular and vertical positions [16]. Nazir et al. stated that radiolucency was seen most frequently in teeth in Class II, Level A, and Level B positions. They explained this situation by the fact that the teeth in Level A, Level B, and Class II positions were partially impacted and partially covered with soft tissue [17].
The incidence of root resorption in adjacent teeth significantly differed by Class II and horizontal positions (p <0.001). However, no significant difference was found between root resorption in adjacent teeth and impacted tooth depth in this study. Subedi et al. reported that root resorption in adjacent teeth was most common when impacted teeth were in Level B and Class II positions [24]. Oenning et al. reported that the possibility of root resorption in adjacent teeth increased when impacted mandibular teeth were in mesioangular and horizontal positions [25].
Conclusion: In the study, it was found that impacted mandibular third molars were associated with some pathologies by their positions. Considering the positions of impacted mandibular third molars in preoperative panoramic radiographs may give an idea about the pathologies that may develop in the future. This study may suggest guiding findings for dentists and oral and maxillofacial surgeons in deciding on prophylactic removal of impacted teeth.
Limitations: The radiographs in the study were analyzed by only one expert. The reliability of the further studies will be contributed when conducted with at least two independent and blind observers. On the other hand, the findings were only radiological preliminary diagnoses, not confirmed by any histopathological examination, and the clinical symptoms of the patients were unknown.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Suri L, Gagari E, Vastardis H. Delayed tooth eruption: Pathogenesis, diagnosis, and treatment. A literature reviews. J Am Orthod Dentofacial Orthop. 2004;126:432-45.
2. Oleo-Aracena MF, Arriola-Guillén LE, Rodríguez-Cárdenas YA, Ruíz-Mora GA. Skeletal and dentoalveolar bilateral dimensions in unilateral palatally impacted canine using cone beam computed tomography. Prog Orthod. 2017;18:7.
3. Reddy KVG, Prasad KVV. Prevalence of third molar impactions in urban population of age 22-30 years in South India: An epidemiological study. J Indian Dent Assoc. 2011;5:609-11.
4. Msagati F, Simon EN, Owibingire S. Pattern of occurrence and treatment of impacted teeth at the Muhimbili National Hospital, Dar es Salaam, Tanzania. BMC Oral Health. 2013; 13:37.
5. Goyal S, Verma P, Raj SS. Radiographic Evaluation of the Status of Third Molars in Sriganganagar Population-A Digital Panoramic Study. Malays J Med Sci. 2016;23:103-112.
6. Rezaei F, Imani MM, Khavid A, Nabavi A. Patterns of mandibular third molar impaction in an Iranian subpopulation. Pesqui Bras Odontopediatria Clín Integr. 2020;20: 5411.
7. Venta I, Ylipaavalniemi P, Turtola L. Long-term evaluation of estimates of need for third molar removal. J Oral Maxillofac Surg. 2000;58:288-91.
8. Sarıca İ, Derindağ G, Kurtuldu E, Naralan ME, Çağlayan F. A retrospective study: Do all impacted teeth cause pathology?. Niger J Clin Pract. 2019;22:527-33.
9. Yilmaz S, Adisen MZ, Misirlioglu M, Yorubulut S. Assessment of Third Molar Impaction Patternand Associated Clinical Symptoms in a Central Anatolian Turkish Population. Med Princ Pract. 2016;25:169-175.
10. Song F, Landes DP, Glenny AM, Shedon TA. Prophylactic removal of impacted third molars: An assessment of published reviews. Oral Surg. 1997;182:339-46.
11. Cederhag J, Lundegren N, Alstergren P, Shi XO, Hellen-Halme K. Evaluation of Panoramic Radiographs in Relation to the Mandibular Third Molar and to Incidental Findings in an Adult Population. Eur J Dent. 2020;1-6.
12. Boeddinghaus R, Whyte A. Dental panoramic tomography: an approach for the general radiologist. Australas Radiol. 2006;50:526–33.
13. Pell G, Gregory B. Impacted mandibular third molars: classification and modified techniques for removal. J Dent Digest. 1933;39:330-338.
14. Winter GB. Principles of exodontias as applied to the impacted third molar. Contemporary Oral and Maxillofacial Sugery, 1st ed. St. Louis American medical books 1926. Editors. Peterson LJ, Ellis E, Hupp JR, Tucker MR. Mosby, St Louis, 1993.p.225-260.
15. Gbotolorun MO, Arotiba GT, Ladeinde AL. Assessment of factors associated with surgical difficulty in impacted mandibular third molar extraction. J Oral Maxillofac Surg. 2007;65:1977-83.
16. Polat HB, Özan F, Kara İ, Özdemir H. Prevalence of commonly found pathoses associated with mandibular impacted third molars based on panoramic radiographs in Turkish population. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;105:41-47.
17. Nazir A, Akhtar MU, Ali S. Assessment of Different Patterns of Impacted Mandibular Third Molars and their Associated Pathologies. J Adv Med Dent Scie. 2014;2:14-22.
18. Mollaoglu N, Centiner S, Gungor K. Patterns of third molar impactions in a group of volunteers in Turkey. Clin Oral Investig. 2002;6:109-113.
19. Blondeau F, Nach GD. Extraction of impacted mandibular third molars: postoperative complications and their risk factors. J Can Dent Assoc. 2007;73:325.
20. Montevecchi M, Checchi V, Bonetti GA. Management of a deeply impacted mandibular third molar and associated large dentigerous cyst to avoid nerve injury and improve periodontal healing: case report. J Can Dent Assoc. 2012;78:59.
21. Patil S, Halgatti V, Khandelwal S, Santosh BS, Maheshwari S. Prevalence of cysts and tumors around the retained and unerupted third molars in the Indian population. J Oral Biol Craniofac Res. 2014;4:82-87.
22. Vigneswaran AT, Shilpa S. The incidence of cysts and tumors associated with impacted third molars. J Pharm Bioallied Sci. 2015;7:251-254.
23. Nurmalitasari S, Savitri Y, Astuti ER. Panoramic radiography of mesioangular third mollar impaction with the second distal molar caries of mandibula. EJMCM. 2020;7:866-873.
24. Subedi S, Koirala U, Shrestha B. Indications for removal of impacted mandibular third molars and associated pathologies. JGMC Nepal. 2020;13:134- 9.
25. Oenning AC, Melo SL, Groppo FC, Haiter-Neto F. Mesial inclination of impacted third molars and its propensity to stimulate external root resorption in second molar a cone-beam computed tomographic evaluation. J Oral Maxillofac Surg. 2015;73:379–386.
Download attachments: 10.4328:ACAM.20727
Katibe Tugce Temur, Ömer Hatipoğlu. A retrospective radiological analysis of impacted mandibular third molar teeth and associated pathologies in a group of adult patients. Ann Clin Anal Med 2021;12(11):1277-1282
Citations in Google Scholar: Google Scholar
Evaluation of inflammatory markers in patients diagnosed with polycystic ovary syndrome (PCOS)
Muzeyyen Uyanık 1, Deniz Sımsek 2, Muzaffer Temur 3
1 Department of Obstetrics and Gynecology, Medicana Bursa Hospital, 2 Department of Obstetrics and Gynecology, University of Health Sciences, Bursa Yuksek Ihtisas Research and Training Hospital, 3 Department of Obstetrics and Gynecology, Doruk Bursa Hospital, Bursa, Turkey
DOI: 10.4328/ACAM.20728 Received: 2021-06-02 Accepted: 2021-08-12 Published Online: 2021-08-19 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1283-1287
Corresponding Author: Muzeyyen Uyanik, Medicana Bursa Hospital, Odunluk, İzmir Yolu Cd, No: 41, 16110, Nilüfer, Bursa, Turkey. E-mail: drmuzeyyenuyanik@gmail.com P: +90 (543) 809 08 82 F: +90 850 460 6334 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2032-178X
Aim: Polycystic ovary syndrome is one of the crucial problems of women of reproductive ages. The incidence is about 10%. The etiology has not been enlightened, however metabolic disorders and chronic inflammation were accused issues. The neutrophil lymphocyte ratio (NLR) and the platelet lymphocyte ratio (PLR) have been explored for the chronic inflammatory state of the patients. We aimed to evaluate these novel inflammatory markers in patients with PCOS as diagnostic markers.
Material and Methods: A prospective case-control study was achieved between June 2020- December 2020. Patients who were diagnosed with PCOS using the Rotterdam consensus criteria, and women who were adjusted for BMI and age as a control group were recruited in the study. Patient characteristics, anthropometric variables, hormonal status, metabolic parameters, high-sensitivity c-reactive protein (hs-CRP), and complete blood parameters were evaluated.
Results: The numbers of the participants in the PCOS group and the control group were 92 and 85, respectively. Fasting insulin, and HOMA-IR were higher in the PCOS group. HsCRP, NLR, and PLR were higher in the PCOS group, which were statistically significant. The discriminative value of NLR for the presence of PCOS was evaluated using ROC curve analysis. The area under the ROC curve was 0.643 (95% CI: 0.563-0.724, p<0.001) for NLR. The optimal cut-off value of NLR for detecting PCOS was ≥ 2.26, with a sensitivity of 57.6 % and a specificity of 62 %.
Discussion: Our study revealed that women with PCOS had a higher level of inflammatory markers, and NLR might be a promising diagnostic marker.
Keywords: PCOS, Inflammation, PLR, NLR, Hs-CRP
Introduction
Despite the name, polycystic ovary syndrome (PCOS) seems to be a morphological description, PCOS is a complex metabolic disorder affecting almost 10% of the women in the reproductive period [1]. Diagnostic criteria for ovulatory dysfunction, hyperandrogenism, and ultrasonographic view of the ovaries were constructed [2]. Women with PCOS may suffer from infertility, hirsutism, acne, pregnancy problems as short-term complications, and diabetes mellitus, coronary heart diseases, dyslipidemia, embolism, and psychosocial problems as long-term problems [3, 4]. The adversity of the PCOS is that its pathophysiology has not been precisely clarified. As the accused factors such as insulin resistance and obesity have taken the essential role, nonetheless, women without these features could also experience PCOS [5, 6]. Besides the lack of pathologic pathways, no markers have been found to diagnose or predict PCOS. Inflammation, especially chronic low inflammation, might play a crucial role in the progress of the disease. The fact is that contemporary studies were not able to depict whether the chronic inflammation was a trigger of the disease or a conclusion of the PCOS. However, low chronic inflammation independently of the PCOS could be attributed with diabetes mellitus or cardiovascular disease [7-9]. Adipose tissue is one of the essential sources of that inflammation. Several studies have been achieved to declare that women with PCOS had higher levels of the inflammatory markers like C-reactive protein, tumor necrosis factor-alpha, interleukin 6, adropin, lipocalin-2 or omentin than in healthy women [10, 11]. During the last decade, physicians have intensified their attention on complete blood count (CBC) parameters, which could be beneficial to expose the inflammatory status of the patients. The neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are considered novel markers of the systemic inflammation. These parameters have been investigated as predictor markers of the diseases associated with chronic inflammation. In the present study, we aimed to expose the association between NLR and PLR with PCOS and the feasibility of these parameters as a diagnostic marker of PCOS.
Material and Methods
A prospective case- control study was achieved in Bursa Yuksek Ihtisas Training and Research Hospital, University of Health Sciences, between June 2020 and December 2020 in the obstetrics and gynecology department after approval of the local ethics committee. Women were diagnosed with PCOS based on two of the three 2003 Rotterdam consensus criteria [2]. Patients who were admitted to our outpatient clinic with normal menstrual cycles and without hirsutism or hyperandrogenism were included in the control group, which was constructed by matching age and BMI with the PCOS group. All procedures were in agreement with the Helsinki Declaration. Written informed consent was obtained from all participants. Anthropometric variables (age, weight, height, and waist circumference) were measured by a physician who was blinded to the study.
The biochemical evaluation was determined in terms of fasting glucose, fasting insulin, high-sensitivity C-reactive protein (hs-CRP), total testosterone, and complete blood count. All samples were obtained from the antecubital vein following at least 12 hours of fasting. Serum glucose and hs-CRP were evaluated using an automated analyzer (Abbott Architect C 16000, IL, USA) with its own kits (Abbott Diagnostics, Wiesbaden, Germany). Total-testosterone levels were measured with CMIA (Beckman Coulter Inc., Brea, CA, USA). Serum insulin levels were measured by an automated analyzer (Abbott Architect I2000, IL, USA) using a chemiluminescent microparticle immunoassay (CMIA) with its own kit (Abbott Diagnostics, Wiesbaden, Germany). The Homoeostasis Model Assessment of Insulin Resistance (HOMA-IR), which was used to delineate insulin resistance, was calculated using the formula: fasting insulin [mU/mL] × fasting glucose [mg/dL]/ 405. For CBC evaluation, blood samples were obtained into 2 mL EDTA tubes and analyzed using an automated hematology analyzer (Mindray BC-6800 Plus, Shenzhen, China) within 1 hour to avoid time-dependent ultrastructural morphological changes in platelets.
Women who had a concomitant disease that can affect endocrinologic hormonal status, such as Cushing Syndrome, hyperprolactinemia, thyroid disorders, pregnancy, breastfeeding, diabetes mellitus, ovarian or adrenal tumors were excluded from the study. Additionally, patients who had any diseases that can affect CBC parameters such as anemia (Hb< 10.5 gr/dl), leukocytosis (white Blood Cell >12.000 μl/ml), thrombocytopenia (Plt < 150.000 μl/ml), auto-immune disease, chronic inflammatory disease, or hematological disorders were excluded.
Statistical Analysis:
We calculated the sample size using a G power calculator (version 3.1). When the power is set to 0.90 and the α-level is 0.05, the sample size for each group should be at least 70. The demographic, laboratory characteristics, anthropometric measures, and CBC parameters were evaluated. Statistical analysis was performed using the SPSS 24.0 (SPSS Inc., Chicago, USA) software for Windows. The normality test was achieved using the Shapiro-Wilk test. Due to the normality results, the Pearson chi-square test or Mann-Whitney U test was used as appropriate. Correlation analysis of inflammatory markers and other parameters were evaluated using Pearson’s correlation analysis. The receiver operating characteristic (ROC) curve was used to determine the diagnostic capacity of inflammatory marker levels for PCOS diagnose. The respective areas under the curve, in which sensitivity was plotted as a function of 1-specificity. All reported confidence interval (CI) values were calculated at the 95% level. An overall p-value of less than 0.05 was considered a statistically significant result.
Results
One hundred patients were included in each group. After considering the exclusion criteria, the number of patients was 85 in the PCOS group and 92 in the control. The mean values for age, BMI, and waist circumferences were similar, and the comparison of the groups did not differ significantly (p>0,005). Despite there was no significant difference in fasting glucose, insulin, and HOMA-IR values, however insulin and HOMA-IR were higher in the PCOS group nonetheless, fasting glucose values were similar. This could be considered as women with PCOS have compensated the fasting glucose by secreting more insulin. Evaluation of the inflammatory markers revealed that Hs-CRP, NLR, and PLR were statistically significantly different when comparing the groups. Descriptive characteristics of the patients, including hormonal status, inflammatory markers, and comparison between groups are presented in Table 1.
Correlation analysis between PLR, NLR levels, and other clinical, biological laboratory markers revealed that there was no significant correlation between these parameters even in the control and PCOS groups. Evaluation of the correlation analysis is determined in Table 2.
The discriminative value of NLR for the presence of PCOS was evaluated using ROC curve analysis (Figure 1). The area under the ROC curve (AUC) was 0.643 (95% CI: 0.563-0.724, p<0.001) for NLR. The optimal cut-off value of NLR for detecting PCOS was ≥2.26, with a sensitivity of 57.6 % and a specificity of 62 %.
Discussion
Polycystic ovary syndrome seems like a benign disease, however, consequences like infertility and long-term complications such as diabetes mellitus and cardiovascular diseases, make PCOS a complex disease. In the studies, the prevalence has been stated as about 10%, however, women who suffered infertility experienced PCOS much more and vice versa [1, 12, 13]. Studies have been intensifying on the etiology of PCOS, and the treatment of infertility chiefly. Contemporary studies have exposed crucial progress about the pathway of the disease, though the proper cause of PCOS is still lacking. Obesity and peripheral insulin resistance are among the main risk factors and concomitant issues of PCOS [1, 9, 13]. Nonetheless, there was no significant difference in terms of BMI and waist circumference in the present study. The main factor in this circumstance was the adjusted BMI and age criteria of the study. The androgenic status of the patient is essential and even one of the diagnostic criteria. We investigated total testosterone in our study and it did not differ significantly, however, it is well known that free testosterone levels show the activity of androgenic status. In some studies, total testosterone was also similar to the control group, yet free testosterone was higher in women with PCOS [14, 15]. Impaired serum glucose homeostasis has been one of the most important and possible accused factors in PCOS, even in some types of the disease, its co-occurrence has not been shown [6]. Despite there was no significant difference between groups, women with PCOS had higher insulin resistance, which was examined with HOMA-IR in the present study, and this was similar to the literature [5, 9, 14].
The focused issue in the etiology of PCOS was the inflammatory process. Several markers of inflammation have been investigated and declared as possible diagnostic markers for PCOS [11, 16]. Complete blood count (CBC) parameters have started to be investigated as novel inflammatory markers. It is feasible and cheap, yet the main point was that most of the mediators have been secreted by lymphocyte, neutrophil, and platelets. Thus, the combination of these parameters like NLR and PLR might be precious markers for diseases that progress with chronic inflammation. We have determined that PLR, NLR, and Hs-CRP have been differed statistically different. These markers were investigated in several studies. There was no consensus on the levels of Hs-CRP in PCOS. We have declared an increased level in patients with PCOS. Studies that determined similar levels of Hs-CRP comparing the controls and women with PCOS, have associated this result with obesity because obesity was one of the main sources of chronic inflammation [17, 18]. In the present study, the patients included in the control group were adjusted with the PCOS group in terms of BMI, and it was revealed that Hs-CRP differed significantly more. Most of the participants in the study were not obese. Thus, our study determined that Hs-CRP was higher in patients with PCOS independent of obesity.
Increased levels of neutrophil- to- lymphocyte ratio and platelet- to- lymphocyte ratio were the main findings of this study. That might be a shred of evidence that PCOS is related to chronic inflammation. Contemporary studies declared that NLR, PLR, and platelet-related parameters factors like Mean Platelet Volume (MPV) were related to the diseases based on chronic inflammation like systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, and Behcet’s syndrome. Recent studies have stated that NLR and PLR were significantly higher in patients with PCOS than in healthy controls. Our findings were similar to them [16, 18-20]. As aforementioned, obesity could be a reason for this chronic inflammation, our study and Yilmaz et al have determined that elevated PLR and NLR were independent of high BMI values [18]. Pergialiotis et al achieved a valuable study that investigated the correlation of PLR and NLR with the metabolic and hormonal parameters, and concluded that these inflammatory markers were associated with follicle-stimulating hormone (FSH), free testosterone, androstenedione, sex hormone-binding globulin (SHBG) [20]. Our correlation analysis revealed that there was no relation between the parameters and PLR, NLR, including BMI, age, HOMA-IR, and testosterone levels. Besides this evidence, we aimed to evaluate NLR as a diagnostic marker for PCOS. The ROC analysis revealed that the optimal cut-off value of NLR for detecting PCOS was ≥2.26, with a sensitivity of 57.6 % and a specificity of 62 %. Although the specificity and sensitivity were not appropriate for determining NLR as a diagnostic tool, the present study was one of the unique study that notice a value for diagnosis. Statistical analyses were not able to establish such a value for PLR and HsCrp in the present study.
The strength of the study was in its prospective design and well-organized participants’ inclusion criteria. The limitation of the study was the lack of an elaborate hormonal status examination. The other limitation was the lack of separation of women in the PCOS group into subgroups in terms of different clinical characteristics. That study was one of the studies that expose the chronic inflammatory status and PCOS. The contemporary studies might be raised from that findings. To sum up, the present study has exposed that women with PCOS had a higher level of chronic inflammatory markers such as PLR, NLR, and Hs-CRP. However, the worth of this evidence is still missing, whether the increased inflammatory is related to infertility or long- term complications like coronary heart diseases, or whether these markers could be used for treatment follow-up. Further studies might enlightened these questions in the near future.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Ehrmann DA. Polycystic ovary syndrome. New England Journal of Medicine. 2005;352(12):1223-1236.
2. ESHRE TR, Group A-SPCW. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertility and sterility. 2004;81(1):19-25.
3. Peigné M, Dewailly D, editors. Long term complications of polycystic ovary syndrome (PCOS). Annales d’endocrinologie; 2014: Elsevier.
4. Homburg R. Pregnancy complications in PCOS. Best Practice & Research Clinical Endocrinology & Metabolism. 2006;20(2):281-292.
5. Shroff R, Syrop CH, Davis W, Van Voorhis BJ, Dokras A. Risk of metabolic complications in the new PCOS phenotypes based on the Rotterdam criteria. Fertility and sterility. 2007;88(5):1389-1395.
6. Guastella E, Longo RA, Carmina E. Clinical and endocrine characteristics of the main polycystic ovary syndrome phenotypes. Fertility and sterility. 2010;94(6):2197-2201.
7. Razavi M, Jamilian M, Kashan ZF, Heidar Z, Mohseni M, Ghandi Y, et al. Selenium supplementation and the effects on reproductive outcomes, biomarkers of inflammation, and oxidative stress in women with polycystic ovary syndrome. Hormone and Metabolic Research. 2016;48(03):185-190.
8. Kruszyńska A, Słowińska-Srzednicka J, Jeske W, Zgliczyński W. Proinsulin, adiponectin and hsCRP in reproductive age women with polycystic ovary syndrome (PCOS)—the effect of metformin treatment. Endokrynologia Polska. 2014;65(1):2-10.
9. Shorakae S, Ranasinha S, Abell S, Lambert G, Lambert E, de Courten B, et al. Inter-related effects of insulin resistance, hyperandrogenism, sympathetic dysfunction, and chronic inflammation in PCOS. Clinical Endocrinology. 2018;89(5):628-633.
10. Ojeda-Ojeda M, Murri M, Insenser M, F Escobar-Morreale H. Mediators of low-grade chronic inflammation in polycystic ovary syndrome (PCOS). Current pharmaceutical design. 2013;19(32):5775-5791.
11. Duleba AJ, Dokras A. Is PCOS an inflammatory process? Fertility and sterility. 2012;97(1):7-12.
12. Rong L, Jie Q, Zhang X-w, Wang S-y, Zhang Q-f, Li L, et al. Characteristics of abnormal menstrual cycle and polycystic ovary syndrome in community and hospital populations. Chinese medical journal. 2010;123(16):2185-2189.
13. Melo AS, Ferriani RA, Navarro PA. Treatment of infertility in women with polycystic ovary syndrome: approach to clinical practice. Clinics. 2015;70(11):765- 769.
14. Kume T, Calan M, Yilmaz O, Kocabas G, Yesil P, Temur M, et al. A possible connection between tumor necrosis factor alpha and adropin levels in polycystic ovary syndrome. Journal of Endocrinological Investigation. 2016;39(7):747-754.
15. Arpaci H. Major determinants of circulating myostatin in polycystic ovary syndrome. Experimental and Therapeutic Medicine. 2019;17(2):1383-1389.
16. Kurt RK, Okyay AG, Hakverdi AU, Gungoren A, Dolapcioglu KS, Karateke A, et al. The effect of obesity on inflammatory markers in patients with PCOS: a BMI-matched case–control study. Archives of gynecology and obstetrics. 2014;290(2):315-319.
17. Kahal H, Aburima A, Ungvari T, Rigby A, Dawson A, Coady A-M, et al. Polycystic ovary syndrome has no independent effect on vascular, inflammatory or thrombotic markers when matched for obesity. Clinical endocrinology. 2013;79(2):252-258.
18. Yilmaz M, Duran C, Basaran M. The mean platelet volume and neutrophil to lymphocyte ratio in obese and lean patients with polycystic ovary syndrome. Journal of Endocrinological Investigation. 2016;39(1):45-53.
19. Çakıroğlu Y, Vural F, Vural B. The inflammatory markers in polycystic ovary syndrome: association with obesity and IVF outcomes. Journal of Endocrinological Investigation. 2016;39(8):899-907.
20. Pergialiotis V, Trakakis E, Parthenis C, Hatziagelaki E, Chrelias C, Thomakos N, et al. Correlation of platelet to lymphocyte and neutrophil to lymphocyte ratio with hormonal and metabolic parameters in women with PCOS. Hormone molecular biology and clinical investigation. 2018;34(3).
Download attachments: 10.4328:ACAM.20728
Muzeyyen Uyanık, Deniz Sımsek, Muzaffer Temur. Evaluation of inflammatory markers in patients diagnosed with polycystic ovary syndrome (PCOS). Ann Clin Anal Med 2021;12(11):1283-1287
Citations in Google Scholar: Google Scholar
Evaluation of the management of acute cholecystitis in very elderly patients
Guner Cakmak, Emre Gonullu, Kayhan Ozdemir, Enes Bas, Ugur Dulger
Department of General Surgery, Sakarya Training and Research Hospital, Sakarya, Turkey
DOI: 10.4328/ACAM.20859 Received: 2021-09-17 Accepted: 2021-10-27 Published Online: 2021-10-31 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1288-1292
Corresponding Author: Guner Cakmak, Sağlık Caddesi, No: 195, Adapazarı, Sakarya, Turkey. E-mail: mdgunercakmak@gmail.com P: +90 264 888 40 00 F: +90 264 275 91 92 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4040-4635
Aim: The objective of this study was to evaluate the characteristics and management of AC in very elderly (>80 years old) patients.
Material and Methods: A total of 345 patients aged 20-89 years, who presented to the emergency department of our hospital and were diagnosed with acute cholecystitis were included in the study. The patients were divided into two groups as < 80 years old and ≥80 years old, and the studied parameters were compared between these two groups. Patients’ demographic data such as age and gender, comorbidities, duration of hospitalization, treatment method, type of cholecystectomy and mortality status were recorded.
Results: The majority of the patients in the ≥ 80 yo group had comorbidities, including hypertension by 39.3%, coronary artery disease by 19.2%, diabetes mellitus by 18.5% and cerebrovascular disease by 14.5%. The rate of the patients undergoing urgent surgery was significantly higher in the ≥ 80 yo group (p=0.02). The rate of the patients undergoing elective surgery was significantly higher in the < 80 yo group (p<0.01). The duration of hospitalization was significantly longer in the patients ≥ 80 yo. No mortality was observed in the <80 yo group, while eight (4.6%) patients in the ≥ 80 yo group died.
Discussion: The management of acute and chronic diseases in very old patients has become important due to the globally increasing elderly population and the corresponding increase in life expectancy. According to our findings, comorbidities, biochemical parameters, hospitalization and mortality were significantly higher in the patients ≥80 yo compared to those <80 yo.
Keywords: Acute Cholecystitis, Cholecystectomy, Comorbidity, Surgical Treatment, Very Elderly
Introduction
Acute cholecystitis (AC), namely gallbladder inflammation, is a severe condition associated with symptoms of upper abdominal pain, fever, and leukocytosis, and sometimes accompanied by gallstones with a mortality rate of about 3% [1, 2]. However, this rate increases with age. Eventually, 20-40% of asymptomatic patients with gallstones develop AC [3]. AC is an important indication for hospitalizations and is associated with an increased economic burden on the health care system [4]. AC leads to complications that require urgent surgery such as gallbladder perforation, gangrene, emphysematous cholecystitis and empyema. Risk factors for these complications include advanced age, male gender, and associated diseases such as diabetes mellitus (DM), fever and significant leukocytosis [5]. In the elderly, AC is one of the most serious conditions requiring surgical treatment. The elderly are especially at high risk for AC, and 6% of elderly patients develop severeAC[6].Theprevalenceofgallstones,whichisthemost common cause of AC, is 15% and 24% in men and women aged 70 years, while these rates increase to 24% and 25% in men and women aged 90 years, respectively [7].
Early laparoscopic cholecystectomy is the treatment of choice for AC in young patients [8, 9]. Whereas in elderly AC patients, characteristics of the disease, comorbidities, and poor functional status make surgical management of AC challenging in this population. The management of AC is contradictory due to the reduced physiological reserve in these patients, and it can cause serious morbidity and mortality [10]. According to the 2017 United Nations report, it is estimated that the population over the age of 60 will increase from 25% to 35% in Europe and from 12.5% to 25% in Asia by 2050 (available at: https://esa. un.org/unpd/wpp/ Publications/Files/WPP2017_KeyFindings. pdf). Global increase in life expectancy makes the management of AC in very elderly patients an important issue to investigate [11].
Although there are studies on the management of AC in elderly patients, the literature data on this subject in very elderly patients are limited. Therefore, the objective of this study was to evaluate the characteristics and management of AC in very elderly (>80 years old) patients.
Material and Methods
Study Design
A total of 345 patients aged 20-89 years, who were admitted to the emergency department of our hospital, and were diagnosed with acute cholecystitis and treated between 2010 and 2020 were retrospectively analyzed. The patients were divided into two groups as < 80 years old and ≥80 years old, and the studied parameters were compared between these two groups. Patients referred from the emergency department to our clinic with the presumed diagnosis of AC were included in the study. Patients with recurrent AC, concurrent acute cholangitis, pancreatitis, gastrointestinal cancer, or biliary tract diseases were excluded from the study.
Data Collection
Patients’ demographic data such as age and gender, comorbidities, biochemical parameters including WBC, NEU (%), NEU, urea and creatinine, duration of hospitalization, treatment method, percutaneous drainage status, type of cholecystectomy and mortality status were obtained from the information system of our hospital and recorded.
Management of the Patients
Blood tests and abdominal sonography were performed to the patients who presented to the emergency department of our hospital with signs and symptoms compatible with AC. When necessary, abdominal CT or MR cholangiography was performed. The diagnosis of AC was based on clinical and laboratory findings, and ultrasonography criteria. In the clinical evaluation, Murphy’s sign, acute upper abdominal pain, right hypochondrial tenderness and fever >37.5oC were investigated. Among the laboratory parameters, the white blood cell (WBC) count of 10×109/L was diagnostic. Ultrasonographic findings included a >5 mm thickened and edematous bladder, distended bladder, pericholecystic fluid and gallstones [12].
Follow-up of the patients was terminated after cholecystectomy in patients who underwent surgery (urgent or elective). Complications and mortality within 30 days were taken into account in all patients. Cholecystectomy operations were categorized as urgent (within 48 hours of hospitalization) or elective (after 48 hours).
All patients were first evaluated in the emergency department and analgesia, proton pump inhibitor, antimicrobial therapy, IV fluid therapy were initiated. The patients were then referred to the wards to receive medical or surgical treatment according to the clinical judgment and the patient’s request. Although laparoscopic cholecystectomy was the standard treatment method, some patients continued antibiotherapy without surgery due to several reasons such as advanced age, comorbidity, concurrent anticoagulant therapy, >7 days symptom duration or patient’s refusal to have surgery. All surgeries were performed by the same team.
Ethical Considerations
Before the beginning of the study, necessary ethical approval was received from the local ethics committee of our hospital. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki.
Statistical Analysis
Data obtained in the study were statistically analyzed using SPSS v. 23 (SPSS, Statistical Package for Social Sciences) for Windows statistical software. The normality of the data was evaluated with the Kolmogorov-Smirnov test. Continuous variables were expressed as means, and categorical variables as frequency and percentage. Mann-Whitney U and Chi-square tests were used in the comparison of the quantitative and qualitative variables between the groups, respectively. The p-values <0.05 were considered statistically significant.
Results
A total of 345 patients aged 20-80 years were included in the study. Patients were divided into two groups as < 80 yo (n:172) and ≥ 80 yo (n:173). Data of the patients were obtained from the information system of the hospital and compared between the two groups. The mean age was 48.49 years in the <80 yogroupand85.73yearsinthe≥80yogroup.Inthe<80yo group, 61.6% (n:106) of the patients were female and 38.4% (n:66) were male, while in the ≥ 80 yo group, 60.7% (n:105) of the patients were female and 39.3% (n:68) were male. No significant difference was found between the groups in terms of gender.
When comorbidities of the patients were examined, the most common comorbidity was hypertension (HT) in both groups. The majority of the patients in the ≥ 80 yo group had comorbidities, including HT by 39.3%, coronary artery disease (CAD) by 19.2%, DM by 18.5% and cerebrovascular disease (CVD) by 14.5%.
In biochemical tests, WBC, NEU (%), NEU, urea and creatinine values were statistically significantly higher in the ≥ 80 yo group compared to <80 yo group (for all p<0.05) (Table 1). The distribution of WBC, NEU(%), NEU and urea values according to the groups is shown in Figure 1.
When treatment methods were examined, urgent surgeries were performed in 8.7% (n:15) of the patients <80 yo and 20.8% (n:36) of the patients ≥ 80 yo. The difference between the two groups was statistically significant, and the rate of the patients undergoing urgent surgery was significantly higher in the ≥ 80 yo group (p=0.02). Elective surgery was performed in 91.3% (n:157) of the patients <80 yo and 13.3% (n:23) of the patients ≥ 80 yo. Accordingly, the rate of the patients undergoing elective surgery was significantly higher in the patients <80 yo (p<0.01). When the type of the cholecystectomy was examined, while laparoscopic surgery was performed in 93.62% (n:161) and open surgery in 6.4% (n:11) of the patients <80 yo, 20.2% (n:35) of the patients ≥ 80 yo underwent laparoscopic surgery and 13.9% (n:11). n:24) open surgery.
Medical therapy alone was not applied in the <80 yo group, while 65.9% (n:114) of the patients in the ≥ 80 yo group underwent medical therapy (p<0.01). 91.3% (n:157) of patients <80 yo and 13.3% (n:23) of patients ≥ 80 yo had medical treatment + surgery. Accordingly, the rate of the patients who underwent medical therapy plus surgery was statistically significantly higher in the patients < 80 yo (p<0.01). While percutaneous drainage was not applied in any patient in the <80 yo group, 15% (n:26) of the patients ≥ 80 yo underwent percutaneous drainage.
It was determined that in the patients <80 yo, the duration of hospitalization differed significantly according to the type of cholecystectomy performed. The duration of hospitalization was significantly longer in the patients who underwent open surgery compared to laparoscopic cholecystectomy (p<0.01). In addition, in the patients ≥ 80 yo, the duration of hospitalization was significantly longer in the patients who underwent open cholecystectomy compared to those administered medical therapy alone (p<0.01). The distribution of the duration of hospitalization according to the groups is presented in Figure 2. While only one (0.6%) patient in the <80 yo group was admitted to the intensive care unit (ICU), 41 (23.7%) patients in the ≥ 80 yo group were admitted to the ICU. No mortality was observed in the <80 yo group, while eight (4.6%) patients in the ≥ 80 yo group died.
Discussion
AC is an increasing problem in the elderly with the global increase in the elderly population. Although with the advances in medicine, the general health status of elderly patients has improved, the presence of comorbidities in this age group complicates the management of AC. Currently, there is no consensus on the management of AC in very elderly patients, and studies on this subject are limited in the literature. In the present study, clinical features and management AC were retrospectively analyzed in 365 patients and compared between the patients < 80 yo and those ≥ 80 yo.
It is known that comorbidities limit treatment options in patients over 80 years of age. [6, 13]. In addition, these patients often have a previous history of biliary disease and concomitant choledocholithiasis [10], which makes treatment difficult together with general status of the patient. The prevalence of comorbidities in elderly patients also makes it difficult to compare the parameters of AC management between young and elderly patients [14].
In a study by Feldman et al. comparing medical and surgical treatment methods in elderly patients with AC, the most common comorbidities were chronic renal failure, congestive heart disease, DM, HT, and CVD [15]. Similarly, in a study by Amaral et al., the most common comorbidities in elderly patients with AC were reported as DM, cardiac diseases and HT, and the rate of comorbidities were significantly higher in the elderly patients compared to young patients [16].
The presence of comorbidities affects the decision for operation. In a study by Nielsen et al, 413 patients >65 yo were evaluated, and multiple comorbidities were found in the majority of the patients. However, the authors proposed that multiple morbidities should not preclude the decision for surgical intervention [17]. In the present study, the presence of comorbidities was significantly higher in the patients ≥80 yo compared to those <80 yo. The most common comorbidities in this group included CAD, HT, DM and CVD. Despite the differences between studies, the most common comorbidities seem to be hypertension, DM, and cardiac diseases in elderly patients with AC. We think that a multidisciplinary approach is needed to minimize the effects of comorbidities, especially in the surgical management of elderly patients.
Some of the laboratory parameters are diagnostic for AC, and a WBCcount>10×109/Lwasusedasadiagnosticcriterioninour study. Among the studied laboratory parameters, WBC, NEU(%), NEU, urea and creatinine values were statistically significantly higher in the ≥ 80 yo group compared to <80 yo group (for all p<0.05). A study by Lulleci et al. compared laboratory findings of AC between the elderly and non-elderly patients, WBC count was significantly higher in the elderly group [18]. Similarly Parker et al. reported elevated WBC counts in 59% of the elderly patients [19]. In another study, WBC count was reported to be ariskfactorforclinicaloutcomes[6].Theseresultsmaybedue to aging immunopathology.
Cholecystectomy is the definitive treatment for AC, and early cholecystectomy is preferred in young patients and even in carefully selected elderly patients [11, 20, 21]. However, many centers prefer conservative treatment and delaying surgery for an elective procedure in elderly patients with AC. Elective laparoscopic cholecystectomy has been reported as an appropriate method for the management of elderly patients with AC [17]. Elective cholecystectomy should be planned for patients in whom urgent intervention is not possible and if there are no contraindications [3]. Nevertheless, urgent laparoscopic cholecystectomy is a commonly used method [22]. In our study, 20.8% of the patients ≥ 80 yo underwent urgent and 13.3% elective surgery. Of the patients in this group, 65.9% received conservative medical therapy.
Laparoscopic cholecystectomy is a useful approach for the treatment of acute cholecystitis in elderly patients with its advantages such as less pain, shorter hospitalization and minimal invasiveness [16]. However, the optimal treatment of AC is controversial in elderly patients and with the aging population, addressing this issue is becoming an increasingly urgent necessity. In our study, open cholecystectomy was performed only in cases where laparoscopy was not considered safe due to comorbidities or local conditions. Accordingly, open cholecystectomy was performed in 24 (13.9%) patients ≥ 80 yo. In a study by Serban et al., the rate of open cholecystectomy was reported to be higher in elderly patients [14].
It is known that postoperative complications are higher and the hospital stay is longer in elderly patients who have undergone surgery [23]. In our study, the duration of hospitalization was longer in patients who underwent open surgery compared to laparoscopy in both groups. In addition, duration of hospitalization was significantly longer in the patients ≥ 80 yo. In the study by Serban et al., length of stay in the hospital was longer in patients undergoing open surgery and those >80 yo [14].
The risk of mortality increases with age in elderly patients with AC. In a meta-analysis by Kamarajah et al. including 99 studies, mortality was found to increase by 10 folds in patients ≥ 80 yo [24]. In our study, while no mortality was observed in the < 80 yo group, the mortality rate was found as 4.6% (n:8) in patients ≥ 80 yo. Open cholecystectomy was performed in all 8 deceased patients. In a study by Escartin et al. on the management of AC in very elderly patients, the mortality rate was reported as 4% in the operated patients > 85.4 yo [3]. However, high mortality rates of 17.5% have been reported in high-risk elderly patients [25].
Study Limitations
This study has some limitations. It was designed as a retrospective study and conducted in a single center. In addition, the follow-up data could not be analyzed. However, the relatively high number of patients is the strength of the study. Considering the scarcity of studies in the literature on the management of AC in very elderly patients, we think that our findings may guide future studies on this subject. Conclusion
The management of acute and chronic diseases in very old patients has become important due to the globally increasing elderly population and the corresponding increase in life expectancy. According to our findings, comorbidities, biochemical parameters, hospitalization and mortality were significantly higher in the patients ≥80 yo compared to those <80 yo. However, there is a need for further multicenter prospective randomized controlled studies on AC management in very elderly patients.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Lee SO, Yim SK. Management of Acute Cholecystitis. Korean J Gastroenterol. 2018; 71(5):264-8.
2. Jang SY, Cha YH, Mun YS, Kim SH, Kim HY, Choy WS. Acute Cholecystitis in Elderly Patients after Hip Fracture: a Nationwide Cohort Study. J Korean Med Sci. 2019; 25:34(5):e36.
3. Escartín A, González M, Cuello E, Pinillos A, Muriel P, Merichal M, et al. Acute Cholecystitis in Very Elderly Patients: Disease Management, Outcomes, and Risk Factors for Complications. Surg Res Pract. 2019; 2019:9709242.
4. Loozen CS, van Santvoort HC, van Duijvendijk P, Besselink MG, Gouma DJ, Nieuwenhuijzen GA, et al. Laparoscopic cholecystectomy versus percutaneous catheter drainage for acute cholecystitis in high risk patients (CHOCOLATE): multicentre randomised clinical trial. BMJ. 2018; 363:k3965.
5. Yusoff IF, Barkun JS, Barkun AN. Diagnosis and management of cholecystitis and cholangitis. Gastroenterol Clin North Am. 2003; 32(4):1145-68.
6. Lee SW, Yang SS, Chang CS, Yeh HJ. Impact of the Tokyo guidelines on the management of patients with acute calculous cholecystitis. J Gastroenterol Hepatol. 2009; 24(12):1857-61.
7. Festi D, Dormi A, Capodicasa S, Staniscia T, Attili AF, Loria P, et al. Incidence of gallstone disease in Italy: results from a multicenter, population-based Italian study (the MICOL project). World J Gastroenterol. 2008; 14(34):5282-9.
8. Fukami Y, Kurumiya Y, Mizuno K, Sekoguchi E, Kobayashi S. Cholecystectomy in octogenarians: be careful. Updates Surg. 2014; 66(4):265-8.
9. Ambe PC, Weber SA, Christ H, Wassenberg D. Primary cholecystectomy is feasible in elderly patients with acute cholecystitis. Aging Clin Exp Res. 2015; 27(6):921-6.
10. Nikfarjam M, Yeo D, Perini M, Fink MA, Muralidharan V, Starkey G, et al. Outcomes of cholecystectomy for treatment of acute cholecystitis in octogenarians. ANZ J Surg. 2014; 84:943-8.
11. Loozen CS, van Ramshorst B, van Santvoort HC, Boerma D. Early Cholecystectomy for Acute Cholecystitis in the Elderly Population: A Systematic Review and Meta-Analysis. Dig Surg. 2017; 34(5):371-9.
12. Miura F, Takada T, Strasberg SM, Solomkin JS, Pitt HA, Gouma DJ, et al. TG13 flowchart for the management of acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2013; 20(1):47-54.
13. Dubecz A, Langer M, Stadlhuber RJ, Schweigert M, Solymosi N, Feith M, et al. Cholecystectomy in the very elderly–is 90 the new 70?. J Gastrointest Surg. 2012; 16(2):282-5.
14. Serban D, Socea B, Balasescu SA, Badiu CD, Tudor C, Dascalu AM, et al. Safety of Laparoscopic Cholecystectomy for Acute Cholecystitis in the Elderly: A Multivariate Analysis of Risk Factors for Intra and Postoperative Complications. Medicina (Kaunas). 2021; 57(3):230.
15. Feldman I, Feldman L, Shapiro DS, Munter G, Yinnon AM, Friedman R. Characteristics and outcome of elderly patients admitted for acute Cholecystitis to medical or surgical wards. Isr J Health Policy Res. 2020; 9(1):23.
16. do Amaral PC, Azaro Filho Ede M, Galvão TD, Ettinger JE, Silva Reis JM, Lima M, et al. Laparoscopic cholecystectomy for acute cholecystitis in elderly patients. JSLS. 2006; 10(4):479-83.
17. Nielsen LB, Harboe KM, Bardram L. Cholecystectomy for the elderly: no hesitation for otherwise healthy patients. Surg Endosc. 2014; 28(1):171-7.
18. Asiltürk Lülleci Z, Başyiğit S, Pirinççi Sapmaz F, Uzman M, Kefeli A, Yeniova AÖ, et al. Comparison of ultrasonographic and laboratory findings of acute cholecystitis between elderly and nonelderly patients. Turk J Med Sci. 2016; 46(5):1428-33.
19. Parker LJ, Vukov LF, Wollan PC. Emergency department evaluation of geriatric patients with acute cholecystitis. Acad Emerg Med. 1997; 4: 51-55.
20. Halpin V. Acute cholecystitis. BMJ Clin Evid. 2014; 2014:0411.
21. Mayumi T, Okamoto K, Takada T, Strasberg SM, Solomkin JS, Schlossberg D, et al. Tokyo guidelines 2018: management bundles for acute cholangitis and cholecystitis. J Hepato-Bil-Pancreat Sci. 2018; 25(1):96–100.
22. Ferrucci L, Fabbri E, Walston JD. Frailty. In: Halter JB, Ouslander JG, Studenski S, High KP, Asthana S, Supiano MA, et al., editors. Hazzard’s geriatric medicine and gerontology. New York: McGraw-Hill Education; 2017. p. 7e
23. Bingener J, Richards ML, Schwesinger WH, Strodel WE, Sirinek KR. Laparoscopic cholecystectomy for elderly patients: gold standard for golden years? Arch Surg. 2003; 138(5):531-6.
24. Kamarajah SK, Karri S, Bundred JR, Evans RPT, Lin A, Kew T, et al. Perioperative outcomes after laparoscopic cholecystectomy in elderly patients: a systematic review and meta-analysis. Surg Endosc. 2020; 34(11):4727-40.
25. Hatzidakis AA, Prassopoulos P, Petinarakis I, Sanidas E, Chrysos E, Chalkiadakis G, et al. Acute cholecystitis in high-risk patients: percutaneous cholecystostomy vs conservative treatment. Eur Radiol. 2002; 12(7):1778-84.
Download attachments: 10.4328:ACAM.20859
Guner Cakmak, Emre Gonullu, Kayhan Ozdemir, Enes Bas, Ugur Dulger. Evaluation of the management of acute cholecystitis in very elderly patients. Ann Clin Anal Med 2021;12(11):1288-1292
Citations in Google Scholar: Google Scholar
Does LENT prognostic score predict mortality? An observational study
Tibel Tuna, Nurhan Köksal, Yusuf Taha Güllü, Sümeyye Kement
Department of Pulmonary Medicine, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey
DOI: 10.4328/ACAM.20885 Received: 2021-10-04 Accepted: 2021-10-21 Published Online: 2021-10-29 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1293-1297
Corresponding Author: Tibel Tuna, Ondokuz Mayıs University, Faculty of Medicine, Department of Pulmonary Medicine, 55200, Samsun, Turkey. E-mail: tibeltuna55@gmail.com P: +90 362 312 19 19 / +90 362 312 40 86 / +90 532 733 61 92 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4386-8259
Aim: Determining the patients with long survival helps determine the best prevention strategies such as pleurodesis or tunneled pleural catheter, providing better palliation by minimizing the symptoms and morbidities associated with MPE relapse. This study aims to evaluate the predictive strength of LENT, a current prognostic score for MPE patients, and determine its effect on survival and importance in clinical decision-making.
Material and Methods: MPE patients between 2008 and 2020 were examined retrospectively. Age, sex, type of cancer, histological type, LDH, blood Neutrophil/ Lymphocyte values were taken, and ECOG, biopsy, and survival rates were calculated. Survival time was calculated as the period between thoracentesis result and death.
Results: The study group consisted of 268 MPE patients, and the average age of patients was 65.3±13.2 years, and 58.2% of the patients were male. Patients with high-risk LENT scores were observed to have 2.8 times more risk compared to the low-risk patients within the period of observation (Hazard Ratio:2.836, p:0.001). The median survival time for moderate-risk patients was shorter than for low-risk group (450 vs. 623 days).
Discussion: The LENT prognostic score is a simple score that can be used on patients suitable for pleural fluid analysis and significantly better than the Eastern Cooperative Oncology Group performance score (ECOG PS) for predicting survival. It is considered to be used conveniently to guide MPE treatments.
Keywords: ECOG, Lung Cancer, Malign Pleural Effusion, Survival
Introduction
Malign pleural effusion (MPE) is the presence of malign cells in pleural fluid and/or parietal pleura [1]. MPE occurs in around 15% of all cancer patients [2]. Approximately 75% of MPE is caused by breast and lung metastases, while only 40% are caused by lung cancer. Moreover, pleural effusion is present in around 15% of lung cancer cases at the time of initial diagnosis [3].
The presence of MPE reduces life expectancy significantly [3]. Although it depends on the type of the underlying malignity, the median survival after diagnosis is specified as 3 to 12 months in guidelines [4]. Correct evaluation of MPE is crucial for planning suitable treatment to achieve the highest benefit for the survival of the patient and to keep the damage at minimal levels [5].
Since they might cause morbidities as well as hospitalization, the treatments applied might cause additional load for patients, loss of life quality and additional costs in health expenditures. Determining the patients with the worst survival has the potential to help increase the quality of life for these patients by focusing on reducing the hardships they experience in their remaining lives. In addition, determining the patients with better survival helps determine good prevention strategies such as pleurodesis or tunneled pleural catheter, providing good palliation by minimizing symptoms and morbidities associated with MPE relapse. The critical point here is to determine which patients will achieve this survival [6]. Therefore, the correct prognostic evaluation of the patients becomes more important. For this purposes, various factors predict negative survival of patients with MPE [3, 7, 8]: high pleural fluid lactate dehydrogenase (LDH; >1,500 IU/L), Eastern Cooperative Oncology Group (ECOG) performance score (3–4), high blood neutrophil: lymphocyte rate (>9), cancer type (lung), low pleural fluid pH (<7.28) and high sVEGFR-1 pleural fluid level (9-13). LENT score (Serum Lactate dehydrogenase (LDH), ECOG PS, blood Neutrophil/Lymphocyte Ratio, tumor type) is a combined scoring method, created when searching for a stronger predictor for oncology cases where malign pleural fluid occurs [2]. The score categorizes patients as low-, moderate-, or high- risk groups based on their survival time. It is reported that 97% of the high-risk group patients, categorized using the LENT scoring system died within six months [2].
This study aims to evaluate the predictive strength of LENT, a current prognostic score for MPE patients and to determine its effect on survival and importance in clinical decision-making. Moreover, it is further aimed to compare the LENT score with ECOG, a traditional but subjective scoring system.
Material and Methods
Study Population and Data Collection
MPE patients between 2015 and 2020 were examined retrospectively. Malign cells of the patients were confirmed with pleural fluid or pleural biopsy. Malign cells were analyzed using conventional cytology using biopsy material and histology analyses were conducted. Ethics committee approval for the study was obtained from the Ondokuz Mayıs University Clinical Trials Ethics Committee, with no. 2020/150.
Measurements
Basal prognostic clinical and laboratory examinations were taken from the hospital’s electronic registry system. Age, sex, type of cancer, histological type, LDH, blood Neutrophil/ Lymphocyte values were taken and ECOG, biopsy, survival rates were calculated. Survival time was calculated as the period between thoracentesis result and death. LENT score was classified as low (0-1), moderate (2-4) and high (5-7) in line with the literature [2]. Performance scores of the patients were calculated using ECOG-PS.
Statistical Analysis
SPSS v21 (Chicago, US) was used for statistical analyses. For the complementary analyses, average, median and percentage distributions are utilized. ROC curves were used for survival analyses, areas under curves (AUC) were shown. Sensitivity and specificity values at the cut-off points were chosen according to YoudenIndex.Kaplan-MeiercurveandCoxregressionanalyses were used for survival and hazard ratio. AUC was calculated for the 1-, 3-, 6-, 12-month periods and overall survival. P<0.050 was considered statistically significant.
Results
The study group consisted of 268 MPE patients, the average age of patients was 65.3±13.2 years, and 58.2% of the patients were male. Among the patients, 39.2% had lung, 22.6% gastrointestinal and renal, 11.2% had hematologic cancer. When the cancers were examined histologically, the most common type was adenocarcinoma (42.6%). During the examined period, 86.9% of the patients were passed away. The socio-demographic characteristics of the patients are presented in Table 1.
When the cut-off point is taken as 4 for the LENT score and 2 for ECOG-PS, the AUC value was found to be 0.624 for the LENT score (p:0.018, sensitivity: 24.9%, specificity 100%) and 0.637 for the ECOG-PS score (p:0.009, sensitivity: 47.2%, specificity 75.3%). It was observed that the LENT score had higher predictivity values for 1-, 6-, and 12-month periods compared to the ECOG-PS score. Table 2 presents the ROC curve values for LENT score and ECOG PS for predicting mortality.
When the 1-, 3-, 6-, and 12-month survival of LENT score groups is examined, it was observed that 33.3% of the low- risk group, 14.8% of the moderate-risk group, and 0.0% of the high-risk group survived. In the 12-month survival period, the survival rates were 76.2%, 55.0%, and 31.0% for the low-, moderate-, and high-risk groups, respectively. Table 3 presents the survival rates for 1-, 3-, 6-, and 12-month periods based on LENT scores.
The median survival time among the LENT score groups was 623 days, 450 days, and 165 days for the low-, moderate-, and high-risk groups, respectively.The Kaplan-Meier survival analysis is presented in Figure 1. The Cox regression model for the LENT score groups in predicting survival in all patients was statistically significant (χ2:27.763, df:2, p:0.001). Patients with high-risk LENT scores were observed to have 2.8 times more risk compared to low-risk patients within the period of observation (Hazard Ratio:2.836, p:0.001). The median survival time of the moderate risk patients was shorter compared to the low-risk group (450 vs. 623 days); however, the risk between these two groups was not considered significant for this model (Hazard Ratio:1.333, p:0,304).
Discussion
In our study, we evaluated the performance of the LENT score in predicting prognosis for patients with MPE. We found out that survival in patients with high LENT scores was shorter. We determined that the LENT score predicts survival in patients with MPE. Taking the predictive values of our study, we observed that the LENT score was higher than the ECOG-PS score for the 1-, 6-, and 12-month periods. Gayaf et al. reported that although the LENT score is equal or superior to the ECOG in terms of predicting survival for 1- or 3-month, the difference decreases in the long-term survival analyses and that the LENT score has almost the same effect as the ECOG PS for overall survival [9].
When the cut-off point is taken as 4 and 2 for the LENT score and ECOG-PS respectively in our study, it was found out that the sensitivity and specificity for the LENT score were 24.9% and 100%, respectively. In another study, it was demonstrated that sensitivity and specificity were 69.8% and 100%, respectively, when the LENT score is >4 [9]. Similarly, our study indicates that the LENT score has a higher specificity and that lower LENT scores can be utilized in clinical practice.
According to our evaluations, median survival times were 623, 450 and 165 days for the low-, moderate-, and high-risk groups in the LENT score chart, respectively. Survival times in the study by Clive et al. were 319, 130, and 44 days, respectively [2]. In the study by Gayaf et al., the median survival times were 662, 119, and 33 days for the low-/moderate-/high-risk groups according to the LENT score, respectively [9]. The most important reason for the longer median survival time in our study compared to other studies is that the patients receiving immunotherapy or other targeted therapies were not excluded. Particularly, it was demonstrated that the survival periods are longer in the lung adenocarcinoma-induced MPE patients who receive treatment with tyrosine kinase inhibitors [10]. In the study by Abisheganaden et al., which had similar results to our research, it was shown that the median survival time of the high-risk patients with LENT score ≥5 (n = 36) was 190.5 days and that more than half of the patients (52.7%) survived for more than six months, while the median survival time of the moderate-risk patients with LENT score 2-4 (n = 34) was 346 days, and 70.5% of these patients survived for more than six months. In the current study, more than half of the patients with EGFR mutation with MPE from lung adenocarcinoma received tyrosine kinase inhibitor treatment [6].
In our study, the Cox regression analysis showed that the LENT score predicted survival in all patients. Patients with high-risk LENT scores were observed to have 2.8 times more risk compared to the low-risk patients within the period of observation. Although the median survival time of moderate- risk patients is shorter compared to the low-risk patients, the risk between these two groups was not statistically significant. In the Cox regression analysis conducted by Gayaf et al., it was shown that there is a significant difference in terms of survival between the moderate and high-risk groups according to the LENT score [9].
Our findings support that the high pleural LDH ratio, which demonstrates localized, acute inflammation, necrosis and cell death in pleural space, is a sign of poor prognosis in malign pleural effusions [11, 12]. Further, some studies proved that the leucocyte subtypes such as neutrophil and lymphocyte counts show the severity of the systemic inflammatory response in cancer patients [13]. In these studies, it was reported that increased serum NLR (neutrophil-lymphocyte ratio) has an adverse effect on overall survival [14]. In a study conducted to predict the survival among patients, it was found out in the multivariate analyses that the serum NLR is a distinct prognostic factor in the patients with MPE and the LENT prognostic score on its own has distinctly higher accuracy compared to the ECOG PS [2]. Since these ratios can be simply calculated in complete blood counts and available at a reasonable cost universally, it increases the value of ratios as biomarkers. Similarly, another study found out that the serum and pleural fluid NLR in lung cancer patients with MPE have an adverse effect on overall survival [15]. It was found out that the survival time is shorter in patients with high LENT scores and longer compared to the values in the ECOG-PS when predictive values for 1-, 6-, and 12-month periods were examined. We believe that, while the LDH and NLR ratios are guiding lights in determining a prognosis, their use in conjunction with the ECOG and tumor type is a better indicator of prognosis.
Our study has certain limitations. Firstly, patients receiving immunotherapy or other targeted therapies were not excluded. Although this inclusion led to an increase in survival periods in our study, it is considered that this situation does not prevent the use of the LENT score for predicting prognosis. Another limitation is that there are missing data regarding whether the effusions were newly diagnosed malign diseases or the presence of recurring/progressive conditions, or any previous treatment for malignity at the time of calculations for the LENT scores. In the literature, there is only one study on whether effusions represent a new malignant diagnosis or a recurring/progressive disease. In this study, no statistically significant difference was found between the progressive disease vs. newly diagnosed disease in the single variant Cox model [2].
Conclusion
The LENT prognostic score is a simple score that can be used in patients suitable for pleural fluid analysis and significantly better than the ECOG PS for predicting survival. It is considered to be used conveniently to guide MPE treatments.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Kasapoglu US, Arinc S, Gungor S, Irmak I, Guney P, Aksoy F, et al. Prognostic factors affecting survival in non-small cell lung carcinoma patients with malignant pleural effusions. Clin Respir J. 2016;10(6):791-9.
2. Clive AO, Kahan BC, Hooper CE, Bhatnagar R, Morley AJ, Zahan-Evans N, et al. Predicting survival in malignant pleural effusion: development and validation of the LENT prognostic score. Thorax. 2014;69(12):1098-104.
3. Anevlavis S, Kouliatsis G, Sotiriou I, Koukourakis MI, Archontogeorgis K, Karpathiou G, et al. Prognostic factors in patients presenting with pleural effusion revealing malignancy. Respiration. 2014;87(4):311-6.
4. Roberts ME, Neville E, Berrisford RG, Antunes G, Ali NJ, Group BTSPDG. Management of a malignant pleural effusion: British Thoracic Society Pleural Disease Guideline 2010. Thorax. 2010;65 (Suppl. 2):ii32-40.
5. Tan C, Sedrakyan A, Browne J, Swift S, Treasure T. The evidence on the effectiveness of management for malignant pleural effusion: a systematic review. Eur J Cardiothorac Surg. 2006;29(5):829-38.
6. Abisheganaden J, Verma A, Dagaonkar RS, Light RW. An Observational Study Evaluating the Performance of LENT Score in the Selected Population of Malignant Pleural Effusion from Lung Adenocarcinoma in Singapore. Respiration. 2018;96(4):308-13.
7. Zamboni MM, da Silva CT, Jr., Baretta R, Cunha ET, Cardoso GP. Important prognostic factors for survival in patients with malignant pleural effusion. BMC Pulm Med. 2015;15:29.
8. Heffner JE, Nietert PJ, Barbieri C. Pleural fluid pH as a predictor of survival for patients with malignant pleural effusions. Chest. 2000;117(1):79-86.
9. Gayaf M, Anar C, Canbaz M, Dogan BI, Erbaycu AE, Guldaval F. Can LENT Prognostic score (LDH, ECOG performance score, blood neutrophil/lymphocyte ratio, tumor type) change the clinical approach in malignant pleural effusion? Tuberk Toraks. 2021;69(2):133-43.
10. Wu SG, Yu CJ, Tsai MF, Liao WY, Yang CH, Jan IS, et al. Survival of lung adenocarcinoma patients with malignant pleural effusion. Eur Respir J. 2013;41(6):1409-18.
11. Bielsa S, Salud A, Martinez M, Esquerda A, Martin A, Rodriguez-Panadero F, et al. Prognostic significance of pleural fluid data in patients with malignant effusion. Eur J Intern Med. 2008;19(5):334-9.
12. Martinez-Moragon E, Aparicio J, Sanchis J, Menendez R, Cruz Rogado M, Sanchis F. Malignant pleural effusion: prognostic factors for survival and response to chemical pleurodesis in a series of 120 cases. Respiration. 1998;65(2):108-13.
13. Paramanathan A, Saxena A, Morris DL. A systematic review and meta- analysis on the impact of pre-operative neutrophil lymphocyte ratio on long term outcomes after curative intent resection of solid tumours. Surg Oncol. 2014;23(1):31-9.
14. Guthrie GJ, Charles KA, Roxburgh CS, Horgan PG, McMillan DC, Clarke SJ. The systemic inflammation-based neutrophil-lymphocyte ratio: experience in patients with cancer. Crit Rev Oncol Hematol. 2013;88(1):218-30.
15. Lee YS, Nam H-S, Lim JH, Kim JS, Moon Y, Cho JH, et al. Prognostic impact of a new score using neutrophil-to-lymphocyte ratios in the serum and malignant pleural effusion in lung cancer patients. BMC cancer. 2017;17(1):1-8.
Download attachments: 10.4328:ACAM.20885
Tibel Tuna, Nurhan Köksal, Yusuf Taha Güllü, Sümeyye Kement. Does LENT prognostic score predict mortality? An observational study. Ann Clin Anal Med 2021;12(11):1293-1297
Citations in Google Scholar: Google Scholar
Results and risk factors of high lactate level after open-heart surgery
Tülay Örki, Pınar Karaca Baysal
Department of Anesthesology and Reanimation, SBU. Kartal Koşuyolu Kalp Hospital, İstanbul, Turkey
DOI: 10.4328/ACAM.20886 Received: 2021-10-05 Accepted: 2021-10-21 Published Online: 2021-10-29 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1298-1302
Corresponding Author: Tülay Örki, Department of Anesthesiology and Reanimation, SBU. Kartal Koşuyolu Kalp Hospital, 34844, İstanbul, Turkey. E-mail: tlaykayacan@yahoo.com.tr P: +90 532 382 35 72 Fax: +90 216 459 63 21 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0166-4234
Aim: The aim of this study is to determine risk factors associated with hyperlactatemia developing after open-heart surgery and to investigate the effects of hyperlactatemia on mortality and morbidity.
Material and Methods: Five hundred seventeen adult patients who underwent elective open-heart surgery were enrolled prospectively. Lactate values were recorded before induction and at the 2nd, 6th, 12th, and 24th hours of admission in the intensive care unit. Lactate cut-off value was found to be 3.05 mmol/L (sensitivity 86.7% and specificity 87.6%) with ROC analysis (AUC =, 911; p <0.01); Group 1 (Lactate <3.05 mmol/L, n = 442) and Group 2 (Lactate ≥ 3.05 mmol/L, n = 75).
Results: Patients with HL had significantly higher EuroSCORE II value (p = 0.018), longer CPB (p = 0.000), and ACCtimes (p = 0.000), and more on-pump need for inotropic agents (p = 0.000). In the HL group, the ventilation time was 25.0 ± 26.9 hours, the length of stay in ICU was 5.4 ± 4.3 days, and the length of hospital stay was 10.9 ± 6.0 days (p <0.01). The mortality rate was 17.3% (p =. 000). In multivariate analysis, CPB time, use of inotropic agents in the intensive care unit, use of IABP and ECMO, and prolonged ventilation time (> 24h) were found to be independent risk factors for hyperlactatemia (p <0.05).
Discussion: According to our study, the lactate threshold at the 24th hour of 3.05 mmol/L predicted postoperative mortality in adult patients who underwent open-heart surgery.
Keywords: Cardiac Surgery, Hyperlactatemia, Morbidity, Mortality, Risk factors
Introduction
Hyperlactatemia (HL) is a common clinical condition following open-heart surgery and has been reported to be associated with morbidity and mortality [1-6]. It has been stated in the literature that high lactate levels result in many complications, including mortality, in the postoperative period [7-10]. Although the exact mechanism of HL in patients undergoing open-heart surgery is not fully explained, many factors are known to play a role in this issue [7]. Some of the causes of postoperative lactate elevation include comorbidities, organ perfusion during the cardiopulmonary bypass period, and difficulties in intraoperative anesthesia management. In addition, decreased cardiac performance and decreased oxygen supply to tissues in the postoperative period have been stated to be the most important cause of postoperative hyperlactatemia [1-7, 11, 12].
In open-heart surgery, it is important whether hyperlactatemia, which occurs as a result of different mechanisms, predicts complications in the post-operative period or to what extent it determines [2,7].
Since there is no perioperative clinical follow-up data in classifications such as EuroSCORE for risk determination before open-heart surgery [7,13]. Therefore, it should be known at what intervals and for how long lactate levels should be monitored to foresee the mortality and morbidity that may develop in the postoperative period. Thanks to the determined risk factors, perioperative anesthesia management, and intensive care follow-up can be made more efficiently and hospital stay periods can be shortened.
In this study, we aimed to investigate how lactate levels affect morbidity and mortality in the first 24 hours postoperatively in patients who underwent open-heart surgery, as well as the factors associated with hyperlactatemia in patients.
Material and Methods
This prospectively planned study was conducted in 517 patients who underwent elective open-heart surgery in our clinic between January 2019 and October 2019, after obtaining Ethics committee approval (Decision number: 2018/6/68, Date 15.11.2018).Those who underwent off-pump surgery, those who had a total circulatory arrest, redo cases, emergency cases, those who had congenital heart surgery, those who underwent heart transplantation and received left ventricular assist device, those who died intra operatively, and those under the age of 18 were excluded from the study.
Our cardiac anesthesia protocol was applied to all patients who provided informed consent before surgery. For the induction of anesthesia, 3mg.kg-1propofol, 0.6 mg.kg-1 rocuronium, and 2-3μgr.kg-1 fentanyl were administered. Maintenance of anesthesia was provided by inhalation of sevoflurane (MAC 1-2%) with 70% O2+ 30% air, and intermittent midazolam, fentanyl, and rocuronium during cardiopulmonary bypass (CPB). Invasive arterial pressure, central venous pressure, peripheral oxygen saturation, 12-lead ECG, and nasal temperature monitoring were performed in all patients.
Operations were performed in company with cardiac arrest using moderate hypothermic (28-320C), antegrade, and/ or retrograde cold blood cardioplegia with cardiopulmonary bypass following standard sternotomy and heparinization. During CPB, non-pulsatile flow was maintained between 2.2- 2.6 L/min/m2, the mean CBP pressure 60-70 mmHg, Hct> 22%, and blood glucose between 100-180 mg/dL. For the targeted mean CPB perfusion pressure, the perfusion flow was increased and/or vasopressor was used when required. CPB output was returned to ACT basal value with protamine.
Blood lactate levels were measured at fixed time intervals. Lactate values from the arterial blood sample were obtained from the standard arterial blood gas analyzer (ABL 800flex, Akın medical). The initial sample (basal) was collected immediately after the intra-arterial catheter was inserted. Subsequent samples were collected at the following intervals: 2nd, 6th, 12th, and 24th hours after admission to the intensive care unit. Mean arterial pressure (MAP) was measured and recorded before the induction of anesthesia. Mean CPB pressure and mean CPB flow were measured and recorded every 20 minutes during the pump.
Data collection
Preoperative data, gender, age, BMI, comorbidities (diabetes, hypertension, dyslipidemia, chronic obstructive pulmonary disease, chronic renal failure, cerebrovascular event (CVD), carotid disease, past MI), EuroSCORE II classification, MAP, serum creatinine and ejection fraction (EF), and type of surgery of each patient were recorded. As intraoperative data, CBP time, aortic cross-clamp (ACC) time, lowest on-pump hematocrit value, mean CBP pressure, the difference between MAP and mean CPB pressure, mean CPB flow, on-pump inotropic agent requirement, and on-pump use of erythrocyte suspension were recorded. As postoperative data, mechanical ventilation time, intensive care unit (ICU) stay and hospital stay, complications (infection, CVD, surgical bleeding, reoperation, dialysis, prolonged mechanical ventilation (> 24 h), use of inotropic agents, IABP, ECMO use), and mortality were recorded.
Statistical Analysis
Statistical analysis was performed using the IBM SPSS 22.0 program. Results were expressed as number of patients and percentage values for categorical variables and as mean ± standard error for continuous variables.
ROC analysis was performed for lactate values at the 2nd, 6th, 12th, and 24th hours of ICU, which best describe the mortality status, and the cut-off value was determined.
In the comparison of the two groups, Chi-square and Fisher’s exact tests were used for qualitative variables, and Independent Sample t-test and Mann Whitney U tests for quantitative variables. Univariate and multivariate logistic regression analyses were used to determine risk factors associated with HL. A p-value of <0.05 was considered statistically significant.
Results
Open-heart surgery was performed on 517 patients (115 Females, 402 Males, age range; 30-82 years) at Koşuyolu Heart Hospital between January 2019 and October 2019. Figure 1 shows the ROC curve comparing the state of predicting mortality of lactate levels at the 2nd, 6th, 12th, and 24th hours of postoperative ICU. In the ROC analysis, among the lactate values measured at the 2nd, 6th, 12th, and 24th hours of the ICU, the cut-off value for lactate at the 24th hour (AUC =, 911; p <0.01) was found to be 3.05 mmol/L (sensitivity 86.7% and specificity 87.6%).
The patients were divided into two groups according to the lactate value of 3.05mmol/L; Group 1 (Lactate <3.05 mmol/L, n = 442) and Group 2 (Lactate ≥ 3.05 mmol/L, n = 75). Age, gender, BMI, MAP, EF, serum creatinine, preoperative lactate, and comorbidities were similar between the two groups. The EuroSCORE II value was found to be significantly higher in the group with HL (p = 0.018) (Table 1).
There was no significant difference between the two groups in the lowest on-pump hematocrit value, erythrocyte suspension delivered on the pump, the mean CPB pressure, the MAP-mean CPB pressure difference, and the mean CPB flow. Patients with HL had significantly longer CPB time (162.4 ± 54.2 vs. 124.0 ± 38.7 min; p = 0.000) and ACC time (107.1 ± 48.1 vs. 79, 8 ± 35.0 min; p = 0.000) and more on-pump inotropic agent requirements (69.3% versus 42.1%; p = 0.000) (Table 2).
Postoperative complications are shown in Table 2. In the comparison between the two groups, there was no statistical difference in terms of bleeding, infection, and CVD values. There were statistical differences in terms of ventilation time, length of stay in ICU and length of the hospital stay, prolonged ventilation (> 24h), reoperation, dialysis, IABP, ECMO, use of inotropic agents in the intensive care unit, and mortality. In patients in the HL group, the ventilation time was 25.0 ± 26.9 hours, the length of stay in ICU was 5.4 ± 4.3 days, and the length of the hospital stay was 10.9±6.0 days. Prolonged ventilation was found to be 30.7%, re-operation: 14.9%, dialysis: 10.7%, IABP use: 20.0%, ECMO use: 9.3%, and use of inotropic agents in the intensive care unit: 60.0% (p<0.01). While the mortality rate was 0.5% in the group with lactate <3.05 mmol/L, it was 17.3% in the group with lactate ≥3.05 mmol/L (p =. 000). Table 3 shows logistic regression analysis for HL risk factors. According to the univariate analysis, risk factors were found to be EuroSCORE II, CPB time, and ACC time, on-pump inotropic agent requirement, use of inotropic agents in the intensive care unit, dialysis, reoperation, IABP, ECMO, and prolonged ventilation (> 24h) (p <0.05). In the Multivariate analysis made accordingly, CPB time, use of inotropic agents in the intensive care unit, IABP, ECMO, and prolonged ventilation (> 24h) were found to be independent risk factors for HL (p <0.05).
Discussion
In our study, the lactate level ≥3.05 mmol/L at the postoperative 24th hour in adult patients undergoing open-heart surgery has been shown to be associated with postoperative complications and mortality. Besides, in multivariate analysis, CPB time, use of inotropic agents in the intensive care unit, use of IABP and ECMO, and prolonged ventilation time were identified to be independent risk factors for the development of HL.
In the literature, lactate values between 2-5 mmol/L were considered to be the threshold value for HL identification after open-heart surgery [2, 8,11,12]. Besides, the incidence of HL in patients was reported to be 10-20% [9,11,12]. In our study, we determined the cut-off value for HL as 3.05 mmol/L with ROC analysis, and we found the HL incidence to be 14.5%, which consistent with the literature.
Studies have reported that HL-related conditions are age, gender, congestive heart failure, low left ventricular ejection fraction, hypertension, diabetes, peripheral circulatory failure, and emergency cases [9-11, 13-18]. When preoperative data that may affect HL in our own patient population were examined, it has been shown that factors such as age, gender, low EF, and comorbidities alone are not effective in the development of hyperlactatemia. In our patient population, it was determined from preoperative data that the EuroSCORE II value was higher in patients with HL. As the EuroSCORE II value is a scoring system consisting of preoperative data, we think that HL is not due to a single cause but multifactorial.
In open-heart surgery, patient management during the CPB time needed in the intraoperative period is vital. Tissue perfusion and circulatory support should be provided effectively throughout the CPB time. Deterioration of cell oxygen delivery during the CPB period and consequently, the activation of the anaerobic metabolic mechanism is the most important reason that increases the lactate level during the perfusion period [5, 6,8,9,11,12].
As stated in Table 2, in our study, during the CPB period, the lowest hematocrit value, mean CPB pressure, MAP-mean CPB pressure difference, and mean CPB flow were similar in both groups and could not be associated with HL. We attribute this to our standardization of parameters such as temperature, flow, perfusion pressure, and avoiding hyperglycemia and hemodilution during the CPB period. While CPB management could be standardized in each patient, the CPB time could not be standardized due to the variable surgical teams and the presence of different cardiac cases, and lactate levels were found to be higher in patients with long CPB time. Lactate levels were found to be higher in patients who needed inotropic support to provide pump perfusion at a certain level in each patient.
HL is known to be bimodal in cardiac surgery [19-21]. Early- onset HL is hyperlactatemia that develops in the operating room or very early following ICU admission. Late-onset HL, on the other hand, is a clinical condition that typically arises within 6-12 hours of ICU admission and continues for up to 24 hours [20]. Hyperlactatemia in our series complies with late-onset HL. While early-onset HL is associated with CPB time, hemodilution, and co-morbidities [11], late-onset HL is associated with the use of β2-agonists such as epinephrine [20], limb ischemia due to the use of mechanical cardiovascular support devices (ECMO and IABP), hepatosplenic and mesenteric ischemia [15]. In our study, the causes of late-onset HL were shown to be patients showing inotropic agent support in the intensive care unit, the use of mechanical support devices (IABP and ECMO), and prolonged mechanical ventilation time. Other causes, which include hepatosplenic and mesenteric ischemia were not present in our patient population [6,9,14,18].
In a cohort study of patients who underwent cardiac surgery and stayed in the intensive care unit for more than 24 hours, the peak lactate level was 3 mmol/L and above, and it was stated that the effect of persistent hyperlactatemia on postoperative morbidity and mortality was higher than that of the highest lactate level at the end of the study [18]. In our study, lactate levels were monitored up to the 24th hour in the ICU. We found that lactate levels that continued to be elevated at the 24th hour were more specific in predicting postoperative morbidity and mortality.
There are many publications reporting that high blood lactate levels are associated with increased postoperative morbidity and mortality in both adult and pediatric cardiac surgery. The common view is that regular and continuous monitoring of lactate levels in the perioperative period will provide success in clinical treatment, and will also shorten the hospital and intensive care periods and bring a cost-effective treatment [1-4, 6,7,22-24]. In our study, patients in the HL group had significantly longer ventilation time (p = 0.000), and length of stay in ICU (p = 0.000) and the length of the hospital stay (p = 0.000). The mortality rate was found to be higher in patients in the HL group (p = 0.000).
Conclusion
According to our study, 3.05 mmol/L lactate threshold value at 24 hours predicts postoperative mortality in adult patients who underwent open-heart surgery. In addition, this value is significantly associated with prolonged ventilation time, prolonged ICU stay, and hospital stay.
Limitations: We consider the variable CPB and PCO times as a result of operations performed by different surgical teams, and no assessment of how long lactate levels remain higher after 24 hours in the intensive care unit as limiting factors for this study.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Kogan A, Preisman S, Bar A, Sternik L, Lavee J, Malachy A, et al. The impact of hyperlactatemia on postoperative outcome after adult cardiac surgery. J Anesth. 2012; 26 (2):174-8.
2. Hajjar L A, Almeida J P, Fukushima J, Rhodes A, Vincent J.V,. Osawa EA, et al. High lactate levels are predictors of major complications after cardiac surgery. J Thorac Cardiovasc Surg. 2013;146(2):455-60.
3. Lopez-Delgado JC, Esteve F, Javierre C, Torrado H, Rodriguez-Castro D, Carrio ML et al. Evaluation of Serial Arterial LactateLevels as a Predictor of Hospital and Long-Term Mortality in Patients After Cardiac Surgery. J CardiothoracVasc Anesth. 2015; 29(6):1441-53.
4. Noguchi S, Saito J, Hashiba E, Kushikata T, Hirota K. Lactate level during cardiopulmonary bypass as a predictor of postoperative outcomes in adult patients undergoing cardiac surgery. JA ClinRep. 2016;2(1):39
5. Jabbari A, Banihashem N, Alijanpour E, Vafaey HR, Alereza H, Rabiee SM. Serum lactate as a prognostic factor in coronary artery bypass graft operation by on pump method. Caspian J Intern Med. 2013;4(2):662-6.
6. Naik R, George G, Karuppiah S, Philip MA. Hyperlactatemia in patients undergoing adult cardiac surgery under cardiopulmonary bypass: Causative factors and its effect on surgical outcome. Ann Card Anaesth. 2016;19(4):668-75.
7. Haanschoten MC, Kreeftenberg HG, Bouwman RA, vanStraten AHM, Buhre WF, Soliman Hamad MA. Use of Postoperative Peak Arterial Lactate Level to Predict Outcome After Cardiac Surgery. CardiothoracVasc Anesth. 2017;31(1):45-53.
8. Mirmohammad-Sadeghi M, Etesampour A, Gharipour M, Saeidi M, Kiani A, Shamsolkotabi H, et al. Relationship between serum lactate levels and morbidity outcomes in cardiovascular patients after CABG. J Surg Pak 2008;13:88–91.
9. Toraman F, Evrenkaya S, Yuce M, Aksoy N, Karabulut H, Bozkulak Y, et al. Lactic acidosis after cardiac surgery is associated with adverse outcome. Heart Surg Forum. 2004;7(2):E155-9.
10. Andersen LW. Lactate elevation during and after majör cardiac surgery in adults: A review of etiology, prognostic value and management. Anesth Analg. 2017; 125(3):743-52.
11. Demers P, Elkouri S, Martineau R, Couturier A, Cartier R. Outcome with high blood lactate levels during cardiopulmonary bypass in adult cardiac operation. Ann Thorac Surg. 2000; 70(6):2082-6.
12. Maillet JM, Le Besnerais P, Cantoni M, Nataf P, Ruffenach A, Lessana A, et al. Frequency, risk factors, and outcome of hyperlactatemia after cardiacsurgery. Chest. 2003; 123(5):1361-6.
13. Raper RF, Cameron G, Walker D, Bowey CJ. Type B lacticacidosis following cardiopulmonary bypass. Crit Care Med. 1997;25(1):46-51.
14. Ranucci M, De Toffol B, Isgro G, Romitti F, Conti D, Vicentini M.. Hyperlactatemia during cardiopulmonary bypass: Determinants and impact on postoperative outcome. Crit Care. 2006; 10(6):R167.
15. Totaro RJ, Raper RF. Epinephrine-induced lactic acidosis following cardiopulmonary bypass. Crit Care Med. 1997; 25(10):1693-9.
16. Takala J, Uusaro A, Parviainen I, Ruokonen E. Lactate metabolism and regional lactate Exchange after cardiac surgery. New Horiz. 1996; 4(4):483-92.
17. Perner A, Jørgensen VL, Poulsen TD, Steinbru ̈chel D, Larsen B, Andersen LW. Increased concentrations of L-lactate in the rectal lumen in patients undergoing cardiopulmonary bypass. Br J Anaesth. 2000; 95(6):764–8.
18. Mak NTJJ, Iqbal S, de Varennes B, Khwaja K. Outcomes of post-cardiac surgery patients with persistent hyperlactatemia in the intensive care unit: a matched cohort study. J Cardiothorac Surg. 2016; 24;11:33
19. Gladden L. B. Lactatemetabolism: A new paradigm for the third millennium. J Physiol. 2004; 558(Pt 1):5-30.
20. Minton J, Sidebotham DA. Hyperlactatemia and Cardiac Surgery. J Extra CorporTechnol. 2017; 49(1):7-15.
21. O’Connor E, Fraser JF.The interpretation of perioperative lactate abnormalities in patients undergoing cardiacsurgery. Anaesth Intensive Care. 2012; 40(4):598- 603.
22. Badreldin AMA, Doerr F, Elsobky S, Brehm BR, Abul-Dahab M, Lehmann T, et al. Mortality prediction after cardiac surgery: blood lactate is indispensible. Thorac Cardiovasc Surg. 2013; 61(8):708-17.
23. Basaran M, Sever K, Kafali E, Ugurlucan M, Sayin OA, Tansel T, et al. Serum lactate level has prognostic significance after pediatric cardiac surgery. J Cardiothorac Vasc Anesth. 2006;20(1):43-7.
24. Kalyanaraman M, De Campli WM, Campbell AI, Bhalala U, Harmon TG, Sandiford P, et al. Serial blood lactate levels as a predictor of mortality in children after cardiopulmonary bypass surgery. Pediatr Crit Care Med. 2008;9(3):285-8.
Download attachments: 10.4328:ACAM.20886
Tülay Örki, Pınar Karaca Baysal. Results and risk factors of high lactate level after open-heart surgery. Ann Clin Anal Med 2021;12(11):1298-1302
Citations in Google Scholar: Google Scholar
Retrieval of a missed intraperitoneal gallstone with early second look laparoscopy
Zeliha Turkyilmaz 1, Orhan Sunar 1, Tuğrul Demirel 1, Osman Kula 2
1 Department of General Surgery, 2 Department of Radiology, Trakya University, Medical Faculty, Edirne, Turkey
DOI: 10.4328/ACAM.20824 Received: 2021-08-19 Accepted: 2021-10-05 Published Online: 2021-10-20 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1303-1305
Corresponding Author: Zeliha Turkyilmaz, Department of General Surgery, Trakya University, Medical Faculty, 22030, Edirne, Turkey. E-mail: turkyilmazz@yahoo.com P: +90 532 708 29 44 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0012-2089
The perforation of the gall bladder is the most common complication in laparoscopic cholecystectomy (LC). Retrieval of spilled gallstones is routine when possible. However, it is not infrequent to leave some. Although significantly rare, abandoned gallstones may cause late and subtle symptoms and even severe intra-abdominal complications. In this study, we present a 60-year-old male patient who had an attack of acute cholecystitis and underwent laparoscopic cholecystectomy 6 weeks later. A second emergency laparoscopy was performed to remove the unremoved gallstone presenting with mild complaints. Postoperative CT might locate missed gallstones in the peritoneal cavity, and early laparoscopy may prevent severe late complications.
Keywords: Gallstones, Laparoscopic Cholecystectomy, Abdominal Abscess
Introduction
The two most common complications in LC are biliary tract injury and gallbladder perforation resulting in gallstone spillage into the abdominal cavity. Although the number of biliary injuries has decreased over time with increasing surgical experience, the frequency of lost stones still remains the same. Traditionally, lost stones have been considered harmless, but there are many reviews that mention complications of this condition [1,2].
Although complications arising from spilled intraperitoneal stones are not common, complications requiring surgery, such as fistula and gallstone ileus, may develop in 0.7-2.3% of cases. The most frequently seen complication of lost stones is intra- abdominal abscess [2].
Case Report
A 60-year-old male admitted to the emergency department 6 weeks ago with sudden onset of pain in the right upper quadrant, which was accompanied with nausea and vomiting. He had type 2 diabetes for 15 years and has been using metformin. He did not have any previous surgery. Physical examination at that time revealed epigastric tenderness and a positive Murphy sign. Abdominal ultrasound showed thickened gall bladder wall of 5.6 mm and multiple stones up to 35 mm with accompanying sludge. He had intravenous antibiotics (ampicillin/sulbactam) for 5 days at the hospital, and after 6 weeks he was discharged with oral antibiotics to refer to the outpatient clinic.
After 6 weeks, the patient whose preoperative examinations were normal, underwent laparoscopic cholecystectomy. Examination revealed thick adhesions of the duodenum and omentum to the gallbladder and liver. All adhesions were taken down precisely, but the gallbladder wall was stone-like hard, which makes it difficult to properly manipulate the organ. Eventually, the fundus was ruptured and a viscous dark biliary fluid with sludge and some stones spilled out. The stones were collected, the fluid was aspirated, and the region was further irrigated and aspirated. The gallbladder was removed with a specimen bag and no further spillage occurred. A drain was placed. Prophylactic antimicrobial therapy with cephalosporins was continued after the operation. on the postoperative first day, WBC was 18,8 ×109/L, and CRP was 23,8 mg/dL. Drain content was serous. The patient was not discharged due to mild to moderate abdominal pain. Although there were no significant findings other than a minimal free fluid in the ultrasonography performed, computed tomography showed a missed gallstone (Figure 1). An immediate laparoscopy was performed on the same day and the retaining gallstone was removed. A drain was placed in the subhepatic space, which was removed gradually. The patient was discharged on postoperative sixth day. The patient had no complaints so far in 18 months period of follow-up.
Discussion
Although the diagnosis of incomplete stones is difficult, the number of missing stones has been reported between 1- 40%, similar to the perforation rates in studies. Most of the lost stones remain clinically asymptomatic, however about 0,04% to 19% of the lost stones can become symptomatic [3]. Asymptomatic stones can be incidentally detected later in life using radiological examinations. Patients may present with abdominal complaints such as pain, mass, obstruction, fever, or fistula. The most common complication due to intraperitoneal stone is intraabdominal abscess formation [1]. Other complications include retroperitoneal abscess, pleural empyema, intestinal obstruction, gastrointestinal fistula, and stone erosion in the lumbar region [4]. Lost gallstones may rarely mimic endometriosis, ovarian tumor, sarcoma, or peritoneal carcinomatosis [5].
Asymptomatic stones can be detected incidentally later in life using radiological examinations. An article reported the presence of a gallstone in the hernia sac during inguinal hernia repair five years after laparoscopic cholecystectomy [6]. Ffactors increasing the possibility of gallbladder perforation and bile leakage include lack of experience in laparoscopy, laser use for dissections, male gender, age, presence of acute cholecystitis and hydropic gallbladder, and previous operation history [7]. It has been reported that the loss of pigment stones, dropped stones larger than 1.5 cm, spilling of more than 15 stones, and stones falling into the perihepatic area have been reported to cause more infectious complications [2,8].
There are researchers who stated that in approximately 20% of cases, gallstones that spilled during surgery were not noticed, and the diagnosis was prolonged due to low clinical suspicion in patients who underwent LC. Delays in treatment decisions often result from subtle and variable symptoms and inadequate imaging [2,8].
As a result, efforts should be made for laparoscopic removal of spilled gallstones when noticed perioperatively. Conversion to an open procedure is not necessary. Conversion to an open procedure should only be considered if the experience of the surgeon with laparoscopy is insufficient. If gallbladder perforation has occurred, the abdominal cavity must be washed routinely to dilute the infected bile. The diagnosis is usually difficult in the early or late postoperative period. Often the most important reason for delayed diagnosis is insufficient suspicion. Abandoned stones after LC may result in focal and sometimes distant infections that may occur even years later and cause mild and atypical symptoms. This insufficient suspicion often results in long-term ineffective investigations for mild and atypical symptoms. Therefore, complications associated with gallstones remaining in the peritoneal cavity should be kept in mind even years after LC. It should be suspected that some of the atypical and mild symptoms may be due to underlying sources. If gallstones are detected during examinations, it is recommended to remove them first by percutaneous and laparoscopic methods.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
Funding: None
References
1. Zehetner J, Shamiyeh A, Wayand W. Lost gallstones in laparoscopic cholecystectomy: all possible complications. Am J Surg. 2007;193(1):73–8.
2. Carmichael SP, Zwischenberger, Brittany A, Bernard, Andrew C. Late Reoperation for Retained Gallstone After Laparoscopic Cholecystectomy. Surg Laparosc Endosc Percutan Tech. 2014; 24 (1):27-8.
3. Nooghabi AJ, Hassanpour M, Jangjoo A. Consequences of Lost Gallstones during Laparoscopic Cholecystectomy: A Review Article. Surg Laparosc Endosc Percutan Tech. 2016; 26(3):183–92.
4. Woodfield JC, Rodgers M, Windsor JA. Peritoneal gallstones following laparoscopic cholecystectomy: Incidence, complications, and management. Surg Endosc. 2004; 18(8):1200–7.
5. Ramamurthy NK, Rudralingam V, Martin DF, Galloway SW, Sukumar SA. Out of sight but kept in mind: Complications and imitations of dropped gallstones. Vol. 200, Am J Roentgenol. 2013; 200(6): 1244–53.
6. Heywood S, Wagstaff B, Tait N. An unusual site of gallstones five years after laparoscopic cholecystectomy. Int J Surg Case Rep. 2019; 56:107-9.
7. Mohiuddin K, Nizami S, Fitzgibbons RJ, Watson P, Memon B, Memon MA. Predicting iatrogenic gall bladder perforation during laparoscopic cholecystectomy: A multivariate logistic regression analysis of risk factors. ANZ Journal of Surgery. 2006; 76(3):130-2.
8. Brockmann JG, Kocher T, Senninger NJ, Schürmann GM. Complications due to gallstones lost during laparoscopic cholecystectomy: An analysis of incidence, clinical course, and management. Surg Endosc. 2002; 16(8):1226-32.
Download attachments: 10.4328:ACAM.20824
Zeliha Turkyilmaz, Orhan Sunar, Tuğrul Demirel, Osman Kula. Retrieval of a missed intraperitoneal gallstone with early second look laparoscopy. Ann Clin Anal Med 2021;12(11):1303-1305
Citations in Google Scholar: Google Scholar
A case of metastatic pancreatic tumor prepared for surgery by applying therapeutic plasmapheresis due to hyperthyroidism
Deniz Öçal 1, Tolga Kalaycı 2
1 Department of Gastroenterology Surgery, 2 Department of General Surgery, Erzurum Regional Education and Research Hospital, Erzurum, Turkey
DOI: 10.4328/ACAM.20634 Received: 2021-04-01 Accepted: 2021-06-22 Published Online: 2021-07-15 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1306-1310
Corresponding Author: Deniz Öçal, Department of Gastroenterology Surgery, Erzurum Regional Education and Research Hospital, Erzurum, Turkey. E-mail: drdenizocal@hotmail.com P: +90 505 297 33 30 Corresponding Author ORCID ID: https://orcid.org/0000-0002-8084-8866
A 64-year-old male patient admitted with complaints of nausea, vomiting, fever, and itching. After evaluation with laboratory tests and magnetic resonance cholangiopancreatography, a stent was placed in the common bile duct with Endoscopic retrograde cholangiopancreatography duo to common bile duct con- striction without tumoral pathology. After 7 days of follow-up, the patient was discharged. Five months later, the patient admitted with similar symptoms. In imaging tools, a mass located in ampullary area without metastasis was found. Surgery was planned for the patient. Unresectable pancreatic head tumor and millimetric liver metastasis were detected during surgery. A biopsy was taken from both the liver and the pancreatic mass, and the operation was terminated. Two months after surgery, the patient was admitted again with obstructive symptoms. The patient had hyperthyroidism on laboratory evaluation. Antithyroid drugs were started, but they were not effective. Therefore, 3 sessions of plasmapheresis were performed to provide euthyroidism to the patient. The patient, who underwent non-resective surgery, was discharged on the 22nd postoperative day.
Keywords: Hyperthyroidism, Plasmapheresis, Intestinal Obstruction, Operation
Introduction
Three treatment options are conventionally used in the treatment of hyperthyroidism: Anti-thyroid drugs, radioactive iodine therapy, and surgery. Anti-thyroid drugs are a safe first- line treatment for most patients. With anti-thyroid drugs, it is aimed to reduce blood thyroid hormone levels and the effects of these hormones. It is also aimed to release thyroid hormones into the blood circulation and prevent their peripheral effects. However, serious side effects such as hepatotoxicity and agranulocytosis can develop due to anti-thyroid drugs [1]. Drugs cannot be used effectively in intestinal obstruction cases. It has been reported that therapeutic plasmapheresis is an effective treatment option in cases where traditional treatment methods are ineffective or cannot be used in the short term for the patient to create euthyroidism before the surgery [2].
In this case report, we aimed to present a hyperthyroid patient with duodenal obstruction due to a periampullary tumor. Since hyperthyroidism cannot be controlled with anti-thyroid drugs and emergency surgery is required for the patient, therapeutic plasmapheresis was used to provide euthyroid state.
Case Report
A 64-year-old male patient was admitted to the Department of Gastroenterology, Erzurum Regional Education and Research Hospital, Erzurum, Turkey with complaints of nausea, vomiting, fever, oral intake disorder and itching in January 2020. In his medical history, the patient had hypertension, diabetes mellitus and goitre. He was taking propylthiouracil (50-milligrams tablets every 8 hours) in addition to anti-hypertensive drugs and antidiabetic drugs. There was no history of surgery.
On evaluation, the vital findings of the patient were as follows: blood pressure: 114/62 mm Hg, pulse rate: 118 beats per minute, oxygen saturation on room air: 96%, and body temperature: 38.1o Celsius. The patient’s sclera was icteric, his skin appeared yellowish. On abdominal physical examination, the patient had abdominal pain in deep palpation in the right upper quadrant. Digital rectal examination was also normal. Other system examinations were normal.
The patient’s pathological laboratory parameters were as follow: white blood cell count: 11.8×103/mm3, alanine aminotransaminase (ALT): 217 U/L [0-55], aspartate aminotransaminase (AST): 65 U/L [5-34], alkaline phosphatase (ALP): 321 U/L [40-150], gamma glutamyl transferase (GGT): 621 U/L [12-64], total bilirubin (TB): 8.2 mg/dL [0.3-1.2], and direct bilirubin (DB): 5.2 mg/dL [0-0.5]. Other laboratory parameters were not remarkable, including tumor markers.
On magnetic resonance cholangiopancreatography (MRCP) scan, gallbladder was hydropic. Common bile duct diameter increased (up to 12 millimeters). Endoscopic retrograde cholangiopancreatography (ERCP) was applied to the patient. During ERCP, it was observed that the distal common bile ducts ended bluntly without tumoral pathology. A stent was placed in the common bile duct with ERCP. The patient was consulted to the general surgery clinic, and control was recommended 10 days later in order not to miss the possibility of any tumor and to renew the tests. After 7 days of follow-up, when the patient’s bilirubin values decreased, the patient was discharged, and control was recommended. Since the beginning of the
COVID-19 pandemic, the patient has not been able to apply to the hospital for control. We determined that the patient did not come for control.
The patient admitted with similar symptoms in June 2020 at our clinic. On evaluation, the vital findings of the patient were as follows: blood pressure: 134/82 mm Hg, pulse rate: 98 beats per minute, oxygen saturation in room air: 95%, and body temperature: 37.2o Celsius. The patient’s sclera was icteric. On abdominal physical examination, the patient had abdominal pain with deep palpation in the right upper quadrant. A digital rectal examination was also normal. Other system examinations were normal. In laboratory findings, patient’s pathological laboratory parameters were as follow: ALT: 135 U/L [0-55], AST: 80 U/L [5-34], ALP: 221 U/L [40-150], GGT: 381 U/L [12-64], TB: 4.2 mg/dL [0.3-1.2], and DB: 2.2 mg/dL [0-0.5]. Other laboratory parameters were not remarkable, including tumor markers.
A lesion with a size of 15 millimeters was observed in the periampullary area in the distal part of the common bile duct, and MRCP was planned for the patient. On MRCP, gall bladder was hydropic. The common bile duct diameter was enlarged, and a stent was seen inside. There was a mass of approximately 22*16 mm in size in the periampullary area. Positron emission tomography (PET) was planned for the patient. On PET scan, there was a mass of approximately 22*18*36 mm in size in the periampullary area (SUV-MAX: 6.59) with heterogeneous hypermetabolic lymph nodes in millimetric sizes (SUV-MAX: 5.36). No distance metastasis was seen on the PET scan. Therefore, surgery was planned for the patient with a diagnosis of periampullary tumor. The surgery was started with a midline upper umbilicus incision. Examination revealed multiple millimetric nodular liver lesions. The gallbladder was hydropic, and there was an immobile lesion at pancreatico-duodenal junction. The mass was considered to be unresectable, and the operation was terminated after cholecystectomy and wedge biopsy from both the liver and the mass. After 2 days of follow- up in the service, the patient was discharged. In pathological evaluation, liver biopsy was consistent with adenocarcinoma metastasis, while pancreatic biopsy was consistent with dysplasia. In addition, the gallbladder pathology was consistent with chronic cholecystitis. Therefore, the patient was referred to oncology for chemotherapy.
Two months after the operation, the patient applied to our clinic again with abdominal pain, fever, vomiting and nausea. When evaluated, the vital findings of the patient were as follows: blood pressure: 94/58 mm Hg, pulse rate: 114 beats per minute, oxygen saturation in the room air: 93%, and body temperature: 37.9o Celsius. On physical examination, the patient had severe cachexia with conjunctival icterus. The thyroid gland was palpable with pain. On physical examination of the abdomen, the patient had abdominal pain with deep palpation in the right upper quadrant.
In laboratory findings, the patient’s pathological laboratory parameters were as follow: White blood cell count: 13.4*103/ mm3, hemoglobin level: 8.2 g/dL [14.1-17.8], ALT: 85 U/L [0- 55], AST: 45 U/L [5-34], ALP: 254 U/L [40-150], GGT: 531 U/L [12-64], TB: 2.1 mg/dL [0.3-1.2], DB: 0.9 mg/dL [0-0.5], thyroid stimulating hormone (TSH): 0.01 μIU/mL [0.55-4.78], freeT4: 2.23 ng/dL [0.70-1.48]. Other laboratory parameters were not remarkable. MRCP was taken to patient. On MRCP, the gallbladder was hydropic. The common bile duct diameter was enlarged, and a stent was seen inside. There was a mass of approximately 27*22 mm in size in the periampullary area (Figure 1).
The patient was hospitalized with the diagnosis of cholangitis. Oral intake was stopped. Intravenous fluid replacement was started. The nasogastric catheter was inserted due to the severe vomiting of the patient. Intravenous piperacillin- tazobactam (4.5-gram vial every 8 hours) and intravenous metronidazole (500 mg/100 mL every 8 hours) were started. Due to the abnormal thyroid function tests, the patient’s anti- thyroid treatment was arranged. The propylthiouracil dose was increased to 100 mg tablets every 8 hours, and propranolol (40 mg tablets every 12 hours from the nasogastric tube) was started. Supraventricular tachycardia (170-180 beats per minute) occurred on the third day of admission. There was no pathology in cardiac evaluation with echocardiography. The patient was transferred to the intensive care unit for follow-up. Heart rate was taken under control with diltiazem intravenous slow infusion. On the fifteenth day of admission, the thyroid function tests were as follows: TSH: 0.00 μIU/mL [0.55-4.78], freeT4: 2.38 ng/dL [0.70-1.48]. Contrast-enhanced abdominal CT was planned for the patient in order to evaluate the digestive system passage due to the prominence of thyrotoxicosis, despite anti-thyroid therapy on the 10th day of his admission. On CT scan, there was almost complete obstruction due to a tumor (Figure 2). A diversion surgery was planned for the continuity of the digestive system. Therapeutic plasmapheresis was started because hyperthyroidism poses a high risk for surgery. After 3 sessions of plasmapheresis with fresh frozen plasma, the patient’s thyroid function tests were as follows: TSH: 0.45 μIU/ mL [0.55-4.78], freeT4: 1.62 ng/dL [0.70-1.48].
The patient was taken to emergency surgery. Examination revealed an immobile lesion surrounding the third part of the duodenum. Diversion surgery was planned. Gastrojejunostomy, choledocojejunostomy and jejunojejunostomy were performed. One of the drains was placed in the subhepatic area and the other in the pelvic cavity. The patient was followed up in the intensive care unit after surgery. Oral intake was started on the postoperative third day. Propylthiouracil treatment was continued with 100 milligrams tablets every 8 hours. Klebsiella pneumoniae grew in the culture examination of intraoperative choledochal bile sample, and amikacin intravenous vial (500 mg/2 mL started every 12 hours). As the patient had persistent fever, contrast-enhanced thorax and abdominal CT scan was performed on the postoperative fifth day. The patient had bilateral pleural effusion and atelectasis on CT scan without abdominal pathology. Escherichia coli grew in the blood culture on the postoperative eighth day, and meropenem 1 gram vial every 8 hours was started. All drains were removed on the 10th postoperative day, and the patient was transferred to the service for follow-up. On the postoperative 12th day, a peri-umbilical abscess was seen, and this abscess was drained. Antibiotherapy was completed according to the culture results. The patient was discharged on the 22nd postoperative day with propylthiouracil (50 mg tablets every 8 hours). No complications were detected in the patient’s follow-up 1 month after discharge. Chemotherapy treatment was started again.
Discussion
Plasmapheresisisatreatmentmethodbasedontakingwhole blood out of the body and separating it into plasma and shaped elements with the help of a plasmapheresis device and re- circulating shaped elements with replacement fluid [3]. The purpose of this method is to quickly remove protein-derived hormones, harmful plasma components, immune complexes and toxins from the circulation. Since most thyroid hormones are bound to plasma proteins in blood circulation, plasmapheresis allows dilution of the concentration of free thyroid hormones. But the therapeutic effect of plasmapheresis is temporary.[4] Plasmapheresis was first shown in a case of thyrotoxicosis that the thyroid hormone level was decreased successfully after plasmapheresis in 1970 [5]. Subsequently, case reports have been published showing that thyroid hormone levels decrease rapidly with therapeutic plasmapheresis applications and a successful clinical response occurs [6]. In the last published American Apheresis Association guideline, it is recommended that the treatment decision should be personalized because the optimal role of therapeutic plasmapheresis in thyrotoxicosis is not fully determined. In the same guideline, clinical improvement can be seen before the decrease in hormone levels, therefore it is recommended to continue plasmapheresis every 2-3 days. Instead of replaced plasma, albumin, fresh frozen plasma, hydroxyethyl starch (HES) or their mixture is used as replacement fluid [4]. Fresh frozen plasma was used as a replacement fluid in this patient.
Fever, urticaria, hypotension, paresthesia due to citrate, decrease in coagulation factors and immunoglobulins and infection transmission risk may be observed depending on the replacement fluid. Rarely, anaphylactoid reactions, resulting from the use of fresh frozen plasma, constitute the most serious complication of plasmapheresis. It is the leading cause of death due to plasmapheresis [7]. In our patient, no complications related to the procedure were observed during three sessions of plasmapheresis.
An important advantage is that fresh frozen plasma is inexpensive and easy to obtain. A review of reported complications from over 15,000 plasma exchange treatments found that adverse reactions were substantially more common with fresh frozen plasma than with albumin replacement (20 versus 1.4 percent) [8].
In conclusion, in our case, effective results were obtained in laboratory and clinically with therapeutic plasmapheresis. It is not a frequently preferred method due to its expensive, invasive nature and technical limitations. Therapeutic plasmapheresis can be a method that can be used as an alternative or additional treatment to standard treatments in cases where primary treatment options are contraindicated or ineffective in the stage of preparing severe hyperthyroid patients for the operation.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Cooper DS. Antithyroid drugs. N Engl J Med. 2005; 352(9):905-17.
2. Braithwaite SS, Brooks MH, Collins S, Bermes EW. Plasmapheresis: an adjunct to medical management of severe hyperthyroidism. J Clin Apher. 1986; 3(2):119- 23.
3. Kaplan AA. Therapeutic plasma exchange: a technical and operational review. J Clin Apher. 2013; 28(1):3-10.
4. Szczepiorkowski ZM, Winters JL, Bandarenko N, Kim HC, Linenberger ML, Marques MB, et al. Guidelines on the use of therapeutic apheresis in clinical practice—evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher. 2010; 25(3):83-177.
5. Ashkar FS, Katims RB, Smoak WM, Gilson AJ. Thyroid storm treatment with blood exchange and plasmapheresis. JAMA. 1970;214(7):1275-9.
6. Herrmann J, Hilger P, Krüskemper H. Plasmapheresis in the treatment of thyrotoxic crisis (measurement of half-concentration times for free and total T3 and T4). Acta Endocrinol Suppl (Copenh). 1973;173:22.
7. Shemin D, Briggs D, Greenan M. Complications of therapeutic plasma exchange: a prospective study of 1,727 procedures. J Clin Apher. 2007; 22(5):270-6.
8. Norda R, Stegmayr BG, Group TSA. Therapeutic apheresis in Sweden: update of epidemiology and adverse events. Transfus Apher Sci. 2003; 29(2):159-66.
Download attachments: 10.4328:ACAM.20634
Deniz Öçal, Tolga Kalaycı. A case of metastatic pancreatic tumor prepared for surgery by applying therapeutic plasmapheresis due to hyperthyroidism. Ann Clin Anal Med 2021;12(11):1306-1310
Citations in Google Scholar: Google Scholar
An analysis of the 50 most cited articles on congenital spinal anomalies
Ahmet Mert 1, Bahri Bozgeyik 2
1 Department of Orthopedic Surgery, Niğde Ömer Halisdemir University, Niğde, 2 Department of Orthopedic Surgery, Gaziantep University, Gaziantep, Turkey
DOI: 10.4328/ACAM.20705 Received: 2021-05-14 Accepted: 2021-08-14 Published Online: 2021-08-19 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1311-1314
Corresponding Author: Bahri Bozgeyik, Department of Orthopedic Surgery, Gaziantep University, Gaziantep, Turkey. E-mail: bahribozgeyik@gmail.com P: +90 507 971 1156 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9832-0648
Aim: In this study, we aimed to identify the 50 most cited articles on congenital spinal anomalies in the literature.
Material and Methods: ‘Congenital spinal anomalies’ and ‘congenital spinal abnormalities’ were used as search words in the Web of Science database. The 50 most cited articles were analyzed. The study was carried out in May 2020. The publications in the study covered the years between 1990-2020. For all the articles, the journal in which they were published, the number of citations, the year of publication, the country of origin for citations, the level of evidence, and the type of study were recorded.
Results: After searching in the Web of Science database, 1632 articles were found in the search results. The number of citations of the articles ranged from 35 to 391. The most cited article was by Bowman et al. titled ‘Spina bifida outcome: 25- year prospective’ published in Pediatric Neurosurgery in 2001. The most published journal was the ‘Spine’ journal. Twenty-six (52%) articles were conducted in the United States of America. The main focus of the articles was on congenital segmentation defects. Original research articles (n = 31) were the most common study type.
Discussion: Congenital spinal anomalies are difficult to diagnose and treat in spinal diseases. Analyzing the studies conducted in the literature will show, which topics are needed for more research and will guide the authors.
Keywords: Congenital Spinal Anomalies, Spine Abnormalities, Most Cited, Anomaly
Introduction
Congenital spinal anomalies can be defined as the generality of many complex diseases such as intraspinal pathologies, segmentation defects, congenital spinal deformities, and tube defects. Diagnostic and treatment processes involve difficulties. Congenital spinal anomalies can be caused by developmental defects in the axial skeletal system and often progress with intraspinal anomalies and other organ and system anomalies [1,2]. Although the etiology of the factors that cause congenital vertebral anomaly still has not been elucidated, environmental, genetic and chemical factors are thought to play a role in the etiology [3]. The diagnosis rates of congenital anomalies,which have attracted attention from the past to the present, have increased due to the increased imaging methods [4]. The number of studies on congenital spinal anomalies has also increased due to increasing diagnosis rates. Previously, there have been many studies analyzing articles on spinal diseases [5- 10]. However, there are no studies in the literature analyzing published articles on congenital spinal anomalies. Our aim in this study is to perform a characteristic analysis of the 50 most cited articles on congenital spinal anomalies.
Material and Methods
On May 20, 2020, the search was made using the terms ‘congenital spine abnormalities’ and ‘congenital spine anomalies’ using the ISI Web of Science platform. The publications obtained as a result of searches using these two keywords were analyzed. Publications were sorted from the most cited to the least cited. The study covered the years between 1990 and 2020. The 50 most cited articles were examined. Articles that were not in English and did not refer to congenital spinal anomalies in the search results were excluded from the study. The authors of the analyzed articles, the number of citations, the country in which they were published, the level of evidence, publication date, the journal in which they were published, and the type of study were evaluated. The focus topics of all articles were examined. In addition, among the 50 most cited articles, the most published journals and the countries where the publications were produced the most were analyzed. The study is a bibliometric analysis, therefore statistical analysis was not performed.
Results
After searching, 1632 articles were found in the search results. The number of citations of the articles ranged from 35 to
391 (average 73.84) (Table 1). The total number of citations of fifty articles was 3692. Eight articles received more than 100 citations. The most cited article was by Bowman et al. titled ‘Spina bifida outcome: 25- year prospective’ published in Pediatric Neurosurgery in 2001 [11].
The articles were published in 30 different journals. Most of the articles were published in the Spine (n = 9) journal. This was followed by the Journal of Bone and Joint Surgery-American volume (n = 7). Three articles were published in the Journal Of Neurosurgery, 3 articles in the Journal Of Pediatric Orthopedics, and 2 articles in the Radiographics journal.
Most of the articles (26) were produced in the USA (52%). The second country was England with three articles (6%) and China with three articles (6%) (Table 2).
Thirty-one (62%) articles were original research articles, 14 (28%) were reviews, and 5 (10%) were case reports. There was only one article with a Level of evidence (LOE) 1 (2%). Seven articles (14%) were LOE II, 24 (48%) articles were LOE III, 11 (22%) articles were LOE IV, and 7 (14%) articles were LOE V. All the articles in our study covered the years 1990-2020. The ten-year interval when the articles were published the most was between 2000 and 2010, with 30 articles .In addition, 19 (38%) articles were published in the 1990-2000 interval and 1 (2%) in the 2010-2020 interval. The oldest article published by Bradfod et al in January-February 1991 was titled ‘Intraspinal Abnormalities And Congenital Spine Deformities – A Radiographic And MRI Study ‘ [12].
Among the 50 most cited articles, the most published topic was congenital segmentation defects of the spine (n = 16), followed by congenital spinal deformities (n = 14), followed by spinal dysraphism, radiological studies, and neurofibromatosis (Table 3).
Discussion
Congenital spinal anomalies are often accompanied by an increased incidence of internal and external spinal abnormalities [13,14]. Pathologies such as spinal dysraphisms, congenital spinal deformities, spinal cord malformations, segmentation anomalies are located in the parts of the congenital spinal anomalies that concern the spine. Studies in the literature have focused especifically on congenital spinal anomalies and the surgical treatment and outcomes of these problems [15-17].
In our study, we tried to reveal the literature analysis of articles on congenital spinal anomalies.
When we looked at our study, we found that the article that received the most citation was related to spina bifida. The study was carried out in 2001, and spina bifida disease was investigated sufficiently in the literature as it is a complex spinal disease that requires long- term follow-up and treatment. In a study conducted with 118 patients, it was shown that 75% of patients reached early adulthood after 25 years of follow-up [11].
Congenital spinal anomalies include many diseases. In our study, we found that the most cited articles were related to segmentation defects. Another topic of interest was congenital spinal anomalies. Considering that segmentation defects cause many spinal deformities, it can be thought that the relationship of spinal deformities with congenital anomalies attracts more attention.
Looking at the level of evidence of the articles, the majority was LoE II-III with 31 articles. There is only one study with the level of evidence I. In the literature, the LoE has been shown to affect clinical efficacy and study plans of the article [18]. In our analysis, the majority of the articles being LoE II-III may reflect a lower level of quality for those articles.
The most cited articles in our study were from the USA (52%). On the other hand, although there were studies in the Middle East and Europe and Far East countries, it is seen that the most research and citation is by far in the USA.
The articles were published in 30 different journals. Most of the articles were published in the Spine journal. The fact that vertebral surgery is performed by both orthopedists and neurosurgeons has led both branches to publish in major journals. In fact, this is an indication of the importance of congenital spinal anomalies and the importance of adding new data to the literature. Original research articles constituted 62% of the most cited studies. It can be clearly seen from the analysis that the original research articles were cited more. When the dates of the most cited articles were analyzed, it was seen that there were 30 articles between 2000-2010. In articles published after 2010, there is only one article among the most cited. Although it is thought that articles close to our time will have a lower number of citations, for example, an article that was published newly, it can be understood that the subject attracted the most attention in the literature between 2000-2010 [19].
Our study has some limitations. Theoretically, the number of citations may have increased after May 20, 2020, when we conducted the study, and this may change the current situation. The other limitation is that the citation analysis can be influenced by many factors, including the publication date of the article, the subject of research, and the fact that a publication is highly cited does not indicate that it is superior to all other cited studies. Despite some limitations, citation analysis is the most ideal method to demonstrate the quality and effectiveness of publications and guides clinicians. Conclusion
Congenital spinal anomalies are difficult for clinicians as there are many points that still need to be clarified, and they will be of interest in the literature. This study is the first to analyze publications in the literature on congenital spinal anomalies and includes an analysis that we think may guide other clinicians in their studies.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Basu PS, Elsebaie H, Noordeen MH. Congenital spinal deformity: a comprehensive assessment at presentation. Spine (Phila Pa 1976). 2002; 27(20):2255-9. DOI:10.1097/00007632-200210150-00014
2. Suh SW, Sarwark JF, Vora A, Huang BK. Evaluating congenital spine deformities for intraspinal anomalies with magnetic resonance imaging. J Pediatr Orthop. 2001; 21(4):525-31.
3. Hensinger RN. Congenital scoliosis: etiology and associations. Spine (Phila Pa 1976). 2009; 34(17):1745-50. DOI:10.1097/BRS.0b013e3181abf69e
4. Upasani VV, Ketwaroo PD, Estroff JA, Warf BC, Emans JB, Glotzbecker MP. Prenatal diagnosis and assessment of congenital spinal anomalies: Review for prenatal counseling. World J Orthop. 2016; 7(7):406-17. DOI:10.5312/wjo. v7.i7.406
5. Lee YC, Brooks F, Sandler S, Yau YH, Selby M, Freeman B. Most Cited Publications in Cervical Spine Surgery. Int J Spine Surg. 2017; 11(3):19. DOI:10.14444/4019
6. Donnally CJ 3rd, Rivera S, Rush AJ 3rd, Bondar KJ, Boden AL, Wang MY. The 100 most influential spine fracture publications. J Spine Surg. 2019; 5(1):97-109. DOI:10.21037/jss.2019.01.03
7. Murray MR, Wang T, Schroeder GD, Hsu WK. The 100 most cited spine articles. Eur Spine J. 2012; 21(10):2059-69. DOI:10.1007/s00586-012-2303-2
8. Skovrlj B, Steinberger J, Guzman JZ, Overley SC, Qureshi SA, Caridi JM, et al. The 100 Most Influential Articles in Cervical Spine Surgery. Global Spine J. 2016; 6(1):69-79. DOI:10.1055/s-0035-1551652
9. Yang G, Li Z, Ye W, Huang S, Liu S, Liu K, et al. Bibliometric Analysis of the 100 Most Cited Articles on Intervertebral Disk Research: From 1900 to 2017 Year. Clin Spine Surg. 2020; 33(3):104-10. DOI:10.1097/BSD.0000000000000863
10. Ankomah F, Ikpeze T, Mesfin A. The Top 50 Most-Cited Articles on Thoracolumbar Fractures. World Neurosurg. 2018; 118:e699-e706. DOI:10.1016/j. wneu.2018.07.022
11. Bowman RM, McLone DG, Grant JA, Tomita T, Ito JA. Spina bifida outcome: a 25-year prospective. Pediatr Neurosurg. 2001; 34(3):114-20. DOI: 10.1159/000056005.
12. Bradford DS, Heithoff KB, Cohen M. Intraspinal abnormalities and congenital spine deformities: a radiographic and MRI study. J Pediatr Orthop. 1991; 11(1):36- 41. DOI: 10.1097/01241398-199101000-00009.
13. Beals RK, Robbins JR, Rolfe B. Anomalies associated with vertebral malformations. Spine (Phila Pa 1976). 1993; 18(10):1329-32. DOI:10.1097/00007632-199308000-00012
14. Basu PS, Elsebaie H, Noordeen MH. Congenital spinal deformity: a comprehensive assessment at presentation. Spine (Phila Pa 1976). 2002; 27(20):2255-9. DOI:10.1097/00007632-200210150-00014
15. Hensinger RN, Lang JE, MacEwen GD. Klippel-Feil syndrome; a constellation of associated anomalies. J Bone Joint Surg Am. 1974; 56(6):1246–53.
16.MacEwenGD,WinterRB, HardyJH. Evaluation of kidney anomalies in congenital scoliosis. J Bone Joint Surg Am. 1972; 54:1451–4.
17. Guerrero G, Saieh C, Dockendorf I, et al. Genitourinary anomalies in children with congenital scoliosis. Rev Chil Pediatr. 1989; 60(5):281–3.
18. Ahmad T, Chinoy MA, Tayyab M. Using levels of evidence to compare clinical impact from research. J Evid Based Med. 2014; 7(1):38-44. DOI:10.1111/ jebm.12085
19. Tekin SB, Karslı B, Büyükbebeci O, Demir İH, Gökalp AY, Kılınçoğlu V. How do vertebroplasty and kyphoplasty affect the quality of life of patients with multiple myeloma spinal metastasis? Eur J Orthop Surg Traumatol. 2020; 30(8):1447-51. DOI:10.1007/s00590-020-02721-3
Download attachments: 10.4328:ACAM.20705
Ahmet Mert, Bahri Bozgeyik. An analysis of the 50 most cited articles on congenital spinal anomalies. Ann Clin Anal Med 2021;12(11):1311-1314
Citations in Google Scholar: Google Scholar
Effect of joint manipulation and muscle energy technique in patients with Chronic Obstructive Pulmonary Disease: A review
Diksha Bains 1, Manu Goyal 1, Aksh Chahal 1, Mohammad Abu Shaphe 2
1 Maharishi Markandeshwar Institute of Physiotherapy and Rehabilitation, Maharishi Markandeshwar, Mullana, Haryana, India, 2 Department of Physical Therapy, College of Applied Medical Science, Jazan University, Kingdom of Saudi Arabia
DOI: 10.4328/ACAM.20707 Received: 2021-05-15 Accepted: 2021-08-07 Published Online: 2021-09-18 Printed: 2021-11-01 Ann Clin Anal Med 2021;12(11):1315-1319
Corresponding Author: Mohammad Abu Shaphe, Department of Physical Therapy, College of Applied Medical Science, Jazan University, Kingdom of Saudi Arabia. E-mail: mshaphe@jazanu.edu.sa P: +96 659 716 55 64 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6046-9543
Aim: Chronic Obstructive Pulmonary Disease (COPD) influences the function of the diaphragm muscle, thus affecting the maximum inspiratory pressure. It is a constantly progressive disease characterized by chronic obstruction of pulmonary flow, which is irreversible in nature. We reviewed the literature for evidence of improvement in pulmonary function through Muscle Energy Technique and Joint Manipulation by decreasing the work of accessory muscles of breathing, improvement in chest expansion, improving thoracic spine mobility, and increasing diaphragm muscle strength.
Material and Methods: Articles used in the review were only in English, and non-English language articles were excluded. The database used to extract the literature was restricted to PubMed, Science Direct, Cochrane. Participants with COPD of both genders between 40 to70 years of age were included. Only articles with randomized controlled trials and non-randomized controlled trials and studies, which used manual therapy involving muscle energy techniques and manipulation were included. Studies that did not use main treatment such as physical hand contact were excluded. Outcome measurements included spirometry, Health-Related Quality of Life, Modified Borg Exertion Scale, pulse oximeter and Maximum Inspiratory Pressure, exercise capacity was measured with 6-minute walk test.
Result: The current evidence regarding the effect of joint manipulation, Muscle Energy Technique, and manual therapy on the musculoskeletal system in pa- tients with COPD is inconclusive. The analysis included six randomized controlled trials and non-randomized controlled trials having dissimilar study design, study population, as well as outcome measures. All studies showed a higher risk of bias.
Discussion: The current study provides less evidence about muscle energy technique and joint manipulations effect on COPD patients but found a significant effect of both techniques in combination with manual therapy on pulmonary functions.
Keywords: Manual Therapy, Joint Mobilization, Thoracic Manipulation, Chronic Disability, Chest Physiotherapy
Introduction
Chronic Obstructive Pulmonary Disease (COPD) is one of the major health issues predicted to be the third leading cause of death and the fifth leading cause of chronic disability [1]. COPD is a progressive condition characterized by chronic obstruction in the flow of the lung, which is irreversible in nature [2] and characterized by loss of pulmonary function with symptoms such as the production of sputum, breathlessness and cough [3]. In return, impaired respiratory rate leads to increased morbidity and mortality by decreasing physical function [4]. COPD accentuates changes in the airway and lung parenchyma, which leads to bronchial hypersecretion and bronchoalveolar instability, resulting in reduced expiratory flow rate and air trapping, which is called “dynamic hyperinflation”. This further leads to increases in Expiratory Reserve Volume (ERV), Residual Volume (RV) and End- Expiratory Lung Volume (EELV) [5]. Phrenic nerve motor innervation, supplying to diaphragm, originates at C3-C5 nerve root and works along with secondary muscles to allow normal respiration [6]. COPD not only affects the lungs but also involves the peripheral muscle system and its function [7]. Therefore, respiratory muscles play important role in the pathogenesis of breathlessness [2]. Pulmonary hyperinflation causes respiratory muscle alteration, which decreases the contraction of the diaphragm, in other words, diaphragm capacity is reduced to generate trans-diaphragmatic pressure. Thus, the workload is transferred to the accessory muscle, which increases airway resistance and limitation of airflow [8].
Over the time, recruitment of accessory respiratory muscle in COPD leads to compensatory shortening and over activation of the scalene, sternocleidomastoid, and trapezius muscles. Manual therapy is becoming increasingly preferred as a treatment for COPD. The aim of manual therapy is to improve function, decrease pain and facilitate movement [9]. Soft tissue mobilization and massage therapy are therapeutic options for the treatment of a pathological condition, which simultaneously affects the musculoskeletal system and other systems of the body [10]. Manual therapy includes soft tissue therapy, joint manipulation, and mobilization have the potential to address variations in breathing mechanics related to decreased function of the lung. It is also used to increase the mobility of the thoracic region, by reducing the work of breathing, as well as manage pain related to musculoskeletal system.[11].
The Muscle Energy Technique (MET) is a form of manual therapy used to improve conditions related to COPD [2]. MET is a technique used to lengthen muscles and fasciae, which resist flexibility. In MET, the patient is required to generate force by triggering the musculotendinous unit against the counterforce applied by the therapist/clinician. MET application consists of contractions 3-5 times for 5 seconds, followed by 3 stretching for 0-60 seconds [12]. Whereas spinal manipulative therapy is a high-speed, low-amplitude force used to mobilize a joint. This technique can increase joint range of motion and decrease the intensity of pain. [11] This high-graded joint manipulation and mobilization is applied to the region of spinal stiffness or paravertebral tissue, which improves the chest wall compliance [13].
Need for Research: It is therefore hypothesized that in COPD, there is tightness of accessory muscles, which may influence the function of the diaphragm muscle, affecting maximum inspiratory pressure and restricted chest mobility. There is a dearth of literature on conclusions following a systematic review studying the combined effect of Joint Manipulation and MET. Thus, the rationale of this short review is to find the effect of Joint Manipulation of the thorax and MET of the accessory muscle of the neck on lung function in patients with COPD. Therefore, the aim of the current review is to synthesize and evaluate studies, which have investigated the effect of joint manipulation and MET on Pulmonary Function Test (Spirometer) and 6-minute walk test in COPD patients.
Material and Methods
The review collected data from randomized controlled trials (RCTs) and non-randomized controlled trials (non-RCTs) and followed the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines (Figure 1).
Articles on manual therapy complemented soft tissue manipulation, stretching, muscle energy technique and thoracic joint manipulation to improve pulmonary function and joint range of motion were used. MET is a manual technique that involves the voluntary contraction of a muscle and increases or decreases the length between origin and insertion. Articles used in the review were in English only and those other than English were excluded. The database used to extract literature were restricted to PubMed, Science Direct and Cochrane. Medical Subject Heading (MeSH) terms or title/abstract keywords and synonyms were used and modified for every database. The articles that were used for review were published from January 2011 to May 2019 (Table 1).
• Chronic Airflow Obstruction, Chronic Obstructive Pulmonary Disease, Chronic Airflow Obstructions, Chronic Obstructive Airway Disease, COAD, Chronic Obstructive Lung Disease, Airflow Obstruction, Chronic, Airflow Obstructions,
• Manipulation, Osteopathic, musculoskeletal manipulation, Diagnostic Techniques and Procedures, Manual therapy, stretching, osteopathic manipulation techniques, joint mobilization, chiropractic, chiropractic manipulation, and MET (post-isometric relaxation and variants)
Eligibility Criteria
Participants: Only participants with COPD were included. Articles with subjects aged 40 to 70 years were included, considering the specifics of both genders.
Interventions: Articles only with RCTs were included and studies with Manual Therapy containing MET and Manipulation were included. Studies were excluded in which main treatment like physical manual contact of hand was not applied (e.g., with mechanical tools or devices) or other than physiotherapy such as tai-chi, point application, yoga, acupressure, acupuncture, Chinese herbal medicine, reflexology, or other traditional Chinese medicine techniques were excluded. In addition, studies based on MET and Thoracic manipulation along with Manual Therapy intervention such as gentle massage, passive stretching were included and other than such treatment studies such as chest physiotherapy, which include chest vibration, percussion, secretion clearance techniques, including postural drainage or facilitatory chest physiotherapy were excluded.
Comparisons: RCTs include conventional therapy (stretching, myofascial release), sham therapy, exercise, and light manual technique
Outcome measures: RCTs included the following outcome measures: spirometry, exercise capacity on the 6-Minute Walk Test (6-MWT), HRQL, Modified Borg Exertion Scale (MBES), pulse oximeter and Maximum Inspiratory Pressure.
Results
Yilmaz Yelvar GD et al. (2016) investigated a study to find out the immediate effect of manual therapy on 30 severe COPD with a mean age of 62.4 ± 6.8 years. Outcome measurements included a spirometer, pulse oximeter, Maximal Expiratory Pressure (MEP), Maximal Inspiratory Pressure (MIP), Dynamic volumes (FEV1, FVC, and VC), modified Borg rating of perceived exertion scale and Visual Analog Scale (VAS) for breathing difficulty taken before and after the 45 minutes of manual therapy included: decompression of the suboccipital, cervical vertebral gliding in the anterior-posterior direction, myofascial release of the trapezius muscles, sternocleidomastoid, intercostal muscle, paravertebral muscle and sternoclavicular, thoracic vertebral joint gliding in the direction from anterior- posterior, diaphragmatic release, rib raising technique, scapula- thoracic joint mobilization. Myofascial release techniques were applied only once, 3–5 minutes for each muscle. The gliding techniques were applied 5 times to each joint for 30 seconds. The study concluded that a single session of manual therapy immediately improved the condition of COPD. There was an improvement in inspiratory muscle strength, an improvement in oxygen saturation, and a significant decrease in fatigue, dyspnea, heart rate, and breathing rate (Table 2).
Engel et al. (2016) included 33 patients with COPD aged 55-70 years in their study to evaluate the effect of manual therapy on pulmonary rehabilitation. Participants were divided into 3 groups and the pulmonary function test was tested using the Forced Expiratory St. George’s Respiratory Questionnaire (SGRQ), Volume in the first second (FEV1), Forced Vital Capacity (FVC), 6-Minute Walk Test (6-MWT), and Hospital Anxiety and Depression (HAD) scale. Group 1 received Pulmonary Rehabilitation (PR) only, Group 2 received Soft Tissue Therapy (ST) and PR and Group 3 received PR, ST, and Spinal Manipulative Therapy (SM). Pulmonary rehabilitation contained 24 weeks of intervention. Week 0-8 for ‘initial assessment’, end of 8th week for ‘introductory stage’, week 16 for ‘maintenance stage’ and week 24 was non ‘interventional phase’ The results of the study indicated that there was a significant increase between 3 groups at 24 weeks for FVC and for 6 MWT for ST+PR, ST+SMT+PR at 16 and 24 weeks there was a significant difference compared to PR group.
In a study by Maskey-Warzechowska et al. (2019), the authors investigated 19 COPD patients with a median age of 68 years, who were randomly allocated into two groups. Group 1 who received osteopathic manual therapy (OMT) (Suboccipital decompression, Deep cervical fascia release, Thoracic lymphatic pump, Diaphragm stretching, or sham therapy include mobilization), and other group received sham therapy, and after 2weeksofintervention,participantwerecrossedoverbefore and after both procedures, pulmonary function and dyspnea were compared during the second session. They concluded that there was no significant effect shown in a single session of OMT and sham therapy, neither on pulmonary function nor on dyspnea before and after OMT or sham procedures.
In a study by Sule et al. (2017), 30 patients with Gold Criteria having severe COPD in the age group of 40-60 years were included, who were divided into 2 groups. One group received 3 repetitions of static stretching for 30-60 seconds, twice a day for 1 week, and the other group received pulsed MET Pulsed MET 20-30 times twice a week for 1 week, and this demonstrated that Pulsed MET showed better results than Static Stretching, as there was a greater improvement in FEV1, a reduction in Respiratory rate, and an increase in oxygen saturation. Muscle strength was also seen with MET, with an increase in muscle strength, FEV1 is increased from 43.27 to 49.4 as compared to static stretching. They concluded that Pulsed MET is more effective in improving FEV1 compared to static stretching in COPD patients, but statically it was less significant.
In a study by Anand et al. (2013), 30 moderates to severe staged COPD patients aged between 40–60 years were included and allocated into two groups. Group 1 received Conventional Chest Physiotherapy (CPT) and Group 2 received CPT with MET. Both groups received 3 sessions for 3 days. This study has shown that significant improvement was seen after three days of a treatment session in both groups, but with greater improvements in CPT with the MET group in the form of increased chest expansion, reduced dyspnea, increased exercise tolerance, regulation of autonomic dysfunction and improved quality of life.
Cruz-Montecinos et al. (2017) performed a study to evaluate the effect of immediate soft tissue therapy on severe COPD patients. The study included 12 stable patients with gold stages 3 and 4 with a mean age of 62.4 years. The pulmonary function test included Total lung Capacity (TLC), Expiratory Reserve Volume (ERV), Pulse Oximetry, Vital Capacity (VC), Residual Volume (RV), Inspiratory Capacity (IC), Airway resistance, Respiratory rate and Heart rate. Participants received an immediate 30-minute session manual therapy, including suboccipital muscle release, myofascial release of the anterior thoracic and anterior cervical, the release of sternum, balance costal ligament, muscle energy techniques for 1 minute 40 seconds for each muscle (1 minute 40 seconds each). Single treatment sessions of soft tissue manual therapy (STMT) had an immediate effect on lung function in patients with severe and more severe COPD. RV (P=0.002), IC (P=0.039) and SpO2 increased from 93% to 96% (P=0.001). Therefore, a single session of STMT has a significant improvement.
Discussion
This systematic review investigated the latest evidence on the effect of joint manipulation and Muscle Energy Technique along with manual therapy on the musculoskeletal system in patients with COPD. The analysis included six RCTs having dissimilar study designs, study population and outcome measures. All studies showed a high risk of bias. The current study findings are not similar to the results of other literature sources. Two current studies have shown that in patients with severe COPD after a single session of intervention, including manual therapy, there may be a positive effect on pulmonary hyperinflation [14, 15]. Cruz-Montecinos et al. (2017) proved that manual therapy resulted in a significant decrease in RV, TLC, and ERV along with anincreaseinoxyhemoglobinsaturation,inspiratorycapacity in the single treatment session [5]. Yilmaz et al. (2016) found a significant progression in FEV1, FVC, the strength of respiratory muscle, oxyhemoglobin saturation, and a decrease in dyspnea perception, following a single session of mobilization of thoracic spine and soft tissue therapy [14].
According to Sule et al., pulsed MET showed better results than static stretching as more improvement is seen in FEV1, reduction in respiratory rate, and increased oxygen saturation. MET is an active technique, whereas stretching is passive. An increase in muscle strength was seen with MET, with an increase in muscle strength, FEV1 increased from 43.3 to 49.4, whereas the group who received MET along with conventional exercise showed a better improvement in FEV1 [14,16].
Anand et al. [17] revealed the potential effect of the application of MET on lung function and also efficiency in improving the conventional chest physiotherapy in patients having COPD. After application of MET to dysfunctional accessory inspiratory muscles, it had significant potential to improve pulmonary function and also better quality of life in COPD patients. This study showed significant improvement in both groups following three days of treatment session. Greater improvements were seen in CPT with MET group by reducing dyspnea, improved chest expansion, tolerance to exercise regulation of autoimmune dysfunction, and improved quality of life [17].
Several limitations of the current review are acknowledged. Alteration in treatment protocol, treatment session duration, as well as in outcome measures between studies likely influenced the results. The populations also were small in size and had a chance of bias. There was no study, which indicated only single MET, and Joint Manipulation had an effect on pulmonary lung functions.
Conclusions
The present study provides less evidence about muscle energy technique and joint manipulations effect on COPD patients but has a significant effect of both techniques in combination with manual therapy on pulmonary functions, health-related quality of life, 6-minute walk test, chest wall mobility, dyspnea and oxyhemoglobin saturation. Furthermore, studies with scientific validity and more evidence are yet to be conducted to assess both muscle energy and the effect of joint manipulations on pulmonary functions in COPD patients.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Donaldson AV, Maddock M, Maetolini D, Polkey MI, Man WDC. Muscle function in COPD: A complex interplay. Int J COPD. 2012; (7):523-35.
2. Baxter DA, Shergis JL, Fazalboy A, Coyle ME. Muscle energy technique for chronic obstructive pulmonary disease: a systematic review. Chiropr Man Therap. 2019; 27(1):1-7.
3. Engel RM, Wearing J, Gonski P, Vemulpad S. The effect of combining manual therapy with exercise for mild chronic obstructive pulmonary disease: Study protocol for a randomized controlled trial. Trials. 2017; 18(1):1-7.
4. Shin DC, Lee YW. The immediate effects of Spinal thoracic manipulation on respiratory function. J Phys Ther Sci. 2016; 28(9):2547-9.
5. Cruz-Montecinos C, Godoy-Olave D, Contreras-Briceno FA, Gutierrez P, Torres- Castro R, Miret-Venegas L, et al. The immediate effect of soft tissue manual therapy intervention on lung function in severe chronic obstructive pulmonary disease. Int J COPD. 2017; (12):691-6.
6. Oliver KA, Ashrut JV. Anatomy of phrenic nerve. Anatomy, Thorax, Phrenic nerves. Tresure Island; Starpearls Publishing; 2020. p.1077-82.
7. Putt MT, Watson M, Seale H, Paratz JD. Muscle stretching technique increases vital capacity and range of motion in patients with Chronic Obstructive Pulmonary Disease. Arch Phys Med Rehabil. 2008; 89(6):1103-7.
8. Clarke S, Munro PE, Lee AL. The Role of Manual Therapy in patients with COPD. Healthcare. 2019;7(1):21-5.
9. Simonelli C, Vitacca M, Vignoni M, Ambrosino N, Paneroni M. Effectiveness of manual therapy in COPD: A systematic review of randomized controlled trials. Pulmonology. 2019; 25(4):236-47.
10. Polastri M, Clini EM, Nava S, Ambrosino N. Manual massage therapy for patients with COPD: A scoping review. Medicina. 2019; 55(5):151.
11. Wearing J, Beaumont S, Forbes D, Brown B, Engel R. The use of spinal manipulative therapy in the management of chronic obstructive pulmonary disease: A systematic review. J Altern Complement Med. 2016; 22(2):108-14.
12. Moore SD, Launder KG, McLoda TA, Shaffer MA. The immediate effects of muscle energy technique on posterior shoulder tightness: a randomized controlled trial. J Orthop Sports Phys Ther. 2011; 41(6):400-7.
13. Maskey- Warzechowska M, Mierzejewski M, Gorska K, Golowicz R, Jesien L, Krenke R. Effect of Osteopathic Manual Therapy on Hyperinflation in patients with Chronic Obstructive Pulmonary Disease: A randomized Cross-Over Study. Adv Exp Med Biol. 2019; (1222):17-25.
14. Yilmaz Yelvar GD, Cirak Y, Demir YP, Dalkilinc M, Bozkurt B. Immediate effect of manual therapy on respiratory functions and inspiratory muscle strength in patients with COPD. Int J COPD. 2016; (11):1353-57.
15. Yilmaz Yelvar GD, Cirak Y, Demir YP, Dalkilinc M, Bozkurt B. Immediate effects of manual therapy in patients with COPD. Eur Resoir J. 2015; 46(59):973.
16. Sule K, Palekar T. Effect of static stretching and pulsed MET on accessory muscle in COPD patients: a comparative Study. Int J Sci Rs Educ. 2017; 5(5):6461- 65.
17. Anand A, Narwal R, Sindhwani G. Accessory inspiratory muscle energy technique effect on pulmonary function in COPD subjects. Indian J Physiother Occup Ther. 2013; 7(3):192.
Download attachments: 10.4328:ACAM.20707
Diksha Bains, Manu Goyal, Aksh Chahal, Mohammad Abu Shaphe. Effect of joint manipulation and muscle energy technique in patients with Chronic Obstructive Pulmonary Disease: A review. Ann Clin Anal Med 2021;12(11):1315-1319
Citations in Google Scholar: Google Scholar