The effect of gender on pain, hip muscle strength, fatigue and functionality in adults patients with Guillain-Barre syndrome
Tuba Can Akman 1, Mehmet Duray 2, Aziz Dengız 1, Nilufer Cetisli Korkmaz 1
1 Department of Physical Therapy and Rehabilitation, Pamukkale University, Denizli, 2 Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Süleyman Demirel University, Isparta, Turkey
DOI: 10.4328/ACAM.20601 Received: 2021-03-18 Accepted: 2021-06-16 Published Online: 2022-06-03 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):712-715
Corresponding Author: Tuba Can Akman, School of Physical Therapy and Rehabilitation, Pamukkale University, Denizli, Turkey. E-mail: firstname.lastname@example.org P: +90 258 2964259 F: +90 258 2964494 Corresponding Author ORCID ID: https://orcid.org/0000-0001-5230-2009
Aim: Patients with Guillain-Barre Syndrome (GBS) commonly suffer motor, sensorial and functional problems. Gender may be the determining factor in the symptoms of these patients. The present study was planned to investigate the effect of gender on the severity of pain, muscle strength, fatigue, and loss of function in patients with GBS.
Material and Methods: Thirty-two adult patients with GBS (11 females, 21 male) were included in the study. Data on pain level, muscle strength, fatigue level, and functionality, which were assessed by using the Visual Analogue Scale (VAS), manual muscle testing, Fatigue Severity Scale and Functional Independence Measures, respectively, were obtained from patient files retrospectively.
Results: The mean age of the women was 55.90 ± 11.97 years, the mean age of the men was 63.14 ± 12.98 years. Bilateral hip extension strength of the women was significantly lower, while fatigue was significantly higher in men (p<0.05). No significant differences were detected in terms of other muscle strengths, pain level and functionality between the groups (p>0.05).
Discussion: It seems that women tend to have greater muscle weakness, while men show higher levels of fatigue in GBS. According to our results, more emphasis should be given to the strengthening of hip muscles in female patients with GBS, while energy conservation techniques should be prioritized in male patients with GBS during treatment.
Keywords: Guillain Barre Syndrome, Pain, Muscle Strength, Fatigue, Functional
Guillain-Barre syndrome (GBS) is caused by autoimmune activation, which the myelin sheath and/or axonal membrane of peripheric nerves . GBS is an acute inflammatory polyneuropathy, which is associated with motor, sensory and autonomic affection. According to physical examination and electrodiagnostic findings, GBS is divided into different categories as acute inflammatory demyelinating polyneuropathy (AIDP), the most common form of GBS, acute motor and sensory axonal neuropathy (AMSAN), acute motor axonal neuropathy (AMAN), and Miller-Fisher Syndrome [2,3]. GBS causes a group of neuropathic findings characterised by especially motor problems including progressive weakness, loss of deep tendon reflexes over time . Motor conduction velocity, distal motor latency, F-response latency decrease in GBS. The severity of symptoms reaches a plateau in less than 4 weeks [5,6].
Initial symptoms, including pain, numbness, sensory impairment, or muscle weakness in extremities, may be located proximally and/or distally. Following the plateau phase, recovery begins in proximal parts of limbs and proceeds to distal parts . It was reported that mild to moderate muscle weakness and functional disability were present in 80% and 66.7% of all patients, respectively . However, sensoria disturbances occur less commonly (26.7%) . Muscle performance is a primary measurement to evaluate the effect of treatment after GBS. On the other hand, sensorial symptoms of GBS, especially, pain have recently become a subject of interest . However, as they are subjectively reported, the underlying mechanisms are not fully understood for pain and fatigue .
Previously, age, diarrhea history, onset of the acute phase symptoms, muscle weakness at hospitalization helps in the analysis of prognostic predictors , however, to our knowledge, there are few studies exist, which reported the effect of gender on GBS symptoms. Some studies showed that male and younger populations are more likely to have GBS and both mortality and morbidity rate in patients with GBS approximately 2 times higher in males than females [4,10,11]. However, Yao et al. reported that gender was not significantly associated with disease severity in patients with GBS .
It seems that the literature on the effect of gender on GBS- related symptoms is controversial. Therefore, the present study was designed to investigate the effects of gender on pain level, muscle strength, fatigue level and functionality in patients with GBS.
Material and Methods
In this retrospective study, 32 patients (11 females, 21 males) who were hospitalized in the neurology service between October 2020 and March 2021 who were diagnosed with GBS were included. Patients who had acute pain, those who had other neurological diseases, who had physical dysfunction due to other problems, and had severe cognitive impairments were excluded. Patients were divided into two groups according to gender as female (Group 1) and male (Group 2). Ethical approval was obtained from the Ethics and Human Research committee of Pamukkale University Hospital (Denizli, Turkey) (60116787-020/66558).
The data regarding demographics (age, gender, height, body weight, and medical history), pain (Visual Analog Scale (VAS)), muscle strength (Medical Research Council Muscle Strength Scale), fatigue (Fatigue Severity Scale (FSS)), and functionality (Functional Independence Measure (FIM)) were obtained from patient files, retrospectively.
The VAS is a self-assessment scale to measure pain intensity. The patient is asked to mark a point on a 10-cm line between 0 (no pain) and 10 (worst pain). The distance from the mark ‘’0’’ indicates the pain level. The VAS was reported to be an easy and usable assessment for patients with GBS .
The Medical Research Council Muscle Strength Scale classifies the limb muscle strength from 0 (no muscle function) to 5 (normal strength) [8,12].
The FSS is a 9-item self-report questionnaire, which evaluates the effect of fatigue on activities. Each item is rated between 1 (no signs of fatigue) – 7 (disabling fatigue), and higher scores indicate increased fatigue severity. FSS is used in many studies and is recommended by the European Inflammatory Neuropathy Cause and Treatment group as it has shown good internal consistency, reliability and validity [9,13].
The FIM consists of 18 items that assess functionality under two major domains and six subscales. Major domains include physical/motor function (13 items) and cognitive function (5 items). Items are scored 1 (total assistance) – 7 (complete independence) .
All statistical analyses were performed using the program SPSS 21.0 (SPSS Inc., Chicago, Illinois, USA). All continuous variables were evaluated for normality using the Shapiro-Wilk test. Continuous variables were expressed as mean ± standard deviation, median (minimum and maximum values), and categorical variables as numbers and percentages. P-values were investigated as two-tailed, and p-values <0.05 were considered statistically significant.
The demographic characteristics of the participants are shown as mean ± SD in Table 1. The average age was 55.90 ± 11.97 years in females and 63.14 ± 12.98 years in males. No statistical differences were found in the BMI scores of the groups (p>0.05).
The clinical outcomes of both groups were presented in Table 2. The female group presented lower hip extensors muscle strength for both sides (right p=0.046, left p=0.025). The male group showed significantly worse fatigue scores (p=0.021). No statistical differences were detected in terms of other muscle strengths, pain level and functionality between groups (p>0.05; Table 2).
The present study indicates that gender may have a potential effect on the disease symptoms in patients with GBS. According to our results, the strength of extensor hip muscles was lower in females with GBS, and the severity of fatigue was higher in males with GBS.
The results of the present study may provide beneficial information for constructing optimal rehabilitation programs. According to our results, hip muscle strength should be developed in both genders, and energy conservation techniques should be given more attention in male patients with GBS.
GBS incidence ranges from 0.62 to 2.66 cases/100,000 people across age groups, and the incidence increases by 20% per 10-year increase in age . The incidence of GBS is higher in males than females. Hauck et al. reported a male to female incidence ratio of 1.5:1 [10,16]. Thus, GBS-related mortality rate is higher among males . Similarly, male patients with GBS make up the majority in our study. All prevalence study results and the lack of the desired level of gender comparisons require symptomatic comparison between the genders for patients with GBS.
Motor and sensory problems dominate the clinical picture in patients with inflammatory neuropathies . The multidisciplinary rehabilitation program is essential to restore functional deficits and sensory symptoms for GBS management . Even though pain and functional loss have been previously reported in patients with GBS [18,19], the difference in pain severity and functionality was not compared according to gender. Current results indicate that pain reduction strategies are important for both groups. However, since females have lower pain thresholds and tolerances, even in healthy people , it should be taken into account that the severity of pain in female with GBS can increase under the influence of the disease. Similarly, the fact that females are more disadvantaged than males in terms of functional-related physical activity status  may also cause a faster decline in female’s functional levels over time.
According to our results, although the severity of pain and functional disability were higher in females, no significant differences were determined between the groups. Thus, pain alleviating strategies should equally be considered in both groups. Improving muscle strength and endurance (especially hip extensors) in females with GBS and more emphasis on fatigue reduction strategies in male patients with GBS will help shorten the rehabilitation process.
There are several limitations to be discussed. The number of participants is limited. In addition, employing objective and detailed measures could provide more reliable results. In this term, dynamometers may be utilized to evaluate muscle strength. Retrospective design is also a limitation of our study. However, uncovering the effect of gender on symptoms is beneficial for establishing optimal treatment protocols in patient with GBS. Our study is the first study in this field and thus provides a basis for further studies. Future prospective studies with a larger number of participants are needed to confirm our results. In addition, future rehabilitation studies based on gender differences will reveal the true importance of our findings.
In conclusion, gender may influence disease symptoms in patients with GBS. Thus, it may be important to prioritize different symptoms for each gender.
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.
1. Candelario-Velazquez C, Rosario-Concepcion R, Diaz N, Crespo M. Rehabilitation outcomes in patients with Guillain–Barré syndrome caused by zika virus. J Int Soc Phys Rehab Med. 2019;2(2):88-93.
2. Hadden RD, Cornblath DR, Hughes RA, Zielasek J, Hartung HP, Toyka KV, et al. Electrophysiological classification of Guillain-Barré syndrome: clinical associations and outcome. Plasma exchange/sandoglobulin Guillain-Barré syndrome trial group. Ann Neurol. 1998;44(5):780-8.
3. Kuwabara S, Yuki N. Axonal Guillain-Barré syndrome: concepts and controversies. Lancet Neurol. 2013; 12(12):1180-8.
4. Ruiz E, Ramalle-Gómara E, Quiñones C, Martínez-Ochoa E. Trends in Guillain-Barré syndrome mortality in Spain from 1999 to 2013. Int J Neurosci. 2016;126(11):985-8.
5. Hughes RA, Cornblath DR. Guillain-Barré syndrome. Lancet. 2005; 366:1653-66.
6. Huzmeli ED, Korkmaz NC, Duman T, Gokcek O. Effect of sensory deficits on balance, functional status and trunk control in patients diagnosed with Guillain-Barre syndrome. Neurosciences.2018; 23(4):301-7.
7. Uncini A, Notturno F, Kuwabara S. Hyper-reflexia in Guillan-Barre syndrome: systematic review. Neurol Neurosurg Psychiatry. 2020; 91(3):278-84.
8. Yao S, Chen H, Zhang Q, Ziyan S, Ju L, Zhiyun L, et al. Pain during the acute phase of Guillain-Barré syndrome. Medicine. 2018; 97(34):e11595
9. Merkies IS, Kieseier BC. Fatigue, pain, anxiety and depression in guillain-barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. Eur Neurol. 2016; 75(3-4):199-6.
10. Rudolph T, Larsen JP, Farbu E. The long-term functional status in patients with Guillain-Barré syndrome. Eur J Neurol. 2008;15(12):1332-7.
11. Sipilä JOT, Soilu-Hänninen M, Ruuskanen JO, Rautava P, Kytö V. Epidemiology of guillain-barré syndrome in Finland 2004-2014. J Peripher Nerv Syst. 2017; 22(4):440-5.
12. Shefner JM. Strength testing in motor neuron diseases. Neurotherapeutics 2017; 14(1):154-60.
13. Armutlu K, Korkmaz NC, Keser I, Sumbuloglu V, Akbiyik DI, Guney Z, et al. The validity and reliability of the Fatigue Severity Scale in Turkish multiple sclaeorsis patients. Int J Rehabil Res 2007;30(1): 81-85.
14. Küçükdeveci AA, Yavuzer G, Elhan AH, Sonel B, Tennat A. Adapatation of the functional independence measure for use in Turkey. Clin Rehabil. 2001; 15(3):311-19.
15. Yoshikawa H. Epidemiology of Guillain-Barre syndrome. Brain Nerve. 2015; 67(11): 1305–11.
16. Hauck LJ, White C, Feasby TE, Zochodne DW, Svenson LW, Hill MD. Incidence of Guillain–Barre syndrome in Alberta, Canada: an administrative data study. J Neurol Neurosurg Psychiatry. 2008;79(3):318–20.
17. Ruiz E, Ramalle-Gómara E, Quiñones C, Martínez-Ochoa E. Trends in Guillain–Barré syndrome mortality in Spain from 1999 to 2013. Int J Neuro. 2016; 126(11): 985-8.
18. Shankar PS. Guillain-Barre Syndrome. RJMS. 2017;7(2):71-5.
19. Petrini L, Matthiesen ST, Arendt-Nielsen L. The effect of age and gender on pressure pain thresholds and suprathreshold stimuli. Perception. 2015; 44(4):587-96.
20. Park H, Suh B. Association between sleep quality and physical activity according to gender and shift work. J Sleep Res. 2019;28(6):1-8.
Download attachments: 10.4328:ACAM.20601
Tuba Can Akman, Mehmet Duray, Aziz Dengız, Nilufer Cetisli Korkmaz. The effect of gender on pain, hip muscle strength, fatigue and functionality in adults patients with Guillain-Barre syndrome. Ann Clin Anal Med 2022;13(7):712-715
IFN-γ, IL-10, ghrelin and nesfatin-1 levels in acute brucella patients
Department of Biochemistry, Health Science Faculty, Cankiri Karatekin University, Cankiri, Turkey
DOI: 10.4328/ACAM.21061 Received: 2022-01-14 Accepted: 2022-05-27 Published Online: 2022-06-13 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):716-720
Corresponding Author: Emrah Caylak, Department of Biochemistry, Health Science Faculty, Cankiri Karatekin University, Cankiri, Turkey. E-mail: email@example.com P: +90 544 613 49 99 F: +90 376 212 00 75 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0408-9690
Aim: This study aimed to investigate gamma interferon (IFN-γ), interleukin-10 (IL-10), ghrelin and nesfatin-1 levels in acute brucella patients and to evaluate the effect of combination of antimicrobial agents after therapy.
Material and Methods: Patients were assigned to the Brucella-infected group if they had confirmed laboratory findings. Sixty brucella-infected patients and thirty healthy individuals were included in the study. Doxycycline-streptomycin (DOX-STR) and doxycycline-rifampicin (DOX-RIF) were used in the treatment of brucellosis.
Results: Significantly increased IFN-γ, IL-10 and ghrelin levels and decreased nesfatin-1 levels were determined in brucella patients compared with healthy controls (p < 0.001). After therapy, IFN-γ, IL-10 and ghrelin levels were significantly lower, and nesfatin-1 levels were significantly higher compared to the pre-treatment group, especially in (DOX-STR) regimen (p < 0.001).
Discussion: It is thought that the rise of free oxygen radicals and the decrease in antioxidant capacity may play a role in the pathogenesis of brucellosis. In this study, the therapeutic power of antibiotic combinations was determined by monitoring inflammatory agents and ghrelin and nesfatin-1 levels measured before and after treatment in patients. Adding ghrelin and nesfatin-1 to effective treatment protocols for brucella will ameliorate their inflammatory status and antioxidant system.
Keywords: Brucellosis, Gamma Interferon (IFN-γ), Interleukin-10 (IL-10), Ghrelin, Nesfatin-1, Antibiotic treatment
Brucellosis is a systemic and inflammatory disease caused by the brucella bacteria, which are gram (-) coccobacillus. It is an important public health problem and especially common in Turkey or developing countries such as the Mediterranean basin of Europe, the Middle East of Asia, and South and Central America. It has a zoonotic character (WHO. Brucellosis fact sheet N173. Geneva, Switzerland: WHO; 1997. p.23-37.); therefore, brucella agents infect humans through direct contact with infected animals or by eating their products. Transmission from animals to humans is commonly caused by Brucella melitensis (sheep and goats) and less often by Brucella abortus (cattle). Symptoms of the disease include loss of appetite and weight, bumpy fever, sweating, fatigue, joint and back pain. In chronic cases, it also causes arthritis, spondylitis, endocarditis, orchitis and osteomyelitis .
Many studies have shown that in inflammatory diseases, various of inflammatory cells are activated and cytokines are secreted, which leads to the over-production of reactive oxygen species (ROS) to kill intracellular pathogens. It has been found that an increment of free radical production and antioxidant depletion, and oxidative stress plays an important role in the pathogenesis of brucellosis [2,3]. It has been postulated that pro-inflammatory Th1 cytokines such as gamma interferon (IFN-γ) and interleukin-12 (IL-12) regulate the initiation of the adaptive immune response against brucellosis and protect the host. Anti-inflammatory Th2 cytokines such as IL-4 and IL-10 support the survival of bacteria and may facilitate pathogenesis .
Eating disorders, obesity and cachexia threaten millions of people around the world. Physiologically, the organism’s short-term food intake control is regulated by the gastrointestinal tract, hypothalamus, and obesity hormones such as leptin, adinopectin, resistin, ghrelin, and nesfatin-1 released from many parts of the body. It is thought that ghrelin and nesfatin-1 play a key role in the regulation of appetite, food intake, energy expenditure, and body weight in the short and long term [4,5]. Ghrelin, first described in 1999 by Kojima et al., is a peptide hormone that is produced by the gastrointestinal system in the human body and plays a central role in the regulation of appetite and body weight. Ghrelin is secreted in an inactive, deacylated form, when ghrelin is acylated, thereby converting to the active form. It has been determined that low ghrelin levels increase calorie intake, leading to obesity or high ghrelin levels are determined in fasting state cachexia and anorexia nervosa . Nesfatin-1, on the other hand, is an anoroxygenic peptide that is formed as a result of the breakdown of a precursor protein called NUCB2, which consists of 82 amino acids synthesized from the hypothalamus and is responsible for regulating appetite and producing body fat. The following studies have reported that excessive nesfatin-1 levels in the brain cause loss of appetite decrease in body fat and weight . In the clinical picture of Brucella, symptoms such as fatigue, loss of appetite and weakness are observed. These studies show that ghrelin and nesfatin-1 may have an effect on diseases such as brucella, which progress with weight loss.
In this study, IFN-γ and IL-10 levels, as indicators of inflammatory agents, and ghrelin and nesfatin-1 levels, which are at different levels in cases such as obesity, weight and appetite loss, and weakness, will be elucidated with healthy controls in acute brucella patients. In addition, it will be tried to determine the therapeutic power of antibiotic combinations used in the therapy of brucellosis by measuring levels before and after treatment.
Material and Methods
Sixty brucella-infected patients and 30 healthy controls attending the outpatient Clinic of Infectious Diseases at the Cankiri State Hospital were included in the study. The study was approved by the Research Ethics Committee of the University of Zonguldak Karaelmas/Turkey. The age range and gender in brucella patients and the control group were 18 – 50 years, 32 men and 28 women / 19 – 45 years, 15 men and 15 women, respectively. Table 1 shows the demographic features of individuals and no statistically significant difference was found between the groups (age, gender, body mass index (BMI), BMI score, and waist circumference).
Patients were assigned to the Brucella-infected group if they had an epidemiological history (contact with animals and animal products), clinical symptoms (hyperhidrosis, undulant fever and joint pain, etc.), and confirmed laboratory findings (determination with blood culture, serum agglutination test [SAT] with titres ≥ 1/160). Exclusion criteria of the study for the patient and control group were pregnancy, drug use, alcohol or tobacco use, obesity (BMI ≥ 30), gastro/metabolic/inflammatory diseases, abdominal surgery.
As ghrelin and nesfatin-1 are peptide hormones, aprotinin (500 Kallikrein units/mL) was put into the blood tubes before the study to protect against serum proteases. Before and after 45 days of antibiotic treatment, blood specimens (5mL) were collected from the participants by venipuncture. The serum samples of 2 mL were stored at –70 °C until further analysis of IFN-γ, IL-10, ghrelin and nesfatin-1 levels.
Serum samples were analyzed for IFN-γ and IL-10 using human enzyme-linked immunosorbent assay (ELISA) kits (Bender MedSystems GmbH, Austria) and the absorbance was determined at 450 nm using a microplate reader (BioTek Microplate Instruments, USA). Serum acylated, desacylated ghrelin and nesfatin-1 levels were evaluated using human ELISA kits (Cat. No: A05106/A05119, SPI-BIO, France; Cat. no. EIA-NES-1, RayBiotech Inc., Georgia). The absorbance values were read at 410 nm and 450 nm using a microplate reader (BioTek Microplate Instruments, USA), spectrophotometrically.
Finally, the mathematical sum of total ghrelin levels with acyl and desacyl ghrelin values was calculated. The same trade kits were used in the determination of acyl and desacyl ghrelin levels so that the total can be calculated correctly.
While evaluating the findings obtained in the study, SPSS program (Statistical Package for Social Sciences 13.0, USA) was used for statistical analysis. The Mann-Whitney-U test and Spearman’s correlation analysis were used to compare the differences between groups. The p-value was 0.001 and all data in the tables were mean ± SD.
In brucellosis, antibiotic combinations such as doxycycline-streptomycin (DOX-STR) and doxycycline-rifampicin (DOX-RIF) are commonly used in treatment (Joint FAO/WHO Expert Committee on Brucellosis. Joint FAO/WHO Expert Committee on Brucellosis: sixth report. WHO Technical Report Series No. 740. Geneva; 1986.p.56-7.). Treatment regimens for patients with brucellosis in this study included 200 mg/day orally doxycycline plus 1 g/day intramuscularly streptomycin for 45 days or 200 mg/day orally doxycycline plus 600 mg/day orally rifampicin for 45 days. Hematological and biochemical parameters at pre- and post-therapy are given in Table 2.
The cytokine, ghrelin and nesfatin-1 parameters for all participants are shown in Table 3. Significantly higher IFN-γ and IL-10 levels were found in the acute brucellosis study group than in controls (p < 0.001). When the two groups were compared based on ghrelin levels, there was a statistically significant increment between the groups (p < 0.001). Significantly decreased nesfatin-1 levels were found in brucellosis patients compared with controls (p < 0.001).
Table 3 also shows outcome data for patients treated with the antibiotic combination DOX-STR or DOX-RIF. When comparing two treatments with the patient group, the cytokine status, ghrelin and nesfatin-1 levels of the patients normalized after the treatment period. When comparing the two treatment regimens, there was no significant difference (p> 0.05). Comparison of different antibiotic combinations showed the benefit of using DOX-STR.
Brucellosis is a disease caused by Brucella spp and these bacteria are taken into the cell by phagocytic cells. During the normal immune response, macrophages and dendritic cells are activated for antigen processing, leading to the production of cytokines. Pro-inflammatory Th1 cytokines such as gamma interferon (IFN-γ) and interleukin-12 (IL-12) activate macrophages to halt the replication of intracellular brucellae and to produce ROS to kill brucella spp. It is thought that the rise of free oxygen radicals and the decrease of antioxidant capacity may play a role in the pathogenesis of brucellosis . Otherwise, IL-10 also inhibits the synthesis of pro-inflammatory cytokines such as TNF-α and IFN-γ .
In the present study, these cytokines (IFN-γ and IL-10) were analyzed and their levels significantly increased in patients with brucellosis compared with healthy subjects. Numerous studies have examined these biomarkers of inflammation in acute brucellosis. Many studies have shown high IFN-γ levels in patients with brucellosis compared with controls [3,8]. IL-10 levels also have been investigated and no difference was found in several studies, but Tang et al.  found that IL-10 levels were higher in acute brucellosis than in controls. The results confirm previous data showing that IFN-γ and IL-10 are involved in the immune response to brucella.
There are many various metabolic functions of ghrelin and nesfatin-1 to regulate appetite, food intake, energy expenditure, and body weight in the short and long term. Recent studies have revealed the functional roles of ghrelin and nesfatin-1 in the immune system, inflammatory stress and disease pathogenesis. In the immune system, ghrelin mRNA expression has been identified in lymphoid organs and B, T, natural killer (NK) cells, monocytes of human and rodent [9,10]. Dixit et al.  have reported the production and secretion of acylated/desacylated forms of ghrelin in T-cell activation. Immune system cells can sense changes in their environment and are affected by changes in circulating hormones and nutrients, and these cells can then influence immune responses and cytokine expression. Pro-inflammatory cytokines produced during inflammation also influence neuroendocrine function and metabolism. Experimental studies have shown that ghrelin levels are associated with the expression of pro-inflammatory cytokines, and exogenously administered ghrelin suppresses the expression/production of these cytokines in inflammation. Recent data have reported that ghrelin levels are increased in many inflammatory diseases such as ulcerative colitis, Crohn’s disease (CD), rheumatoid arthritis, pancreatitis, and spondylitis .
Kilic et al.  observed that the serum ghrelin levels significantly decreased in brucella patients compared with controls. There were no other studies in the literature. In this study, serum ghrelin levels were significantly higher in brucella patients compared to healthy individuals. This finding was consistent with various studies that have shown an increase in serum ghrelin levels in inflammatory diseases.
Studies over the past decade have identified nesfatin as a potent antioxidant and anti-inflammatory mediator. Inflammatory diseases lead to the activation of neutrophils, increased production of pro-inflammatory cytokines and overgeneration of reactive oxygen species. The levels of nesfatin in these diseases have been examined, and one of which is diabetic neuropathy (DN). It has been shown that nesfatin-1 inhibits overproduction of ROS in PC12 cells following high-glucose exposure, in vitro model for DN . In chronic gastric ulcers, it also promoted the healing by partially reversing the down-regulation of superoxide dismutase mRNA . Myocardial infarction (MI) often causes oxidative stress and inflammation, and plasma nesfatin-1 levels were found significantly lower than in healthy controls . Intraperitoneal administration of nesfatin-1 had a protective effect by lowering pro-inflammatory cytokines against isoproterenol induced MI in rats . Also, nesfatin-1 ameliorated the experimental renal ischemia-reperfusion injury in rats by decreasing malondialdehyde level and increasing SOD and catalase activities . Nesfatin-1 exerts its antioxidant and anti-inflammatory effects by inhibiting the overproduction of ROS and maintaining the balance of oxidant/antioxidant systems, regulating the inflammatory cells by inhibiting neutrophil infiltration and decreasing the release of inflammatory mediators. According to the literature, this study is the first to report serum nesfatin-1 levels in patients with brucellosis. The levels of nesfatin-1 were significantly lower in pre-treatment brucella patients, and treatment of patients with antibiotic combination, especially (DOX-STR), will ameliorate their nesfatin-1 levels.
It is thought that the increment of ROS and the decrement of antioxidant capacity may play a role in the pathogenesis of brucellosis. In this study, the levels of the inflammatory biomarkers and serum ghrelin and nesfatin-1 were determined in brucella patients, and the recent data suggest that ghrelin and nesfatin-1 as an anti-inflammatory agent and immune-regulating hormones/cytokines may be valuable in the treatment of inflammatory diseases.
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.
1. Yagupsky P, Morata P, Colmenero JD.. Laboratory Diagnosis of Human Brucellosis. Clin Microbiol Rev. 2019;33(1):e00073-19.
2. Celli J. Surviving inside a macrophage: the many ways of Brucella. Res. Microbiol. 2006;157:93-98.
3. Akbulut H, Celik I, Akbulut A. Cytokine levels in patients with brucellosis and their relations with the treatment. Indian J Med Microbiol. 2007;25:387-90.
4. Caylak E. Ghrelin Appetite Hormone in Health and Disease. In: eLS. Chichester: John Wiley & Sons, Ltd; 2012.p.1-9.
5. Caylak E. Anorexigenic Peptides in Health and Disease. In: eLS. John Wiley & Sons, Ltd: Chichester;2012.p.1-9.
6. Baatar D, Patel K, Taub DD. The effects of ghrelin on inflammation and the immune system. Mol Cell Endocrinol. 2011;340(1):44-58.
7. Trinchieri G. Interleukin-10 production by effector T cells: Th1 cells show self control. J Exp Med. 2007;204(2):239-43.
8. Tang Y, Ma C, Sun H, Yang S, Yu F, Li X, Wang L. Serum Levels of Seven General Cytokines in Acute Brucellosis Before and After Treatment. Infect Drug Resist. 2021;14:5501-10.
9. Hattori N. Expression, regulation and biological actions of growth hormone (GH) and ghrelin in the immune system. Growth Horm IGF Res. 2009;19(3):187-97.
10. Taub DD, Murphy WJ, Longo DL. Rejuvenation of the aging thymus: growth hormone-mediated and ghrelin-mediated signaling pathways. Curr Opin Pharmacol. 2010;10(4):408-24.
11. Dixit VD, Schaffer EM, Pyle RS, Collins GD, Sakthivel SK, Palaniappan R, et al. Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest. 2004;114(1):57-66.
12. Kilic N, Kilic SS. Decreased levels of ghrelin in brucellosis. J Anim and Vet Adv. 2012;11:1552-4.
13. Nazarnezhad S, Rahmati M, Shayannia A, Abbasi Z, Salehi M, Khaksari M. Nesfatin-1 protects PC12 cells against high glucose-induced cytotoxicity via inhibiting oxidative stress, autophagy and apoptosis. Neurotoxicology. 2019;74:196-202.
14. Szlachcic A, Sliwowski Z, Krzysiek-Maczka G, Majka J, Surmiak M, Pajdo R, et al. New satiety hormone nesfatin-1 protects gastric mucosa against stress-induced injury: mechanistic roles of prostaglandins, nitric oxide, sensory nerves and vanilloid receptors. Peptides. 2013;49:9-20.
15. Dai H, Li X, He T, Wang Y, Wang Z, Wang S, et al. Decreased plasma nesfatin-1 levels in patients with acute myocardial infarction. Peptides. 2013;46:167-71.
16. Meeran MFN, Laham F, Al-Taee H, Azimullah S, Ojha S. Protective effects of α-bisabolol on altered hemodynamics, lipid peroxidation, and nonenzymatic antioxidants in isoproterenol-induced myocardial infarction: in vivo and in vitro evidences. J Biochem Mol Toxicol. 2018;32:e22200.
17. Jiang G, Wang M, Wang L, Chen H, Chen Z, Guo J, et al. The protective effect of nesfatin-1 against renal ischemia-reperfusion injury in rats. Ren Fail. 2015;37(5):882-89.
Download attachments: 10.4328:ACAM.21061
Emrah Caylak. IFN-γ, IL-10, ghrelin and nesfatin-1 levels in acute brucella patients. Ann Clin Anal Med 2022;13(7):716-720
Matrix hythm therapy in chronic neck pain: A pilot study
Ayşe Nur Oymak Soysal 1, Ummuhan Baş Aslan 2, Emine Aslan Telci 2, Erhan Ozfidan 3
1 Department of Therapy and Rehabilitation, Sarayköy Vocational High School, Pamukkale University, Denizli, 2 Department of Physiotherapy and Rehabilitation, School of Physical Therapy and Rehabilitation, Pamukkale University, Denizli, 3 Department of Physical Medicine and Rehabilitation, Private Tekden Hospital, Denizli, Turkey
DOI: 10.4328/ACAM.21063 Received: 2022-01-14 Accepted: 2022-06-09 Published Online: 2022-06-23 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):721-725
Corresponding Author: Ayşe Nur Oymak Soysal, Department of Therapy and Rehabilitation, Sarayköy Vocational High School, Pamukkale University, Sarayköy, Denizli, 20300, Turkey. E-mail: firstname.lastname@example.org P: +90 258 415 15 00 Corresponding Author ORCID ID: https://orcid.org/0000-0001-5383-7937
Aim: The aim of this study was to determine the effects of Matrix Rhythm Therapy (MRT) with combined physiotherapy treatment on pain intensity, muscle spasm, disability level and depressive symptoms in chronic neck pain.
Material and Methods: A total of 26 participants with a mean age of 44,46 ± 9,98 years were randomly divided into two groups (intervention and control group). Each participant was treated with ten sessions of a combined physiotherapy program, including hot pack, transcutaneous electrical nerve stimulation, therapeutic ultrasound and conventional massage, exercises and patient education. Additionally, the intervention group received five sessions of MRT. Pain intensity, muscle spasm, disability level and depressive symptoms were assessed before and after the treatment program.
Results: There was a statistically significant improvement in pain, muscle spasm and disability levels after treatment in both groups (p<0.05), except for depression scores (p>0.05). The difference in change values in terms of activity pain and muscle spasms was found in favor of the intervention group (p<0.05), but there was no difference between the groups in terms of rest pain, disability level and depression scores (p>0.05).
Discussion: The findings of the study suggest that both the combined physiotherapy program and the MRT application in addition to the combined physiotherapy program have a positive effect on pain, muscle spasms and disability levels in patients with chronic neck pain. On the other hand, MRT increased the efficiency of the combined physiotherapy treatment in the terms of activity pain and muscle spasm in patients with chronic neck pain.
Keywords: Neck pain, Physiotherapy Modalities, Massage, Spasm
Neck pain is a common health problem. Between 14 and 71 % of adults are experienced pain at some point in their life . Chronic neck pain causes physical problems, disabilities, depression, insomnia and a decrease in quality of life .
The non-surgical management for chronic neck pain includes modalities such as medication, spinal injections, physiotherapy. Electrotherapy, exercise, manual therapy, patient education are commonly used as physiotherapy methods . Exercise therapy and patient education as an active therapy constitute a significant part of therapy in chronic neck pain. Heat applications and electrotherapy modalities, which constitute passive physiotherapy are used in order to increase the effectiveness of therapy [1,4]. In the treatment of back pain, both a patient-specific therapy program may be developed and a standard therapy protocol may be preferred in .
In chronic neck pain, complementary approaches such as massage, acupuncture, exercise, mechanical traction, herbal medicine, cupping, and electrotherapy are considered alternative therapies due to their benefits and safety . There are different types of massage applications, such as vibration. Vibration massage is used to improve circulation and facilitate muscle relaxation . With mechanical devices, vibration treatment can be applied safely and more locally .
Matrix Rhythm Therapy (MRT) is a novel application of the vibro-massage method used in sports clubs, physiotherapy and rehabilitation centers and spas. A few studies and clinical experience indicate the efficiency of MRT [9,10]. The effect of MRT in chronic neck pain is unclear. The aim of this study was to investigate the efficiency of MRT with combined physiotherapy modalities in patients with chronic neck pain.
Material and Methods
This study was a pilot study. The subjects were assessed and treated in the physical therapy department of a private hospital in Denizli, Turkey.
The study included 26 participants aged between 25-65 years (mean age: 44,46 ± 9,98 years) who were diagnosed with chronic neck back pain by a specialist physician. The patients were randomly divided into two groups as the intervention and control groups. Randomization was allocated using the numbered envelopes method. Figure 1 shows a flow chart of the study design.
Inclusion criteria were age between 25 and 65 years, the presence of neck pain for at least 3 months. Patients with radiculopathy who had motor findings, who underwent any operations due to neck problems, who had systemic, neurologic and psychiatric diseases, inflammatory or infectious diseases, a history of malignity, congenital anomalies and individuals for whom physical therapy methods were contraindicated (sensory loss, having pacemaker) were excluded from the study. Ethical approval for this study was obtained from University Ethics Committee and registered on https://clinicaltrials.gov/ with ClinicalTrials.gov identifier: NCT04696341. Written informed consent was obtained from the patients.
Assessments were made before and after treatments. All assessments were done by the same physiotherapist (FU) before therapy and at the end of treatment sessions according to standardized test protocols and under the same conditions. The physiotherapist who performed the assessments did not know which group the subjects belonged to. Demographic data of the participants were recorded through face-to-face interviews. Pain intensity and muscle spasm were assessed with the Visual Analog Scale (VAS), disability level was assessed with the Neck Disability Index (NDI), and depressive symptoms were assessed with Beck Depression Inventory (BDI).
Pain intensity was assessed using a Visual Analogue Scale (VAS) measuring 10 cm (0: I have no pain, 10: I have an intolerable pain). Participants were asked to mark the severity of pain they felt during rest and activity on VAS . Muscle spasm in the cervical region was assessed using a VAS measuring 10 cm (0: no spasm, 10: the most severe spasm) .
The Turkish version of the Neck Disability Index (NDI) was used to assess the disability caused by neck pain. NDI is composed of a total of 10 questions of which 4 are about subjective symptoms (pain intensity, headache, concentration and sleeping) and 6 about daily life activities (personal care, lifting, reading, work, driving and recreation). Each section is scored between 0 and 5 .
The Turkish version of BDI  was used to assess the depressive symptoms of the participants. Each item of the questionnaire (in total 21 items) is scored between 0 and 3. Depressive symptoms are classified scores between 0 and 9 as “minimal depression”, 10–18 as “mild depression”, 19–29 as “moderate depression”, and scores of 30 and above as “severe depression” .
The intervention was performed by the same physiotherapist (AOS) who has an MRT certificate. A combined physiotherapy program was applied to both groups 5 days a week (on weekdays) in 10 sessions over a period of 2 weeks. In combined physiotherapy program, hotpack (HP) was applied as a superficial heating agent to the cervical and upper thoracic regions for 20 minutes, and ultrasound (US) was applied as a deep heating agent for 5 minutes (intensity: 1.5 watts/cm2, frequency: 1 MHz), 20 minutes of conventional transcutaneous electrical nerve stimulation (TENS) was applied for relieving pain (frequency: 100 Hz, duration: 50ms) and conventional massage (using stroking, kneading and friction techniques for 5 minutes). After these passive physiotherapy modalities, normal range of motion exercises, posture exercises, stretching exercises and isometric exercises were instructed as part of active physiotherapy. Patients were also given home-based exercise programs and recommendations . This treatment program was a routine therapy program for the patients with chronic neck pain at the study hospital.
Five sessions of MRT (2., 5., 6., 8., 10. sessions) were added at combined physiotherapy to IG. Matrix Rhythm Therapy was applied to the cervical and thoracic regions using 10 Hz frequency for 30 min (15 min for the right and left sides of each). Longitudinal stroking, compression and spooning techniques are specific methods of MRT. MRT was initiated from the side with less pain. The application was started from occipital region and proceeded towards paravertebral muscles. Longitudinal stroking was done paralleled to muscle fibers for the purpose of superficial relaxation. Applications to paravertebral muscles were proceeded inferiorly segment by segment. Afterwards, upper, middle and lower parts of trapezius muscle were taken and proceeded towards latissimus dorsi muscle. After longitudinal strokings, application was made by keeping the logarithmic probe steady at the points of fibrositis using compression (compression of the tissue between the hand of the physiotherapist and logarithmic probe) and spooning techniques (pulling the logarithmic probe by rotating) in trapezius muscle. Compression technique was applied to the upper part of trapezius muscle, where muscle spasm was severe. The pressure was reduced by changing the direction of the device in the areas where muscle spasms and sensitivity were greater.
The data were analyzed with the SPSS (Statistical Package Program for Social Sciences) package program. Continuous variables were expressed as mean, standard deviation, and categorical variables were expressed as numbers and percentages. The normality of data was examined with the Kolmogorov-Smirnov Z test. The Mann–Whitney U test was used to compare differences between independent groups. The Wilcoxon paired sample test was used to compare differences between dependent groups. The effect size (Cohen d value) was calculated based on the pre-treatment and post-treatment values of the groups. Effect size values were classified as small 0.20–0.49, medium 0.50–0.79, large 0.8 and higher.
In the present study, 26 participants completed evaluation and treatment. The mean duration of disease was 4,45± 3,4 years and 4,36± 3,6 years for the intervention group and control group, respectively. There was no statistical difference between the groups in terms of demographic characteristics and clinical data (p> 0.05) (Table 1).
A statistically significant improvement was found in terms of resting and activity pain, muscle spasms and NDI Index scores after treatment compared to the pre-treatment period in both groups (p<0.05). On the other hand, there was no change in BDI scores after treatment (p>0.05) (Table 2).
The effect sizes of the rest pain, activity pain and muscle spasm in the intervention group were high.
On the other hand, the effect size of the disability level and depression scores was small. In the control group, the effect size of muscle spasm was large, the effect size of pain scores was medium, and effect size of the disability level and depression scores were small.
When the groups were compared for changes, there were no significant differences between the groups in rest pain, disability level and depression scores (p>0.05). But there were statistically significant differences in activity pain and muscle spasm when the groups were compared for changes (p<0.05) (Table 3).
In the current study, patients with chronic neck pain received active and passive physiotherapy modalities as part of a combined physiotherapy program. Both the combined physiotherapy program and the MRT application in addition to the combined physiotherapy program have been found to have a positive effect on pain intensity, muscle spasms and disability level in patients with chronic neck pain. On the other hand, MRT applied in addition to the combined physiotherapy program, had a greater effect on activity pain and muscle spasm compared with the combined physiotherapy program alone.
In the literature, studies are available indicating the positive effects of combined physiotherapy program composed of active and passive modalities on pain, muscle spasm and level of disability [15-16]. Similar findings were obtained during the study; we found an improvement in pain, muscle spasm, the disability level in the group who received combine physiotherapy program.
Physiotherapy modalities are often included in neck rehabilitation programs. According to Smidt et al., the studies supporting the effectiveness of exercise therapy in neck pain are insufficient, and exercise therapy is widely used in the treatment of chronic neck pain in order to improve physical function and reduce symptoms . Guidelines recommend the use of exercise on its own, or in combination with other non-pharmacological therapies . Hayden et al. found that applying exercise together with other conservative methods was more effective for reducing pain and improving functionality compared to applying exercise alone . According to Skillgate et. al, management of non-specific neck pain disorders often includes massage therapy, as well as exercise therapy, little is known about the effectiveness, side effects and cost-effectiveness of such therapies . Previous studies about the effect of massage on neck pain have been done with different doses and types .
MRT is a vibro-massage therapy and is defined as a vibro-massage modality targeted to muscle structure . Studies about the effectiveness of MRT in pain are insufficient. Jager et al. evaluated the effect of MRT on the severity of pain, sleep pattern and spine flexibility in patients with back and low back pain. In this study, it was reported that MRT was superior to conservative treatment .
In a study by Özcan et al., they investigated the effect of MRT on pain, disability level and quality of life in chronic low back pain. Both the combined physiotherapy program (hot pack, transcutaneous electrical nerve stimulation, therapeutic ultrasound, home exercise, and patient education program) and the group that received six sessions of MRT in addition to the combined physiotherapy program improved pain, disability level, and quality of life .
One of the mechanisms of action of MRT in reducing pain and spasm may be the effect of MRT in increasing blood circulation. Taspinar et al. compared the immediate effect of one 30-minute MRT session and one of 30-minute classical massage session on peripheral blood circulation in the lower extremities. As a result of the study, they found that both massages increased peripheral blood circulation, but MRT led to a greater increase .
This study has limitations. The main limitation of the study is that MRT used in a combined physiotherapy program. Tsao states the difficulty of determining the effectiveness of the massage applied together with many therapies . According to Ylinen, studies that used combined therapy carried a risk, additional application was not sufficient for indicating effectiveness if several therapies are working at the same time . Therefore, there is a need for future studies on MRT massage applied alone. The other limitation is the lack of follow- up to find the long-term effects of MRT.
The findings of the study indicated that combined physiotherapy treatment including active and passive physiotherapy modalities was an effective treatment approach in patients with chronic neck pain. MRT also increased the efficiency of combined physiotherapy treatment. Further studies are needed to determine the effectiveness of MRT application without the combination of other physiotherapy treatment methods and objective muscle spasm assessment methods with follow-up in patients with chronic neck pain.
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: The study supported by Pamukkale University Scientific Research Projects Commission (2011SBE002) for photocopy the test protocols.
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.
1. Saturno PJ, Medina F, Valera F, Montilla J, Escolar P, Gascón JJ. Validity and reliability of guidelines for neck pain treatment in primary health care: A nationwide emprical analysis in Spain. Int J Qual Health Care. 2003; 15(6): 487-93.
2. Durmuş D, Alaylı G, Tufekci T, Kuru O. A randomized placebo-controlled clinical trial of phonophoresis for the treatment of chronic neck pain. Rheumotol Int. 2014; 34(5): 605-11.
3. Skillgate E, Bill AS, Cote P, Viklund P, Peterson A, Holm LW. The effect of massage therapy and\or exercise therapy on subacute or long-lasting neck painthe Stockholm neck trial (STONE): study protocol for a randomized controlled trial. Trials. 2015; 16(16): 414-25.
4. Irnich D, Behrens N, Molzen H, Köning A, Gleditsch J, Krauss M, et al. Randomised trial of acupuncture compared with conventional massage and ‘sham’ laser acupuncture for treatment of chronic neck pain. BMJ. 2001; 322(7302): 1574-8.
5. Descarreaux M, Normand MC, Laurencelle L, Dugas C. Evaluation of a specific home exercise program for low back pain. J Manipulative Physiol Ther. 2002; 25(8): 497-03.
6. Wu Z, Kong L, Zhu Q, Song P, Fang M, Sun W, et al. Efficacy of tuina in patients with chronic neck pain: study protocol for a randomized controlled trial. Trials. 2019; 20(59): 1-10.
7.Benjamin PJ, Lamp PS. Understanding Sports Massage. Human Kinetics. United States: Medicine; 2005. p. 2-9.
8. Ferrandiz S. Massage and health. J.Rev Enferm. 2003;26(5):8-12.
9. Randoll UG, Hennig FF. A new approach for the treatment of low back pain, Matrix-Rhythm-Therapy. Osteoloige. 2001; (Suppl. ): 66.
10. Taşpınar F, Baş Aslan U, Sabir N, Cavlak U. Implementation of Matrix Rhythm Therapy and Conventional Massage in Young Females and Comparison of Their Acute Effects on Circulation. J Altern Complement Med. 2013; 19(10): 826-32.
11. Moses MJ, Tishelman JC, Stekas N, Jevotovsky DS, Vasquez-Montes D, Karia R, et al. Comparison of Patient Reported Outcome Measurement Information System with Neck Disability Index and Visual Analog Scale in Patients With Neck Pain. Spine (Phila Pa 1976). 2019; 44(3):162-7.
12. Akaltun MS, Koçyigit BF, Assessment of the responsiveness of four scales in geriatric patients with chronic neck pain. Rheumatol Int. 2021; 41(10):1825-31.
13. Aslan E, Karaduman A, Yakut Y, Aras B, Şimşek IE, et al. The cultural adaptation, reliability and validity of neck disability index in patients with neck pain: a Turkish version study. Spine. 2008;33(11): 362-5.
14. Ulusoy M, Şahin NH, Erkmen H. Turkish version of the Beck Anxiety Inventory: Psychometric properties. J Cogn Psychother. 1998; 12(2): 163-72.
15. Hidalgo B, Hall T, Bossert J, Dugeny A, Cagnie B, Pitance L. The efficacy of manual therapy and exercise for treating non-specific neck pain: A systematic review. J Back Musculoskelet Rehabil. 2017;30(6):1149-69.
16. Hou CR, Tsai LC, Cheng KF, Chung KC, Hong CZ. Immediate effects of various physical therapeutic modalities on cervical myofascial pain and trigger-point sensitivity. Arch Phys Med Rehabil. 2002; 83(10): 1406-14.
17. Smidt N, de Vet HCW, Bouter LM, Dekker J. Effectiveness of exercises therapy: a best- evidence summary of systematic reviews. Aust J Physiother. 2005; 51(2): 71-85.
18. Shipton EA. Physical Therapy Approaches in the Treatment of Low Back Pain. Pain Ther. 2018; 7(2): 127-37.
19. Hayden JA, van Tulder MW, Malmivaara A, Koes BW. Exercise therapy for treatment of non-specific low back pain. Cochrane Database Syst Rev. 2005; 20(3):CD000335. DOI: 10.1002/14651858.CD000335.pub2.
20. Field T. Massage Therapy Research Review. Complement Ther Clin Pract. 2016; 24: 19-31.
21. Blozik E, Laptinskaya D, Herrmann-Lingen C, Schaefer H, Kochen MM, Himmel W, et al. Depression and anxiety as major determinants of neck pain: a cross-sectional study in general practice. BMC Musculoskelet Disord. 2009; 26: 10-13.
22. Jager PA, Chan D, Muderrisoglu HF. Matrix rhythm therapy application to patient with back pain.Turk J Phys Ther Rehabil. 2008;19 (10):217.
23. Özcan NT, Başakcı Çalık B, Kabul EG. The effectiveness of matrix rhythm therapy in patients with chronic low back pain. Spine (Phila Pa 1976). 2021; 46(12):781-7.
24. Tsao JC. Effectiveness of massage therapy for chronic, nonmalignant pain: A review. Evid Based Complement Alternat Med. 2007; 4(2): 165-79.
25. Ylinen J. Physical exercises and functional rehabilitation for the management of chronic neck pain. Europa Medicophys. 2007; 43(1): 119-32.
Download attachments: 10.4328:ACAM.21063
Ayşe Nur Oymak Soysal, Ummuhan Baş Aslan, Emine Aslan Telci, Erhan Ozfidan. Matrix rhythm therapy in chronic neck pain: A pilot study. Ann Clin Anal Med 2022;13(7):721-725
Pattern and microbiological features of diabetic foot ulcers
Gülşah Baycelebi 1, Hasan Ergenc 2, Zeynep Ergenc 2, Özlem Karaca Ocak 3, Kerim Güzel 4, Feyzi Gökosmanoğlu 5
1 Department of Internal Medicine, Atasam Hospital, Samsun, 2 Department of Internal Medicine, Ayancık Government Hospital, Sinop, 3 Department of General Surgeon, Medicana International Hospital, Samsun, 4 Department of General Surgeon, Faculty of Medicine, Biruni University, İstanbul, 5 Department of Endocrinology and Metabolic Diseases, Faculty of Medicine, Biruni University, İstanbul, Turkey
DOI: 10.4328/ACAM.21092 Received: 2022-01-31 Accepted: 2022-06-10 Published Online: 2022-06-21 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):726-730
Corresponding Author: Hasan Ergenc, Department of Internal Medicine, Ayancık Government Hospital, Sinop, Turkey. E-mail: email@example.com P: +90 368 613 10 27 F: +90 368 613 16 87 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0519-0264
Aim: Diabetic Foot Ulcers (DFUs) are a common complication of type-1 and type-2 diabetes and a significant cause of morbidity and mortality. About 10-15% of patients with diabetes develop foot ulcers. Due to insufficient diagnosis and treatment, amputations in patients occurs and treatment costs increase, which brings a serious financial burden to the patient and the country. This study aimed to evaluate the clinical and microbiological data on diabetic foot infections in our clinic.
Material and Methods: In this study, 62 diabetic foot patients who were followed up with the diagnosis of diabetic foot in our internal medicine clinic between 2016 and 2022 were retrospectively analyzed. Bacterial identification, antimicrobial therapy, and ulcer classification data, such as cultures and biopsies, were obtained from patient files and electronic records. Patients were divided into two groups: medical treatment and surgical treatment. Surgical interventions and amputations were made in line with the decisions of the diabetic foot council.
Results: A total of 62 patients, 40 (64,5%) male, and 22 (35,5%) female, were included in the study. Diabetic chronic microvascular complications were found in 49 patients and osteomyelitis in 43 patients. All of these 43 cases were amputated. The distribution of DFUs according to pathophysiological etiology was most frequently neurogenic (46.7%). Bacteria were isolated from 24 patients, and the most frequently isolated bacteria was Staph. Aureus. Other patients who did not detect growth in the culture received empirical antibiotic therapy. When patients in medical and surgical treatment groups were compared, hypertension, hyperlipidemia, bacterial growth in culture, gender, and oral antidiabetic drug or insulin use properties were statistically similar. The presence of peripheral vascular disease, poor glycemic control, osteomyelitis, sedimentation >70 mm/hr, and diabetic complications were statistically significantly higher in the surgical group.
Discussion: Poor glycemic control and diabetic chronic complications increase the risk of diabetic foot infections. It may be possible to protect patients from DFUs through glycemic control, prevention and early treatment of chronic complications.
Keywords: Diabetic Infections, Microbiological Data, Amputation
Diabetic foot infection usually starts as a superficial infection. If it is not treated, it can quickly progress to the subcutaneous tissues and affect muscles, tendons, bones, and joints. It can progress to septic gangrene and lower extremity amputation. Approximately 60% of non-traumatic lower extremity amputations occur in diabetic patients .
Major risk factors for diabetic foot and lower extremity amputations are neuropathy, nephropathy, ischemia (peripheral vascular disease), hypertriglyceridemia, smoking, and poor glycemic control . Especially, diabetic neuropathy and peripheral artery disease are the two most important risk factors playing a role in developing diabetic foot ulcers. About 25% of diabetic patients have lower extremity infections. Furthermore, about 50% of them result in hospitalization for severe infection, and 25% result in lower extremity amputation . It is reported that the probability of having a second amputation within 1-3 years in a diabetic patient who has had one amputation is 22-42%. The cost of treatment, which is already high, increases 5-8 times with amputation . In diabetic foot ulcer cultures, gram-positive aerobic bacteria; Staph. Aureus, Coagulase-negative Staphylococcus, Enterococcus spp., Group D streptococcus are isolated at a rate of 52%, and gram-negative bacilli, Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter spp. in a rate of 42 % .
Diabetic foot is a severe cause of morbidity and mortality. Due to the delay and inadequacies in treatment, the hospitalization period of patients is prolonged. This results in loss of labor, disability, and psychosocial trauma, and treatment costs bring a severe financial burden to the patient and the country. This study aims to evaluate the clinical and microbiological data and amputation rates of complex cases discussed in the diabetic foot council and compare them with other literature studies.
Material and Methods
Our study is a cross-sectional descriptive study in which the data of 62 patients, followed in our internal medicine clinic between 2016-2022, were obtained retrospectively from patient files and electronic records. Those who underwent surgery and/or amputation in external center clinics with the diagnosis of DFUs, patients with superficial infection (stage 1) on an outpatient basis, those who received empirical treatment without culture and further examination in the follow-ups, patients under the age of 18, pregnant women, cancer patients, kidney and liver patients were excluded. Patients with insufficiency were not included in the study. Patients with stages 2-5, whose DFUs classification was made in our clinic, those who had deep tissue culture, and complex cases who underwent further examination were included in the study.
DFUs were established in patients with clinical, laboratory, and radiological findings, and it was staged according to the Wagner-Meggitt classification. The approval of the ethics committee was received from the ethics board of the university with the number 2018/167 on 12/07/2018. Routine biochemical parameters, C-Reactive protein (CRP), Erythrocyte Sedimentation rate (ESR), and complete blood count were evaluated. Culture samples were taken only as deep tissue culture and abscess culture. Swab cultures were not evaluated within the scope of the study. At the time of culture taking, 39 patients received empirically prescribed oral antibiotic therapy. Deep tissue cultures and other chronic complications related to diabetes were screened. Radiological imaging (direct X-rays, MRI, and bone and leukocyte-marked scintigraphy) findings were obtained retrospectively from patient files.
Patients’ age, gender, smoking, diabetic comorbidities, growth in wound culture, hypertension, hyperlipidemia, and treatment methods were recorded. Patients were divided into a medical treatment group and surgical treatment (debridement, amputation, and medical treatment) group. It was seen that the decision of amputation was taken together with orthopedics and traumatology, cardiovascular surgery specialists, dermatology, endocrinology, plastic and reconstructive surgery specialist, and infectious diseases specialists.
Analysis of data was performed using SPSS 22.0 statistical package program. The Kolmogorov-Smirnov test was used to determine whether the continuous variables showed normal distribution or not. The t-test was used in the comparison of two independent groups. Pearson’s chi-square test and Fisher’s exact chi-square test analyzed categorical data. Statistical significance level was determined as p<0.05.
Sixty-two patients were included in the study. Patients were 52.4 ± 6 years old, and 40 (%64.5) were male, 22 (%35.5) were female. In the treatment of diabetes 67.7% (n=42) used insulin and %32.2 (n=20) oral antidiabetic drugs. The mean duration of diabetes was 14.2 ±5 years. Diabetic chronic microvascular complications were found in 79% (n=49), peripheric vascular disease in 40% (n=25), hypertension in 56.4% (n=35), and hyperlipidemia in 38.7% (n=24) of subjects when diabetic complications were examined. Osteomyelitis was detected in 69.3% (n=43) of patients radiologically and clinically. All patients with osteomyelitis had a high erythrocyte sedimentation rate (ESR>70 mm/hr ).
When the patients in the medical treatment and surgical treatment groups were compared, no statistically significant difference was found between surgical treatment and parameters such as hypertension, hyperlipidemia, bacterial growth in the culture, gender, use of oral antidiabetic drugs or insulin. A statistically significant difference was found between surgical treatment and the presence of peripheral vascular disease, osteomyelitis, sedimentation >70 mm/hr, diabetic microvascular complications, and poor glycemic control (Table 1).
All patients were classified according to the Wagner-Meggitt classification at the time of admission to the hospital (Table 2). Thirty-six of the 43 patients who underwent amputation were stage 3, and 7 were stage 4. The distribution of diabetic wounds according to the pathophysiological etiology was as follows: %46.7 (n=29) neurogenic, %25.8 (n=16) neuroischemic and %27.4 (n=17) ischemic. Deep tissue culture with a cotton swab was taken during debridement from all patients. Bacteria were isolated from 24 patients (%38.7). The distribution of these patients was as follows: Staph. aureus 12, P. aeruginosa 5, E. coli 5, Citrobacter 1, Strep. agalactiae 1. It was seen that patients with no growth in the culture received antibiotic treatment. No bacterial growth was detected in the tissue cultures of these patients.
Staphylococcus aureus (50%) was the most common bacteria, while Pseudomonas aeruginosa (20.8%) and Escherichia coli (20.8%) bacilli were found to be the most common gram-negative bacteria. Of the 12 Staph aureus isolates, 4 (16.6%) were Methicillin-resistant Staph aureus (MRSA). Extended Spectrum Beta-Lactamase (ESBL) positivity was 32.5%. Staph. aureus (vancomycin, linezolid, Teicoplanin, trimethoprim-sulfamethoxazole, levofloxacin, Fusidic acid) were sensitive, and oxacillin, cefoxitin, cefazolin were resistant. Pseudomonas aeruginosa (imipenem, meropenem, piperacillin-tazobactam, cefoperazone -sulbactam, ceftazidime) was detected as sensitive. Escherichia coli (amikacin, trimethoprim-sulfamethoxazole, imipenem, meropenem, Ertapenem) was sensitive, and ciprofloxacin, piperacillin-tazobactam were resistant. Strep. agalactiae (vancomycin, Teicoplanin) and Citrobacter (amikacin, imipenem) were sensitive.
Diabetic foot lesions may present as lesions ranging from simple superficial hyperemia to ulceration, osteomyelitis, and gangrene. Diabetic lower extremity ulcers can be classified as non-leg-threatening, leg-threatening, and life-threatening ulcers . In our study, we found foot and/or finger threatening ulcers in 43 patients in the surgical treatment group and life-threatening ulcers in 4 patients in the medical treatment group. A retrospective evaluation of 24 isolates detected in 62 diabetic foot ulcer patients was performed in our study. Most of the isolates were gram-positive bacteria, and most were staphylococcus strains (50%). Among Gram-negative bacteria, Pseudomonas aeruginosa (20.8%) and Escherichia coli (20.8%) bacilli predominated.
Isolation of causative bacteria is very important for determining the suitable treatment protocol in diabetic foot ulcers. Multiple bacteria may be responsible for the presence of deep tissue infection and osteomyelitis. Therefore, in addition to swab culture, the microbiological examination should be performed by taking samples from purulent drainage in deep tissues, necrotic tissues, and, if necessary, bone tissue during debridement . Gram-positive bacteria gram-negative aerobic and anaerobic bacteria are isolated in diabetic foot ulcers. Generally, the causative agents in severe ulcers are polymicrobial bacteria such as P. aeruginosa, Staph. aureus and Enterococcus spp. It has been reported that polymicrobial infections develop more frequently in patients receiving empirical antibiotic therapy. Because of this, it is imperative to use appropriate antibiotics in the treatment of diabetic foot infections.
Drug selection should be made by evaluating the severity of the infection, duration of the diabetic wound, and previous antibiotic exposure . In our study, bacterial isolation was achieved in deep tissue culture in %38.7 (n=24) of the cases. The isolated bacteria were Staph. aureus (%50), E. coli (%20.8), Pseudomonas (%20.8), Citrobacter (%4.1), Strep. Agalactiae (%4.1), which is consistent with literature. It is shown in the studies that Staph. aureus (%47.5), Pseudomonas spp. (%16.9), E. coli (%10.2), Streptococcus spp. (%8.5), Enterobacter spp. (%7.0), Proteus spp. (%6.7) and Acinetobacter spp. (%3.2) are isolated in the cultures . Our study detected bacterial isolation in tissue cultures at a much lower rate than in the literature. The data of culture positivity lower than expected can be explained by the fact that most of our patients received antibiotic treatment before coming to our clinic. The patients were difficult cases referred to our clinic from primary and secondary medical centers. There was no statistically significant difference between bacterial isolation in culture, medical treatment, and surgical treatment. There was no statistically significant difference between medical and surgical treatment in terms of bacterial growth in tissue culture.
Although DFUs are usually polymicrobial infections, they were monomicrobial infections in our study [10,11]. DFUs have been reported as polymicrobial infections in studies [12,13]. In our study, most patients with DFUs had a history of antibiotic use, and sensitive bacteria could not be detected due to antibiotic use. However, only resistant organisms could be detected, which may explain monomicrobial dominance. S.aureus strains that we detected in the etiology in our study showed 100% sensitivity to Teicoplanin, Linezolid, and Vancomycin. S.aureus Cefoxitin, Oxacillin, Cefazolin were resistant to a certain extent (27.3-89%). All strains of MRSA were susceptible to Teicoplanin, Vancomycin, and Levofloxacin. E. coli strains Amikacin, Imipenem, Meropenem showed 90-95.4% sensitivity. Pseudomonas aeruginosa was 80.4-100% sensitive to Imipenem, Cefoperazone-Sulbactan, Piperacillin-Tazobactam, Ceftazidime.
Diabetic neuropathy, peripheral vascular disease, foot deformity, previous diabetic foot ulcer, and amputation are the most critical risk factors for diabetic foot . In our study, at least one diabetic neuropathy, retinopathy, and nephropathy were present at a rate of %79 (n=49). Various studies have shown that 40-60% of patients undergoing amputation because of the diabetic foot have neuropathy. In our study, diabetic chronic complications were 61.2% (n=38) in the surgical treatment group and 17.7% (n=11) in the medical treatment group. We found more chronic complications in the surgical treatment group than in the medical treatment group. Studies have shown that poor glycemic control is a significant risk factor for diabetic foot and amputation . In our study, the relationship between the presence of poor glycemic control and amputation was statistically significant. Atherosclerosis begins at an earlier age in diabetics and tends to progress more rapidly. Foot ulcer and amputation are the primary macrovascular complications associated with diabetes. Studies have shown that peripheral vascular disease is a predictive factor for diabetic foot ulcers . In our study, we found peripheral vascular disease at a very high rate of 40.3% (n=25), hypertension at a rate of 56.4 % (n=35), and hyperlipidemia at a rate of 38.7% (n=24). The relationship between the presence of peripheral vascular disease and surgical treatment and undergoing amputation was statistically significant. There was no statistically significant difference between hypertension and hyperlipidemia and surgical treatment. The International Diabetes Federation recommends reducing such diabetes-related complications as the primary goal since diabetic patients have a high lifetime risk of developing foot ulcers of 25% .
In our study, osteomyelitis was found at a rate of 69.3% (n=43). At least one finger amputation was performed in cases with osteomyelitis. The amputation rates reported in Turkey were found to be 36.7-37 % . In developed countries, the prevalence of diabetic foot has been reported as 10-15%, and amputation prevalence is 15% . In our research, amputation rates are higher than in developed countries, which is compatible with the data of our country. The reason for the high rate of amputation is the insufficient number of centers where diabetic foot patients can be treated and the delay in the admission of patients to these centers. Studies have shown that the best inflammatory marker for osteomyelitis is sedimentation rate . In our study, a significant correlation was found between sedimentation >70 mm/hr, the presence of osteomyelitis, and undergoing amputation. Studies have found that 5% of diabetic patients with DFUs required major amputation during the 12-month follow-up period. It shows that the most important cause of non-traumatic lower extremity amputation is diabetic foot ulcers [21,22].
Studies indicate that most diabetic foot ulcers can be prevented with a multidisciplinary approach. Follow-up and treatment of diabetic foot ulcers by a team lead to successful results . All patients in our study were diagnosed and treated in our clinic with a multidisciplinary approach. Together with appropriate antibiotic therapy, surgical drainage, debridement, and resection of dead tissue should be performed, appropriate wound care should be applied, and metabolic disorders should be corrected. The treatment of diabetic foot infections is usually started empirically, and there is no standard approach to antibiotic use and duration of treatment. The antibiotic regimens used were not superior to each other. However, there is a common view that antibiotic treatment is unnecessary in uninfected ulcers .
Our study showed that empiric antibiotic treatment was started before culture at a rate of %51.6 (n=32). Ampicillin-sulbactam, piperacillin-tazobactam, ertapenem, and moxifloxacin were given to 12 patients with a moderate infection piperacillin-tazobactam, imipenem, and meropenem treatment were given to 26 patients having a more severe infection, even if there was no growth in the culture. The aim of surgery in the treatment of diabetic foot ulcers is to clean the infected and necrotic tissue to a level that will allow the granulation tissue to provide secondary healing to come out . In our study, early local surgical procedure (incision, debridement) was performed in 19 patients, and at least one finger amputation was performed in 43 patients.
This study has some limitations. The study was designed retrospectively and should be supported by prospective studies. The number of patients in the study is low. In addition, because the study was performed retrospectively, patients’ backgrounds and other comorbid diseases could not be evaluated in detail.
In our study, Staph was most commonly found in DFUs infections. E.coli and Pseudomonas aeruginosa are the most common gram-negative bacillus when detecting aureus. In line with these findings, it can be said that antibiotics (Teicoplanin, Vancomycin, and Linezolid) with 100% sensitivity in gram-positive infections will be an appropriate choice in the empirical treatment of DFUs. High sensitivity to Vancomycin and Teicoplanin should be considered in MRSA infections. In the empirical treatment of gram-negative infections, it may be more appropriate to use Amikacin and Imipenem, Meropenem. Dominant isolated organisms and local antimicrobial susceptibility patterns should be considered when in selecting antibiotic therapy.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Miyan Z, Fawwad A, Sabir R, Basit A. Microbiological pattern of diabetic foot infections at a tertiary care center in a developing country. Age Years. 2017;53:10-20.
2. Alhubail A, Sewify M, Messenger G, Masoetsa R, Hussain I, Nair S, et al. Microbiological profile of diabetic foot ulcers in Kuwait. PloS one. 2020;15(12):244-306.
3. Anyim O, Okafor C, Young E, Obumneme-Anyim I, Nwatu C. Pattern and microbiological characteristics of diabetic foot ulcers in a Nigerian tertiary hospital. Afr Health Sci. 2019;19(1):1617-27.
4. Hassan MA, Tamer TM, Rageh AA, Abou-Zeid AM, Abd El-Zaher EH, Kenawy ER. Insight into multidrug-resistant microorganisms from microbial infected diabetic foot ulcers. Diabetes Metab Syndr 2019;13(2):1261-70.
5. Ertugrul BM, Buke C, Ersoy OS, Ay B, Demirez DS, Savk O. Intralesional epidermal growth factor for diabetic foot wounds: the first cases in Turkey. Diabet Foot Ankle. 2015;11(6):28419.
6. Zubair M. Prevalence and interrelationships of foot ulcer, risk-factors and antibiotic resistance in foot ulcers in diabetic populations: a systematic review and meta-analysis. World J Diabetes. 2020;11(3):78-89.
7. Perim MC, Borges JD, Celeste SR, Orsolin ED, Mendes RR, Mendes GO, et al. Aerobic bacterial profile and antibiotic resistance in patients with diabetic foot infections. Revista da Sociedade Brasileira de Medicina Tropical. 2015;48:546-54.
8. Yusuf N, Zakaria A, Omar MI, Shakaff AY, Masnan MJ, Kamarudin LM, et al. In vitro diagnosis of single and poly microbial species targeted for diabetic foot infection using e-nose technology. BMC Bioinformatics 2015;16(1):158.
9. Anvarinejad M, Pouladfar G, Japoni A, Bolandparvaz S, Satiary Z, Abbasi P, Mardaneh J. Isolation and antibiotic susceptibility of the microorganisms isolated from diabetic foot infections in Nemazee Hospital, Southern Iran. J Pathog. 2015; 2015. DOI: 10.1155/2015/328796
10. Jnana A, Muthuraman V, Varghese VK, Chakrabarty S, Murali TS, Ramachandra L, et al. Microbial community distribution and core microbiome in successive wound grades of individuals with diabetic foot ulcers. Appl Environmen Microbiol. 2020;86(6):26-19.
11. Akhi MT, Ghotaslou R, Asgharzadeh M, Varshochi M, Pirzadeh T, Memar MY, et al. Bacterial etiology and antibiotic susceptibility pattern of diabetic foot infections in Tabriz, Iran. GMS Hyg Infect Control 2015; 86(6):10-20.
12. Shareef J, Sunny S, Bhagavan KR. Study on bacteriological profile and antibiotic susceptibility pattern in patients with diabetic foot ulcers in a tertiary care teaching hospital. Journal of Social Health and Diabetes. 2018;6(1):40-7.
13. Yerat RC, Rangasamy VR. A clinicomicrobial study of diabetic foot ulcer infections in South India. Int J Med Public Health. 2015;5:236-41.
14. Noor S, Ahmad J, Parwez I, Ozair M. Culture-based screening of aerobic microbiome in diabetic foot subjects and developing non-healing ulcers. Frontiers in Microbiology. 2016;7:17-92.
15. Al-Rubeaan K, Al Derwish M, Ouizi S, Youssef AM, Subhani SN, Ibrahim HM, et al. Diabetic foot complications and their risk factors from a large retrospective cohort study. PLoS One 2015;10(5). DOI: 10.1371/journal.pone.0124446.
16. Delea S, Buckley C, Hanrahan A, Mc Greal G, Desmond D, Mc Hugh S. Management of diabetic foot disease and amputation in the Irish health system: a qualitative study of patients’ attitudes and experiences with health services. BMC Health Serv Res 2015;15(1):251.
17. Uivaraseanu B, Bungau S, Tit DM, Fratila O, Rus M, Maghiar TA, et al. Clinical, pathological and microbiological evaluation of diabetic foot syndrome. Medicina. 2020;56(8):380.
18. Malone M, Johani K, Jensen SO, Gosbell IB, Dickson HG, Hu H, et al. Next generation DNA sequencing of tissues from infected diabetic foot ulcers. EBioMedicine. 2017;21:142-9.
19. Ahmad J. The diabetic foot. Diabetes Metab Syndr 2016; 10(1):48-60.
20. Van Asten SA, Peters EJ, Xi Y, Lavery LA. The Role of Biomarkers to Diagnose Diabetic Foot Osteomyelitis. A Meta-analysis. Curr Diabetes Re. 2016; 12(4):396-402
21. Sekhar S, Unnikrishnan MK, Rodrigues GS, Vyas N, Mukhopadhyay C. Antimicrobial susceptibility pattern of aerobes in diabetic foot ulcers in a South-Indian tertiary care hospital. Foot. 2018;37:95-100.
22. Mutonga DM, Mureithi MW, Ngugi NN, Otieno FC. Bacterial isolation and antibiotic susceptibility from diabetic foot ulcers in Kenya using microbiological tests and comparison with RT-PCR in detection of S. aureus and MRSA. BMC Res Notes. 2019;12(1):244.
23. Nteleki B, Njokweni M. Want to avoid DFUs? A multidisciplinary team approach works best. J Wound Care. 2015;24(2):8-14.
24. Rysková L. Diabetic foot infections. Vnitr Lek. 2015;61(6):587-91.
25. Xie Y, Xu Y, Chen K, Chen C, Huang J, Chen Q, Shi P. Microbiological and Antimicrobial Pattern of Diabetic Foot Ulcers at a Tertiary Care Center in East China. Int J Low Extrem Wounds. 2021; DOI: 10.1177/15347346211055972.
Download attachments: 10.4328:ACAM.21092
Gülşah Baycelebi, Hasan Ergenc, Zeynep Ergenc, Özlem Karaca Ocak, Kerim Güzel, Feyzi Gökosmanoğlu. Pattern and microbiological features of diabetic foot ulcers. Ann Clin Anal Med 2022;13(7):726-730
Evaluation of the effect of analgesic nociceptive monitorization in cases of urological surgery undergoing general anesthesia and spinal anesthesia
Mehmet Tepe 1, Hasan Hüsnü Yüce 2
1 Department of Anesthesiology and Reanimation, Faculty of Medicine, Adiyaman University Adiyaman, 2 Department of Anesthesiology and Reanimation, Private Meydan Hospital, Sanliurfa, Turkey
DOI: 10.4328/ACAM.21095 Received: 2022-02-02 Accepted: 2022-03-08 Published Online: 2022-06-07 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):731-735
Corresponding Author: Mehmet Tepe, Department of Anesthesiology and Reanimation, Medical School, Adiyaman University, 02100, Adiyaman, Turkey. E-mail: firstname.lastname@example.org P: +90 505 351 92 30 F: +90 416 223 16 93 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2596-1284
Aim: In this study, it was aimed to identify and compare the effectiveness of spinal block and general anesthesia and to evaluate postoperative pain relations using the analgesic nociceptive index (ANI) monitoring in urologic surgery cases under general anesthesia and spinal anesthesia.
Material and Methods: Sixty patients were included in this study. The ANI palette was placed 2 cm below sternum xiphoid projection noninvasively, and ECG palette was placed to the V5 chest leads place, and ANI values after general anesthesia or spinal anesthesia and in set time intervals measurements were performed for each patient. In order to evaluate postoperative pain of patients, the visual analogue pain scale (VAS) and ANI values were recorded.
Results: Study groups were compared in terms of median ANI values at the intraoperative 0, 5, 10, 15, 20, 25, 30, 60, 90, and 120 Minutes, and there was no significant statistical difference between the two groups. Study groups were compared in terms of postoperative median ANI values. There was no significant statistical difference between the two groups. There was a low and negligible negative correlation between postoperative ANI values and postoperative VAS values. It was not statistically significant (P <0.05).
Discussion: When the study groups were compared, ANI values showed no significance in terms of intraoperative and postoperative measurements. The presence of a low and negligible negative correlation between postoperative ANI and VAS values measured in these groups is assumed to be insignificant.
Keywords: ANI, VAS, General Anesthesia, Spinal Anesthesia, Urologic Surgery
Postoperative pain is acute pain that begins with surgical trauma and gradually decreases with tissue healing . In addition to the unpleasant feeling of postoperative pain, the stress, response, and hyper metabolism developed after surgery can impair the neuroendocrine system, respiratory system, cardiovascular and gastrointestinal system functions, and increase the rate of postoperative mortality and morbidity. Therefore, effective pain management is an important part of postoperative patient care .
Appropriate and adequate postoperative pain management is an important factor contributing to the acceleration of postoperative recovery and healing, shortening the hospital stay and reducing the management costs .
The Analgesic Nociceptive Index (ANI) calculates the parasympathetic reflex cycle strength. ANI is based on electrocardiography (ECG) data obtained using two electrodes placed on the patient’s chest. The ANI index is indicated on a scale from 0 to 100. The displayed ANI value is the result of calculations made in an average of 64 seconds and progresses in 1-second windows. A patient experiencing pain responds to painful stimuli by activating his sympathetic tonus, so ANI values decrease with pain .
The Visual Analogue Scale (VAS) (0: The patient marked the severity of the pain on a 10 cm line, one end of which indicates no pain, and the other end represents unbearably severe pain) is a pain assessment scale .
The study aims to prevent misevaluation of pain perception as a result of anxiety during and after surgery in patients undergoing spinal anesthesia or general anesthesia, and to determine the effectiveness of spinal block under adequate sedation with adequate general anesthesia and spinal block without sedation before hemodynamic parameters, using analgesic nociceptive index monitoring, and thus, to detect the need for intraoperative sedation and anesthesia in the early period and to follow up postoperative pain with more objective criteria.
Material and Methods
The approval from the Clinical Trials Ethics Committee of Harran University Faculty of Medicine has been obtained (Approval No: 20.03.2015/3). The study is supported by Harran University Scientific Research Board with the date of 02/09/2015 and project no. 15100. Patients between the ages of 18-80, included in the I-II-III risk group of the American Society of Anesthesiologists (ASA), who were scheduled for elective endoscopic surgery between 01/10/2015 and 01/12/2015 in the operating room of Harran University Faculty of Medicine Research and Practice Hospital were included in the study. In any group, patients with liver and/or kidney failure, obese patients (BMI>30), trauma patients, cancer patients, ASA-IV patients, emergency surgery, cardiac arrhythmia, those with an implanted pacemaker, patients on beta blocker, those with a history of chronic pain, and those who did not want to participate in the study were considered as exclusion criteria. Sixty patients without exclusion criteria are included in the study. Study groups were divided into 3 groups with 20 patients in each group according to the type of anesthesia applied. Groups were determined by random matching. It is determined as Group1: general anesthesia, Group2: spinal anesthesia, Group3: spinal + sedation anesthesia. Patients to be included in the study were visited before surgery, and verbal and written consent was obtained one day before the operation. Age, comorbidities, previous surgeries, and drug use of the patients have been recorded.
In patients who were taken to the operating room without premedication, heart rate was monitored using ECG, non-invasive blood pressure, and peripheral oxygen saturation were monitored using pulse oximetry. General anesthesia has been prepared for possible complications. Peripheral vascular cannulation was performed on the dorsal side of the hand with a 20 G cannula, and an isotonic solution of 10 ml/kg/hour was given intravenously to finish in 30 minutes for pre-load. We performed fluid loading before anesthesia to prevent the negative effect of anesthesia-induced vasodilation on tissue perfusion by increasing intravascular volume.
All preparations (for induction of 0.1 mcg/kg remifentanil + 2 mg midazolam + 2 mg/kg propofol + for muscle relaxation with 0.6 mg/kg rocuronium) have been made for the group to be administered general anesthesia. Total intravenous anesthesia (TIVA) (propofol (4-6 mg/kg/h) + remifentanil (0.15 mcg/kg/min)) preparation has been made for the maintenance of general anesthesia.
The patients have been placed in a sitting position for spinal anesthesia. The lumbar region has been cleaned with an antiseptic solution and covered. After local anesthesia with 2 ml of 2% lidocaine was applied to all patients, 12.5 mg (the dose according to the desired level of the blockade) Bupivacaine hydrochloride (0.5% Heavy Marcaine, Dextrose monohydrate 80 mg/ml, Astra Zeneca, Turkey) was administered to the subarachnoid space after free CSF flow is observed by entering through the L3-4 space with a 25G Quincke spinal needle. At the end of the procedure, the patient was placed in a supine position and the head has been elevated. The sensorial block level of the patients is checked with the “Pinprick” test. After the block reached T4 level, the operation started. It has been done by recording ANI values and hemodynamic parameters to be obtained by placing an analgesic nociceptive index (ANI, MetroDoloris, Loos, France) palette 2 cm below the sternum xiphoid process in a non-invasive way in patients who will undergo urological surgery, and by placing the ECG palette in the region corresponding to the V5 chest derivation, in the forms prepared at the specified time intervals (0,5,10,15,20,25,30,60,90,120 minutes) during anesthesia application and after the anesthesia. In addition, visual analog pain scale (VAS: 0: no pain, 5: moderate pain, 10: excruciating pain) and postoperative ANI values have been recorded to evaluate postoperative pain of the patients (5,10,15,30,60 minutes) in the post-recovery unit.
The Chi-square test was used for categorical variables. One-way ANOVA (One-Way Analysis of Variance) test was used if the distribution is normal and the variances are homogeneous for continuous variables. Tukey’s test was used as the Posthoc test to find out which groups the difference was associated with. Welch ANOVA test was used for continuous variables if the distribution was normal but the variances were not homogeneous. The Tamhane T2 test was used as the Posthoc test to find out which groups the difference was associated with. If the distribution is not normal for continuous variables, the Kruskal-Wallis test was used and p<0.05 is accepted as significant. The groups were analyzed in pairs with the Mann-Whitney U test to find out which groups the difference was associated with, and the Bonferroni correction was used (p<0.05/3 is considered significant). Correlation coefficients and statistical significance were calculated with Spearman’s test for the relationships between variables, at least one of which is not normally distributed. The results were evaluated at the 95% confidence interval, and the significance was at the p<0.05 level.
The average age of the patients participating in the study was 47.5, with a minimum value of 18 and a maximum value of 80. When the study groups formed according to the type of anesthesia applied were compared in terms of average age, no statistically significant difference was found (p>0.05) (Table1).
The most common comorbidities detected in the participants are previous surgery with 23.33% followed by previous surgery + drug use with 20%. No concomitant disease was detected in 10% of the group.
The most common postoperative complication in the participants was hypertension with 3.33%, and the second most common complication was nausea-vomiting with 1.66%. The patients were given ondansetron 0.1 mg/kg (Ondaren 8 mg, Vem Medicine, Istanbul, Turkey) for the treatment of postoperative nausea, and antihypertensive medication was administered for hypertension. On the other hand, postoperative complications were not observed in 95% of the participants.
When the average ANI values of the study groups at intraoperative 0.5,10,15,20,25,30,60,90,120 minutes were compared, no statistically significant difference was found (p>0.05) (Table 2) (Figure 1).
When the study groups were compared in terms of mean ANI values at postoperative 5,10,15,30,60 minutes, no statistically significant difference was found (p>0.05) (Table 3).
There was a low or insignificant negative correlation between the postoperative ANI value and the postoperative 5,10,15,30,60-minute VAS value and it was not statistically significant (respectively r= -0.070 and p>0.05; r= -0.094 and p>0.05; r= -0.043 and p>0.05; r= 0.008 and p>0.05; r= -0.070 and p>0.05) (Figures 2, 3).
The analgesic nociceptive index is a form of monitoring that has been used and popularized in the last few years. It has been frequently used and studied intraoperatively and postoperatively, especially in general anesthesia patients. Studies on ANI are increasing day by day, and publications are mostly made for the evaluation of pain during general anesthesia and postoperative pain. Publications on regional anesthesia have been limited to caudal and epidural anesthesia [6,7].
In our study, 60 elective urological cases were evaluated. They are divided into 3 groups as general anesthesia, spinal anesthesia, and spinal anesthesia under sedation. Intraoperative and postoperative ANI values have been measured. No significant difference was found intraoperatively in the measurements. No significant difference was found in the postoperative measurements. However, there was a low or insignificant negative correlation between postoperative ANI value and postoperative VAS value, but it was not statistically significant.
Logier et al. found the ANI index with the technique they described for the measurement of heart rate variability. The calculation of ANI is to build on the respiratory cycle flow over the R-R interval obtained from the ECG. Therefore, if the parasympathetic tonus is dominant, there will be a little decrease in heart rate with each inspiration and an increase in the R-R interval, which will cause respiratory arrhythmia. Filtered R-R analysis yields great variability. However, if the parasympathetic tonus is reduced, the effect of each respiratory cycle is diminished. Therefore, the effect of parasympathetic tonus on the R-R interval can be used to predict parasympathetic tonus, and consequently, the setting of analgesia and nociception can be predicted. Parasympathetic tonus decreases due to increased nociception depending on decreased analgesia or increased sympathetic activity, which leads to a decrease in ANI. ANI can provide a greater technological advantage, as it uses the wavelet formula (filters allow detection of individual frequency domains without phase shift, which allows distinguishing between sympathetic and parasympathetic effects), which is more mathematical than past pain parameters .
Le Guen et al. have evaluated labor pain by comparing ANI values with VAS values in 45 pregnant women who had an epidural catheter. Regular measurements were made during uterine contractions and also every 5 minutes, and obtained results were parallel to VAS values .
Migeon et al. used ANI monitoring for the early assessment of pain after skin incision in 58 pediatric cases over 2 years of age who underwent caudal anesthesia and supplemented with sevoflurane inhaled anesthetic. They have stated that the patients are administered regional anesthesia during sevoflurane inhalation and that an increase of more than 10% during the surgical incision showed that the block is ineffective. Nineteen cases were evaluated as an unsuccessful block. They have found that pupil diameter monitoring (PD) changes were consistent with ANI .
In their study of 120 patients, Abdullayev et al. accepted the numerical rating scale (NRS) as the subjective component of pain and ANI values as the objective component of pain. They stated that there was a negative linear relationship between ANI and NRS and stated that higher NRS values meant lower ANI scores in case of pain .
In the study by Dostalova et al., seventy-two adults scheduled for elective neurosurgery spinal procedures were randomized into the ASA I-III patient ANI group, the Surgical Plethysmographic Index (SPI) group, and the control group, and it was stated that the intraoperative use of anesthesia and opioids was managed according to a strict protocol. They reported that both ANI and SPI guidance significantly changed intraoperative opioid use, but no changes were observed in postoperative cortisol levels and postoperative pain .
Jiao et al. presented a meta-analysis of ten studies examining the effects of Analgesia Nociception Index, Surgical Plet Index (SPI), and pupillometry monitoring methods in terms of intraoperative opioid administration and analgesia method. In the meta-analysis, it has been found that nociception measurement-guided analgesia reduces intraoperative opioid consumption compared to conventional analgesia, and that SPI-guided intraoperative opioid administration was less than traditional analgesia, and that the difference between ANI-guided analgesia and standard clinical care was not statistically significant .
Although it was stated in previous studies that ANI monitoring is effective in detecting the need for intraoperative opioids in the early period and monitoring postoperative pain, our results support the work of Dostalova and Jiao. Considering the VAS values, we have evaluated that ANI is not an effective monitoring technique in the intraoperative and postoperative pain follow-up of patients, since it has a low and insignificant negative correlation with ANI.
Our study has had several limitations. Although ethical committee approval and voluntary participant consent were obtained, no clinical trial registration was made. We have had three groups as general, spinal, spinal + sedation. Our results may have been influenced by the choice of anesthesia and the opioid strategy used in the groups. Differences in the unmeasured depth of anesthesia may have affected the observed results. Due to the limited sample size, our study was not powerful enough to detect more subtle differences between groups in the postoperative period.
As a consequence, we found that the use of ANI as a form of pain monitoring that can provide an independent, continuous, non-invasive measurement of intraoperative and postoperative pain is not significant in urological cases under general anesthesia, spinal anesthesia, and sedated spinal anesthesia.
Although it is concluded in our study that the use of ANI monitoring in both intraoperative and postoperative pain control monitoring is not significant, it should be supported by new studies to be carried out in this direction, and thus, the use of ANI monitoring in patients receiving anesthesia will become more convenient.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Uludağ Ö, Kavak GÖ, Tokgöz O, Çelik F, Tüfek A, Yıldırım ZB, et al. The Effect of Postoperative Tramadol Consumtion of Lornoxicam and Paracetamol Used in Preemptive. Van Med J. 2012;19(1):27-32
2. American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116(2):248-73.
3. Uludag O, Şanlı D, Kara İ. Postoperative pain. In: Sargın M, editor. Complications in anesthesia. Ankara: Akademsiyen Press; 2019.p.325-50.
4. Gruenewald M, Herz J, Schoenherr T, Thee C, Steinfath M, Bein B. Measurement of the nociceptive balance by Analgesia Nociception Index and Surgical Pleth Index during sevoflurane-remifentanil anesthesia. Minerva Anestesiol. 2015;81(5):480-9.
5. Kara I, Tuncer S, Erol A, Reisli R. Preemptif deksketoprofen kullanımının postoperatif ağrı ve tramadol tüketimine etkisi (The effects of preemptive dexketoprofen use on postoperative pain relief and tramadol consumption). Agri. 2011;23(1):18-21.
6. Le Guen M, Jeanne M, Sievert K, Al Moubarik M, Chazot T, Laloë PA, et al. The Analgesia Nociception Index: a pilot study to evaluation of a new pain parameter during labor. Int J Obstet Anesth. 2012;21(2):146-51.
7. Migeon A, Desgranges FP, Chassard D, Blaise BJ, De Queiroz M, Stewart A, et al. Pupillary reflex dilatation and analgesia nociception index monitoring to assess the effectiveness of regional anesthesia in children anesthetised with sevoflurane. Paediatr Anaesth. 2013;23(12):1160-5.
8. Logier R, Jeanne M, De Jonckheere J, Dassonneville A, Delecroix M, Tavernier B. PhysioDoloris: a monitoring device for analgesia / nociception balance evaluation using heart rate variability analysis. Annu Int Conf IEEE Eng Med Biol Soc. 2010; 1194-7.
9. Abdullayev R, Uludag O, Celik B. Analgesia Nociception Index: assessment of acute postoperative pain. Brazilian Journal of Anesthesiology. 2019;69(4):396-402.
10. Dostalova V, Schreiberova J, Bartos M, Kukralova L, Dostal P. Surgical Pleth Index and Analgesia Nociception Index for intraoperative analgesia in patients undergoing neurosurgical spinal procedures: a comparative randomized study. Minerva Anestesiol. 2019;85(12):1265-72.
11. Jiao Y, He B, Tong X, Xia R, Zhang C, Shi X. Intraoperative monitoring of nociception for opioid administration: a meta-analysis of randomized controlled trials. Minerva Anestesiol. 2019;85(5):522-30.
Download attachments: 10.4328:ACAM.21095
Mehmet Tepe, Hasan Hüsnü Yüce. Evaluation of the effect of analgesic nociceptive monitorization in cases of urological surgery undergoing general anesthesia and spinal anesthesia. Ann Clin Anal Med 2022;13(7):731-735
Intracranial lipomas: Clinical and radiological analysis of 153 cases and review of the literature
Ziya Asan 1, Aydan Koysuren 2, Hatice Duygu Ciftci Sivri 3
1 Department of Neurosurgery, Faculty of Medicine, Ahi Evran University, 2 Department of Neurology, Kirsehir Training and Research Hospital, 3 Department of Emergency Medicine, Kirsehir Training and Research Hospital, Kirsehir,Turkey
DOI: 10.4328/ACAM.21104 Received: 2022-02-12 Accepted: 2022-03-12 Published Online: 2022-03-13 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):736-740
Corresponding Author: Ziya Asan, Department of Neurosurgery, Faculty of Medicine, Ahi Evran University, 40100, Kirsehir, Turkey. E-mail: email@example.com P: +90 533 650 26 41 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8468-9156
Aim: It is aimed to describe the localization distribution of lipomas in cases diagnosed with intracranial lipoma, HU value measurements in CT examinations, and point value measurements in MRI and discuss them in the light of the literature.
Material and Methods: Cases diagnosed with intracranial lipoma were recorded retrospectively by scanning the radiology database and polyclinic records. The localization of the lipomas was recorded by measuring the HU value on CT imaging and spot value measurements on MRI T2 sequence imaging. The same data were recorded and compared in control radiological examinations.
Results: A total of 153 cases were diagnosed with intracranial lipoma, and falx lipoma (n:72) was the most common. Intra-calvarial lipoma, which was not defined in the literature, was detected in 21 cases. In CT examinations, the mean HU value at the time of initial diagnosis was -57.91 ± -12.81; In the examination of MRI T2 sequences, it was recorded as 1384.23 ± 101.62. In control radiological examinations, no statistically significant difference was detected between HU values in CT examinations and point values in MRI examinations.
Discussion: It was determined that intracranial lipomas did not differ in their quantitative radiological examinations. Epilepsy resistance to medical treatment is observed in almost all cortical lipomas. Association with central nervous system anomalies is seen only with callosal lipomas.
Keywords: Intracranial Lipoma, HU Value, Hounsfield Unit, Lipoma
Intracranial lipomas are very rare, usually asymptomatic, and often detected incidentally. They are detected in 0.1% to 0.5% of all intracranial space-occupying lesions . They are considered congenital malformations after abnormal differentiation of the meninges primitiva and are not considered true neoplasms . They are frequently seen with central nervous system anomalies such as corpus callosum agenesis, spina bifida, and cortical malformations [3,4]. Although they are frequently located cisternally, they can rarely be located on the surface of the cerebral hemispheres [5,6]. It is recommended that they be treated conservatively as much as possible since surgical interventions are high-risk and the complication rate is high in symptomatic cases due to their tight adhesion to the adjacent tissues .
Although radiological examinations are typical, they show similar features in qualitative evaluations in computed tomography (CT) examinations . Quantitative differential diagnosis can be made with Hounsfield Unit (HU) value measurements in CT examinations, and HU values are in the range of -30 – -130 . Magnetic Resonance Imaging (MRI) examinations are seen as high-signal on T2-weighted images and low-signal on fat-suppressed T1-weighted images and do not show contrast enhancement [8,10].
Material and Methods
Cases who applied to our institution between 2013-2021 and were found to have intracranial lipoma after radiological examinations were identified. For this purpose, cranial CT and MRI images of cases with intracranial lipoma were obtained by scanning the radiological database of the institution. Demographic data of the cases were obtained by retrospectively examining the polyclinic records. Demographic and radiological data of the cases were recorded by creating a database in an Excel file.
Localizations of lipomas were determined in CT and MRI examinations, and were divided into groups. Cases according to the localization of lipomas, falx, convexity, cisternal, calvarial, pericallosal, and choroid plexus localized groups were recorded. In order to make the differential diagnosis of intracranial lipomas from other structures, HU values were measured in CT examinations. The highest HU values obtained at the central and peripheral points of the lesion were recorded. The same values were compared in the control CT examinations. In cases followed by MRI examination, point measurements were made over the Picture Archiving and Communication Systems (PACS) instead of HU value measurements and compared. In MRI images, point measurement values were performed on the images in the T2 sequence.
In cases with cisternally located lipoma, their potential to cause ventricular dilatation was evaluated using the Ewans score.
Ethics Committee approval for this study was retrieved from Kirsehir Ahi Evran University Clinical Studies Ethics Committee. File No: 20-17-13/143. Due to the study’s retrospective nature, informed consent was not obtained from all the cases.
All the data were tabulated in Microsoft Excel 2007 data sheet with proper headings. Data were expressed as Mean and Standard deviation (SD) for continuous variables. For categorical variables, the data were represented as count and percentage. The comparison of means between the two groups was done using Student’s ‘t-test, provided the data is normally distributed; otherwise, the Mann-Whitney’ U’ test was used. Comparison of categorical variables was performed using the Chi-square test. P <0.05 is considered significant. Statistical analysis was done using IBM SPSS20.0.
A total of 153 cases matching the study criteria were identified. The mean age of the cases was 24.27±10.10 years, 97 cases were female, and 56 cases were male. Headache (n:37; 24.18%) and dizziness (n:25, 16.33%) were recorded as the most common presenting symptoms in symptomatic cases; 91 (59.48%) cases were diagnosed incidentally, and 88 (57.52%) cases were diagnosed as intracranial lipoma after cranial CT examination after head trauma. Three cases were followed up with the diagnosis of epilepsy resistant to medical treatment and were followed up due to convexity localized lipoma. The demographic distribution of the cases is shown in Table 1.
The most common lipoma in the falx (n:72, 47,06%) was determined when evaluated according to their localization. Pericallosal lipoma was detected in 9 (5,88%) cases (Figure 1). Cisternally located lipoma was detected in 42 (27,45%) cases (Figure 2,3). In 21 (13,73%) cases, a lipoma was detected in the calvarium. The distribution of lipomas according to their localization is shown in Table 2.
In 81 cases evaluated with CT examination at two different times, the mean HU value in the first CT examination was determined as -57.91 ± -12.81. In control ct examinations, the mean HU value was determined as -53.92 ± -12.75, and no statistically significant difference was found between the two groups (p:0,089). The mean control CT examination evaluation period was 22.08 ± 7.02 months. The point value was 1416.96 ± 95.82 in the first MRI examination of 90 cases evaluated by MRI and 1384.23 ± 101.62 in the control MRI examination. No statistical difference in point value was detected in the radiological examinations of these cases. The mean follow-up period was calculated as 17.49 ± 5.88 months. HU and point average values according to their localization are shown in Table 2.
There was no statistically significant difference in Ewan’s scores after CT and MRI examinations of cases with cisternally located lipoma. However, over 13% of Ewan’s score changes were detected in the evaluations of the cases. Ewan’s score increased by 12 (7,8%) cases and decreased by 8 (5,2%) cases.
Comparative results of different series according to localization of lipomas are shown in Table 3.
Intracerebral lipomas are benign formations that are rarely detected. They are thought to arise due to abnormal development and differentiation of the meninges primitiva in the Subarachnoid cisterns. They are most commonly detected adjacent to the midline structures of the brain or inside the cisternae [5,6,11]. They are generally asymptomatic formations and are frequently detected incidentally [12,13]. The radiological findings are typical, and it is not difficult to make a differential diagnosis with different formations radiologically. It is known that they do not enhance contrast in radiological examinations with contrast . In some lipomas, the presence of calcified areas that can be detected more easily on computed tomography can be demonstrated .
Intracranial lipomas are formations detected concerning the subarachnoid space and are often adjacent to the structures in the midline . Regarding lipomas considered to be benign, no case of lipoma showing parenchymal invasion or detected within the parenchyma has been encountered in the series in the literature. Rarely cases of atypically located lipoma far from the midline have been reported. It has been determined that approximately half of the corpus callosum lipomas are associated with callosal agenesis [17,18]. It has been reported that lipomas with a soft consistency adhere tightly to the surrounding tissues, and surgical complication rates are high in these cases . For this reason, conservative treatment methods are recommended as much as possible in symptomatic cases . It is known that epileptic seizures are most frequently encountered in extra-axial and sylvian localization .
Cisternally located lipoma was detected in 42 of the 153 cases evaluated, and when compared with the series in the literature, proportional differences are striking. When the studies in the literature are evaluated, it is noteworthy that the localization rates show significant differences. The lack of large series with many cases related to intracranial lipomas may explain this difference. When all series are taken into account, it is noteworthy that lipomas are mainly located adjacent to the falx or cisternal.
Calvarial lipoma cases that were not defined in previous studies were detected in 21 (13,72%) cases in this study. The HU value average of the structures described as calvarial lipomas was -55.08 ± -7.07, and when their differential diagnosis was made radiologically, they were found to be lipomas.
It was determined that there was no statistically significant difference in HU values in 81 cases evaluated with CT examinations (p:0,089). This finding supports that lipomas do not undergo physiological and anatomical changes over time. For this reason, it may not be necessary to follow up radiologically in diagnosed cases. However, in cisternal located lipomas, the potential to cause communicating type ventricular dilatation can be considered due to its effects on CSF flow pathways, even if no dimensional change has occurred.
It was noted that there were frequently recurrent epileptic seizures and multiple antiepileptic uses in all 3 cases with localized cortical lipoma. It has been reported that patients with localized cortical lipoma have a very high incidence of epileptic seizures. Although they do not show a significant mass effect, it is known that cortically localized lipomas form a high rate of epileptic focus on cortical surfaces. In these cases, surgical intervention is not recommended to eliminate the epileptic seizure focus. It has been reported that surgical intervention in lipomas with highly adhesive properties can lead to high surgical complications and morbidity. In these cases, it is recommended to continue antiepileptic therapy, including polypharmacy, despite resistant epilepsy.
Although it has been reported that central nervous system anomalies are frequently seen in cases with intracranial lipoma [19,20], these data should not be considered valid for all cases of intracranial lipoma. Except for callosal localized lipomas, no central nervous system anomaly was detected in any cases. In pericallosal lipoma cases, callosal agenesis was detected at a rate of 77,78% (n:7), and cognitive impairment was detected in these cases as a clinical finding. No significant mass effect was observed in cisternal or falx adjacent lipomas.
Intracranial lipomas are formations seen approximately two times more frequently in women, and are mostly asymptomatic and detected incidentally. They are most commonly detected in falx, cisternal and pericallosal locations. Since no change in HU value was detected in the cases followed up with CT examinations, it is thought that they did not undergo any structural changes. Cisternally located lipomas may have the potential to cause communicative ventricular dilatation.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Gradowska K, Czech-Kowalska J, Jurkiewicz E, Komornicka J, Dobrzanska A. Lipomas of the central nervous system in the newborns – a report of eight cases. Pol J Radiol. 2011; 76(4): 63-8.
2. Niwa T, de Vries LS, Manten GT, et al. Interhemispheric Lipoma, Callosal Anomaly, and Malformations of Cortical Development: A Case Series. Neuropediatrics. 2016; 47(2): 115-8.
3. Beşir FH, Özkan F. İntrakranial lipomun tanı ve tedavi yönteminde BT ve MRG (CT and MRI in the diagnosis and treatment of intracranial lipoma). Abant Med J. 2012; 1(1): 35-6.
4. Truwit CL, Barkovich A J. Pathogenesis of intracranial lipoma: an MR study in 42 patients. AJR Am J Roentgenol. 1990; 11(4): 665-74.
5. Gossner J. Small intracranial lipomas may be a frequent finding on computed tomography of the brain. A case series. Neuroradiol J. 2013; 26(1): 27-9.
6. Saatçi İ, Aslan C, Renda Y, Besim A. Parietal lipoma associated with cortical dysplasia and abnormal vasculature: case report and review of the literature. AJNR Am J Neuroradiol. 2000; 21(9): 1718-21.
7. Bahadir YM, Emrah E, Ayhan T. Lipomas of quadrigeminal cistern: report of 12 cases with clinic and radiologic features. Turk Neurosurg. 2015; 25(1): 16-20.
8. Seidl Z, Vaneckova M, Vitak T. Intracranial Lipomas: A Retrospective Study. Neuroradiol J. 2007; 20(1): 30-6.
9. Caballero PJCA. Interhemispheric lipoma associated with agenesis of the corpus callosum. Neurología. 2012; 27(8): 515-7.
10. Jabot G, Stoquart-Elsankari S, Saliou G, Toussaint P, Deramond H, Lehmann P. Intracranial lipomas: clinical appearances on neuroimaging and clinical significance. J Neurol. 2009; 256(6): 851-5.
11. Yildiz H, Hakyemez B, Koroglu M, Yesildag A, Baykal B. Intracranial lipomas: importance of localization. Neuroradiology. 2006; 48(1): 1-7.
12. Romano N, Castaldi A. Imaging of intracranial fat: from normal findings to pathology. Radiol Med. 2021; 126(5): 971–8.
13. Karakas E, Dogan MS, Cullu N, et al. Intracranial lipomas: clinical and imaging findings. Clin Ter. 2014; 165(2): e134-8.
14. Taydas O, Ogul H, Kantarci M. The clinical and radiological features of cisternal and pericallosal lipomas. Acta Neurol Belg. 2020; 120(1): 65-70.
15. Bourekas EC, Varakis K, Bruns D, et al. Lesions of the Corpus Callosum: MR Imaging and Differential Considerations in Adults and Children. Am J Roentgenol. 2002; 179(1): 251-7.
16. Mukherjee P, Street I, Irving RM. Intracranial lipomas affecting the cerebellopontine angle and internal auditory canal: a case series. Otol Neurotol. 2011; 32(4): 670-5.
17. Gökduman CA, İplikçioğlu C, Çoşar M, Ceylan D, Arslan M, Başocak K. İntrakranyal Yerleşimli Lipomlar (Intracranial Localized Lipomas). Türk Nöroşirurji Dergisi/Turkish Journal of Neurosurgery. 2004; 14(3): 172-7.
18. Gaskin CM, Helms CA. Lipomas, lipoma variants, and well-differentiated liposarcomas (atypical lipomas): results of MRI evaluations of 126 consecutive fatty masses. Am J Roentgenol. 2004; 182(3): 733-9.
19. Keleşoğlu K, Sivri M., Erdoğan H, Koplay M, Güneyli S. İntrakranial lipomlar: Yerleşim yerleri ile birlikte bilgisayarlı tomografi ve manyetik rezonans görüntüleme bulguları (Intracranial lipomas: Computed tomography and magnetic resonance imaging findings with localizations). Genel Tip Dergisi/ Journal of General Medicine. 2015; 25(4): 126-31.
20. Yilmaz N, Unal O, Kiymaz N, Yilmaz C, Etlik O. Intracranial lipomas – a clinical study. Clin Neurol Neurosurg. 2006; 108(4): 363-8.
Download attachments: 10.4328:ACAM.21104
Ziya Asan, Aydan Koysuren, Hatice Duygu Ciftci Sivri. Intracranial lipomas: Clinical and radiological analysis of 153 cases and review of the literature. Ann Clin Anal Med 2022;13(7):736-740
Comparison of first admission hemogram parameters and chest computed tomography findings of pediatric COVID-19 patients
Eyüp Sarı 1, Ramiz Yazici 2, Bensu Bulut 3, Gülnur Çoban 4, Dilek Atik 5, Cengizhan Kilicaslan 6
1 Department of Pediatric, Faculty of Medicine, Health Sciences University Gülhane, Ankara, 2 Department of Emergency Medicine, Hitit University, Çorum Erol Olçok Education and Research Hospital, Çorum, 3 Department of Emergency Medicine, Faculty of Medicine, Medipol University, Istanbul, 4 Ankara Provincial Health Directorate Bilkent Public Hospitals Presidency, Ankara, 5 Department of Emergency Medicine, Faculty of Medicine, Karaman University, Karaman, 6 Department of Pediatrics, Medical School, Aksaray University, Aksaray, Turkey
DOI: 10.4328/ACAM.21106 Received: 2022-02-13 Accepted: 2022-05-10 Published Online: 2022-05-28 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):741-745
Corresponding Author: Cengizhan Kilicaslan, Department of Pediatrics, Medical School, Aksaray University, Aksaray, Turkey. E-mail: firstname.lastname@example.org P: +90 505 271 94 17 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6093-7132
Aim : We use computed tomography, which is one of the frequently used imaging tests, both as a disease diagnosis method and to follow the clinical course in COVID-19 patients. This also means radiation exposure. Radiation exposure, especially in pediatric patients, can cause life-threatening diseases. Is there a blood parameter that will reduce this undesirable event and allow estimation of computed tomography findings? Are hemogram analysis, one of the most commonly used blood tests, and tomography findings of the disease related? We designed this study based on the questions.
Material and Methods: Among the patients under the age of 18 who applied to the emergency department, those with a positive reverse transcription-polymerase chain reaction (RT-PCR) and chest CT and hemogram were included in the study. Chest CT findings were classified according to the CO-RADS classification. We compared the CO-RADS classification with hemogram parameters and the ratios of these parameters.
Results: Platelet-to-lymphocyte ratio (PLR) rates were found to be significantly lower as imaging findings became more severe (<0.05). The ratio of MedianPlatelet Volume and Platelet (MPV/Plt) was found to be significantly higher as the imaging findings worsened (p<0.05). When the relationship between laboratory parameters according to imaging groups in our study was evaluated, there was a moderate negative correlation between lymphocyte and platelet levels and imaging findings (p<0.05). A moderate positive correlation with the monocyte level was found (p<0.05).
Discussion: For the CO-RADS classification, it can be said that the patient was established to classify possible COVİD-19 patients only according to chest CT. There is no study in the literature on the classification of pediatric patients with RT-PCR positive definite COVID-19 according to chest CT scans and the comparison of laboratory findings of patients with this classification. The combination of laboratory parameters and CO-RADS classification will guide clinicians in pediatric COVID-19 patient management.
Keywords: Pediatric COVID-19, CO-RADS, Emergency Department, Hemogram Parameters
The disease identified as COVID-19, meaning “coronavirus disease 2019”, by the World Health Organization (WHO) in February 2020 was first detected in Wuhan Province of Hubei state in China. Since then, the rapidly spreading disease has spread country-wide in China and all over the globe, and a pandemic was announced by the WHO on March 11, 2020. Coronaviruses are human and animal pathogens that can cause disease and cause the clinical presentation of acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2) (available at: http://www.who.int/dg/speeches/detail/who-director-general-s-remarks-at-the-media-briefing-on-2019-ncov-on-11-february-2020 and https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19—11-march-2020). COVID-19 is rare in children compared with adults. According to data from the Centers for Disease Control and Prevention (CDC) in the United States of America, pediatric COVID-19 cases account for approximately 9% of total COVID-19 cases [https://www.cdc.gov/covid-data-tracker/index.html#demographics ]. A previous study focusing on minor patients with SARS-CoV-2 confirmed by laboratory analysis emphasized that COVID-19 may be observed in children at any age, with a prevalence according to age distribution: 7% below 1 month of age, 22% between 1 month and 1 year; 10% between 1 year and 2 years; 11% between 2 years and 5 years; 16% between 5 years and 10 years; and 34% between 10 years and 18 years . Spread from COVID-19 patients at home is the most common source of spread in the majority of pediatric cases [2,3]. The literature review stressed that COVID-19 was spread by adults; however, the spread of COVID-19 by asymptomatic children was also considered [4-6]. A review of hospitalization rates due to COVID-19 revealed higher hospitalization rates in children below 2 years of age than in other age groups [5-7].
A comprehensive study that also reviewed laboratory data of children with COVID-19 below 18 years of age concluded that hemogram parameters of many patients were normal. However, there are studies reporting higher lymphopenia levels , a study revealing a neutropenia rate of 13% , and studies indicating that neutrophilia and lymphopenia were detected when the clinical manifestation became severe .
A previous study conducted on 674 pediatric patients with COVID-19 infection using imaging methods performed computed tomography (CT) in 605 patients. Among children who underwent CT, 29% presented frosted glass findings, including bilateral findings in 23% and unilateral findings in 27%; however, approximately 33% of the children who had CT examinations did not present any findings .
We aimed to compare thoracic CT findings with hemogram parameters and the ratio of these parameters in patients below 17 years of age diagnosed with a positive reverse transcription-polymerase chain reaction.
Material and Methods
This study was conducted in Ankara, the capital city of Turkey; the record system data of patients were reviewed between March 15, 2021, and June 15, 2021. All patients were selected from pediatric patients who were referred to the COVID-19 emergency department. The study included RT-PCR-positive patients below 18 years of age whose thoracic CT scan and hemogram parameters were available. Patients were divided into 5 age groups: 0 to 2 years, 3 to 5 years, 6 to 10 years, 11 to 15 years, and 16 to 17 years. The CT findings of such patients were categorized according to the CO-RADS classification. Patients are evaluated in 7 categories in this system. CO-RADS 0 represents patients who could not be classified due to deficient or insufficient examination because of severe artifacts, whereas CO-RADS 6 represents RT-PCR-positive patients. This includes the categorization of images without any suspicion of COVID-19 in first- and second-category patients. Normal or non-infectious changes are defined as CO-RADS 1; infectious findings beyond COVID-19 are categorized as CO-RADS 2; images suspected for COVID-19 or any other infection are classified as CO-RADS 3; suspected images of COVID-19 are defined as CO-RADS 4, and typical involvement is classified as CO-RADS 5. The patients who were referred to the pediatric COVID-19 emergency department and had imaging analyses were listed; those with CT scan findings were enrolled (Figure 1).
All statistical analyses were performed using SPSS version 20.0 for Windows. The Kolmogorov-Smirnov test and skewness-kurtosis method were used to evaluate the normal distribution of all variables. Descriptive statistical methods were used for demographic analyses of the patients. Chi-square and Fisher’s exact tests were used to compare categorical variable rates. Numerical data are expressed as mean ± standard deviation and minimum-maximum values. Nonparametric variables obtained in the study that were carried out within the scope of clinical research were assessed through the Kruskal-Wallis H and Mann-Whitney U statistical tests for statistical evaluation depending on categorical (nominal or ordinal) and numeric independence status. Laboratory parameters were evaluated by the receiver operating characteristic (ROC) curve according to the imaging results of pediatric COVID-19 patients. Parameters including AUC <0.6 and statistically insignificant parameters (P>0.05) were excluded during the evaluation of the ROC analysis. The results were evaluated for significance level at p<0.05.
In the present study, 114 pediatric patients who met the research criteria were enrolled between March 15, 2020, and June 15, 2020. The study included 55 males (48.2%) and 59 (51.8%) females. The average age of the pediatric patient group was 10.6±5.9 (median 12) years. The distribution of patients according to age group is shown in Table 1. Imaging findings of patients were divided into groups according to CO-RADS classification. Accordingly, the groups were classified according to tomography imaging as follows: 52.6% (n=60) CO-RADS 1, 9.6% (n=11) CO-RADS 2, 7.9% (n=9) CO-RADS 3, 14% (n=16) CO-RADS 4, and 15.8% (n=18) CO-RADS 5. A statistically significant difference was found between CT imaging findings according to the age groups (x2 2:33.114; p=0.070).
Laboratory parameters of pediatric COVID-19 patients
The imaging findings and laboratory parameters of COVID-19 patients are summarized in Table 2. Lymphocyte and platelet levels were found to be significantly lower when imaging findings became more severe according to CO-RADS classification (<0.05). The monocyte parameter was significantly higher when imaging findings became more severe (<0.05). The platelet-to-lymphocyte ratio (PLR) was found to be significantly lower when imaging findings became more severe (<0.05). The median platelet volume to platelet (MPV/Plt) ratio was significantly higher when imaging findings became more severe (p<0.05). Evaluation of the association based on imaging groups revealed a moderately negative correlation between lymphocyte and platelet levels of laboratory parameters and imaging findings (<0.05). A moderately positive association was also detected for monocyte levels (<0.05). There were no differences between groups for WBC, neutrophil, MPV, RDW laboratory parameters or neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), or imaging findings (>0.05).
Lymphocyte, Monocyte, PLR, ROC analyses of COVID-19 patients
The AUC, cut-off, sensitivity and specificity of the ROC curve and laboratory parameters were analyzed to guide clinicians in patient monitoring through the imaging findings of COVID-19 patients. The patients were divided into two groups: those without imaging findings (CO-RADS 1-2) and those with imaging findings (CO-RADS 3-5), and cut-off values of laboratory parameters were calculated. Any p-value above 0.05 (p>0.05) was accepted as insignificant. Accordingly, laboratory parameters of WBC, lymphocytes, monocytes, platelets, RDW, and MPV/PLT ratio were accepted as statistically significant
(p<0.05). Table 3 summarizes the ROC curve, AUC, cut-off, sensitivity and specificity for these parameters (Figures 2, 3).
This study was conducted to review 114 RT-PCR-positive pediatric patients who underwent chest CT scans. A negative association was detected between severe lesions detected by CT, settlement and progression of typical COVID-19 findings (by CO-RADS classification) and lymphocytes, platelets and PLR; however, a linear association was detected between monocyte count and MPV/PLT.
Studies reviewing the changes in hemogram parameters during COVID-19 infection have been published in the literature. Tezer H. et al. reported in their manuscript on COVID-19 in children that lymphocyte counts may be decreased. However, the association between the severity of COVID-19 infection and imaging was not mentioned . González-Dambrauskas S. et al. indicated in their study on pediatric critical care and COVID-19 that critical patients present lymphopenia and leukocytosis. The aforementioned study did not include 17 pediatric patients monitored in the intensive care unit . Song W. et al. included 16 children in their study with the title of clinical characteristics of pediatric patients, and lymphopenia was detected in 1 patient. Imaging and laboratory findings were not compared in this study, although CT images of the patients were included in the study . Ma H. et al. enrolled 158 patients, including 50 RT-PCR-positive patients, in their study and detected lymphopenia in 30% and thrombocytopenia in 16% of PCR-positive patients. However, the severity of CT findings or disease was not compared with the aforementioned findings . Dink Y. et al. detected lymphopenia-leukocytopenia as a common laboratory finding in their meta-analysis; however, they did not include other hemogram parameters or ratios . Ghayda Abou R. et al. stated in their meta-analysis that lymphopenia is a patognomonic finding, and there is an association between disease severity and lymphopenia level . Comparison of our findings with other studies stated above advances our study due to its larger patient series and positive PCR values in all patients; moreover, our findings are supported by current data in the literature. In our study, where typical/diffuse findings (CO-RADS classification) and laboratory parameters were compared, a positive significant association and PLR ratio between monocyte count, MPV/PLT ratio and disease severity and a negative significant association between PLR ratio and disease severity by imaging were important outcomes that should be emphasized because such evaluations were not sufficiently addressed in pediatric patients in the literature. Monocytes are an important blood component that increases in infectious conditions, including viral and bacterial infections . MPV is higher in conditions presenting with thrombocytopenia, including sepsis, immune thrombocytopenia and respiratory diseases . Such results were not surprising in our findings.
A previous study on leukocyte levels, which were not significantly associated with CT findings, reported that leukocyte levels were normal in 88% of the patients . A review of the meta-analysis reveals that there are studies reporting an increase in the neutrophil count in pediatric COVID-19 infection; however, other studies indicate a decrease in the neutrophil count. This variability in the neutrophil value detected in pediatric patients with COVID-19 infection explains why the NLR rate, which provides significant results in adults with COVID-19 infection, is also not significant in children . Although monocyte and lymphocyte values were found to be significantly correlated with CT image classification, the MLR ratio was not significant in our study. Further multicenter studies with a prospective design considering the clinical conditions in larger patient series should focus on these parameters.
Analysis of chest CT results of patients included in our study revealed findings for COVID-19-induced pneumonia in 38% of the patients. The ratio of PCR-positive patients without CT findings was approximately 50%; this finding complies with the data obtained from a meta-analysis conducted by Merkus JFM P. et al. .
CO-RADS is a system developed to evaluate the suspicion of COVID-19 infection in chest CT and to standardize communication. A previous study on the evaluation of CO-RADS reported that 93% of patients categorized as CO-RADS 5 were RT-PCR-positive. In the aforementioned study, 7% of patients classified as CO-RADS 3 were not clinically considered to have COVID-19 and were RT-PCR-negative . A comprehensive study reviewed RT-PCR-positive pediatric patients with CT findings consistent with COVID-19 and concluded that half of the patients were below 2.5 years of age . The CO-RADS classification was reviewed according to the age groups in our study; the age group of 0 to 2 years had the highest level of CT findings consistent with CT findings by 73%.
The CO-RADS classification was only established to classify possible COVID-19 patients based on thoracic CT. There is no study on the classification of pediatric patients diagnosed with COVID-19 by positive RT-PCR evidence according to thoracic CT scans or a comparison of laboratory findings of the patients in the literature. The combination of laboratory parameters and CO-RADS classification could guide clinicians in pediatric COVID-19 patient management. Further randomized and controlled trials with larger patient series are required to consolidate current findings and to address parameters without any significant associations.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Götzinger, F., Santiago-García, B., Noguera-Julián, A., Lanaspa, M., Lancella, L., Carducci, F. I. C., … & Riordan, A. (2020). COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study. The Lancet Child & Adolescent Health, 4(9), 653-661.
2. Liguoro I, Pilotto C, Bonanni M, Ferrari ME, Pusiol A, Nocerino A, et al. SARS-COV-2 infection in children and newborns: a systematic review. Eur J Pediatr. 2020; 179(7):1029-46.
3. Kim J, Choe YJ, Lee J, Park YJ, Park O, Han MS, et al. Role of children in house hold transmission of COVID-19. Arch Dis Child. 2021;106(7):709-11.
4. Huff HV, Singh A. A symptomatic transmission during the COVID-19 pandemic and implications for public health strategies. Clin Infect Dis. 2020; 71(10): 2752-6.
5. Kim L, Whitaker M, O’Halloran A, Kambhampati A, Chai SJ, Reingold A, et al. Hospitalization Rates and Characteristics of Children Aged <18 Years Hospitalized with Laboratory-Confirmed COVID-19 – COVID-NET, 14 States, March 1-July 25, 2020. MMWR Morb Mortal Wkly Rep. 2020; 69(32):1081-8.
6. Han MS, Choi EH, Chang SH, Jin BL, Lee EJ, Kim BN, et al. Clinical characteristics and Viral RNA Detection in Children With Coronavirus Disease, 2019 in the Republic of Korea. JAMA Pediatr. 2021; 175(1):73–80.
7. Tian Y, Rong L, Nian W, He Y. Review article: gastrointestinal features in COVID-19 and the possibility of faecal transmission. Aliment Pharmacol Ther. 2020; 51(9):843-51.
8. Liguoro I, Pilotto C, Bonanni M, Ferrari ME, Pusiol A, Nocerino A, et al. SARS-COV-2 infection in children and newborns: a systematic review. Eur J Pediatr. 2020;179(7):1029–46.
9. Venturini E, Palmas G, Montagnani C, Chiappini E, Citera F, Valeria A, et al. Severe neutropenia in infantswith severe acute respiratory syndrome caused by the novel coronavirus 2019 infection. J Pediatr 2020; 222:259-61.
10. Jimeno, S., Ventura, P. S., Castellano, J. M., García-Adasme, S. I., Miranda, M., Touza, P., … & López-Escobar, A. (2021). Prognostic implications of neutrophil-lymphocyte ratio in COVID-19. European journal of clinical investigation, 51(1), e13404.11. Tezer H, Bedir Demirdağ T. Novel coronavirus disease (COVID-19) in children. Turk J Med Sci. 2020; 50(SI-1):592-603.
12. González-Dambrauskas S, Vásquez-Hoyos P, Camporesi A, Díaz-Rubio F, Piñeres-Olave BE, Fernández-Sarmiento J, et al. Critical Coronavirus and Kids Epidemiology Cake Study. Pediatric Critical Careand COVID-19. Pediatrics. 2020; 146(3):e20201766.
13. Song W, Li J, Zou N, Guan W, Pan J, Xu W. Clinical features of pediatric patients with corona virus disease (COVID-19). J Clin Virol. 2020; 127:104377.
14. Ma H, Hu J, Tian J, Zhou X, Li H, Laws MT, et al. A single-center, retrospective study of COVID-19 features in children: a descriptive investigation. BMC Med. 2020; 18:123.
15. Ding Y, Yan H, Guo W. Clinical Characteristics of Children With COVID-19: A Meta-Analysis. Front Pediatr. 2020; 8:431.
16. Ghayda RA, Lee J, Lee JY, Kim DK, Lee KH, Hong SH, et al.Correlations of Clinical and Laboratory Characteristics of COVID-19: A Systematic Review and Meta-Analysis. Int J Environ Res Public Health. 2020;17(14):5026.
17. Dutta P, Nahrendorf M. Regulation and consequences of monocytosis. Immunol Rev. 2014; 262(1):167-78.
18. Norrasethada L, Khumpoo W, Rattarittamrong E, Rattanathammethee T, Chai-Adisaksopha C, Tantiworawit A. The use of mean platelet volume for distinguishing the causes of thrombocytopenia in adult patients. Hematol Rep. 2019; 11(1):7732.
19. Merkus PJFM, Klein WM. The value of chest CT as a COVID-19 screening tool in children. Eur Respir J. 2020; 55(6):2001241.
20. Prokop M, Van Everdingen W, Van Rees Vellinga, T, Quarles van Ufford H, Stöger L, Beenen L et al. CO-RADS: A Categorical CT Assessment Scheme for Patients Suspected of Having COVID-19-Definition and Evaluation. Radiology. 2020; 296(2):E97-E104.
Download attachments: 10.4328:ACAM.21106
Eyüp Sarı, Ramiz Yazici, Bensu Bulut, Gülnur Çoban, Dilek Atik, Cengizhan Kilicaslan. Comparison of first admission hemogram parameters and chest computed tomography findings of pediatric COVID-19 patients. Ann Clin Anal Med 2022;13(7):741-745
Evaluation of intraductal breast papilloma based on immunohistochemical analysis of p16, p53 and ki-67
Osman Erdogan 1, Alper Parlakgumus 2, Ugur Topal 3, Tugba Toyran 4, Zeynel Abidin Tas 5, Oktay Irkorucu 6
1 Department of Surgical Oncology, Konya Numune Hospital, Konya, Turkey, 2 Department of Surgical Oncology, Adana City Training and Research Hospital, Adana, Turkey, 3 Department of Surgical Oncology, Başakşehir Çam and Sakura City Hospital, Istanbul, Turkey, 4 Department of Pathology, Faculty of Medicine, Cukurova University, Adana, Turkey, 5 Department of Pathology, Adana City Training and Research Hospital, Adana, Turkey, 6 Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
DOI: 10.4328/ACAM.21107 Received: 2022-02-13 Accepted: 2022-03-17 Published Online: 2022-03-18 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):746-749
Corresponding Author: Osman Erdogan, Department of Surgical Oncology, Konya Numune Hospital, Konya, Turkey. E-mail: email@example.com P: +90 507 763 01 21 / :+90 332 235 45 00 F: +90 332 235 67 36 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9941-2704
Aim: This study aimed to evaluate preoperative features, postoperative outcomes, and the positivity rates of immunohistochemical staining with p16, p53 and Ki-67 in patients undergoing surgery for intraductal papilloma.
Material and Methods: The study included 33 patients aged >18 years, diagnosed with intraductal papilloma between 2011 and 2020. Data about demographic features (age and gender), clinical picture, results of pathological examinations (if present), type of surgery, and immunohistochemical staining with p16, p53 and Ki-67 were obtained. In addition, the patients were divided into 2 groups: <50 years (Group1), ≥50 years (Group2). These 2 groups were compared in terms of the abovementioned parameters.
Results: All patients were female, with a mean age of 49.75 years. Papilloma rates were equal in right and left breasts. Discovery of a mass was the most common cause for presentation (72.7%). P16 and p53 were positive in Group1 and Group 2, with rates of 90.9% and 81.8%, respectively, and the mean Ki-67 index was 2.7. All patients aged <50 years were stained with p16. The distribution of p53staining was similar in both groups (p=0.817). The mean Ki-67 index was higher in women aged >50 years (2.1 vs 3.8) (p=0.018).
Discussion: This study showed high rates of p16 and p53 positivity in patients with intraductal papilloma. Although there was no difference in the distributions of p16 and p53 between the groups, the Ki-67 index was higher in patients aged >50 years. Multicentre studies with long-term follow-ups are needed to reveal the prognostic importance of tumor-suppressing genes such as p16 and p53.
Keywords: Papilloma, p16, p53, Ki-67, Breast
Intraductal papilloma is a benign tumor localized in the ducts of the breasts. It is caused by abnormal growth of ductal epithelial cells. Histologically, intraductal papilloma is characterized by a fibrovascular nucleus lined with both epithelial and myoepithelial cells .
P16, also called p16INK4a, is a cyclin-dependant kinase inhibitor 2A. It is a protein that reduces cell division and functions as a tumor suppressor by slowing the cell cycle from the G1 phase to the S phase. Mutations of tumor-suppressing gene p53 are the most common genetic abnormality in human cancers. Therefore, high concentrations of p53 accumulation are a potential sign of malignancy and can be associated with a poor prognosis in some types of tumors. The Ki-67 antigen is a marker of cell cycle and proliferation; it is usually utilized to predict proliferation and shows cellular growth rate [2,3].
Objective etiological factors in intraductal papilloma are not yet clear; therefore, evaluating immunohistochemical expressions like p16 and p53 will be beneficial. Nevertheless, there have been few studies about this issue in the literature [4,5].
The present study evaluated preoperative features, postoperative outcomes, and positivity rates of immunohistochemical staining with p16, p53 and Ki-67 in patients undergoing surgery for primary intraductal papilloma.
Material and Methods
Data related to patients undergoing surgery for intraductal papilloma in the general surgery clinics of Adana City Training and Research Hospital between 1 July 2011 and 31 October 2017 and in the general surgery clinics of Adana City Training and Research Hospital between 31 October 2017 and 15 November 2020, and were gathered from the relevant hospital electronic databases and patient files and retrospectively analyzed.
The inclusion criteria were age >18 years and intraductal papilloma diagnosis. The exclusion criteria were incomplete treatment, missed post-surgery follow-up appointments, missing data, and age <18 years. Data on demographic characteristics (age and gender), clinical presentation, pathological features (if present), and type of surgery were collected from both electronic databases and patient files from the hospitals. Immunohistochemical staining with p16, p53 and Ki-67 was performed on specimens available in the pathology laboratories. Obtained data were compared between women aged 18–50 years and those aged ≥50 years.
The study was approved by the hospital’s institutional review board (IRB No. 22.04.2021/79/1375). Since the study was retrospective, patient consent could not be obtained.
Data were analyzed using Statistical Package Program for Social Sciences 25. Data on categorical variables were expressed in numbers and percentages, and data about continuous variables were expressed as mean and standard deviation (in the median and minimum–maximum values, when necessary).
The study included 33 female patients with a mean age of 49.75 years. Papilloma rates were equal in right and left breasts. Mass was the most common symptom upon presentation (72.7%). The most common type of surgery was surgical excision (66.7%). P16 and p53 were positive (to varying degrees) in 90.9% and 81.8% of Group 1 and Group 2, respectively, and the mean Ki-67 index was 2.7. Patient demographic and clinical features are presented in Table 1.
Out of 33 patients, 20 were aged ≥50 years and 13 were aged <50 years. The rate of patients presenting with a mass was higher in Group 2 (100%) than Group 1 (55%) (p = 0.018). P16 was positive in all patients aged <50. The distribution of p53 positivity was similar in both groups (p = 0.817); however, the Ki-67 index was higher in patients aged >50 years (2.1 vs 3.8) (p = 0.018). Table 2 shows the distributions of p16 and p53 positivity, and Ki-67 index, by age groups.
Papillary lesions of the breast vary from benign intraductal papilloma to invasive carcinoma. They are found during autopsy in 35% of women aged 20–54 years. Intraductal papilloma accounts for less than 10% of benign breast lesions and less than 1% of malignant breast tumours . Clinically, they may present with spontaneous nipple discharge or a palpable mass; however, most of them are detected in routine screenings . The mean age of patients in the present series was 49 years, which is consistent with the literature. In addition, as expected, symptoms on presentation were mass and nipple discharge. Patients aged >50 years were routinely screened, and some patients were diagnosed with intraductal papilloma during screenings.
The American Society of Breast Surgeons, in its consensus guidelines for managing high-risk lesions, recommends that most intraductal papillomas without atypia be removed. However, it is stated that the decision to remove lesions should be individualized, considering lesion size, symptomatology, palpability, and breast cancer risk (available at: https://www.breastsurgeons.org/resources/statements). In the present series, 75.8% of patients were treated with surgical excision, as recommended in the guidelines.
Breast cancers represent complex and heterogeneous diseases with unclear etiology. The molecular events involved in the transformation from benign intraductal papilloma into malignant lesions are still largely unknown. Prior studies have shown a relationship between the prognosis of breast carcinoma and p16 and p53. However, the roles of p16 and p53 in breast cancer subtypes have not been thoroughly described [8,9,10]. In addition, in intraductal papilloma, the expression and prognostic importance of p16 and p53 are unclear.
In a series of 400 cases, Shan et al. evaluated the expression and prognostic importance of p16 and p53 in several breast cancer subtypes. They found that p16 was more downregulated (had low expression) in luminal-A subtypes of ductal carcinoma in situ compared to subtypes of other breast cancers. An analysis of the correlation between p16 and p53 in several breast cancer subtypes revealed that when p16 was downregulated, immunohistochemical staining with p53 was negative only in luminal-A subtypes of ductal carcinoma in situ. P16 is clearly important in luminal subtypes, and especially the luminal-A subtype. This marker is closely related to a favourable prognosis. P53 also plays an essential role in subtypes of triple-negative breast cancer. P16 and p53 have different roles in different subtypes of breast cancer. It has been shown that p16 expression in luminal-A subtypes can be associated with progression from ductal carcinoma in situ to invasive ductal carcinoma, and both p53 and p16 expressions are essential in terms of triple-negative breast cancer development in cases of ductal carcinoma in situ and invasive ductal carcinoma .
In a systematic review, da Costa et al. analyzed 12 studies showing p53 expression in women diagnosed with benign breast disease. Most of the selected studies focused on the analysis of p53 expression in breast tissue with non-proliferative lesions. When all types of breast tissue were compared, 34.39% of patients with benign breast disease showed p53 expression . In the current series, 81.8% of patients with benign breast disease showed p53 expression, which is higher than reported in the literature.
In a study by Hashmi et al., Ki-67 index in several intrinsic and histological types of breast cancer was evaluated; a high Ki-67 index was found in HER2/neu and triple-negative intrinsic breast cancer subtypes and metaplastic and medullary breast cancer types. Thus, all categories of breast cancer were regarded as aggressive phenotypes. In addition, tumor grade, considered a prognostic factor in breast cancer, was significantly related with Ki-67 index . In the present study, the Ki-67 index was higher in patients aged >50 years, although it was relatively low in intraductal papilloma overall.
This study has several limitations: the sample size was small, the design was retrospective, and long-term follow-ups were missing.
In conclusion, p16 and p53 had a high rate of positivity in intraductal papilloma. While there was no difference in the distributions of p16 and p53 between age groups, the Ki-67 index was higher in patients aged >50 years. Multicentre studies with long-term follow-ups are needed to reveal the prognostic significance of the tumour-suppressing genes p16 and p53.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Hashmi AA, Faraz M, Rafique S, Adil H, Imran A. Spectrum of Papillary Breast Lesions According to World Health Organization Classification of Papillary Neoplasms of Breast. Cureus. 2020; 12(10):e11026
2. Zhang H, Xiong Y, Zhang S, Zhang Y, Wang YH, Li T. Clinicopathologic and immunohistochemical study of 187 cases of intraductal papillary neoplasm of breast. Zhonghua Bing Li Xue Za Zhi. 2011; 40(11):726-31
3. Furuya C, Kawano H, Yamanouchi T, Oga A, Ueda J, Takahashi M. Combined evaluation of CK5/6, ER, p63, and MUC3 for distinguishing breast intraductal papilloma from ductal carcinoma in situ. Pathol Int. 2012;62(6):381-90
4. Hodorowicz-Zaniewska D, Szpor J, Basta P. Intraductal papilloma of the breast – management. Ginekol Pol. 2019;90(2):100-3
5. Michel-Ruddy JA, Tran TT, Ozao-Choy JJ, Venegas RJ, Dauphine C. Intraductal papilloma: An unusual presentation. Breast J. 2021;27(3):278-9
6. Boufelli G, Giannotti MA, Ruiz CA, Barros N, Chala LF, Maesaka JY, et al. Papillomas of the breast: factors associated with underestimation. Eur J Cancer Prev. 2018;27(4):310-4
7. Limberg J, Kucher W, Fasano G, Hoda S, Michaels A, Marti JL. Intraductal Papilloma of the Breast: Prevalence of Malignancy and Natural History Under Active Surveillance. Ann Surg Oncol. 2021;28(11):6032-40
8. Shan M, Zhang X, Liu X, Qin Y, Liu T, Liu Y, et al. P16 and p53 play distinct roles in different subtypes of breast cancer. PLoS One. 2013 ;8(10): e76408
9. Andrikopoulou A, Terpos E, Chatzinikolaou S, Apostolidou K, Ntanasis-Stathopoulos I, et al. Zagouri F. TP53 mutations determined by targeted NGS in breast cancer: a case-control study. Oncotarget. 2021 ;12(21):2206-14
10. Rana MK, Rana APS, Khera U. Expression of p53 and p16 in Carcinoma Breast Tissue: Depicts Prognostic Significance or Coincidence. Cureus. 2021;13(11):e19395.
11. Costa RSS, Silva IFD. P53 Expression in benign Breast Disease Development: A Systematic Review. Asian Pac J Cancer Prev. 2020;1;21(9):2485-91
12. Hashmi AA, Hashmi KA, Irfan M, Khan SM, Edhi MM, Ali JP, et al. Ki67 index in intrinsic breast cancer subtypes and its association with prognostic parameters. BMC Res Notes. 2019;12(1):605
Download attachments: 10.4328:ACAM.21107
Osman Erdogan, Alper Parlakgumus, Ugur Topal, Tugba Toyran, Zeynel Abidin Tas, Oktay Irkorucu. Evaluation of intraductal breast papilloma based on immunohistochemical analysis of p16, p53 and ki-67. Ann Clin Anal Med 2022;13(7):746-749
The effect of the COVID-19 pandemic period on the prevalence of metabolic syndrome in patients with schizophrenia and bipolar disorder
Emine Nur Çorum 1, Emrullah Dündar 2
1 Department of Occupational Therapy, 2 Department of Psychiatry, Fatih Community Mental Health Center, Haseki Education and Research Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.21108 Received: 2022-02-13 Accepted: 2022-03-18 Published Online: 2022-03-21 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):750-753
Corresponding Author: Emine Nur Çorum, Fatih Community Mental Health Center, Haseki Education Research Hospital, 34091, İstanbul, Turkey. E-mail: firstname.lastname@example.org P: +90 212 531 51 04 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9661-4423
Aim: This study aimed at investigating the impact of COVID-19 lockdown on metabolic profile in bipolar disorder and schizophrenia patients at the time of COVID-19.
Material and Method: This study was completed with 190 individuals diagnosed with schizophrenia (116) and bipolar disorder (74). Waist circumference and blood pressure measurements were taken on the same date as triglyceride, glucose and HDL data in the electronic recording system of the participants. Initial assessment data are measurements within 3 months prior to the publication of the first case in Turkey. The second evaluation data, on the other hand, is the data obtained within 3 months after the date of removal or relaxation of the restrictions, which is defined as the normalization period.
Results: A significant increase was observed in the incidence of metabolic syndrome in the participants after the COVID-19 lockdown. In addition, a significant increase in glucose, triglyceride and diastolic blood pressure values, and a significant decrease in HDL values were detected. There was no significant change in systolic blood pressure and waist circumference values.
Discussion: It has been shown that the COVID-19 lockdown increases the incidence of metabolic syndrome in patients with schizophrenia and bipolar disorder and causes irregularities in metabolic syndrome parameters.
Keywords: Metabolic Syndrome, Schizophrenia, Bipolar Disorder, COVID-19 Lockdown
The recent novel coronavirus-2019 (COVID-19) worldwide pandemic emerged as a pneumonia pandemic in China in December 2019 . The first case of coronavirus emerged in Turkey on 11 March 2020, and on the same date the World Health Organization declared a pandemic . The government of Turkey enforced many measures to mitigate the spread of COVID-19, such as enforcing spatial distancing, the use of medical face masks, closing schools, and encouraging self-isolation . In addition to these, governments and national health authorities have acted swiftly, recommending ‘isolation’ policies and/or various levels of social restraint/isolation to reduce the infection rate . Like many countries, a strict lockdown has been declared in Turkey to practice social distancing and prevent the spread of infection .
These restrictions were initially considered the most effective way to prevent the spread of the infection. However, over time, it was seen that they brought some problems with them. Motor inactivity, changes in sleep and eating patterns, less exposure to daylight, and disruption in medical controls have led to the emergence of some metabolic problems or worsening .
According to the definition of the International Diabetes Federation, metabolic syndrome (MetS) is defined by a combination of abdominal obesity, high blood pressure, low high-density lipoprotein cholesterol (HDL-C), high triglycerides and hyperglycemia .
Metabolic syndrome now affects more than a billion people throughout the world based on current estimates . Although MetS affects almost every part of society, it is even more important for individuals with serious mental illnesses (SMI) such as schizophrenia (SCH) and bipolar disorder (BD). This population has a greater risk of early all-cause mortality than the general population. Epidemiological studies show that patients with severe mental illness have a decreased life expectancy of 7-24 years. About 60% of the mortality in psychiatric patients is due to physical comorbidities, mainly cardiovascular diseases . All components of the metabolic syndrome are shown as independent risk factors for cardiovascular disease .
It is known that social isolation, physical inactivity and metabolic problems are common in BD and SCH patients. However, the effects of the quarantine period on this patient group have not been investigated. The aim of this study was to examine the effect of the first pandemic period on metabolic syndrome prevalence and metabolic parameters such as Blood pressure, Glucose levels, abdominal obesity in patients with sch and BD. Knowing the effect of the COVID-19 lockdown period on metabolic parameters will provide data for such situations that may occur in the future and help to take the necessary precautions in advance.
Material and Methods
This study was completed with 190 individuals diagnosed with SCZ (116) and BD (74) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). The inclusion criteria of the participants were defined as a continuation of at least 1 year of disease treatment at Fatih Community Mental Health Center and being over 18 years old. The interview team consisted of a psychiatrist and an occupational therapist. Verbal informed consent was obtained from the participants or their caregivers before inclusion in the study. Ethics committee approval (2020-194) was obtained in accordance with the principles of the Declaration of Helsinki before starting the study.
Participants’ age, gender, educational status, employment status, marital status, presence of chronic disease, and diagnosis of psychiatric disease were questioned.
Diagnosis of the Metabolic Syndrome
In the study, the diagnosis of metabolic syndrome was made in accordance with the definition set by the National Cholesterol Education Program-Adult Treatment Panel-III . According to this definition, five criteria are shown for diagnosing metabolic syndrome. 1) Fasting blood glucose above 110 mg/dL, 2) Arterial blood pressure above 130/85 mmHg, 3) Waist circumference over 102 cm in men and 88 cm in women, 4) Serum triglyceride (TG) level > 150 mg/ dl, 5) Serum HDL concentration is <40 mg/dl for male individuals and <50 mg/dl for female individuals. In addition, a criterion for metabolic syndrome was considered to be met if the individual was receiving antihypertensive therapy, insulin or hypoglycemic therapy, TG-lowering therapy, and/or HDL-raising therapy.
The data of the participants, collected in two different periods, were obtained from the electronic recording system and from the waist circumference and blood pressure measurements.
First assessment: The first case in Turkey was seen on March 11, 2020, and after which partial and full lockdowns were applied to individuals according to age groups. Initial assessment data are data for the 3 months before the first case release.
Second assessment: The normalization period or new normal period refers to the period when restrictions were lifted or relaxed in Turkey on May 11, 2020. Data were collected within 3 months after 11 May 2020.
Data analysis was done with SPSS version 22. Descriptive statistics (mean, standard deviation (SD) and frequency) were calculated for all demographic and clinical variables. The dependent sample t-test and Wilcoxon T-test were used to examine the relationship between continuous variables. The McNemar test was used in the analysis of categorical metabolic syndrome criteria. The limit of significance was chosen as p≤0.05 for all statistics.
SCZ was diagnosed in 61.1% of the participants and 38.9% were patients with BD; 64.2% of the patients were male; 62.1% of the participants did not receive post-primary education, 78.4% were single, 83.7% were not working and 77.9% had no chronic diseases. The mean age of the participants was calculated as 43.52 years (SD=12.15) and their sociodemographic characteristics are presented in Table 1.
There was no significant difference in the number of participants with low HDL (HypoHDL), high blood pressure (hypertension), high glucose (hyperglycemia), and high waist circumference before and after COVID-19 lockdown (p=0.472, p=0.063, p=0.824, p= p= 0.501). On the contrary, a significant increase was observed in the incidence of high TG (hyperTG) and metabolic syndrome (p=0.010, p=0.0008). (Figure 1).
There was a significant increase in glucose, triglyceride and diastolic blood pressure values of the participants (p= 0.022, p=0.000, p= 0.008). A significant decrease in the HDL value (p= 0.041) was detected. There were no significant changes in systolic blood pressure and waist circumference values (Table 2).
The present study aimed at investigating the impact of COVID-19 lockdown on metabolic profile in BD and SCZ patients at the time of COVID-19. To the best of our knowledge, this is the first study to investigate the impact of the COVID-19 lockdown on the frequency of metabolic syndrome in patients with BD and SCZ.
According to the results of our study conducted in patients with BD and SCZ, it was revealed that the frequency of metabolic syndrome increased after the lockdown period compared to before. When metabolic syndrome parameters were examined separately, it was determined that there was an increase in the average of glucose, triglyceride and diastolic blood pressure, and a decrease in the average of HDL. In addition, it was found that the incidence of hyperTG increased significantly.
Our study showed that the incidence of metabolic syndrome increased in BD and SCZ patients after the COVID-19 lockdown. In this case, immobility, which is a natural consequence of the lockdown process, may have been effective. It is known that decreased physical activity is a risk factor for metabolic syndrome. Risks of inactivity are underscored by data that shows that sitting >42 hours per week had a 4%-12% attributable risk of metabolic syndrome, and high serum triglyceride levels . BD and SCZ patients are a group with more social isolation than healthy individuals before the pandemic . However, the lockdown that came with the pandemic process also prevented these patients from accessing Community Mental Health Centers, and thus a state of complete inactivity occurred.
Eating habits, which are stated to have changed during the lockdown process, may have also been effective in the increase in the frequency of metabolic syndrome . Based on available evidence, it is known that altered eating habits, increases in insulin resistance, total body fat, belly fat, and inflammatory cytokines are the main metabolic consequences. All these factors are strongly associated with the development of the metabolic syndrome .
On the contrary, in a study conducted on healthy participants, it was found that there was no change in the incidence of metabolic syndrome between before and after the COVID-19 lockdown . According to another study investigating the effects of COVID-19 lockdown, weight gain and sleep changes were more common in the group with psychiatric illness than in the healthy group . This may be due to the BD and SCZ patient group being in the risk group for metabolic syndrome. Controlled studies are needed to understand this more clearly.
In the group of patients with cardiovascular risk, it is stated that physical inactivity during COVID-19 lockdown is the cause of hyperTG and hypoHDL . Patients with schizophrenia and bipolar disorder are also shown in the cardiovascular risk group . In this patient group, there is a risk of cardiovascular disease due to genetic predisposition, as well as many risk factors such as antipsychotic drugs used, poor diet, physical inactivity, high smoking and obesity . The causal role of different lipid subfractions in the development of vascular diseases has been known for many years . In the results of our study, it was found that an increase in the average TG value and a decrease in the average HDL was observed after the COVID-19 quarantine, which supports the literature. This result shows that the COVID-19 lockdown process is not well managed for patients with schizophrenia and bipolar disorder, and that the lipid profile of the patients deteriorates and also poses a cardiovascular risk.
In our study, we found that after the COVID-19 lockdown, diastolic blood pressure increased significantly compared to before, and there was no significant difference in systolic blood pressure. In a study conducted during the COVID-19 lockdown in a healthy population, it was found that diastolic and systolic blood pressures decreased . Hypertension has been reported as one of the causes of increased cardiovascular risk in SCZ and BD patients. The reason for high blood pressure is that they have less access to preventive interventions . Considering this information and the result we found together, it can be thought that patients could not take measures for high blood pressure on their own during the COVID-19 lockdown period, due to the limited access to healthcare facilities.
It is known that a decrease in recommended physical activity from a relatively high level to a low level for 14 days leads to metabolic disparities such as increased intra-abdominal and ectopic and hyperinsulinemia, even in young healthy adults . According to the findings of our study, although there was no significant increase in the incidence of hyperglycemia in patients with BD and SCZ after the COVID-19 lockdown, a significant increase was found in the mean plasma glucose.
The COVID-19 lockdown has been a period of increased metabolic syndrome for SCZ and BD patients. We tried to collect possible reasons for this situation. In line with all this information, it can be said that the fact that SCZ and BD patients were not given a special intervention regarding the COVID-19 lockdown and compliance with the new rules affected them negatively in terms of metabolic syndrome criteria. It is important to develop intervention strategies for this group in the future.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Satici B, Saricali M, Satici SA, Griffiths MD. Intolerance of Uncertainty and Mental Wellbeing: Serial Mediation by Rumination and Fear of COVID-19. Int J Ment Health Addict. 2020;1-12.
2. Rasanathan K, Evans TG. Primary health care, the Declaration of Astana and COVID-19. Bull World Health Organ. 2020;98(11):801-8.
3. Saricali M, Satici SA, Satici B, Gocet-Tekin E, Griffiths MD. Fear of COVID-19, Mindfulness, Humor, and Hopelessness: A Multiple Mediation Analysis. Int J Ment Health Addict. 2020; 1-14.
4. King AJ, Burke LM, Halson SL, Hawley JA. The Challenge of Maintaining Metabolic Health During a Global Pandemic. Sports Med. 2020;50(7):1233-41.
5. Ghosal S, Bhattacharyya R, Majumder M. Impact of complete lockdown on total infection and death rates: A hierarchical cluster analysis. Diabetes Metab Syndr Clin Res Rev. 2020;14(4):707-11.
6. Lippi G, Henry BM, Sanchis-Gomar F. Physical inactivity and cardiovascular disease at the time of coronavirus disease 2019 (COVID-19). Eur J Prev Cardiol. 2020;27(9):906-8.
7. Eckel RH, Alberti K, Grundy SM, Zimmet PZ. The metabolic syndrome. The Lancet. 2010;375(9710):181-3.
8. Saklayen MG. The Global Epidemic of the Metabolic Syndrome. Curr Hypertens Rep. 2018;20(2):12.
9. Penninx BWJH, Lange SMM. Metabolic syndrome in psychiatric patients: overview, mechanisms, and implications. Dialogues Clin Neurosci. 2018;20(1):63-73.
10. Gurusamy J, Gandhi S, Damodharan D, Ganesan V, Palaniappan M. Exercise, diet and educational interventions for metabolic syndrome in persons with schizophrenia: A systematic review. Asian J Psychiatry. 2018;36:73-85.
11. Grundy SM, Brewer HB, Cleeman JI, Smith SC, Lenfant C. Definition of Metabolic Syndrome. Circulation. 2004;109(3):433-8.
12. Xiao J, Shen C, Chu MJ, Gao YX, Xu GF, Huang JP, et al. Physical Activity and Sedentary Behavior Associated with Components of Metabolic Syndrome among People in Rural China. PLoS One. 2016;11(1):e0147062.
13. Costa R, Bastos T, Gomes E, Corredeira R. Physical Activity During the COVID-19 Pandemic in People with Severe Mental Disorders: An Overview of the Portuguese Reality. Acta Médica Port. 2021;34(9):569.
14. Martinez-Ferran M, de la Guía-Galipienso F, Sanchis-Gomar F, Pareja-Galeano H. Metabolic Impacts of Confinement during the COVID-19 Pandemic Due to Modified Diet and Physical Activity Habits. Nutrients. 2020;12(6):1549.
15. Kwon JY, Song SW, Kim HN, Kang SG. Changes in Body Mass Index and Prevalence of Metabolic Syndrome during COVID-19 Lockdown Period. Korean J Fam Pract. 2021;11(4):304-11.
16. Solé B, Verdolini N, Amoretti S, Montejo L, Rosa AR, Hogg B, et al. Effects of the COVID-19 pandemic and lockdown in Spain: comparison between community controls and patients with a psychiatric disorder. Preliminary results from the BRIS-MHC STUDY. J Affect Disord. 2021;281:13-23.
17. Perrone MA, Feola A, Pieri M, Donatucci B, Salimei C, Lombardo M, et al. The Effects of Reduced Physical Activity on the Lipid Profile in Patients with High Cardiovascular Risk during COVID-19 Lockdown. Int J Environ Res Public Health. 2021;18(16):8858.
18. Sud D, Laughton E, McAskill R, Bradley E, Maidment I. The role of pharmacy in the management of cardiometabolic risk, metabolic syndrome and related diseases in severe mental illness: a mixed-methods systematic literature review. Syst Rev. 2021;10(1):92.
19. Bruckert E, Labreuche J, Deplanque D, Touboul PJ, Amarenco P. Fibrates Effect on Cardiovascular Risk Is Greater in Patients With High Triglyceride Levels or Atherogenic Dyslipidemia Profile: A Systematic Review and Meta-analysis. J Cardiovasc Pharmacol. 2011;57(2):267-72.
20. Girerd N, Meune C, Duarte K, Vercamer V, Lopez-Sublet M, Mourad JJ. Evidence of a Blood Pressure Reduction During the COVID-19 Pandemic and Associated Lockdown Period: Insights from e-Health Data. Telemed E-Health. 2022;28(2):266-70.
21. Ayerbe L, Forgnone I, Addo J, Siguero A, Gelati S, Ayis S. Hypertension risk and clinical care in patients with bipolar disorder or schizophrenia; a systematic review and meta-analysis. J Affect Disord. 2018;225:665-70.
22. Füzéki E, Groneberg DA, Banzer W. Physical activity during COVID-19 induced lockdown: recommendations. J Occup Med Toxicol. 2020;15(1):25.
Download attachments: 10.4328:ACAM.21108
Emine Nur Çorum, Emrullah Dündar. The effect of the COVID-19 pandemic period on the prevalence of metabolic syndrome in patients with schizophrenia and bipolar disorder. Ann Clin Anal Med 2022;13(7):750-753
The importance of inflammatory parameters in the management of adhesive small bowel obstructions
Gökhan Yılmaz 1, Yusuf Tanrıkulu 2, Süleyman Kargın 2, Ceren Şen Tanrıkulu 3, Beslen Göksoy 4
1 Department of General Surgery, Faculty of Medicine, Medipol University, Istanbul, 2 Department of General Surgery, Faculty of Medicine, KTO Karatay University, Konya, 3 Department of Emergency Medicine, Health Sciences University, Konya City Hospital, Konya, 4 Department of General Surgery, Sancaktepe Şehit Prof. Dr. Ilhan Varank Research and Education Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.21109 Received: 2022-02-14 Accepted: 2022-03-17 Published Online: 2022-03-18 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):754-758
Corresponding Author: Gökhan Yilmaz, Department of General Surgery, Faculty of Medicine, Medipol University, Istanbul, Türkey. E-mail: email@example.com P: +90 505 682 12 87 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0889-9586
Aim: In the present study, we aimed to examine the role of the Neutrophil-lymphocyte ratio (NLR) and Platelet-Lymphocyte ratio (PLR), which are cheap and easy-to-calculate markers, in surgical treatment decisions for patients with ASBO.
Material and Methods: A total of 103 patients with ileus or similar diagnosis in system records and who underwent bridectomy due to brid ileus, as stated in the surgery notes, were included. The age of patients at the time of application, gender, previous abdominal surgeries, whether they had previous surgery due to ileus, and duration of hospitalization were recorded. NLR and PLR ratios were obtained using a simple calculation model.
Results: According to the data obtained, the sensitivity and specificity values of WBC at 11.10 cut-off value were found to be 72.34% and 85.71%, while the sensitivity and specificity values of CRP at 2.13 were found to be 59.57% and 85.71%. The same values were found to be 82.98% and 85.71%, and 61.70% and 100% for NLR and PLR, respectively. The Youden Index was used to compare the accuracy rates, and NLR with a value of 0.68 was found to be the best parameter.
Discussion: In conclusion, various studies examining the estimation of the need for surgical treatment in patients with ASBO and emphasizing mostly radiological results have been published. Although the present study was not designed to evaluate all radiological, biochemical, and clinical parameters regarding the decision of surgical treatment for the patients, it provides evidence that NLR can be a critical indicator in this matter.
Keywords: Bowel Obstruction, Neutrophil-Lymphocyte Ratio, Platelet-Lymphocyte Ratio, Inflammatory Markers, CRP, Blood Count
Adhesive small bowel obstruction (ASBO) is one of the common causes of particular conditions requiring emergency surgery. In a study examining 87 studies including a total of 110076 patients, the incidence of ASBO following all abdominal surgeries was calculated as 2.4% . The first step in the diagnosis of ASBO is a detailed anamnesis and physical examination. These patients may generally complain of a variety of symptoms such as colicky abdominal pain, nausea, and vomiting in relation to a history of previous abdominal surgery.
Although abdominal X-ray is the primary imaging method used in suspected intestinal obstruction, it is not sufficient to determine the etiology of the obstruction. Computed tomography is the most convenient imaging method to determine the underlying causes of obstruction . If there is no objective evidence such as strangulation, peritonitis, and intestinal ischemia leading to urgent surgical intervention, the choice of non-operative management or surgical treatment depends on the physician’s experience .
The non-operative management duration is a topic of discussion, and surgery delays have been shown to increase morbidity and mortality . Nevertheless, it is stated that the time taken to wait for the ASBO to heal spontaneously may lead to additional morbidity, because this approach leads to unnecessary delays for patients in need of surgery .
The definitive diagnosis of ASBO is determined through a holistic evaluation of the patient’s clinical condition, medical history, physical examination results, hematological and biochemical parameters, and radiological imaging studies. There is no generally recognized standard treatment approach among surgeons. Laboratory tests might be useful to estimate the degree of systemic disease, and various biochemical indicators have been tried in planning the treatment of ASBO . Nevertheless, typical markers of inflammation such as WBC count and CPR levels are not able to distinguish between inflammation due to ASBO and inflammation caused by other inflammatory conditions.
Neutrophil-lymphocyte ratio (NLR) and Platelet-Lymphocyte ratio (PLR) taken from complete blood count parameters are signs of the inflammatory response . These parameters might be useful to guide clinicians regarding the inflammatory process and clinical outcomes of ASBO. Rapid medical or surgical treatment decision for ASBO might reduce mortality and morbidity rates. In the present study, we aimed to examine the role of NLR and PLR, which are cheap and easy-to-calculate markers, in surgical treatment decisions for patients with ASBO.
Material and Methods
Study Groups and Study Design
The present retrospective study was conducted in a multi-centered setting after obtaining ethics committee approval. Patients who were considered to have adhesive small bowel obstruction were included in the study between January 01, 2015 and December 31, 2020. Patient data were derived from archive records and hospital automation systems. A total of 103 patients with small bowel obstruction or a similar diagnosis in the system records and who underwent adhesiolysis due to adhesive bowel obstruction as stated in the surgery notes were included in the present study. Seven patients with cancer and/or foreign body-associated obstruction, six patients with peritoneal carcinomatosis, six patients with mesenteric ischemia associated obstruction, 11 patients with obstruction due to incarcerated hernia, and five patients who underwent surgery for other reasons and bridectomy incidentally were excluded from the study. Moreover, patients under 18 years of age, pregnant patients, and those without abdominal tomography were not included in the study. Eventually, 68 patients with adhesive small bowel obstruction were included in the study. The patients were divided into two groups as surgical treatment group (n = 21) and medical treatment group (n = 47).
The age of patients at the time of application, gender, previous abdominal surgeries, whether they had previous surgery due to bowel obstruction, and duration of hospitalization were recorded.
Patients with suspected ASBO were detected by evaluating the clinical status, medical history, physical examination results, hematological and biochemical parameters, and radiological imaging of patients. In detailed evaluations, urgent surgical exploration was performed objectively in patients with signs of strangulation, bowel ischemia, or peritonitis. Other patients were followed up for nonoperative treatment. Intestinal decompression was achieved by inserting a nasogastric tube, and a long nasointestinal tube was not used. Patients who were scheduled for nonoperative treatment were administered water-soluble contrast agents, and whether there was a transition to the colon was followed up using direct abdominal radiography. Non-operative follow-up lasted for 72 hours. Patients whose obstruction continued after 72 hours, nasogastric tube drained more than 500 cc daily, and patients with developing signs of peritonitis and intestinal ischemia such as increased abdominal pain, WBC (WBC > 10000/mm³) and CRP (CRP > 75 mg/l) were operated. Treatment of the patients whose abdominal pain regressed, who had no signs of ischemia and peritonitis, and whose contrast agent advanced to the colon, was terminated.
CBC and CRP analyses were performed on venous blood samples obtained from patients. NLR and PLR ratios were obtained using a simple calculation model.
All statistical analyses were performed using SPSS version 18.0 software (SPSS Inc., Chicago, IL, USA). Data distribution was evaluated using the Kolmogorov-Smirnov test. Continuous variables were presented as mean ± standard derivation (SD), and categorical variables were presented as frequencies (n/percentages). The significance of each difference between continuous variables was examined using the Independent Samples t-test or the Mann-Whitney U-test. The significance of each difference between categorical variables was compared using Pearson’s Chi-squared test. Receiver Operating Characteristic (ROC) curve analysis was used to define the optimal cut-offs of the diagnostic tests, for which sensitivities, specificities, positive and negative predictive values, and area under the curve (AUC) were calculated. Youden’s index was used to optimize the accuracies of all calculations. A p-value <0.05 was considered to reflect statistical significance.
In the present study, 21 patients who underwent surgical treatment and 47 patients who received medical treatment for ASBO were examined. The demographic data of the patients in each group are summarized in Table 1. According to the results, the average age of the patients in the surgical treatment group was 62.33 ± 18.39 years, and the mean age of the patients in the medical treatment group was 58.21 ± 16.48 years. There was no difference between the groups in terms of mean age (p = 0.081). The hospitalization duration of the patients in the surgical treatment group was statistically higher than in the medical treatment group (p < 0.001). Gastrointestinal surgery was the most common type of surgery that led to small bowel obstruction in both groups. Furthermore, the number of patients who were previously operated for small bowel obstruction was higher in the surgical group (p = 0.014).
The distribution of biochemical and inflammatory markers of the groups is presented in Table 2. According to the results, the mean WBC, CRP, NLR, and PLR were statistically higher in the surgical treatment group (p-values <0.001, 0.002, <0.001, and <0.001, respectively). Mean potassium values were lower in the surgical treatment group (p = 0.002)
When the patients’ responses to the water-soluble contrast agent therapy administered for treatment during hospitalization were evaluated, the decision on urgent surgery decision was made for five (23.8%) patients in the surgical treatment group according to their results at the time of application without any treatment. The remaining 16 (76.2%) patients received medical treatment, and no opaque transition to the cecum was observed at the 24th and 48th hours. In the medical treatment group, eight patients (17%) had an improvement in terms of the small bowel obstruction in the early stage without any contrast agent therapy. Contrast agent transition to the cecum was observed at the 24th hour in 30 (63.8%) of the remaining patients and at the 48th hour in five (10.6%) patients.
The general accuracy rates of inflammatory markers, which might be used to determine patients who would be healed through medical treatment and those who would require surgical treatment are presented in Table 3. ROC curves are presented in Figure 1. According to the data obtained, the sensitivity and specificity values of WBC at 11.10 cut-off value were found to be 72.34% and 85.71%, while the sensitivity and specificity values of CRP at 2.13 were found to be 59.57% and 85.71%, respectively. The same values were found to be 82.98% and 85.71%, and 61.70% and 100% for NLR and PLR, respectively. The Youden Index was used to compare accuracy rates, and NLR with a value of 0.68 was found to be the best parameter.
Intestinal obstruction is the partial or complete obstruction in the advancement of intestinal contents in the gastrointestinal tract for any reason. Most of the time, it can be difficult for surgeons to decide which patient is to be followed up non-operatively and which patient should be operated. We considered that calculating the NRL value might be a guide for surgical treatment decisions in these patients. We aimed to compare these parameters with the classical inflammation markers, WBC count, and CRP value. In our study, the sensitivity and specificity values of the patients operated for adhesive small bowel obstruction were found to be 72.34% and 85.71% for WBC, 59.57% and 85.71% for CRP, 82.98% and 85.71% for NLR, and 61.70% and 100% for PRL, respectively. NLR was found to be the best parameter in terms of comparing the accuracy ratios with each other.
The World Society of Emergency Surgery revised and updated the protocol that was published in 2013 for ASBO treatment in 2017. In a condition where it is observed that the water-soluble contrast agent does not transmit into the colon within 24–36 hours, surgical treatment is recommended. On the other hand, it has been stated that patients who do not have strangulation and peritonitis results and elevated levels of CRP and WBC can be followed up to 72 hours nonoperatively .
Pedro et al. stated that 61% of surgical interventions were performed later than 24 hours after hospitalization in their study evaluating 4163 patients who underwent laparotomy for ASBO. When they classified mortality and complication development in 24-hour increments according to the time from hospitalization to surgery, they found that patients who were operated after 72 hours of follow-up had a 3-fold increase in mortality and a 2-fold increase in the incidence of systemic infectious complications in contrast with those who were operated within 24 hours . Some studies have shown that operation of patients who are followed up for ASBO within 24 hours decreases recurrence rates and provides a long-term cost advantage.. Moreover, patients may be discharged early. This situation reveals the need to investigate many parameters that can enable an early decision to perform surgical treatment for patients with ASBO. Young et al. stated in their study that the number of operations, WBC count, CRP level, and BMI before ASBO are statistically significant factors that aid in early selection of patients requiring surgery . As a result of our study, we believe that NLR and PRL (p:0,001, p:0,001) may show systemic inflammation and infection in the early period and contribute to early surgical decision in ASBO cases
The reason for using NLR and PLR as diagnostic markers is due to neutrophilia and lymphopenia that develop as a result of the systemic inflammatory immune response . NLR and PLR are used as auxiliary markers in the diagnosis and prognosis of diseases leading to systemic inflammation and infection, such as malignancy, mesentery artery disease, acute appendicitis, acute cholecystitis, acute pancreatitis, and community-acquired infections . Kaplan et al. examined the combination of NLR and PLR in patients with pancreatitis in 2018 and stated that it can be used as a diagnostic marker for pancreatic abscesses .
Although some studies in the literature state that NLR can be an indicator in determining the prognosis of ASBO, there is no study comparing the effectiveness of NLR, PLR, WBC, and CRP values in terms of making surgical treatment decisions for these patients . However, there are some studies revealing the contribution of CRP and WBC values to the diagnosis and treatment of patients with intestinal obstruction. Costa et al. recommend surgery when the WBC count in patients diagnosed with intestinal obstruction is above 18 x 109/L . Even though there is an increase in biomarkers such as WBC, urea, and creatinine due to dehydration in intestinal obstruction, the diagnostic value of CRP is also quite limited . Fujii et al. have stated that CRP has no value in terms of estimating the development of postoperative intestinal obstruction . In our study, WBC (p < 0.001) and CRP (p = 0.002) values were significantly higher (statistically) in the group that underwent the operation, and their sensitivity and specificity were found to be 72.34% and 85.71%, and 59.57% and 85.71%, respectively. On the contrary, Lapsekili et al. did not find any statistically significant difference in WBC and CRP values between the patients who were provided with surgical and non-operative management (p = 0.225 for WBC, p = 0.67 for CRP). Alternatively, in the stated study, they evaluated all cases with intestinal obstruction and did not study ASBO cases separately. In correlation with our study, they found that NLR value was significantly higher (statistically) in cases who were treated surgically (p: 0.023). In our study, sensitivity and specificity values for NLR and PLR were 58.14% and 100%, and 62.79% and 92.86%, respectively. Lapsekili et al. found the sensitivity and specificity for NRO as 43% and 78%, respectively. Even though there was no statistically significant difference in CRP levels and WBC, neutrophil, and lymphocyte counts between the two groups, they stated that the high NLR value in intestinal obstruction cases who underwent surgical treatment could be a useful reference for future studies .
As a result of our study, we believe that NLR (EF: 0.68) with the highest Youden index value may show systemic inflammation and infection in the early period in ASBO cases when comparing accuracy rates. Bacterial translocation is defined as the passage of viable bacteria from the intestinal intraluminal segment to mesenteric lymph nodes and distant organs . In intestinal obstruction, intestinal peristalsis is disrupted, and bacterial overgrowth triggers and accelerates translocation . Deitch et al. showed that the incidence of this phenomenon was significantly higher in patients who underwent laparotomy for intestinal obstruction, in contrast to the control group, by isolating viable bacteria from mesenteric lymph nodes (59% vs 4%; p < 0.001) . In conclusion, various studies examining the estimation of the need for surgical treatment in patients with ASBO and emphasizing mostly radiological results were published . But also there are many studies in the literature that evaluated the changes in NLR and PLR values, which are considered cheap and easily calculated parameters capable of detecting systemic immune response [22,23].
The present study was not designed to evaluate all radiological, biochemical, and clinical parameters regarding the decision of surgical treatment for the patients, it provides evidence that NLR can be a critical indicator in this matter. However, we still believe that more comprehensive and prospective studies should be carried out.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Ten Broek RPG, Krielen P, Di Saverio S, Coccolini F, Biffl WL, Ansaloni L et al. Bologna guidelines for diagnosis and management of adhesive small bowel obstruction (ASBO): 2017 update of the evidence-based guidelines from the world society of emergency surgery ASBO working group. World J Emerg Surg. 2018;13:24
2. Azagury D, Liu RC, Morgan A, Spain DA. Small bowel obstruction: A practical step-by-step evidence-based approach to evaluation, decision making, and management. J Trauma Acute Care Surg. 2015; 79(4):661-8.
3. Assenza M, De Gruttola I, Rossi D, Castaldi S, Falaschi F, Giuliano G. Adhesions small bowel obstruction in emergency set¬ting: conservative or operative treatment? G Chir. 2016; 37(4):145-9.
4. Keenan JE, Turley RS, McCoy CC, Migaly J, Shapiro ML, Scarborough JE. Trials of nonoperative management exceeding 3 days are associated with increased morbidity in patients undergoing surgery for uncomplicated adhesive small bowel obstruction. J Trauma Acute Care Surg. 2014; 76(6):1367–72.
5. Teixeira PG, Karamanos E, Talving P, Inaba K, Lam L, Demetriades D. Early operation is associated with a survival benefit for patients with adhesive bowel obstruction. Ann Surg. 2013; 258(3):459-65.
6. Murasaki M, Nakanishi T, Kano KI, Shigemi R, Tanizaki S, Kono K, et al. Point-of-care procalcitonin may predict the need for surgical treatment in patients with small bowel obstruction Am J Emerg Med.2020;38(5):979-82.
7. Xie X, Feng S, Tang Z, Chen L, Huang Y, Yang X. Neutrophil-to-Lymphocyte Ratio Predicts the Severity of Incarcerated Groin Hernia. Med Sci Monit. 2017;23: 5558-63
8. Colonna AL, Nickolas RB, Nelson SD, Nelson EN Hunter MC, Nirula R. Nonoperative management of adhesive small bowel obstruction: what is the break point? The American Journal of Surgery. 2016;212(6):1214-21.
9. Cho YJ, Park IN, Kim J, Cho HJ, Gwak GH, Yang KH, et al. Factors Predicting the Need for Early Surgical Intervention for Small Bowel Obstruction. Ann Coloproctol. 2020;36(4):223-8.
10. Shimoyama Y, Umegaki O, Agui T, Kadono N, Minami T. Neutrophil to lymphocyte ratio and platelet to lymphocyte ratio are superior to other inflammation- based prognostic scores in predicting the mortality of patients with gastrointestinal perforation. JA Clin Rep. 2017;3(1):49.
11. Destek S, Yabacı A, Abik YN, Gül VO, Değer KC, Predictive and prognostic value of L-lactate, D-dimer, leukocyte, C-reactive protein and neutrophil/lymphocyte ratio in patients with acute mesenteric ischemia. Ulus Travma Acil Cerrahi Derg. 2020;26(1):86-94.
12. Kaplan M, Ates I, Oztas E, Yuksel M, Akpinar MY, Coskun O, et al. A New Marker to Determine Prognosis of Acute Pancreatitis: PLR and NLR Combination. J Med Biochem. 2018;37(1):21–30.
13. Yoon JB, Lee SH, The neutrophil-to-lymphocyte ratio has feasible predictive value for hospital mortality in patients with small bowel obstruction in the emergency department. Am J Emerg Med. 2021;44;428-33
14. Costa G, Ruscelli P, Balducci G, Buccoliero F, Lorenzon L, Frezza B, et al. Clinical strategies for the management of intes¬tinal obstruction and pseudo-obstruction. A Delphi Consensus study of SICUT (Società Italiana di Chirurgia d’Urgenza e del Trauma). Ann Ital Chir. 2016;87:105-17.
15. van Oudheusden TR, Aerts BA, de Hingh IH, Luyer MD. Challenges in diagnosing adhesive small bowel obstruction. World J Gastroenterol. 2013;19(43):7489-93.
16. Fujii T, Sutoh T, Kigure W, Morita H, Katoh T, Yajima R, et al. C-reactive protein level as a possible predictor for early postoperative ileus following elective surgery for colorectal cancer. Hepatogastroenterology. 2015; 62(138):283-85
17. Lapsekili E, Bilge S. Contribution of neutrophil-to-lymphocyte ratio to decisions regarding surgical therapy in patients diagnosed with intestinal obstruction Hippokratia. 2019; 23(4):160-4
18. Doudakmanis C, Bouliaris K, Kolla C, Efthimiou M, Koukoulis GD. Bacterial translocation in patients undergoing major gastrointestinal surgery and its role in postoperative sepsis. World J Gastrointest Pathophysiol. 2021;12(6):106-14.
19. Haraux E, Canarelli JP, Khorsi H, Delanaud S, Bach V, Gay-Quéheillard J. In vitro smooth muscle contractility before and after relief of experimental obstruction in the rat: application to the surgical management of ileal dilatation. J Pediatr Surg. 2014;49(3):399-404.
20. Deitch EAE. Simple intestinal obstruction causes bacterial translocation in man. Arch Surg. 1989;124(6):699-701.
21. Zielinski MD, Eiken PW, Bannon MP, Heller SF, Lohse CM, Huebner M, et al. Small bowel obstruction who needs an operation? A multivariate prediction model. World J Surg. 2010;34(5):910-19
22. Suppiah A, Malde D, Arab T, Hamed M, Allgar V, Smith AM, et al. The prognostic value of the neutrophil-lymphocyte ratio (NLR) in acute pancreatitis: identification of an optimal NLR. J Gastrointest Surg. 2013;17(4):675-81.
23. Akalın Ç. The evaluation of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in anorectal abscess.Ulus Travma Acil Cerrahi Derg. 2020;26(6):887-92
Download attachments: 10.4328:ACAM.21109
Gökhan Yılmaz, Yusuf Tanrıkulu, Süleyman Kargın, Ceren Şen Tanrıkulu, Beslen Göksoy. The importance of inflammatory parameters in the management of adhesive small bowel obstructions. Ann Clin Anal Med 2022;13(7):754-758
A comparison of miRNAs with proinflammatory cytokines and procalcitonin of sepsis in the intensive care unit
Semiha Orhan 1, Kemal Yetiş Gülsoy 2, Esra Örenlili Yaylagül 3, Halit Bugra Koca 4, Lütfi Yavuz 5, Celal Ulger 6
1 Department of Intensive Care Unit, Afyonkarahisar University of Health Sciences, Afyonkarahisar, 2 Department of Intensive Care Unit, Burdur Public Hospital, Burdur, 3 Nutrition and Dietetics, Faculty of Health Sciences, Adnan Menderes University, Aydin, 4 Department of Biochemistry, Afyonkarahisar University of Health SciencesAfyonkarahisar, 5 Department of Anaesthesiology and Reanimation, Antalya University of Health Sciences Training and Research Hospital, Antalya, 6 Department of Biology, Art and Science Faculty, Adnan Menderes University, Aydin, Turkey
DOI: 10.4328/ACAM.21110 Received: 2022-02-14 Accepted: 2022-03-18 Published Online: 2022-03-24 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):759-764
Corresponding Author: Semiha Orhan, Department of Intensive Care Unit, Afyonkarahisar University of Health Sciences, Afyonkarahisar, Turkey. E-mail: firstname.lastname@example.org P: +90 532 728 19 79 Corresponding Author ORCID ID: https://orcid.org/0000000326176197
Aim: The development of sepsis, the low efficacy of antibiotics used, long-term antibiotic use, and the development of resistance to antibiotics are significant problems in patients in intensive care units. The use of biological markers is promising for the diagnosis and treatment of sepsis. In this study, proinflammatory cytokines, procalcitonin and four miRNA expressions were analyzed in a time-dependent manner in a patient group and control group, and the correlations between them were examined.
Material and Methods: The study included 30 patients in the intensive care unit who were diagnosed with sepsis and applied with SOFA and APACHE-2 scoring and 30 control subjects. Serum samples were taken at 24 hours, 72 hours, and on the 7th day. Analyses according to time were made for interleukin-1 beta, interleukin-6, interleukin-10, TNF-alpha, procalcitonin and four miRNAs (miR-122, miR-146a, miR-150, and miR-223) in the collected samples and comparisons were made between the patients and the control group.
Results: At 24 hours, there was a decrease in the miRNA-146a, miRNA-150, and miRNA-122 values and an increase in the miRNA-223 values in the sepsis group compared to the control group. At 72 hours, a decrease was observed in the miRNA-146a, miRNA-150, miRNA-122, and miRNA-223 values in the sepsis group compared to the control group.
Discussion: When procalcitonin and inflammatory cytokines were compared with selected miRNAs in the diagnosis, treatment follow-up, and prognosis of sepsis in the intensive care unit, a correlation between procalcitonin levels, proinflammatory cytokines and miRNA-150, miRNA-146a, and miRNA-223 was found.
Keywords: Gene Expression, miRNA, Procalcitonin, Sepsis, qRT-PCR
The development of sepsis, low efficacy of antibiotics used, long-term antibiotic use, and the development of resistance to antibiotics are significant problems in patients in ICUs.
The beginning of the pathophysiology of sepsis is the formation of the natural immune response to an infectious pathogen. Cytokines are important in ensuring that the infection remains localized and preventing systemic spread .
In addition to the relationship of procalcitonin with bacterial infections, elevated levels may also be seen in conditions other than infection, such as trauma, acute pancreatitis. Therefore, procalcitonin is an insufficient biomarker in the diagnosis of sepsis .
Different studies related to sepsis have determined that miRNA 150, miRNA 146a, miRNA 223, and miRNA 122 expressions show significant differences [3-7]. Determination of the serum levels of these candidate miRNAs has the potential to be a guide to diagnosis and treatment.
The aim of this study was to compare procalcitonin and proinflammatory cytokines with selected miRNAs in the diagnosis, treatment and prognosis of sepsis in ICU patients.
Material and Methods
Approval for the study was granted by the Clinical Research Ethics Committee of Suleyman Demirel University School of Medıcıne (decision no:31, dated:2016). The study included patients aged >18 years who were diagnosed with sepsis in the Intensive Care Unit (ICU) and not taking antibiotics. Patients who were admitted to the ICU with a diagnosis of sepsis or were taking antibiotics for any infection before the diagnosis of sepsis was made in the ICU were excluded from the study even if they were diagnosed with sepsis.
Of the patients in the ICU throughout the study period, a total of 30 were included for analysis, including 16 females and 14 males. A control group was formed of 30 patients without a diagnosis of sepsis matched to the study group. Serum samples were taken from both groups.
To evaluate the efficacy of antibiotic treatment started within 24 hours of the sepsis diagnosis, blood samples were taken at 72 hours and on the 7th day after starting antibiotics.
Preparation of the serum samples
For the miRNA assays, 10cc blood samples were taken into sterile tubes not containing anticoagulant (DNase-RNase free) at room temperature from both the patient and control groups.
RNA extraction was performed from the serum using Trizol® LS (ThermoFisherScientific), which is used for total RNA isolation from tissue fluids. To determine the amplification efficacy of the miRNA extraction performance, 100 fmol synthetic Caenorhabditiselegans miRNA (cel-miR-39) prepared in water not containing nuclease was added to the serum (spike-in) and the extraction procedures were applied according to the manufacturer’s protocol.
cDNA Synthesis and qRT-PCR
Using the TaqMan® Advanced MiRNAcDNA Synthesis kit (Thermo Fisher) for the miRNA assays, cDNA synthesis was applied from total RNA. For the assays of the cDNAs synthesised with TaqMan® Fast Advanced Master mix and the related miRNAs (hsa-miR-150, hsa-miR-146a, hsa-miR-223, hsa-miR-122, and cel-miR-39), the TaqMan® Advanced miRNA test systems were used. Reactions were made with the StepOne RT-PCR system (Applied Biosystem) and Relative Quantification (RQ) values were obtained.
ELISA analyses of the cytokines and procalcitonin amounts
In the measurements of serum interleukin-1beta (IL-1β), IL-6, IL-10, and TNF-α levels, the eBioscience IL-1β High Sensitivity Human ELISA Kit was used. For the measurement of serum procalcitonin levels, the Biovendor Human Procalcitonin ELISA Kit was used.
Data obtained in the study were analyzed statistically using SPSS vn 23.0 software (Statistical Package for Social Sciences, IBM, Chicago, IL, USA). Conformity of the data to normal distribution was assessed using the Kolmogorov-Smirnov and Shapiro-Wilk tests. Repeated measurement variance analysis was applied to data showing a normal distribution and the Friedman test to data not showing a normal distribution. When a significant difference was determined as a result of the tests, multiple comparison tests were applied to determine which time measurement had created the difference.
When a difference emerged in the measurements in the repeated measurement variance analysis, Bonferroni multiple comparison tests were used for data with normal distribution. For data not showing normal distribution, when a difference emerged in the Friedman test, the Dunn test was used to determine the level of significance.
The Mann Whitney U-test was applied in comparisons between the study group and the control group, and the Wilcoxon Signed Ranks test was used in the comparisons of time-related changes. A value of p<0.05 was accepted as statistically significant.
A total of 120 serum samples were examined: 30 samples from the control group and 90 from the study group, 30 at each of three different time points (24 hours, 72 hours, 7 days). Analyses of proinflammatory cytokines (TNF-α, IL-1β, IL-6, IL-10), procalcitonin, and 4 miRNAs (miR-122, miR-146a, miR-150, miR-223) were performed. Comparisons were made between the study group and the control group, and between the time measurement points in the study group.
In the analysis of miRNA-146a expression, a significant decrease was determined in the study group compared to the control group and according to time (Figure 1A-1B). In the time related changes of the miRNA results, a statistically significant difference between the values at 24 hours and 72 hours (p=0.005) and between 24 hours and 7 days (p=0.0001) (Figure 1B) was determined.
In the analysis of miRNA-150 expression, a significant decrease was determined in the study group compared to the control group at 72 hrs and 7 days (Figure 1C). In the time related changes of the miRNA-150 results of the study group, a statistically significant difference between the values at 24 hours and 72 hours (p=0.013) and between 24 hours and 7 days (p=0.002) (Figure 1D) was determined.
In the analysis of miRNA-223 expression, a significant decrease was determined in the study group compared to the control group at 72 hrs (Figure 1E). In the time related changes of the miRNA-223 results in the study group, a statistically significant difference between the values at 24 hours and 72 hours (p=0.0001) and the difference between 24 hours and 7 days was not statistically significant (p=0.166) (Figure 1F).
In the analysis of miRNA-122 expression, no significant difference was determined between the study group and the control group (Figure 1G). In the time-related changes of the miRNA-122 results of the study group, a statistically significant difference between the values at 24 hours and 72 hours (p=0.041) and between 24 hours and 7 days (p=0.027) (Figure 1H) was determined.
The TNF-α results in the study group were found to be statistically significantly higher than in the control group at 72 hours and 7 days (Figure 2A). When the TNF-α results were evaluated according to time, no statistically significant difference was determined between the values at 24 hours and 72 hours (p=0.318), and a statistically significant decrease was observed between 24 hours and 7 days (p=0.049) (Figure 2B).
The IL-1β results in the study group were found to be statistically significantly higher than in the control group at 24 hours, 72 hours, and 7 days (Figure 2C). When IL-1β results were evaluated according to time, a statistically significant difference was determined between the values at 24 hours and 72 hours (p=0.011), and between 24 hours and 7 days (p=0.001) (Figure 2D).
The IL-6 results in the study group were found to be statistically significantly higher than in the control group at 24 hours, 72 hours, and 7 days (Figure 2E). When IL-6 results were evaluated according to time, a statistically significant difference was determined between the values at 24 hours and 72 hours (p=0.0001), and between 24 hours and 7 days (p=0.0001) (Figure 2F).
The IL-10 results in the study group were found to be statistically significantly higher than in the control group at 24 hours, 72 hours, and 7 days (Figure 2G). When IL-10 results were evaluated according to time, a statistically significant difference was determined between the values at 24 hours and 72 hours (p=0.0001), and between 24 hours and 7 days (p=0.0001) (Figure 2H).
The procalcitonin results in the study group were found to be statistically significantly higher than in the control group at 24 hours, 72 hours, and 7 days (Figure 2I). When the procalcitonin results were evaluated according to time, a statistically significant difference was determined between the values at 24 hours and 72 hours (p=0.026), and between 24 hours and 7 days (p=0.0001) (Figure 2J).
Microbiological culture is the gold standard for the differentiation of sepsis from other non-infectious diseases. However, as this technique takes a long time, diagnosis and treatment are delayed. Therefore, several studies have been conducted to determine the ideal biomarker for sepsis.
Studies published in the literature that have examined procalcitonin and cytokine levels to evaluate the duration of antibiotic use in ICU patients with sepsis have not included patients using antibiotic treatment on admission to ICU [8-12]. Taking the above-mentioned literature and meta-analyses into consideration, the patients included in the current study were those being followed up in ICU who developed sepsis and who had not previously received antibiotic treatment, to be able to create a more homogenous standardized group. This study aimed to compare candidate miRNAs with procalcitonin and proinflammatory cytokines in the evaluation of the efficacy of antibiotic treatment in patients being followed up in ICU who were diagnosed with sepsis and started antibiotic treatment within the first 24 hours.
miRNAs directly target signal proteins and control NF-κB activity in immune cells, and are therefore defined as regenerators of the immune system . A link between miRNA in particular and NF-κB has been shown in in-vitro studies.
It has been reported that miRNA-146a and miRNA-146b are expressed as a response to the microbial component and proinflammatory cytokines. In another study, Funahashi et al. showed that miRNA-146a has an anti-inflammatory role and reduced excessive inflammation by regulating IRAK-1 and TRAF6, thereby modulating NF-κB transcriptional activity. In an in-vitro environment, miRNA-146a has been shown to trigger severe sepsis in macrophages and to be correlated with sepsis severity at the cellular level .
In another study that analyzed chemokines and cytokines in sepsis patients, changes in miRNA-146 were shown to be correlated with polymorphonuclear cells in peripheral blood. IL-6, which is an important inflammatory mediator in sepsis, was reported to increase, while miRNA-146 decreased .
The IL-6 level increases more rapidly in sepsis and reaches a peak level at the end of the second hour. The elevated serum level lasts longer than for TNF-α and IL-1 . Procalcitonin (PCT) is produced as a response to endotoxin or through mediators (IL-1, TNF-α, IL-6) expressed as a response to bacterial infections. It is correlated with the severity of bacterial infection .
In the current study, miRNA-146a was determined to be significantly reduced in the sepsis group compared to the control group at 24 hours, 72 hours, and 7 days of treatment, and a significant increase was determined in proinflammatory cytokine and procalcitonin levels, which was consistent with findings in the literature. In addition, a significant decrease was determined in the miRNA-146a levels in the sepsis group at 72 hours and 7 days compared to the values at 24 hours, and there was a significant decrease in proinflammatory cytokines and procalcitonin levels.
Roderburg C et al. compared 138 patients meeting sepsis criteria and 76 healthy control subjects, and reported that the serum miRNA-150 level was slightly reduced in the sepsis group, and was therefore not suitable as a marker for the diagnosis of sepsis. However, a correlation between serum miRNA levels and hepatic and renal function disorders, and low serum miRNA-150 levels were reported to be associated with a poor prognosis . In a study of 120 sepsis patients and 50 healthy control subjects, Ma et al. showed that miRNA-150 was significantly decreased in the sepsis group compared to the control group, and there was a negative correlation between IL-6, TNF-α, and miRNA-150 values .
In the current study, the miRNA-150 level was observed to be decreased in the sepsis patients compared to the control group, but at 24 hours this decrease was not statistically significant. These differences from previously published results are most probably related to the size and characteristics of the patient groups analyzed in different studies. A statistically significant decrease was seen in the miRNA-150 levels of the sepsis group after 72 hours and 7 days of sepsis treatment compared to the control group. When the sepsis antibiotic treatment was evaluated over time, a significant decrease was determined in the miRNA-150 level of the sepsis group at 72 hours and 7 days compared to the value at 24 hours. The proinflammatory cytokines and procalcitonin values were seen to be significantly increased at 24 hours when sepsis was diagnosed, and significantly decreased after 72 hours and 7 days of treatment. Roderburg et al. determined no correlation between serum miRNA-150 levels and markers of bacterial infection and inflammation such as CRP or procalcitonin .
In addition to miRNA-122 being known to be a miRNA associated with the liver, it has also been stated to be a biomarker in the diagnosis and prognosis of sepsis . In a study of 108 sepsis patients in the first 24 hours of admission to ICU and 20 control subjects, miRNA-122 expression was seen to be 40-fold higher in sepsis patients with a mortal course compared to the control group, and 6-fold higher in the patients with sepsis who survived .
In the current study, an increase was seen in miRNA-122 levels at 24 hours following the diagnosis of sepsis compared to the control group, and a decrease was determined after 72 hours and 7 days of treatment. Within the sepsis group, there was a significant decrease in the miRNA-122 levels at 72 hours and 7 days. Moreover, a parallel decrease was seen in proinflammatory cytokines and procalcitonin levels.
In a study by Wang et al of 166 patients diagnosed with sepsis and 24 control subjects, serum samples were taken from the sepsis patients within 24 hours. There was a diagnosis of severe sepsis and septic shock in 123 patients and mild sepsis in 43. The miRNA-223 expression level was reported to be significantly higher, and the miR-499-5p, miR-122, and miR-193b levels were significantly lower in mild sepsis, severe sepsis, and septic shock patients compared to the control group. In addition, the miRNA-223 expression level was statistically slightly elevated in the septic shock and severe sepsis group compared to the mild sepsis group .
In the current study, an increase, but not at a significant level, was seen in the miRNA-223 levels of the sepsis group compared to the control group, a statistically significant decrease was determined after 72 hours of sepsis treatment, and on the 7th day, an increase was seen, which was not statistically significant because of the increase in standard deviation.
In this study, which compared selected miRNAs with procalcitonin and inflammatory cytokines in the diagnosis, treatment follow-up, and prognosis of patients diagnosed with sepsis in ICU, a relationship was determined between miRNA-150, miRNA-146a, and miRNA-223, and proinflammatory cytokines and procalcitonin levels. Based on this study, by increasing the number of patients and with data obtained from comprehensive analysis systems such as all miRNA pool microarray or new-generation sequencing, new biomarkers will be able to be established for the diagnosis, treatment follow up, and prognosis of sepsis.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Funding: This work was supported by generous funding from the Scientific and Technological Research Council of Turkey (TUBITAK) 3001 AR-GE (217S211).
Conflict of interest
1. Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, Vincent JL. Sepsis and septic shock. Nat Rev Dis Primers. 2016; 30(2):16045.
2. Bréchot N, Hékimian G, Chastre J, Luyt CE. Procalcitonin to guide antibiotic therapy in the ICU. Int J Antimicrob Agent. 2015;46(1):19-24.
3. Wang JF, Yu ML, Yu G, Bian JJ, Deng XM, Wan XJ, et al. Serum miR-146a and miR-223 as potential new biomarkers for sepsis. Biochem Biophys Res Commun. 2010;394(1):184-8.
4. Vasilescu C, Rossi S, Shimizu M, Tudor S, Veronese A, Ferracin M, et al. MicroRNA finger prints identify miR-150 as a plasma prognostic marker in patients with sepsis. PLoSOne. 2009;4(10):e7405.
5. Wang HJ, Zhang PJ, ChenWJ, Feng D, Jia YH, Xie LX. Four serum microRNAs identified as diagnostic biomarkers of sepsis. J Trauma Acute Care Surg. 2012;73(4): 850–4.
6. Benz F, Roy S, Trautwein C, Roderburg C, Luedde T. Circulating MicroRNAs as Biomarkers for Sepsis. Int J Mol Sci. 2016;17(78):1-17.
7. Wang HJ, Yu B, Deng J, Jin Y, Xie L. Serum miR-122 correlates with short-term mortality in sepsis patients. Crit Care. 2014;704(6):12-8.
8. Hochreiter M, Köhler T, Schweiger AM, Keck FS, Bein B, von Spiegel T, et al. Procalcitonin to guide duration of antibiotic therapy in intensive care patients: a randomized prospective controlled trial. Crit Care. 2009;13(3):R83.
9. Schroeder S, Hochreiter M, Koehler T,Schweiger AM, Bein B, Keck FS, et al. Procalcitonin (PCT)-guided algorithm reduces length of antibiotic treatment in surgical intensive care patients with severe sepsis: results of a prospective randomized study. Langenbecks Arch Surg. 2009;394(2):221-6.
10. Branche AR, Walsh EE, Vargas R, Hulbert B, Formica MA, Baran A, et al. Serum Procalcitonin Measurement and Viral Testingto Guide Antibiotic Use for Respiratory Infections in Hospitalized Adults: A Randomized Controlled Trial. J Infect Dis. 2015(11)212:1692-700.
11. Kopterides P, Siempos II, Tsangaris I, Tsantes A, Armaganidis A. Procalcitonin-guided algorithms of antibiotictherapy in theintensive care unit: a systematic review and meta-analysis of randomized controlled trials. Crit Care Med. 2010;38(11):2229-41.
12. Rhee C. Using Procalciton into Guide Antibiotic Therapy. Open Forum Infect Dis. 2016; 7;4(1)ofw249. DOI: 10.1093/ofid/ofw249.
13. Ma X, Becker BLE, Barker JR, Li Y. MicroRNAs in NF-kappa-B signaling. J Mol Cell Biol. 2011;3(3):159-66.
14. Funahashi Y, Kato N, Masuda T, Nishio F, Kitai H, Ishimoto T, et al. miR-146a targeted to splenic macrophages prevents sepsis-induced multiple organ injury. Lab Invest. 2019;99(8):1130–42.
15. Zhou J, Chaudhry H, Zhong Y, Ali MM, Perkins LA, Owens WB, et al. Dysregulation in microRNA expression in peripheral blood mono nuclear cells of sepsis patients is associated with immunopathology. Cytokine. 2015;71(1):89-100.
16. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014;6(10):a016295
17. Brodská H, Malíčková K, Adámková V, Benáková H, Šťastná MM, Zima T. Significantly higher procalcitonin levels could differentiate Gram-negative sepsis from Gram-positive and fungal sepsis. Clin Exp Med. 2013;13(3):165–70.
18. Roderburg C, Luedde M, Cardenas DV, Vucur M, Scholten D, Frey N, et al. Circulating MicroRNA-150 Serum LevelsPredictSurvival in Patientswith Critical Illness and Sepsis. PLoS ONE.2013;8(1): e54612.
19. Ma Y, Liu Y, Hou H, Yao Y, Meng H. MiR-150 predicts survival in patients with sepsis and inhibits LPS-induced inflammatory factors and apoptosis by targeting NF-kB1 in human umbilical vein endothelial cells. Biochem Biophys Res Commun 2018;500(3):828-37.
20. Rahmel T, Schäfer ST, Frey UH, Adamzik M, Peters J. Increased circulating microRNA-122 is a biomarker for discrimination and risk stratification in patients definedby sepsis-3 criteria. PLoS ONE. 2018;13(5):e0197637.
Download attachments: 10.4328:ACAM.21110
Semiha Orhan, Kemal Yetiş Gülsoy, Esra Örenlili Yaylagül, Halit Bugra Koca, Lütfi Yavuz, Celal Ulger. A comparison of miRNAs with proinflammatory cytokines and procalcitonin of sepsis in the intensive care unit. Ann Clin Anal Med 2022;13(7):759-764
Effect of korean red ginseng on colon anastomotic healing: A randomised controlled experimental study
Ufuk Tali 1, Mehmet Tolga Kafadar 2, Mustafa Cömert 3
1 Department of General Surgery, Mehmet Akif Ersoy State Hospital, Çanakkale, 2 Department of General Surgery, School of Medicine, Dicle University Diyarbakır, 3 Department of General Surgery, School of Medicine, Bülent Ecevit University, Zonguldak, Turkey
DOI: 10.4328/ACAM.21112 Received: 2022-02-15 Accepted: 2022-03-19 Published Online: 2022-03-28 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):765-769
Corresponding Author: Mehmet Tolga Kafadar, Dicle University School of Medicine Department of General Surgery, Diyarbakır, Turkey. E-mail: email@example.com P: +90 412 248 80 01 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9178-7843
Aim: Although vegetable medicinal products are used worldwide, their beneficial and harmful effects have not been well documented. The aim of this study was to assess the effect of Korean red ginseng (KRG) on the healing of experimental colonic anastomosis in a rat model.
Material and Methods: Forty rats were randomized into four groups as follows: control groups (A and B) and KRG groups (C and D). Surgical procedure consisted of a transection and handsewn anastomosis of the ascending colon. Animals daily received either KRG (50ml/kg) or an equal volume of water by gavages 5 days before operation and then the surgery was done. Rats in Groups A and C were sacrificed on postoperative day (POD) 3, rats in Groups B and D were sacrificed on POD 7. Anastomotic complications and anastomotic bursting pressure measurements were recorded. Following these measurements, the anastomotic segment was resected for hydroxyproline (HPO) and histopathological evaluation.
Results: No significant differences were found in anastomotic complications. The colonic bursting pressures in the KRG groups were statistically significantly better than in the control groups. The hydroxyproline content was also significantly higher in Group C than in Group A. Histological examination confirmed that KRG treatment significantly increased neovascularization, fibroblastic activity and collagen content compared with controls on POD 7.
Discussion: Peri-operative administration of the KRG has a positive influence on the healing of colonic anastomosis in rats.
Keywords: Korean Red Ginseng, Colon, Anastomosis
Colonic leaks occur as a consequence of defective anastomotic healing and are regarded as a troublesome issue in colorectal surgery. Defective colonic anastomotic healing results from many factors, including tension on the anastomosis line, ischemia, distal obstruction, infection, surgical technique, malnutrition, various medications, and disordered collagen metabolism . Diverse causes of defective colonic anastomotic healing make surgery even more complicated [2,3]. In the study by Neumann et al. , despite recent advances in surgical techniques and technologic devices, the anastomosis leakage rate was reported to be 37% in colorectal cancer patients. A healthy colonic anastomosis requires ample tissue perfusion and adequate oxygen content .
Red Ginseng root (Panax ginseng Meyer) has found clinical use in China, Korea and Japan to treat a variety of disorders, including atherosclerosis, hepatic disorders, cerebrovascular disorders, hypertension, and post-menopausal disorder . Red Ginseng root extracts in the form of topical ointment have also been administered for clinical purposes to treat atopic suppurative dermatitis, open wounds, and inflammatory skin conditions. Triterpene glycosides known as ginsenosides are the main active compounds found in ginseng, which have been scrutinized for their pharmacological properties. According to previous reports, ginsenoside Rg1 induces functional neovascularization into a polymer scaffold in vitro and angiogenesis in vivo . In contrast, ginsenoside Rb1 and Rb2 inhibit angiogenesis, while the latter favors the proliferation of epidermal cells and improves wound healing [8,9]. According to a report by Morisaki et al. , Korean Red Ginseng (KRG) induced angiogenesis both in vitro and in vivo, in endothelial cell culture and in an animal model. Nevertheless, it has been understudied how and to what degree would KRG’s angiogenic action affect colonic anastomosis. In this study, we investigated the effects of KRG on colonic anastomosis in rats.
Material and Methods
The experimental protocols were conducted with the approval of the Animal Research Committee at Bülent Ecevit University, Zonguldak. All animals were maintained in accordance with the recommendations of the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Ethical approval was received for this study from the ethics committee of Bülent Ecevit University, Zonguldak. Statistical analysis was performed with the SPSS version 13.0 ® software package (IBM, New York, USA).
Animals and Experiments
Forty female Wistar rats weighing 200 to 250 g were housed individually in cages, were allowed free access to standard rat chow and water before and after the experiments. The animal rooms were windowless with temperature (22±2°C) and lighting controls. The rats daily received either KRG (Sunsam Co Ltd, Namwon-Si Jeollabukdo, Korea) (50ml/kg) or an equal volume of water via gavages 5 days before the operation and then surgery. The animals were fasted overnight preoperatively but were given free access to water. The rats were divided into four groups after the operation (n = 10): postoperative day (POD) 3 untreated control group (Group A), POD 7 untreated control group (Group B), POD 3 KRG group (Group C) and POD 7 KRG group (Group D).
Mechanical and antibacterial bowel preparation was not performed. After 12 h fasting, all rats were anesthetized with 5 mg/kg xylazine (Rhompun, Abdi Ibrahim, Istanbul, Turkey) and 40 mg/kg ketamine hydrochloride (Ketalar, Eczacıbasi, Istanbul, Turkey). To prevent postoperative dehydration, 5 ml of Ringer’s lactate solution was injected subcutaneously. Through a midline incision, the right colon was transected and an end-to-end anastomosis was created using a single layer of 6 interrupted 6–0 polypropylene sutures (6–0 monofilament polypropylene; Prolene, Dogsan, Besiktas, Istanbul, Turkey). The abdominal muscle layers and skin incision were closed separately with running sutures (3–0 silk, Dogsan, Besiktas, Istanbul, Turkey). All anastomoses were done by the same surgeon, who was experienced in the techniques. The rats were anesthetized using the same method on POD 3 and POD 7. A repeat laparotomy was made through the same midline incision and the peritoneal cavity was opened. Anastomotic bursting pressure was measured as described below. The anastomotic segment was isolated from the surrounding tissue, and a part of it was collected for hydroxyproline assay as a marker of collagen content, and another part was collected for histopathologic examination. The animals were then sacrificed with an excess dose of ether.
Measurement of Bursting
Pressure. The anastomosis line was found and the intestine was cut out 2 cm proximally and 2 cm distally to the anastomosis region using the same method used by Li et al. . One end was sutured and the other end was tied after an 18 g intraluminal catheter placement. A three-way cannula was placed on the tip of the catheter. One end was connected to intraluminal side and the other end was connected to the manometer. Methylene blue, diluted with saline, was administered at 6 ml/min speed with an infusion pump. The pressure when the blue colored fluid was seen, or the time when a sudden drop in pressure was seen, was defined as the burst pressure and was recorded in mm Hg.
Measurement of Hydroxyproline Level
Tissue samples were homogenized and stored at -40°C. An autoclave was used to hydrolyze the specimens. Chloramine-T was added to provide oxidation at room temperature. Finally, Ehrlich reactive was also used to stain samples measured at 550 nm using a spectrophotometer . Hydroxyproline levels were calculated as μg/g wet tissue weight from the calibration curve. These assessments were provided by a biochemist blinded to the study.
Histopathological examinations were conducted by the same pathologist. The sample pieces were prepared in a paraffin block after which their thin cross-sections were dyed using “hematoxylin-eosin” (H-E) dye and examined under a light microscope. The images were recorded on a computer. Histopathological staging of the anastomotic line was conducted according to the Ehrlich-Hunt Model . Evaluation criteria in this model are the number of inflammatory cells, fibroblasts, neovascularization, and collagen.
Statistical analysis was performed with the SPSS version 13.0 software package (IBM, New York, USA). Continuous variables were given with mean, median, standard deviation, minimum and maximum values. Normality analyses were performed using the Shapiro-Wilk test in order to evaluate the distribution of the data. Then, dual and triple comparisons among groups were performed using the Mann-Whitney U and Kruskal-Wallis Tests, respectively. P-values less than 0.05 were considered statistically significant.
No anastomotic complications (dehiscence of the anastomosis or death) occurred in the animals, and a gross observation of circumferential healing of anastomotic lines was documented. Anastomotic wound healing was evaluated by means of bursting pressure, hydroxyproline content and histopathological assessment.
Bursting Pressure and Hydroxyproline Content
In all subjects, the bursting was observed at the anastomotic line, mean anastomotic bursting pressures were 43.00±10.27 mmHg in Group A, 70.40±8.39 mmHg in Group B, 84.60±13.10 mmHg in Group C and 159.00±19.07 mmHg in Group D (Table 1). Mean bursting pressure was higher in the subjects who were treated with KRG than in those who were not treated with KRG. Significant statistical differences have been detected among Groups A and C, and Groups B and D (p=0.003 and p<0.001 respectively).
According to hydroxyproline levels (mcg/tissue) of the subjects, mean values of the groups were detected as 174.4 ± 14.85 for Group A, 195.64 ± 9.52 for Group B, 184.62 ± 7.65 for Group C, and 190,86 ± 16.04 for Group D (Table 1). There was significantly greater anastomotic hydroxyproline content in Group C than in Group A (p=0.012). Mean values in Groups B and D were nearly similar, and Group B had higher hydroxyproline concentrations compared with Group D.
According to histopathological staging results based on the Ehrlich-Hunt model, the average values of the groups were detected as 5.20 ±1.13 for Group A, 8.30±2.49 for Group B, 6.00±1.88 for Group C, and 11.60±2.22 for Group D (Table 1). To evaluate wound healing in the anastomotic line, according to the histopathological staging based on the Ehrlich-Hunt model, fibroblastic activity, neovascularization, and collagen measured in Group A and Group C in the POD 3 are in low degrees, and the difference was insignificant. However, inflammatory cell infiltration was higher in Group A compared to Group C, but was not find statistically significant (Table 1). There were significant differences in fibroblastic activity, collagen, and neovascularization between the POD 7 groups (p<0.001, <0.001 and p=0.002 respectively), whereas there was no significant difference in inflammatory cell infiltration between Group B and Group D (Table 1). Sample microscopic images of the histopathological examination are shown in Figures 1 and 2.
A large variety of local or systemic factors affect anastomotic healing, of which tissue perfusion and oxygenation are the two major determinants [5,14]. Colonic anastomoses suffer from a greater rate of leaks compared to other parts of the gastrointestinal system due to some of their unique biological differences, including low collagen content, high collagenase activity, poor collateral circulation, and the lack of a serosa in the extra peritoneal rectum. Studies on colonic anastomosis have focused on certain substances that have proven effective in improving the pathophysiological healing process. Various modes of action to achieve that goal include hastening wound healing, promoting vascularization, and eliminating septic factors. Local tissue perfusion at the site of anastomosis is usually regarded as the most important factor for proper healing . Body sites where tissue repair or regeneration takes place are in an increased need for nutrients, various growth factors, and molecular oxygen to meet their heightened metabolic needs, a task, which is fulfilled by angiogenesis . Therapeutic angiogenesis refers to attempts to promote new vessel development, which can be achieved by KRG . Ginsenosides are the major active constituent of ginseng. To date, in excess of 40 different ginsenosides with distinct pharmacological actions have been isolated. Ginsenosides can be categorized into three main categories by their chemical structure, which include the protopanaxadiols (PPD) (e.g. Rb1, Rb2, Rc, Rd, Rg3, Rh2), protopanaxatriols (PPT) (e.g. Re, Rf, Rg1, Rg2, Rh1) and the oleanolic acid derivatives . KRG is rich in ginsenosides and thus exerts a significant pharmacological action on vascular regeneration. In a recent study, Kimura et al.  studied mice to examine the effects of total ginseng saponins and various ginsenosides on burn wound healing. The authors showed that ginsenoside Rb1 greatly promoted neovascularization in the sites adjacent to burn wounds at a dose of 100 fg–1 ng per wound area, making it the most effective agent for wound healing. We estimated that, having an angiogenic action, KRG would hasten anastomotic healing. Our results suggest that our hypothesis was true in that they showed impressive angiogenic action in KRG groups, while the control groups continued to have poor capillary circulation. It is well known that oxygen has a critical role in anastomotic healing . However, it is not entirely clear by which cellular and molecular mechanisms of tissue hypoxia impair anastomotic healing. Although hypoxia provides a starting stimulus for neovascularization, its effects are not long-lived. Angiogenesis referring to novel vessel development is critical for wound healing. Vascular endothelial growth factor (VEFG) and nitric oxide (NO) are two critical compounds that operate on a molecular level in the process of angiogenesis . Sengupta et al.  showed that ginsenoside Rg1 increased functional neovascularization into a polymer scaffold in vivo, while proliferation and chemo invasion of tube-like capillary formation by human umbilical vein endothelial cells (HUVECs) increased the expression of nitric oxide synthetase, phosphatidylinositol-3 kinase, and the Akt pathway. Similarly, Kimura et al.  demonstrated that ginsenoside Rb1 stimulated VEGF production and improved skin wound repair. However, Sengupta et al. used greater Rb1 concentrations than Kimura et al (100 fg, 10 pg and 1 ng per wound or per ml), in vivo or in vitro. One study reported that when infused at low doses (6 or 60 μg day-1), ginsenoside Rb1 upregulated Bcl-xL expression and eliminated ischemic neuronal death, although it failed to do so at high doses (3 or 12mg day-1) . The reason why ginsenoside Rb1 appears to be more pharmacologically active at low doses should be further studied. Our results unequivocally showed new capillary formation in the KRG groups, although its molecular mechanisms and contribution to the healing process are not entirely clear.
Anastomosis failure is characterized by excessive collagen degradation or defective new collagen synthesis. Kiyama et al.  reported that when they inhibited collagenase activity, they observed reduced collagenolysis by promoting the storage of collagen at the anastomosis site and wound healing. PMNLs possess granulocyte collagenase activity that is held responsible for excessive collagen breakdown and slowing down anastomotic healing. We showed lower inflammatory cell infiltration scores in the KRG group compared to controls, although the difference did not reach statistical significance. We thus selected the amount of tissue hydroxyproline as a marker of collagen synthesis, and found higher hydroxyproline levels in the groups administered POD 3 KRG although we observed similar hydroxyproline levels in groups treated with POD 7. The bursting pressure is a surrogate marker for the mechanical strength of an anastomosis and has been found to increase in a progressive fashion following the establishment of colonic anastomoses. In a study of Sapidis et al., the administration of synbiotics in conjunction with glutamine resulted in increasing the mechanical strength of the anastomosis, thus increasing the bursting pressure and decreasing or effacing of anastomotic dehiscence and limiting bacterial translocation . We found higher bursting pressures in colonic anastomoses of the KRG groups than the controls.
The most well-known effects of KRG are the vasorelaxing effects. Matsuda et al.  used the hydrogen gas clearance method to examine the vasorelaxing effects of KRG in rats and found that the perfusion of liver, spleen, kidney, and gastric mucosa was improved by KRG. KRG has also been reported to exert a dose-dependent protective action on gastric mucosa injured by HCl/ethanol- and indomethacin by increasing blood flow to gastric mucosa and inhibiting lipid peroxidation. Fibroblasts constitute the major cells that produce much of the collagen needed during wound healing. These cells start to migrate and accumulate in the wound area at significant numbers by the second day after surgery  and then return to normal numbers. Our study demonstrated greater fibroblast migration into the wound area in the KRG group compared to the POD 7 group. Hence, we suggest that KRG increased colonic blood flow by inducing vasorelaxation and stimulating fibroblast migration into anastomosis site.
To date, no study has determined that any KRG dose has a positive effect on anastomotic healing. The KRG dose used in this study was determined on the basis of previously reported doses effective on angiogenesis , which was a lower dose since higher doses did not show any notable effect on angiogenesis. To our best knowledge, our study is the first in this field of research. It is therefore a complicated task to assess the dose and the mode of administration (single dose or continuous treatment) of the agent based on the results of this study. Whereas it is currently unknown exactly which mechanisms of KRG administration lead to improved anastomotic wound healing, it is plausible that this effect is brought about by an increase in neoangiogenesis, fibroblastic activity, and collagen synthesis.
We are of the opinion that our findings may assist clinicians and researchers to develop potential therapies and approaches to improve colonic anastomotic healing and reduce the morbidity and mortality rates of anastomotic leaks. We therefore urge the researchers to conduct further studies to investigate the potential of KRG for improving anastomotic healing and reducing the rate of colonic anastomosis dehiscence.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Kandis H, Karapolat S, Yildirim U, Saritas A, Gezer S, Memisogullari R. Effects of Urtica dioica on hepatic ischemia-reperfusion injury in rats. Clinics. 2010; 65(12):1357-61.
2. Ferhatoğlu MF, Kıvılcım T, Vural G, Kartal A, Filiz Aİ, Kebudi A. Comparison of the effects of two different marine-derived omega-3 fatty acid sources, krill oil, and fish oil, on the healing of primary colonic anastomoses after colectomy applied Wistar albino rat model. Ulus Travma Acil Cerrahi Derg. 2019; 25(4):324-30.
3. Holmer C, Praechter C, Mecklenburg L, Heimesaat M, Rieger H, Pohlen U. Anastomotic stability and wound healing of colorectal anastomoses sealed and sutured with a collagen fleece in a rat peritonitis model. Asian J Surg. 2014;37(1):35-45.
4. Neumann PA, Twardy V, Becker F, Geyer C, Schwegmann K, Mohr A, et al. Assessment of MMP-2/-9 expression by fluorescence endoscopy for evaluation of anastomotic healing in a murine model of anastomotic leakage. PLoS One. 2018;13(3):e0194249.
5. Guzel S, Sunamak O, As A, Celik V, Ferahman M, Nuri MM, et al. Effects of hyperbaric oxygen and Pgg-glucan on ischemic colon anastomosis. World J Gastroenterol. 2006;12(9):1421-5.
6. Yamamoto M. Current status of Ginseng research in Japan. In: Proceedings of the International Symposium on Ginseng Research, ROC, editors. Ha H, Yamamoto M, Joo CN, Kuo SC. Taichuu: LifeMedical Research Institute, China Medical College; 1988. p. 12–26.
7. Sengupta S, Toh SA, Sellers LA, Skepper JN, Koolwijk P, Leung HW, et al. Modulating angiogenesis: the yin and the yang in ginseng. Circulation. 2004;110(10):1219-25.
8. Sato K, Mochizuki M, Saiki I, Yoo YC, Samukawa K, Azuma I. Inhibition of tumor angiogenesis and metastasis by a saponin of Panax ginseng, ginsenoside-Rb2.Biol Pharm Bull. 1994;17(5):635-9.
9. Choi S. Epidermis proliferative effect of the Panax ginseng ginsenoside Rb2. Arch Pharm Res. 2002;25(1):71-6.
10. Morisaki N, Watanabe S, Tezuka M, Zenibayashi M, Shiina R, Koyama N, et al. Mechanism of angiogenic effects of saponin from ginseng Radix rubra in human umbilical vein endothelial cells. Br J Pharmacol. 1995;115(7):1188-93.
11. Li Y, Bao Y, Jiang T, Tan L, Gao Y, Li J. Effect of the combination of fibrin glue and growth hormone on incomplete intestinal anastomoses in a rat model of intra-abdominal sepsis. J Surg Res. 2006;131(1):111-7.
12. Reddy GK, Enwemeka CS. A simplified method for the analysis of hydroxyproline in biological tissues. Clin Biochem. 1996;29(3):225-9.
13. Ehrlich HP, Tarver H, Hunt TK. Effects of vitamin A and glucocorticoids upon inflammation and collagen synthesis. Ann Surg. 1973;177(2):222-7.
14. Ferhatoglu MF, Kıvılcım T, Senol K, Vural G, Kartal A, İncir S, et al. The Positive Effects of the Human Amniotic Membrane on the Healing of Staple Line After Sleeve Gastrectomy Applied Long-Evans Rat Model. Obes Surg. 2019;29(11):3560-8.
15. Jackson JR, Seed MP, Kircher CH, Willoughby DA, Winkler JD. The codependence of angiogenesis and chronic inflammation. FASEB J. 1997;11(6):457-65.
16. Griffith LG, Naughton G. Tissue engineering–current challenges and expanding opportunities Science. 2002;295(5557):1009-14.
17. Kim YM, Namkoong S, Yun YG, Hong HD, Lee YC, Ha KS, et al. Water extract of Korean red ginseng stimulates angiogenesis by activating the PI3K/Akt-dependent ERK1/2 and eNOS pathways in human umbilical vein endothelial cells. Biol Pharm Bull. 2007;30(9):1674-9.
18. Cheng Y, Shen LH, Zhang JT. Anti-amnestic and anti-aging effects of ginsenoside Rg1 and Rb1 and its mechanism of action. Acta Pharmacol Sin. 2005;26(2):143-9.
19. Kimura Y, Sumiyoshi M, Kawahira K, Sakanaka M. Effects of ginseng saponins isolated from Red Ginseng roots on burn wound healing in mice. Br J Pharmacol. 2006;148(6):860-70.
20. Thornton FJ, Barbul A. Healing in the gastrointestinal tract. Surg Clin North Am. 1997; 77(3):549-73.
21. Li J, Zhang YP, Kirsner RS. Angiogenesis in wound repair: angiogenic growth factors and the extracellular matrix. Microsc Res Tech. 2003;60(1):107-14.
22. Zhang B, Hata R, Zhu P, Sato K, Wen TC, Yang L, et al. Prevention of ischemic neuronal death by intravenous infusion of a ginseng saponin, ginsenoside Rb1, that upregulates Bcl-XL expression J Cereb Blood Flow Metab. 2006;26(5):708-21.
23. Kiyama T, Onda M, Tokunaga A, Efron DT, Barbul A. Effect of matrix metalloproteinase inhibition on colonic anastomotic healing in rats. J Gastrointest Surg. 2001;5(3):303-11.
24. Sapidis N, Tziouvaras C, Ioannidis O, Kalaitsidou I, Botsios D. The effect of glutamine and synbiotics on the healing of colonic anastomosis. Rev Esp Enferm Dig. 2014;106(4):255-62.
25. Matsuda H, Kubo M. Pharmacological study on Panax ginseng C. A. Meyer. VI. Cardiovascular Effect of Red ginseng (1). Shoyakugaku Zasshi.1985; 39:277-81.
Download attachments: 10.4328:ACAM.21112
Ufuk Tali, Mehmet Tolga Kafadar, Mustafa Cömert. Effect of korean red ginseng on colon anastomotic healing: A randomised controlled experimental study. Ann Clin Anal Med 2022;13(7):765-769
Evaluation of risk factors that play roles in retinopathy of prematurity
Seda Gümüştekin 1, Şahin Takçı 2
1 Department of Pediatrics, Erciyes University, Kayseri, 2 Department of Pediatrics, Ondokuz Mayıs University, Samsun, Turkey
DOI: 10.4328/ACAM.21113 Received: 2022-02-22 Accepted: 2022-04-12 Published Online: 2022-04-14 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):770-774
Corresponding Author: Seda Gümüştekin, Department of Pediatrics, Erciyes University, Kayseri, Turkey. E-mail: firstname.lastname@example.org P: +90 554 206 60 04 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0738-4265
Aim: Increasing survival rates of preterm babies have made it necessary to focus on complications of prematurity, such as retinopathy of prematurity (ROP). The present study aimed to investigate factors that may be involved in the development of ROP.
Material and Methods: Between February 2011 and March 2018, the medical records of babies born at 32 weeks of gestation or earlier and examined for ROP at Gaziosmanpaşa University, Neonatal Intensive Care Unit (NICU) were analyzed retrospectively. Risk factors that may be associated with the development of ROP in infants were determined.
Results: A total of 193 infants were included in the study. Mean gestational age at birth and birth weight were 30.1 ± 1.9 weeks and 1487 ± 395 grams, respectively. ROP was detected in 61 (34%) of the infants, and 11 (18.1%) of those required treatment. Comparison of the characteristics of infants with and without ROP showed that gestational age at birth, birth weight, need for positive pressure ventilation in the delivery room, need and number of blood transfusions, Patent Ductus Arteriosus (PDA), Intraventricular Hemorrhage (IVH), presence of Bronchopulmonary Dysplasia (BPD), hyperglycemia, hemoglobin and hematocrit levels at discharge, period of oxygen support, time to achieve full enteral nutrition, and length of hospital stay were significant factors related to the development of ROP. In multivariate logistic regression analyses, birth weight, gestational age at birth, and period of oxygen support were the only independent risk factors.
Discussion: It is extremely important to identify risk factors for ROP and to take timely preventive and therapeutic measures for better premature outcomes.
Keywords: Prematurity, Retinopathy of Prematurity, Risk Factors
Retinopathy of prematurity (ROP) is a disease of preterm infants characterized by abnormal proliferation of retinal vessels, the exact pathogenesis of which has not been fully elucidated . Despite advances in neonatal care and management, ROP remains the leading cause of childhood vision impairment worldwide. Increasing survival rates of preterm infants due to developments in neonatal care have led to an increase in the rate of ROP, which can cause vision problems and blindness. Although the pathogenesis of ROP has not been fully elucidated, it is thought to develop in a two-stage process. Retinal vascularization, which begins in the intrauterine environment delays after premature birth (Phase 1), whereas the retina continues to develop. The oxygen demand of the retina in which vascularization has delayed is not met and it becomes hypoxic. This hypoxia in the retina initiates the second phase [1–3].
Studies on the etiology of ROP have reported various risk factors covering the perinatal period to date [1–5]. It is extremely important to establish the frequency and risk factors for each NICU to develop appropriate preventive strategies and to have better premature outcome. The present study investigated the frequency and risk factors of ROP in premature infants followed up in our NICU.
Material and Methods
Between February 2011 and March 2018, the medical records of babies born at 32 weeks of gestation or earlier were examined for ROP in the NICU of Gaziosman Paşa University University were retrospectively reviewed. The first examinations were performed in the NICU at 4–6 weeks after birth or 31–33 weeks postconception. Ophthalmological follow-up was performed in the ophthalmology department. The most advanced ROP stage was taken into account for this study. The study was approved by the Institutional Ethics Committee (approval number: 2018/03: 83116987-161).
Delivery type, birth percentile, period of oxygen support, development of proven sepsis, maternal risk factors, Apgar scores at 1 and 5 min, number of transfusions, development of intraventricular hemorrhage (IVH), presence of Patent Ductus Arteriosus (PDA), presence of bronchopulmonary dysplasia (BPD), multiple pregnancy, and length of hospital stay were recorded. Daily blood glucose levels in the first 24 hours and hematologic parameters at discharge were noted. Maternal demographic data and risk factors were also recorded. The babies were divided into premature infants with and without ROP, and risk factors were compared between the two groups.
Data for continuous variables are shown as the mean ± standard deviation (SD) or median (interquartile range). Data for categorical variables are shown as numbers (%). Differences in continuous variables between groups were analyzed using the independent samples t test, Mann–Whitney U test, or one-way analysis of variance (ANOVA), and categorical variables were compared using Kruskal–Wallis variance analyses or the x2 test. The relations between numerical values were evaluated via Pearson’s correlation analyses. Logistic regression analyses were used to examine causal relationships between dependent variables and independent variables when the outcome (dependent) variable was binary (binary/dichotomous). Statistical analyses were performed using IBM SPSS Statistics 19 (SPSS Inc., Somers, NY). In all analyses, p < 0.05 was taken to indicate statistical significance.
A total of 402 infants were examined for ROP during the study period, and 193 of those whose medical records were completely accessible were included in the study. Overall, 96 (49.7%) were female. The mean gestational age at birth and birth weight were 30.1 ± 1.9 weeks and 1487 ± 395 g, respectively. ROP was detected in 61 (34.6%) of the infants. Figure 1 shows the percentages of ROP development zones and stages. Four of the patients with ROP had plus disease. Eleven (18.1%) of the infants received treatment. Comparison of characteristics of the infants with and without ROP indicated that gestational age at birth, birth weight, application of positive pressure ventilation at birth, need and number of blood transfusions, PDA, IVH, presence of BPD, presence of hyperglycemia, hemoglobin and hematocrit levels at discharge, period of oxygen support, transition to enteral nutrition, and length of hospital stay were significant factors for the development of ROP (Table 1). The mean glucose level in the first 28 days was 106 ± 7.9 mg/dL in infants with ROP, and 92.1 ± 10.5 mg/dL in those without ROP (p < 0.001) (Figure 2).
Maternal demographic data and risk factors were compared between the two groups, and no significant effects of multiple pregnancy, use of assisted reproductive techniques, smoking during pregnancy, prepregnancy body mass index (BMI), parity, gestational age, premature rupture of membranes, chorioamnionitis, gestational hypertension, or preeclampsia on the development of ROP were found (Table 2).
The risk factors affecting the development of ROP were evaluated via multivariate logistic regression analyses, and birth weight (odds ratio [OR]: 0.997; 95% confidence interval [CI]: 0.996–999), gestational age at birth (OR: 0.691; 95% CI: 0.530–0.880), and period of oxygen support (OR: 0.703; 95% CI: 0.522–0.881) were identified as independent risk factors (Table 3).
In recent years, the number of preterm births has gradually increased due to the development of assisted reproductive techniques, and survival rates of low-birth-weight infants have increased with advances in neonatology. As a result, the incidence of ROP is gradually increasing . The most important risk factor for ROP is immaturity as determined by low gestational age and birth weight. Other risk factors include oxygen toxicity, acidosis, IVH, PDA, sepsis, hyperbilirubinemia, low Apgar scores, mechanical ventilation, and the requirement for blood transfusion [2–7].
Many studies have shown that the frequency of ROP increases with the degree of prematurity. In a study population of 6998 babies conducted by the ET-ROP study group, the incidence of ROP was reported to be 89% in babies born at ≤27 weeks, 52.7% in babies born at 28–31 weeks, and 14.2% in babies born at ≥32 weeks . The multicenter TR-ROP study conducted in Turkey in a population of 6115 babies indicated that the rate of severe ROP in babies born before gestational week 28 was 21.6%, and 2.2% in those born between 29 and 32 weeks . In the same study, it was reported that ROP developed in 67 babies at 33 weeks or later. In the present study, the ROP rate in babies born before 32 weeks was 34.6%. Therefore, broad range of ROP screening criteria could be considered in Turkey.
In the CRYO-ROP study, the incidence of ROP was 65.8% in babies weighing less than 1251 g and 81.6% in those weighing less than 1000 g . A multicenter study conducted in Turkey showed an incidence of ROP of 42% in infants with a birth weight of 1500 g or less compared to 14.5% in those with birth weight of 1501–2000 g. In addition, 8.2% of babies with a birth weight of 1000 g or less and 0.6% of babies with a birth weight above 1500 g were diagnosed with severe ROP . In the present study, the incidence and severity of ROP increased with decreasing birth weight and gestational age.
With regard to the relationship between ROP and period of oxygen support, Huang et al. examined 108 premature babies with birth weight below 2000 g and found that the ROP group had a longer period of oxygen support and required a longer period of mechanical ventilation than the non-ROP group . In the SUPPORT study, when high (91–95%) and low (85–89%) oxygen saturations were compared in babies born between 24 and 28 weeks, the mortality rate was found to increase in the low oxygen saturation group, while the rate of severe ROP in survivors was decreased . Many later studies have been conducted to determine the effects of oxygen support on ROP, and most have found that high-level oxygen support is associated with increases in the incidence and severity of ROP. Although oxygen support is among the definite risk factors of ROP, no definitive data are available on how the concentration and period of oxygen support affect ROP. In the present study, the incidence and severity of ROP increased with increasing period of oxygen support.
Poor weight gain after birth is an indicator of poor health status in newborn infants. Aydemir et al. reported that babies with severe ROP gained 6.7 ± 4 g/day in the first 4 weeks of their lives, while those of normal weight and without ROP gained 9.3 ± 4.5 g/day, and they concluded that poor weight gain at 4 weeks was the result of various comorbidities rather than being an independent risk factor . In addition, insufficient nutrition from energy and protein may cause a decrease in the plasma level of IGF-I . The provision of sufficient energy from parenteral and enteral sources in the first 4 weeks of life is effective for reducing the risk for severe ROP in extremely premature infants . In the present study, the mean weight gain on day 28 in patients without ROP was 321.1 g, while it was only 300.7 g in patients with PR, but the difference was not statistically significant.
The rate of transition of patients to full enteral nutrition is an important parameter affecting an infant’s growth and development. Proper parenteral and enteral nutrition is essential for good developmental progress. Early transition to full enteral feeding can also be effective for reducing various risk factors that may affect the development of ROP. In a study conducted in North America, the long-term use of total parenteral nutrition was shown to increase the risk of developing ROP regardless of weight gain . In a cohort study conducted in Egypt, long-term parenteral nutrition was identified as a risk factor for the development of ROP . In the present study, the transition time to full enteral nutrition was 17.8 ± 8.4 days in infants with ROP and 10.7 ± 6.4 days in those without ROP. The development and severity of ROP increased with increasing time to transition to full enteral nutrition (p <0.05).
Hyperglycemia seen in very-low-birth-weight infants is an important risk factor in mortality and morbidity of premature babies, particularly in the first week of life . Premature babies are born with a lower IGF-I level than term babies . IGF-I has an anti-insulin resistance effect, and therefore hyperglycemia in premature infants may be a clinical presentation of low IGF-I . A meta-analysis conducted showed that hyperglycemia was significantly associated with ROP. However, in further analyses, this relationship disappeared after correcting for other factors . In Garg et al., the mean glucose level in the first 3 days of life in infants with ROP was 103 ± 4 mg/dL, while it was 89 ± 36 mg/dL in those that did not develop ROP, and the relationship between hyperglycemia and ROP was significant . In the present study, the mean glucose level at 28 days was 106 ± 7.9 mg/dL in the ROP group, while it was 92.1 ± 10.5 mg/dL in the non-PR group (p < 0.001). Thus, the frequency of ROP was higher in babies with hyperglycemia.
Although many risk factors for the development of ROP were identified in the present study, only low gestational age, low birth weight, and longer period of oxygen support were determined to be independent risk factors. It is extremely important to identify the risk factors for ROP and to take timely preventive and therapeutic measures for better premature outcomes.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Jung JL, Wagner BD, McCourt EA, Palestine AG, Cerda A, Cao JH, et al. Validation of WINROP for detecting retinopathy of prematurity in a North American cohort of preterm infants. J AAPOS. 2017;21(3):229-33.
2. Zhang G, Yang M, Wu Z, Lam W, Lian C, Zhao G, et al. Changes in the Incidence of Retinopathy of Prematurity in Extremely Low Birth Weight Infants in South China From 2004 to 2018. Ophthalmic Epidemiol. 2021;28(4):359-64.
3. Tawfik S, Mansour A, Selim NL, Habib AM, Fouad YA, Tawfik MA, et al. Analysis of a two-year independent screening effort for retinopathy of prematurity in rural Egypt. BMC Ophthalmol. 2021;21(1):445.
4. Kang HG, Choi EY, Cho H, Kim M, Lee CS, Lee SM. Oxygen care and treatment of retinopathy of prematurity in ocular and neurological prognosis. Sci Rep. 2022;12(1):341.
5. Lundgren P, Athikarisamy SE, Patole S, Lam GC, Smith LE, Simmer K. Duration of anaemia during the first week of life is an independent risk factor for retinopathy of prematurity. Acta Paediatr. 2018;107(5):759-66.
6. Bortea CI, Stoica F, Boia M, Iacob ER, Dinu M, Iacob R, et al. Risk Factors Associated with Retinopathy of Prematurity in Very and Extremely Preterm Infants. Medicina (Kaunas). 2021;57(5):420.
7. Ng TR, Wong IB, Ngo CS, Niduvaje K, Ngiam XY, Sensaki S, et al. Case control study of risk factors and ophthalmological outcomes of very low birth weight infants with Type 1 retinopathy of prematurity. Singapore Med J. 2020;61(8):426-34.
8. Good WV, Hardy RJ, Dobson V, Palmer EA, Phelps DL, Quintos M, et al. The incidence and course of retinopathy of prematurity: findings from the early treatment for retinopathy of prematurity study. Pediatrics. 2005;116(1):15-23.
9. Bas AY, Demirel N, Koc E, Ulubas Isik D, Hirfanoglu IB, Tunc T, et al. Incidence, risk factors and severity of retinopathy of prematurity in Turkey (TR-ROP study): a prospective, multicentre study in 69 neonatal intensive care units. Br J Ophthalmol. 2018;102(12):1711-16.
10. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: natural history ROP: ocular outcome at 5(1/2) years in premature infants with birth weights less than 1251 g. Arch Ophthalmol. 2002;120(5):595-9.
11. Bas AY, Koc E, Dilmen U; ROP Neonatal Study Group. Incidence and severity of retinopathy of prematurity in Turkey. Br J Ophthalmol. 2015;99(10):1311-14.
12. Huang ZN, Yin DM, Huang DR, Liang SX. [Screening analysis of retinopathy of prematurity and treatment of threshold retinopathy of prematurity]. Zhonghua Yan Ke Za Zhi. 2006;42(6):496-500.
13. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Carlo WA, Finer NN, Walsh MC, Rich W, Gantz MG, Laptook AG, et al. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med. 2010;362(21):1959-69.
14. Aydemir O, Sarikabadayi YU, Aydemir C, Tunay ZO, Tok L, Erdeve O, et al. Adjusted poor weight gain for birth weight and gestational age as a predictor of severe ROP in VLBW infants. Eye (Lond). 2011;25(6):725-9.
15. Stoltz Sjöström E, Lundgren P, Öhlund I, Holmström G, Hellström A, Domellöf M. Low energy intake during the first 4 weeks of life increases the risk for severe retinopathy of prematurity in extremely preterm infants. Arch Dis Child Fetal Neonatal Ed. 2016;101(2):108-13.
16. Wu C, Löfqvist C, Smith LE, VanderVeen DK, Hellström A; WINROP Consortium. Importance of early postnatal weight gain for normal retinal angiogenesis in very preterm infants: a multicenter study analyzing weight velocity deviations for the prediction of retinopathy of prematurity. Arch Ophthalmol. 2012;130(8):992-9.
17. Ali AA, Gomaa NAS, Awadein AR, Al-Hayouti HH, Hegazy AI. Retrospective cohort study shows that the risks for retinopathy of prematurity included birth age and weight, medical conditions and treatment. Acta Paediatr. 2017;106(12):1919-27.
18. Paulsen ME, Brown SJ, Satrom KM, Scheurer JM, Ramel SE, Rao RB. Long-Term Outcomes after Early Neonatal Hyperglycemia in VLBW Infants: A Systematic Review. Neonatology. 2021;118(5):509-21.
19. Cakir B, Hellström W, Tomita Y, Fu Z, Liegl R, Winberg A, et al. IGF1, serum glucose, and retinopathy of prematurity in extremely preterm infants. JCI Insight. 2020;5(19):e140363.
20. Lei C, Duan J, Ge G, Zhang M. Association between neonatal hyperglycemia and retinopathy of prematurity: a meta-analysis. Eur J Pediatr. 2021;180(12):3433-42.
21. Garg R, Agthe AG, Donohue PK, Lehmann CU. Hyperglycemia and retinopathy of prematurity in very low birth weight infants. J Perinatol. 2003;23(3):186-94.
Download attachments: 10.4328:ACAM.21113
Seda Gümüştekin, Şahin Takçı. Evaluation of risk factors that play roles in retinopathy of prematurity. Ann Clin Anal Med 2022;13(7):770-774
Results of treatment for acute and chronic extensor pollicis longus tendon ruptures
Numan Atılgan 1, Numan Duman 2, Tahsin Sami Colak 3, Mehmet Demiryurek 3
1 Department of Orthopedics and Traumatology, Sanliurfa Mehmet Akif Inan Training and Research Hospital, Sanliurfa, 2 Department of Orthopedics and Traumatology, Faculty of Medicine, Uskudar University, Istanbul, 3 Department of Orthopedics and Traumatology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
DOI: 10.4328/ACAM.21115 Received: 2022-02-20 Accepted: 2022-03-21 Published Online: 2022-03-22 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):775-778
Corresponding Author: Numan Duman, Department of Orthopaedics and Traumatology, Faculty of Medicine, Uskudar University, Istanbul, Turkey. E-mail: email@example.com P: +90 507 657 15 42 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0183-4520
Aim: In this study, we aimed to observe the results of primary tendon repair in acute EPL tendon ruptures and the results of EIP tendon transfer for chronic EPL tendon ruptures.
Material and Methods: The study included patients diagnosed and operated for EPL tendon rupture and followed-up in our clinic between January 2012 and December 2020. Patients were separated into two groups according to the surgical procedure. Group A consisted of 13 patients who had EIP tendon transfer, and group B consisted of 18 patients who underwent primary EPL tendon repair. Preoperative and postoperative functional results of the groups were compared.
Results: Group A had EIP tendon transfer surgery; ten patients were male (76.9%), and three were female (23.1%). The injury was on the right side in 69.2% of the patients and on the left side in 30.8% of the patients. All patients in group B had primary tendon repair. In group B, 14 patients (77.8%) were males, and four were female (22.2%). The mean q DASH score was 66.53±10.99 for group A and 55.66±7.78 for group B. Postoperative q DASH score was 22.76 for group A, and 11.10 for group B. The joint range of motion was similar in both groups.
Discussion: In acute EPL tendon ruptures, primary tendon repair is the first treatment to be chosen, while in chronic EPL tendon ruptures, EIP tendon transfer may be the first treatment option given our clinical results.
Keywords: Tendon transfer, Rupture, Thumb
Extensor pollicis longus tendon injuries constitute an important part of hand injuries . EPL tendon inserts into the distal phalanx of the thumb, extends the distal phalanx and helps with the extension of the metacarpophalangeal joints and, can be injured by a sharp, penetrating, or blunt trauma; however, spontaneous rupture is also possible. Vascular supply to the tendon is diminished over the Lister tubercle, which is the riskiest location for the spontaneous rupture of the tendon . Spontaneous EPL ruptures are usually seen in rheumatoid arthritis, steroid treatment and also after distal radius fractures. The exact mechanism of EPL rupture has not been clarified yet.
The treatment option for acute EPL tendon injuries is primary repair, but for chronic ruptures several methods were described, for example, tendon grafting and tendon transfers. However, it is not always possible due to neglected late representing cases and tendon retraction. EIP transfer is the most commonly preferred, gold standard surgical treatment in these cases . In this study, we wanted to observe the results of primary tendon repair in acute EPL tendon ruptures and the results of EIP tendon transfer for chronic EPL tendon ruptures.
Material and Methods
This study included a total of 31 patients who applied to University of Necmettin Erbakan Faculty of Medicine Orthopedics and Traumatology clinic with EPL tendon injury between January 2012 and December 2020. Patients were diagnosed with EPL tendon injury by physical examination, x-ray, and magnetic resonance imaging. Thirteen patients in group A had EIP transfer. Eighteen patients in group B had primary tendon repair. Disabilities of arm, shoulder, and hand (DASH) score was used to measure treatment effectiveness both preoperatively and postoperatively. In addition, we measured the range of motion of the thumb, flexion and extension restriction degree, metacarpal, and interphalangeal range of motions with a goniometer to assess the functional effectiveness.
The patient’s first evaluation was performed with clinical examinations followed by x-ray imaging. Patients with non-pathological x-ray findings were examined with MRI and were diagnosed with EPL tendon rupture.
Chronic EPL tendon injury patients constituted group A, thus were not eligible for primary tendon repair. The loss of extension in the thumb was recorded visually before the surgery (Figure 1).
Regional block anesthesia was administered, and surgery was performed under a tourniquet. A longitudinal incision was made on the first metacarp. The distal end of the injured EPL tendon was found and injured ends were debrided.
EIP tendon was found, and the tendon was incised and separated following the second incision on the distal end of the second metacarp. The third incision was made on the proximal end of the EIP tendon, EIP was released and transferred to its new place subcutaneously (Figure 2).
EIP tendon was transferred to EPL tendon using the Puvertaft method, while checking for an excursion (Figure 3). The hand was splintered while the thumb was in extension and the wrist was in the neutral position.
Patients in group B had primary tendon repair. Modified Kessler core suturation and epitendinous suturation were used for the repair. Patients used hand splints after the surgery for 30 days. Physical therapy was initiated one week after the surgery. Patients were followed for 20 weeks.
The study was approved by the Ethics Committee of University of Necmettin Erbakan Faculty of Medicine (protocol no 2021/3550).
The data obtained from the research were transferred from the excel file to the database created in the SPSS (Statistical Package For Social Sciences) 18.0 package program, and statistical analyzes were performed with this program.
Arithmetic mean±standard deviation and median (minimum, maximum) were used to express the descriptive statistics, while numbers and percentages were used for the categorical data.
Compliance of numerical data with normal distribution was examined using visual (histogram graph) and analytical methods (Kolmogorov-Smirnov/Shapiro Wilk tests). In the comparison of the two groups, Student’s t-test was used when numerical data were normally distributed, and the Mann-Whitney U test was used for the data that were not normally distributed.
Since it was determined that the Sollerman function test scores of the patients were normally distributed, the dependent groups Student’s t-test was used for comparisons between the operated and healthy sides. Since preop q DASH, postoperative q DASH, and Geldmacher scores did not show normal distribution, the comparisons made for the preoperative and postoperative side operated at two different time periods and for the healthy side were compared using the Wilcoxon paired-sample test.
A p-value of <0.05 was considered statistically significant.
Both patient groups were able to use their hands in their daily activities without any problems.
Group A included a total of 13 patients with EPL tendon injuries. Ten of the patients were male (76.9%), and 3 were female (23.1%). The mean age of the patients was 50.23±10.65 (29-67) years. Nine patients (69.2%) had a right-sided injury, while 4 (30.8%) had a left-sided injury; 61.6% of the patients had a chronic extensor tendon injury, 23.1% had blunt trauma, and 15.3% spontaneous tendon rupture (Table 1).
Two patients in group A had complications (14.4%). One patient had tendon adhesion, and one patient had hyperemia around the incision. A detailed description of the patients’ functional outcomes in group A is shown in Table 2.
Q DASH scores of patients in group A were 66.53±10.99 (42.3-82.6) preoperatively and 23.68±8.68 (14.4-47.3) postoperatively. The difference between preoperative and postoperative scores was statistically significant (Z=-3.18; p<0.001).
Postoperative Geldmacher mean score was 18.77±2.38 (min:16; max:22) for group A and 20.62±1.50 (min:18; max:22) for the uninjured side in the same group. The difference between healthy and injured sides was statistically significant (Z=-2.36; p=0.01).
In group A mean sollerman hand function test score was 64.77±5.48 (min:57; max:73) postoperatively, while the score was 69.77±2.68 (min:65; max:73) for the uninjured side. Differences between two groups were statistically significant (t=-2.60; p=0.023); GA (-9,17 – -0,82)
In group B, 14 patients (77.8%) were male and 4 (22.2%) were female. The mean age for group B was 41.17±14.60 (19-65) years. Fourteen patients had a right-sided injury (77.8%), and four had a left-sided injury (22.2%). The trauma mechanism in 88.9% of cases was sharp penetrating injury, while in 11.1%, it was blunt trauma (Table 1). Only 2 patients (11.1%) had complications. One patient had a rupture of the repaired tendon, and one had adhesion. A detailed description of patients’ functional outcomes in group B is given in Table 2.
Q DASH score of patients was 55.66±7.78 (43-69) preoperatively and 11.15±7.49 (7-33,3) postoperatively. Preoperative scores were significantly higher than postoperative scores (Z=-3.72; p<0.001).
In group B, the mean Geldmacher score was 19.44±2.89 (min:12; max:22) postoperatively and 21.11±3.30 (min:10; max:24) for the noninsured side. There was no statistically significant difference between the injured and noninjured sides (Z=-1.95; p=0.05).
In group B, the mean postoperative Sollerman functional test score was 67.50±6.48 (min:52; max:76), while it was 71.28±2.56 (min:67; max:76) for the non injured side. Differences between the groups were statistically significant (t=-2.28; p=0.036); GA (-7,27 – -0,28).
Functional outcomes comparable with the uninjured side can be achieved by primary tendon repair. While EIP tendon transferred patients were able to use their thumbs independently in their daily activities. Primary repair is the most common surgical treatment for acute EPL tendon injuries. However, in chronic cases, end-to-end repair is not possible due to the shortening of the tendon and muscular retraction on the proximal stump. EIP tendon is superficial, easy to harvest with a small incision, and works synergistically with EPL; thus, EIP is considered the most suitable tendon for transferring to EPL tendon. EPL plays a significant role in thumb function . Although the most common reason of EPL ruptures in our study was pentran trauma, spontaneous late ruptures can also be seen after recurrent microtraumas, Tenosynovitis spontaneous EPL tendon ruptures were seen in two patient in our study . Non-traumatic rupture of the EPL tendon is rare . Many treatment modalities, including grafting and tendon transfers, have been described in cases where primary repair cannot be performed. One of the methods is palmaris longus (PL) tendon grafting. Although Al-Qattan and Mohrij et al. recommended PL tendon grafting in their research, the method has disadvantages; there are two different tendon anastomosis sites, and the graft is avascular . Other possible tendons available for EPL transfer are extensor indices proprius, extensor carpi radials longs, extensor policies breves, abductor policies longs, and extensor digit minimi. Extensor indices proprius tendon has the most compatible excursion and orientation; thus, it is the gold standard tendon for transfer operations [8-11].
The most common argument against EIP tendon transfer is the extension weakness in the second finger after the surgery. Lemmen et al. study did not report any difference in range of motion, but there was a %38 loss of motor power. There was no difference in MCP joint range of motion in operated and non-operated sites . Matter V et al. reported a mean independent extension force of 11 N vs. 5.6 N and dependent force of 20 N vs. 10.9 N in the second finger and contralateral side at 41-month follow-up after EIP tendon transfer . In accordance with this study, we compared the strength and range of motion of the second metacarp to non operated sight for group A patients, we did not see any functional limitations.
Primary end-to-end repair is the gold standard the surgical modality in acute EPL tendon injury. Especially in neglected chronic EPL tendon injuries where primary repair is not possible, EIP tendon transfer is one of the upcoming treatment options and reveals good functional outcomes without donor site morbidity.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Acar E, Armangil M. El yaralanmalari. In: Cander B, editor. Acil Tıp Temel Başvuru Kitabı (Basic guide to emergency medicine). Istanbul: Istanbul Tip Kitabevleri; 2020. p. 3461-4.
2. Barrera J, Ryu J, Yao J. Bony Incarceration of the Extensor Pollicis Longus Tendon Mimicking Rupture. J Wrist Surg. 2019; 8(3): 245-9.
3. Bullón A, Bravo E, Zarbahsh S, Barco R. Reconstruction after chronic extensor pollicis longus ruptures: a new technique. Clin Orthop Relat Res. 2007; 462: 93-8.
4. Shah MA, Buford WL, Viegas SF. Effect of extensor pollicis longus transposition and extensor indicis proprius transfer to extensor pollicis longus on thumb mechanics. J Hand Surg Am. 2003; 28(4): 661-8.
5. Jung SW, Kim CK, Ahn BW, Kim DH, Kang SH, Kang SS. Standard versus over-tensioning in the transfer of extensor indicis proprius to extensor pollicis longus for chronic rupture of the thumb extensor. J Plast Reconstr Aesthet Surg. 2014; 67(7): 979-85.
6. Abdelillah R, Abbassi N, Erraji M, Abdeljawad N, Yacoubi H, Daoudi A. Subcutaneous rupture of the extensor tendon of the thumb: report of 5 cases. Pan Afr Med J. 2014; 17:285.
7. Al-Qattan MM, Al Mohrij SA. A modified technique of two-staged extensor tendon reconstruction in zones 6–8 in a patient with absent palmaris/plantaris tendons: A case report. Int J Surg Case Rep. 2019; 55: 99-102.
8. Pillukat T, Prommersberger KJ, van Schoonhoven J. Comparison of the results between reconstruction of the extensor pollicis longus tendon using a free interposition tendon graft and extensor indicis transposition. Handchir Mikrochir Plast Chir. 2008; 40(3): 160-4.
9. Germann G, Wagner H, Blome-Eberwein S, Karle B, Wittemann M. Early dynamic motion versus postoperative immobilization in patients with extensor indicis proprius transfer to restore thumb extension: a prospective randomized study. J Hand Surg Am. 2001; 26(6): 1111–5.
10. Low CK, Pereira BP, Chao VT. Optimum tensioning position for extensor indicis to extensor pollicis longus transfer. Clin Orthop Relat Res. 2001; 388: 225–32.
11. Sperati G, Ceri L. Transposition of the extensor indicis proprius (eip) for inveterate post-traumatic rupture of the extensor pollicis longus (epl) of the hand. 12 clinical cases. Acta Biomed. 2019; 90(12-S): 147-51.
12. Lemmen MH, Schreuders TA, Stam HJ, Hovius SE. Evaluation of restoration of extensor pollicis function by transfer of the extensor indicis. J Hand Surg Br. 1999; 24(1): 46-9.
13. Matter-Parrat V, Prunières G, Collon S, Facca S, Liverneaux P, Hidalgo Diaz JJ. Active extensor indicis proprius extension strength after its use as a tendon transfer: 19 cases. Hand Surg Rehabil. 2017; 36(1): 36-40.
Download attachments: 10.4328:ACAM.21115
Numan Atılgan, Numan Duman, Tahsin Sami Colak, Mehmet Demiryurek. Results of treatment for acute and chronic extensor pollicis longus tendon ruptures. Ann Clin Anal Med 2022;13(7):775-778
An assesment of relationship between serum preptin levels and anti-mullerian hormone in infertile womens with polycystic ovary syndrome
Mehmet Ak, Mustafa Bertan Demir
Department of Obstetrics and Gynecology, Kayseri City Education and Research Hospital, Kayseri, Turkey
DOI: 10.4328/ACAM.21117 Received: 2022-02-19 Accepted: 2022-03-22 Published Online: 2022-03-28 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):779-782
Corresponding Author: Mehmet Ak, Department of Obstetrics and Gynecology, Kayseri City Education and Research Hospital, 38072, Kayseri, Turkey. E-mail: firstname.lastname@example.org P: +90 506 684 90 49 F: +90 352 315 77 00 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3384-0586
Aim: Despite the clear relationship between AMH, insulin and androgen levels, the relationship between preptin and AMH levels is not known. The close metabolic similarity between preptin and insulin suggests that there may be a relationship between this peptide and AMH. This study was planned to reveal the relationship between serum preptin, AMH, insulin and other metabolic parameters in infertile women with polycystic ovary syndrome (PCOS).
Material and Methods: Thirty infertile women with PCOS and 30 age- and BMI- matched control patients who did not have clinical and laboratory findings of PCOS were included in the study. In addition to serum preptin and AMH levels, other hormonal parameters such as insulin, androgens and HOMA-IR were measured on the third day of the cycle. Human preptin ELISA kit was used for preptin measurement. AMH Gen II ELISA kit was used for AMH measurement. The correlation between AMH, preptin, HOMA-IR and other endocrine and demographic parameters were evaluated.
Results: Serum total testosterone, insulin, LH levels and HOMA-IR of patients in the PCOS group were significantly higher than in the non-PCOS control group. FSH levels were similar in both groups. Median AMH levels in the PCOS groups were 8.44 (3.40–18.34) ng/mL. Median AMH levels in the non-PCOS control group were 3.50 (1.80–8.13) ng/mL. AMH values in the PCOS group were found to be significantly higher than in the control group (p<0.001). Serum preptin levels in the PCOS group were approximately six times higher than in the control group (244.13 (27-367) pg/mL vs. 42.22 (13-56) pg/mL, p <0.002). A positive and significant correlation was found between serum preptin levels and AMH (r=0.76, p <.05) and HOMA-IR (r=0.69, p <.02) values. A positive and significant correlation was found between AMH levels and both serum LH (r=0.70, p <.05) and testosterone levels (r=0.88, p <.01).
Discussion: This clinical study showed for the first time a positive relationship between serum preptin levels and AMH values in PCOS patients.When our study and the literature were reviewed together, it was observed that serum preptin levels increased in PCOS patients with a clinical picture similar to metabolic syndrome. Preptin’s relationship with other endocrine and demographic parameters is similar to insulin. In our study, the only point different from other studies is the positive correlation between preptin and serum AMH values. Despite the small number of our cases, this study has clinical significance as it is the first study to examine the relationship between preptin and AMH and insulin levels. We will be able to make clearer comments on this issue thanks to studies investigating serum and intra-follicular AMH and preptin values in PCOS cases simultaneously.
Keywords: PCOS, HOMA-IR, Preptin, AMH, Insulin
Anti-Mullerian hormone (AMH) is a glycoprotein hormone that is synthesized locally by granulosa cells but provides clear information about the ovarian reserve by entering the systemic circulation . Serum AMH levels are significantly higher in anovulatory PCOS patients than in normo-ovulatory women . AMH is one of the 35 different members of the transforming growth factor-β superfamily  and shows its basic functions in the ovaries and other reproductive organs . AMH prevents premature recruitment and maturation of follicles by blocking the stimulatory effect of FSH on the aromatase enzyme . The gene encoding AMH is on the short arm of chromosome 19 , and the ability of granulosa cells to synthesize AMH decreases with age and decreases to undetectable levels in circulation after menopause . Although there are fluctuations in AMH levels in different phases of the cycle, these changes are not significant enough to affect the amount of AMH to be measured . In addition to the increase in AMH mRNA levels, the increase in both follicle number and granulosa cell mass are the main causes of AMH elevation in PCOS cases .
Preptin is a peptide secreted from the pancreas together with insulin and stimulates insulin secretion. Similar to insulin, glucose stimulates preptin release from pancreas . A correlation between insulin resistance and serum preptin levels has been reported in PCOS patients [11,12]. Celik et al. showed that serum preptin levels in PCOS cases were significantly higher than in healthy controls . Despite increasing serum preptin levels in PCOS cases, follicular fluid preptin levels have been reported to be low and it has been interpreted that this may contribute to the anovulation seen in PCOS . The correlation between serum AMH levels and hyperandrogenism and LH is a known fact [14,15]. Similarly, a positive correlation was reported between AMH values and insulin levels, and insulin resistance . Until now, there has been no study investigating the relationship between serum AMH and preptin levels in PCOS cases. Despite the clear relationship between AMH, insulin and androgen levels, the relationship between perptin levels and AMH is not known. The close metabolic similarity of preptin to insulin suggests that there may be a relationship between this peptide and AMH. This study was planned for the first time to reveal the relationship between serum preptin, AMH, insulin and other metabolic parameters in infertile PCOS patients.
Material and Methods
This case-controlled study was conducted on 60 patients who applied to the Kayseri City Hospital with the complaint of infertility between May and December 2021. While 30 participants consisted of infertile patients diagnosed with PCOS, the remaining 30 consisted of infertile patients without clinical and laboratory findings of PCOS. Patients in both groups were matched for age and BMI. PCOS was defined according to the revised Rotterdam criteria, which require two of the following three manifestations: (i) oligo-anovulation or anovulation; (ii) high concentrations of androgen in the bloodstream and/or clinical signs of androgen surplus (hyperandrogenism); and (iii) polycystic ovaries shown by ultrasonography. All women in the PCOS group were subjected to progesterone-induced withdrawal bleeding to determine their follicular phases.
Serum samples were taken on the third day of the cycle from the patients in PCOS and control groups for measuring AMH and preptin levels. In addition to demographic characteristics of women in PCOS and control group, age, body mass index (BMI) (kg/m2), total testosterone, fasting glucose, fasting insulin, serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were also measured. Fasting serum insulin levels were also measured in autoanalyzer using electrochemiluminescence immunoassay. Insulin resistance was measured using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) according to the following formula: fasting insulin (mIU/L) × fasting plasma glucose (mg/dL)/405. The study was approved by the local Research Committee of Kayseri City Hospital and all patients signed informed consent before the inclusion.
Serum preptin levels were measured using the Human preptin ELISA kit. The measurement was made in accordance with the working procedures defined in the kit catalog. The intra-(within-day) and inter-assay (between days) coefficients of variation for follicular fluid and serum preptin were <8% and <12%, respectively. The minimum detection limit of preptin was 25 pg/mL. The assay range was 5 – 1500 pg/mL.
After venous blood collection, serum for assay of AMH was separated and frozen. All samples were analyzed using an ultra-sensitive AMH Gen II ELISA kit (Beckman-Coulter, Inc., Webster, NY, USA). The lower limit of AMH detection was 0.16 μg/l. Inter-assay variation was 10% at 0.27 μg/l. All values were expressed in ng/mL.
The Statistical Package for Social Sciences, version 21.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. To assess the normality of data, the Kolmogorov–Smirnov tests were used. While normally distributed data are presented as mean ± standard deviation, non-normally distributed data are presented as median (range). The Mann–Whitney test was used for non-normally-distributed data. Spearman’s correlation analysis was used for detecting correlation between AMH, preptin, insulin, HOMA-IR and other measured variables.
The demographic and laboratory findings of each group of participants are shown in Table 1. The patients in the PCOS group and non-PCOS control group were found to be similar in terms of age and body mass index (kg/m2) values. The median AMH level in the PCOS group was 8.44 (3.40–18.34) ng/mL. Median AMH level in the non-PCOS control group was 3.50 (1.80–8.13) ng/mL. AMH values in the PCOS group were found to be significantly higher than in the control group (p<0.001). Serum preptin levels in the PCOS group were approximately six times higher than in the control group (244.13 (27-367) pg/mL vs. 42.22 (13-56) pg/mL, p <0.002).
A positive and significant correlation was found between serum preptin levels and AMH (r=0.76, p <.05) and HOMA-IR (r=0.69, p<.02) values. Likewise, a positive and significant correlation was found between AMH levels and both serum LH (r = 0.70, p <.05) and testosterone levels (r = 0.88, p <.01). However, we could not find any correlation between serum preptin levels and serum testosterone and LH levels. We found a positive and significant correlation between AMH levels and serum insulin levels. Similarly, we found a significant correlation between serum preptin and insulin levels. We found no correlation between serum preptin levels and BMI and patient age. Although we could not find any correlation between AMH levels and BMI values we found a negative and significant correlation between patient age and AMH values.
Our study is the first clinical study to show the positive relationship between serum preptin levels and AMH values in PCOS patients. Similar to the results of previous studies, the serum preptin levels of our PCOS patients were found to be significantly higher than in the control group without PCOS clinic. The relationship between serum preptin levels and other endocrine parameters was very similar to the correlation characteristics of insulin found in PCOS patients. Similar to insulin, serum preptin levels were positively correlated with serum levels of AMH. Preptin also showed a significant correlation with serum insulin and HOMA-IR values. Unlike insulin, we could not find a correlation between preptin levels and LH, testosterone BMI and age values of PCOS patients.
In a recent study by Celik et al [12,13] serum and follicular fluid preptin levels of PCOS patients were evaluated, and serum preptin levels were found to be significantly higher than follicular fluid. In the control group, serum and follicular fluid preptin levels were found to be similar. In the light of these data, the authors mentioned the existence of resistance that prevents preptin transport between serum and follicular fluid in PCOS cases. The authors also emphasized that preptin resistance may be associated with anovulation, which is the main finding of PCOS . In our study, while only serum preptin levels were measured, follicular fluid preptin levels were not measured. If there is low intra-follicular preptin concentration and resistance to transfer of serum preptin to the follicle in PCOS as reported in the previous study, how does the stimulatory effect of preptin on AMH occur? Since we have found a positive correlation between preptin and AMH, we think that enough preptin passes from the circulation to the follicle to stimulate AMH levels. However, in order to clarify this idea, studies comparing intra-follicular preptin levels and AMH levels are needed.
We have encountered a total of four studies evaluating preptin levels in PCOS patients [12,13,17,18]. In two studies conducted by Celik et al [12,13], serum preptin levels in PCOS cases were reported to be higher than in healthy controls. Similarly, a positive correlation was found between serum preptin levels and HOMA-IR and androgen levels in these two studies. In a study by Senturk et al , no difference was found between PCOS and healthy control groups in terms of serum preptin levels. Mierzwicka et al , on the other hand, could not detect a correlation between endocrine parameters and preptin levels, despite high levels of preptin in PCOS. Serum preptin levels were also investigated in cases of gestational diabetes, a metabolic disease similar to PCOS. Aslan et al  reported that maternal serum and cord blood preptin increased in GDM patients and correlated with HOMA-IR levels. Aydin et al  investigated the plasma and colostrum preptin levels in GDM patients and found high preptin levels in both circulation and colostrum.
When our study and the literature were reviewed together, it was observed that serum preptin levels increased in PCOS patients with a clinical picture similar to metabolic syndrome. Preptin’s relationship with other endocrine and demographic parameters is similar to insulin. Preptin is a proinsulin-like growth factor II E-peptide, which is evidence to explain its insulin-like effects . In our study, the only point that differs from other studies is the positive correlation between preptin and serum AMH values. We do not know clearly by what mechanism preptin increases AMH levels. Preptin increases androgen synthesis by making insulin resistance and hyperinsulinemia and stimulates AMH synthesis indirectly in increasing androgens. Despite the small number of our cases, this study has clinical significance as it is the first study to examine the relationship between preptin and AMH and insulin levels. We will be able to make clearer comments on this issue thanks to studies investigating serum and intra-follicular AMH and preptin values in PCOS cases simultaneously.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Ersahin AA, Arpaci H, Ersahin SS, Celik N, Acet M. AFC vs. AMH: prediction of ovarian response in women with endometrioma undergoing controlled ovarian stimulation. Eur Rev Med Pharmacol Sci. 2017;21(10):2499-503.
2. Laven JS, Mulders AG, Visser JA, Themmen AP, De Jong FH, Fauser BC. Anti-Müllerian hormone serum concentrations in normoovulatory and anovulatory women of reproductive age. J Clin Endocrinol Metab. 2004;89(1):318-23.
3. di Clemente N, Jamin SP, Lugovskoy A, Carmillo P, Ehrenfels C, Picard J-Y, et al. Processing of anti-mullerian hormone regulates receptor activation by a mechanism distinct from TGF-beta. Mol Endocrinol. 2010;24(11):2193-206.
4. Bedenk J, Vrtačnik-Bokal E, Virant-Klun I. The role of anti-Müllerian hormone (AMH) in ovarian disease and infertility. J Assist Reprod Genet. 2020;37(1):89-100.
5. Dilaver N, Pellatt L, Jameson E, Ogunjimi M, Bano G, Homburg R, et al. The regulation and signalling of anti-Müllerian hormone in human granulosa cells: relevance to polycystic ovary syndrome. Hum Reprod. 2019;34(12):2467-79.
6. Unal E, Yıldırım R, Tekin S, Demir V, Onay H, Haspolat YK. A Novel Mutation of AMHR2 in Two Siblings with Persistent Müllerian Duct Syndrome. J Clin Res Pediatr Endocrinol. 2018;10(4):387-90.
7. Roudebush WE, Kivens WJ, Mattke JM. Biomarkers of Ovarian Reserve. Biomark Insights. 2008;3(1):259-68.
8. Streuli I, Fraisse T, Chapron C, Bijaoui G, Bischof P, de Ziegler D. Clinical uses of anti-Müllerian hormone assays: pitfalls and promises. Fertil Steril. 2009;91(5):226-30.
9. Catteau-Jonard S, Jamin SP, Leclerc A, Gonzalès J, Dewailly D, di Clemente N. Anti-Mullerian hormone, its receptor, FSH receptor, and androgen receptor genes are overexpressed by granulosa cells from stimulated follicles in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2008;93(11):4456-61.
10. Buchanan CM, Phillips AR, Cooper GJ. Preptin derived from proinsulin-like growth factor II (proIGF-II) is secreted from pancre¬atic islet beta-cells and enhances insulin secretion. Biochem J 2001; 360(2):431–9
11. Yang G, Li L, Chen W, Liu H, Boden G, Li K. Circulating preptin levels in normal, impaired glucose tolerance, and type 2 diabetic subjects. Ann Med 2009; 41(1):52–6.
12. Celik O, Celik N, Hascalik S, Sahin I, Aydin S, Ozerol E. An ap¬praisal of serum preptin levels in PCOS. Fertil Steril 2011; 95(1):314–6.
13. Celik N, Aydin S, Ugur K, Yardim M, Acet M, Yavuzkir S, et al. Patatin-like phospholipase domain containing 3-gene (adiponutrin), preptin, kisspeptin and amylin regulates oocyte developmental capacity in PCOS. Cell Mol Biol (Noisy-le-grand). 2018;64(15):7-12.
14. Piouka A, Farmakiotis D, Katsikis I, Macut D, Gerou S, Panidis D. Anti-Mullerian hormone levels reflect severity of PCOS but are negatively influenced by obesity: relationship with increased luteinizing hormone levels. Am J Physiol Endocrinol Metab. 2009;296(2):E238-43.
15. Tal R, Seifer DB, Khanimov M, Malter HE, Grazi RV, Leader B. Characterization of women with elevated antimüllerian hormone levels (AMH): correlation of AMH with polycystic ovarian syndrome phenotypes and assisted reproductive technology outcomes. Am J Obstet Gynecol. 2014;211(1):59.e1-8.
16. La Marca A, Malmusi S, Giulini S, Tamaro LF, Orvieto R, Levratti P, et al. Anti-Müllerian hormone plasma levels in spontaneous menstrual cycle and during treatment with FSH to induce ovulation. Hum Reprod. 2004;19(12):2738-41.
17. Mierzwicka A, Kuliczkowska-Plaksej J, Kolačkov K, Bolanowski M. Preptin in women with polycystic ovary syndrome. Gynecol Endocrinol. 2018;34(6):470-5.
18. Şentürk Ş, Hatirnaz S, Kanat-Pektaş M. Serum Preptin and Amylin Levels with Respect to Body Mass Index in Polycystic Ovary Syndrome Patients. Med Sci Monit. 2018;24(21):7517-23.
19. Aslan M, Celik O, Karsavuran N, Celik N, Dogan DG, Botan E, et al. Maternal serum and cord blood preptin levels in gestational diabetes mellitus. J Perinatol. 2011;31(5):350-5.
20. Aydin S, Celik O, Gurates B, Sahin I, Ulas M, Yilmaz M,et al. Concentrations of preptin, salusins and hepcidins in plasma and milk of lactating women with or without gestational diabetes mellitus. Peptides. 2013;49:123-30.
Download attachments: 10.4328:ACAM.21117
Mehmet Ak, Mustafa Bertan Demir. An assesment of relationship between serum preptin levels and anti-mullerian hormone in infertile womens with polycystic ovary syndrome. Ann Clin Anal Med 2022;13(7):779-782
Predictors of hospitalization and short-term mortality among lung cancer patients in the emergency department
Yasemin Söyler, Pınar Akın Kabalak, Feza Uğurman
Department of Chest Diseases, Ankara Ataturk Chest Diseases and Thoracic Surgery Training and Research Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.21119 Received: 2022-02-20 Accepted: 2022-03-23 Published Online: 2022-03-28 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):783-787
Corresponding Author: Yasemin Söyler, Kuşcağız Mahallesi, Sanatoryum Cad., 06280, Keçiören, Ankara, Turkey. E-mail: email@example.com P: +90 535 843 07 36 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0507-0767
Aim: Lung cancer is one of the leading reasons for emergency department (ED) visits. In this study, we aimed to determine the reasons for ED visits and to identify predictive factors for hospitalization and short-term mortality (30-days mortality).
Material and Methods: We conducted a retrospective, observational study on lung cancer patients admitted to ED of a tertiary hospital between 01 January 2018 and 01 January 2020. Patients’ demographic data, main symptoms on admission, laboratory parameters, and radiological findings were recorded. Logistic regression analysis was employed to identify the predictive factors for hospitalization and short-term mortality.
Results: A total of 200 lung cancer patients (174 males, 36 females, mean age 64± 9.5 years) were included in the study. Respiratory symptoms (44.5%), clinical deterioration (23%), and pain (10.5%) were the most common main symptoms; 25% of patients had pneumonia on admission; 53% of patients were hospitalized and 4% of patients died in ED. Among the hospitalized patients, the length of stay in the hospital was 9.5 (1-56) days, during which 48 deaths (41.4%) were recorded. Among all patients, 41% died within 30 days after ED visits. In multivariate logistic regression, the presence of pneumonia was found to be a statistically significant predictive factor in both hospitalization (OR=5.420; 95%CI, 2.114 – 13.898; p < 0.001) and short-term mortality. (OR=0.241; 95%CI, 0.109 – 0.534; p < 0.001).
Discussion: The presence of pneumonia on admission is an important risk factor for hospitalization and short-term mortality. These relationships should be kept in mind for the careful management of lung cancer patients in ED.
Keywords: Emergency Department, Hospitalization, Lung Cancer, Pneumonia, Short-Term Mortality
Lung cancer is a major public health problem worldwide, and almost one-quarter of all cancer deaths are due to lung cancer. Although there is an increase in survival for most cancer types, the 5-year relative survival rate for lung cancer is still low, approximately 21% due to being diagnosed at a distant stage [1,2]. Recent studies have shown that lung cancer is also one of the leading reasons for emergency department (ED) visits due to being a difficult disease to deal with complications related to the tumor itself and the treatment process [3,4]. Symptoms of disease burden or progression, and toxicity associated with anti-cancer treatments may result in ED visits . Some ED visits may be the result of acute onset problems and life‑threatening conditions, while some of them are not urgent. For instance, inadequate symptom palliation during routine cancer controls may lead to unnecessary ED visits. These unnecessary visits are likely to become an important problem for the ED system in daily practice. Unfortunately, they are also disturbing and distressful for patients . Moreover, an ED visit is itself an indicator of poor-quality care for patients with cancer and an indicator of poor prognosis [6,7]. It is therefore important to understand why lung cancer patients visit ED and how these visits can be minimized. In this context, we sought to determine the reasons for ED visits and to identify predictive factors for hospitalization and short-term mortality.
Material and Methods
Study design and population
We conducted a retrospective and observational study. Two hundred lung cancer patients over the age of 18 years who visited our hospital’s ED between 01 January 2018 and 01 January 2020 were enrolled. If patients had more than one visit, their last ED visit was evaluated. Data were collected from hospital databases and/or patients’ files. Patients whose clinical information could not be reached (n = 6), patients who refused admission to hospital (n = 7), patients who were transferred to another hospital (n = 4) and patients who had a cancer other than lung cancer (n = 9) were excluded from the study (Figure 1).
Patients’ demographic features like age, sex, comorbid diseases, presence of chronic obstructive pulmonary disease (COPD), routine laboratory parameters, presence of pneumonia and cancer status (clinical stage, histological type, metastasis site, type of cancer treatment) were collected. The clinical stage was classified as early stage for TNM I-II, locally advanced stage for TNM IIIA-B-C and advanced stage for TNM IV . The presenting symptom, which was defined as the main symptom causing the visit to ED, was evaluated. These symptoms were grouped as respiratory (dyspnea, cough, sputum, chest pain and hemoptysis), gastrointestinal (nausea, vomiting, diarrhoea/constipation, abdominal pain, a decrease in spontaneous food intake and bleeding), neurological (dizziness, headache, emotional problems, and loss of consciousness), clinical deterioration, pain and fever. Patient outcomes after initial assessment (discharged from ED, hospitalized from ED, died in ED) were recorded. If a patient was hospitalized length of stay in the hospital and patient outcomes after hospitalization (discharged from hospital, died in hospital) were also recorded. The predictive factors for hospitalization and short-term mortality (mortality rate within 30 days after ED visit) were evaluated with univariate and multivariate analyses.
This study was approved by the medical specialty education board of our centre [(Decision no: 643, Date: 19.09.2019 and Decision no:19, Date: 06.01.2022 (readjustment)] and was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent was waived because of the retrospective nature of the study.
SPSS Inc. Released 2009. PASW Statistics for Windows, Version 18.0. Chicago: SPSS Inc. was used for the database and statistical analyses. Baseline characteristics of study were generated using frequency and descriptive analyses. Continuous data were described as mean ± standard deviation (SD) for normal distributions, and median (minimum – maximum value) for skewed distribution and categorical variables, expressed as either frequency (percentage) Chi square was used to compare non-parametric factors between groups. For parametric variables, Student’s t-test or variance analyses were used. To determine where the differences originated from, post-hoc analysis and Bonferroni correction have been applied. The short-term mortality was calculated using life-tables. Multivariate logistic regression analysis was employed to identify the predictive factors for hospitalization and short-term mortality by performing stepwise variable selection on those variables with a univariate p-value < 0.05. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CI). Any p-value < 0.05 was considered significant.
A total of 200 lung cancer patients (174 males, 36 females, mean age 64 ± 9.5 years) were included in the study. A majority of patients (n = 128, 64%) had at least one comorbid disease, and chronic obstructive lung disease (COPD) was accompanied in 36% (n = 72) of patients. Pneumonia was present in 25% (n = 50) of patients on admission. The most frequent histological type was squamous cell carcinoma (n = 87, 43.5 %) and the most frequent stage was advanced stage (n = 106, 53%). The most applied treatment type was chemotherapy/tyrosine kinase inhibitors (TKIs) (n = 70, 35%), followed by best supportive care (BSC) (n = 63, 31.5%). Respiratory symptoms (n = 89, 44.5%), clinical deterioration (n = 46, 23%), and pain (n = 21, 10.5%) were the most common main symptoms (Table 1).
The treatment of 76 (38%) patients was completed in ED and they were discharged. One hundred and sixteen (53%) patients were hospitalized from ED, and 8 (4%) patients died in ED. Demographic, clinical characteristics and laboratory parameters according to patients’ outcomes after initial assessment (discharged from ED, hospitalized from ED and died in ED) were compared (Table 2). According to post-hoc analysis and Bonferroni correction, CRP (p < 0.001), stage (p = 0.004), existence of comorbidity (p = 0.025) and presence of pneumonia (p < 0.001) were significantly associated with outcomes after initial assessment.
The mean length of stay in hospital was 9.5 (1 – 56) days, during which 48 deaths (41.4%) were recorded. Comparison of demographic, clinical characteristics and laboratory parameters of hospitalized patients [(discharged from hospital (n = 68, 58.6%), died in hospital (n = 48, 41.4%)] is shown in Table 3.
Based on the univariate regression analyses, the existence of comorbidity, the presence of COPD, the presence of pneumonia, histological type of tumor, clinical stage, the presence of cranial metastasis and increased CRP levels were found to be statistically significant predictive factors for hospitalization. In the multivariate logistic regression, the presence of pneumonia (OR = 5.420; 95% CI, 2.114 – 13.898; p < 0.001), histological type of tumour (OR = 1.951; 95% CI, 1.223 – 3.114; p = 0.005) and increased CRP levels (OR = 1.005; 95% CI, 1.001 – 1.008; p = 0.016) were found to be statistically significant predictive factors for hospitalizations.
Among all patients, eighty-two (41%) of them died within 30 days after ED visits. Based on univariate regression analyses, the presence of pneumonia, clinical stage, presenting symptom, the presence of cranial metastasis and the presence of bone metastasis were found to be statistically significant predictive factors for short-term mortality. In the multivariate logistic regression, the presence of pneumonia was found to be a statistically significant predictive factor for the short-term mortality (OR = 0.241; 95% CI, 0.109 – 0.534; p < 0.001).
Lung cancer patients frequently visit EDs from the beginning of the diagnostic process till the end of their lives for cancer related or unrelated reasons. Although ED visits have a negative effect the system, it would be inappropriate to expect this situation to disappear completely . For this reason, clinicians should determine reasons, focus on the management of symptoms and minimise the number of visits at least. According to our study, the most common main symptoms are respiratory symptoms, clinical deterioration, and pain. Importantly, the presence of pneumonia is the predictive factor for both hospitalization, and short-term mortality.
As expected, the most common symptoms are respiratory symptoms, suggesting that clinicians should question respiratory symptoms more thoroughly at routine cancer controls and properly administer antibiotics, corticosteroids, bronchodilator therapies, long-term oxygen therapy, or non-invasive mechanical ventilation if necessary [3,9–12]. Clinical deterioration, also defined as alteration of general state, poor clinical condition, poor performance status or deteriorated general health, was the second reason for ED visits in our study. This is a general term that can be associated with hypoxia, infections, fluid and electrolyte disorders, dehydration, cachexia, metastasis, fatigue or weakness . It is also common in patients who received chemotherapy, suggesting that the side effects of the treatment may cause this. In addition, patients with locally advanced and advanced stages, possibly related to the natural course of cancer, are mostly presented with clinical deterioration [3,9–12]. The high number of advanced-stage patients or the high number of patients receiving chemotherapy is likely to be the reason for the frequent occurrence of clinical deterioration in our study. To avoid unnecessary ED visits, adequate information about the natural course of cancer, and education about appropriate symptom management and treatment side effects are important issues. Thereby, patients and their caregivers could be prepared for expected problems and could solve some of them at their homes instead of EDs. ED visits could be reduced through these approaches and also substantial palliative care [7,10]. Pain is the other common reason for ED visits in our study in line with previous studies [3,9–12]. As known, pain management needs to begin as soon as possible, since uncontrolled pain can cause frequent ED visits, and comprehensive pain management with the patient’s primary care physician or pain specialist may reduce ED visits related to this symptom [13-15].
Identifying risk factors for hospitalization and mortality after ED visit is important to be more cautious to these patients, and to inform patients and their caregivers. Previous studies have revealed that the rate of hospitalization, ICU requirement and mortality after ED visits was higher in patients with lung cancer [9,11,12,16,17]. Consistent with these studies, 58% of patients hospitalized from ED, and 41% of patients died within 30 days in our study. A previous study also showed that arrival type and time, known lung disease, clinical deterioration, senility, and having bradycardia or tachycardia were independent predictors for hospitalization . Another study, which was related to advanced cancer patients, has found that the presence of lung tumor, the presence of respiratory and neurological symptoms, icterus and high levels of calcium were risk factors for death after ED visits . In our study, the histological type of tumor and increased CRP levels were found to be independent predictive factors for hospitalization. It cannot be ruled out that the higher number of patients with squamous cell carcinoma may have influenced this result. Moreover, the presence of pneumonia is found to be an independent predictive factor for both hospitalization and short-term mortality in our study. It should be noted that pneumonia is a common disease and results in high fatality. Patients are likely to require more frequent ED visits because both cancer and pneumonia may worsen clinical conditions . Given these issues, it is not surprising that hospitalization and death are frequent in lung cancer patients with pneumonia.
Our study has several limitations. This is a retrospective and single-center study, which was conducted in a chest diseases hospital with staff experienced in lung cancer and oncological emergencies. Thus, it may be difficult to generalize our results to ED of general hospitals. Although we classified patients according to their main symptoms on the basis of reviewing their medical records, it is possible that two or more main symptoms coexisted in some cases. Additionally, there are differences in request for place of death (home/hospital) between patients/caregivers. Thus, this could affect outcome results.
Our findings showed that lung cancer patients frequently visit ED due to respiratory symptoms, clinical deterioration and pain. Moreover, the presence of pneumonia on admission is an important risk factor for hospitalization and short-term mortality. These relationships should be kept in mind for the careful management of lung cancer patients in ED.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1): 7-30.
2. Haince JF, Joubert P, Bach H, Bux RA, Tappia PS, Ramjiawan B. Metabolic fingerprinting for the detection of early-stage lung cancer: From the genome to the metabolome. Int J Mol Sci. 2022;23(3): 1215
3. Rivera DR, Gallicchio L, Brown J, Liu B, Kyriacou DN, Shelburne N. Trends in adult cancer–related emergency department utilization: An analysis of data from the nationwide emergency department sample. JAMA Oncol. 2017;3(10): e172450.DOI: 10.1001/jamaoncol.2017.2450
4. Gallaway MS, Idaikkadar N, Tai E, Momin B, Rohan EA, Townsend J, et al. Emergency department visits among people with cancer: Frequency, symptoms, and characteristics. J Am Coll Emerg Physicians Open. 2021;2: e12438. DOI: 10.1002/emp2.12438
5. Fessele K, Hayat M, Atkins R. Predictors of Unplanned Hospitalizations in Patients With Nonmetastatic Lung Cancer During Chemotherapy. Oncol Nurs Soc. 2017;44(5): E203-E12.
6. Delgado-Guay MA, Kim YJ, Shin SH, Williams J, Allo J, Bruera E, et al. Avaidoble and unavoidable visits to the emergency department among patients with advanced cancer receiving outpatient palliative care. J Pain Symptom Manage. 2015;49(3): P497-504.
7. Minami S, Yamamoto S, Ogata Y, Takeuchi Y, Hamaguchi M, Koba T, et al. Emergency department visits after hours by lung cancer patients in Japan. Support Care Cancer. 2013; 21: 2443–51.
8. Rami-Porta R, Bolejack V, Giroux DJ, Chansky K, Crowley J, Asamura H, et al. The IASLC Lung Cancer Staging Project : The New Database to Inform the Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol. 2014;9(11): 1618-24.
9. Tanriverdi O, Beydilli H, Yildirim B, Karagoz U. Single center experience on causes of cancer patients visiting the emergency department in southwest Turkey. Asian Pacific J Cancer Prev. 2014;15(2): 687-90.
10. Verhoef MJ, de Nijs E, Horeweg N, Fogteloo J, Heringhaus C, Jochems A, et al. Palliative care needs of advanced cancer patients in the emergency department at the end of life: an observational cohort study. Support Care Cancer. 2020;28(3):1097-107.
11. Kotajima F, Kobayashi K, Sakaguchi H, Nemoto M. Lung cancer patients frequently visit the emergency room for cancer-related and -unrelated issues. Mol Clin Oncol. 2014;2: 322-6.
12. Gorham J, Ameye L, Berghmans T, Sculier JP, Meert AP. The lung cancer patient at the emergency department: A three-year retrospective study. Lung Cancer. 2013;80(2): 203-8.
13. Elsayem AF, Elzubeir HE, Brock PA, Todd KH. Integrating palliative care in oncologic emergency departments: Challenges and opportunities. World J Clin Oncol. 2016;7(2): 227-33.
14. Scholer AJ, Mahmoud OM, Ghosh D, Schwartzman J, Farooq M, Cabrera J, et al. Improving cancer patient emergency room utilization: A New Jersey state assessment. Cancer Epidemiol. 2017;51: 15-22.
15. Grewal K, Krzyzanowska MK, McLeod S, Borgundvaag B, Atzema CL. Outcomes after emergency department use in patients with cancer receiving chemotherapy in Ontario, Canada: a population-based cohort study. C Open. 2020;8(3): E496-E505.
16. Henson LA, Higginson IJ, Gao W, BuildCARE. What factors influence emergency department visits by patients with cancer at the end of life? Analysis of a 124,030 patient cohort. Palliat Med. 2018;32(2): 426-38.
17. Shin SH, Lee H, Kang HK, Park JH. Twenty-eight-day mortality in lung cancer patients with metastasis who initiated mech.
Download attachments: 10.4328:ACAM.21119
Yasemin Söyler, Pınar Akın Kabalak, Feza Uğurman. Predictors of hospitalization and short-term mortality among lung cancer patients in the emergency department. Ann Clin Anal Med 2022;13(7):783-787
Evaluation of disease spectrum diagnosed with bone marrow biopsy at a tertiary healthcare center in Turkey
Ahmet Seyhanlı 1, Yazgulu Cansu Ozkan 2, Sermin Ozkal 3, Guner Hayri Ozsan 4, Fatih Demırkan 4, Inci Alacacıoglu 4
1 Department of Hematology, Sivas Numune Hospital, Sivas, 2 Department of Internal Medicine, Dokuz Eylül University Faculty of Medicine, Izmir, 3 Department of Pathology, Dokuz Eylül University Faculty of Medicine, Izmir, 4 Department of Hematology, Dokuz Eylül University Faculty of Medicine, Izmir, Turkey
DOI: 10.4328/ACAM.21122 Received: 2022-02-21 Accepted: 2022-03-21 Published Online: 2022-03-22 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):788-791
Corresponding Author: Ahmet Seyhanlı, Department of Hematology, Sivas Numune Hospital, Sivas, Turkey. E-mail: firstname.lastname@example.org P: +90 555 395 72 31 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6082-2995
Aim: Bone marrow examination (BME) is commonly implemented to diagnose hemato-oncological diseases. There are only a few reports on diseases diagnosed via the BME and diagnostic yield in patients who applied to the hematology department. This study aimed to identify the primary indications and diagnoses of BME in patients who underwent bone marrow biopsy at Dokuz Eylul University in Turkey.
Material and Methods: We retrospectively reviewed demographic and laboratory data of 505 patients from January 2014 to September 2021. The cases under the age of 18 years were excluded. The patients were also stratified according to demographic data and diagnoses.
Results: Among the 505 bone marrow biopsies (BMB) studied, 386 (76.4%) procedures were performed to evaluate suspected malignancy and 119 (23.6%) for non-malignant indications. The primary indications for BME were: cytopenia (117, 23.2%), plasma cell neoplasm (PCN) (94, 18.6%), and myeloproliferative neoplasms (93, 18.4%). The most common diagnoses among all patients were PCN (110, 21.8%). Non-malignant outcomes comprised 3.2% of the total outcomes with 16 cases, of which thrombocytopenia due to peripheral destruction (immune thrombocytopenia) was the most common with eight (1.6%) patients. The majority of patients diagnosed with myelodysplastic syndrome and CLL were seen in patients aged 65 years and older.
Discussion: There is little published literature on the bone marrow profile, especially in geriatric patients. The higher incidence of hematological diseases in patients under 65 years of age can be attributed to more common BME procedures, which leads to earlier diagnosis.
Keywords: Hematologic Diseases, Trephine Biopsy, Bone Marrow
The bone marrow examination (BME) is commonly implemented to diagnose hemato-oncological diseases. Aspiration of the cellular component, bone marrow biopsy (BMB), or both are used for BME. BMA provides cellular material for cytogenetic and molecular evaluation, microbiologic cultures, and flow cytometry. BMB enables evaluating the cellularity, finding focal lesions, and establishing the diagnosis of infiltrated bone marrow by various pathologic conditions. Most BMEs are performed on the posterior superior iliac spine (PSIS) in adults. The World Health Organization recommends a minimum of 1.5 cm long biopsy specimen for diagnosis . BME is a low-risk invasive procedure but not entirely free of risk; the British Society of Hematologists reported a severe adverse event rate ranging from 0.05% to 0.12%. Hemorrhage was the most commonly reported adverse event. Prolonged severe pain, nerve compression, pelvic fractures, and sepsis indirectly attributable to the procedure were also reported [2,3]. Therefore, a real diagnostic approach is required. The most common reasons for BME have been for the diagnosis of hematological malignancies [4,5]. The diagnostic spectrum via BME at our institution has not been previously studied in Turkey. We evaluated the indications and diagnostic yields of BME at the Dokuz Eylul University Hospital in Turkey.
Material and Methods
We analyzed the BME results of 505 patients (18 years or older) between January 2014 and September 2021 in the outpatient and inpatient hematology service at Dokuz Eylul University Hospital in Turkey. Ethical clearance was obtained from our local ethics committee. The demographic and clinical data, laboratory parameters of the patients were retrospectively evaluated. After obtaining informed consent, we performed the procedure with local anesthesia to the PSIS. Most of the procedures consisted of aspiration and biopsy. However, we did not analyze the results of aspiration in the present study and only evaluated BMB indications and diagnosis in the proper groups for comparison. This study was approved by the Ethics Committee of Dokuz Eylul University (Approval date: 29.03.2021, Issue number: 2021/10-48).
Data were analyzed using SPSS 24.0 software (IBM SPSS Inc, Chicago, IL, USA). Numerical variables were presented as median/mean ±standard deviation, and categorical variables were presented as number (n) and percentage (%).
The median age was 62 (20-90) years. Among the 505 patients, 300 (59.4%) were men, and 205 (40.6%) were women. Of these 505 BMB studied, 386 (76.4%) procedures were performed to evaluate suspected malignancy and 119 (23.6%) for non-malignant indications. The primary indications for BME were cytopenia 117 (23.2%), plasma cell neoplasm (PCN) 94 (18.6%), and myeloproliferative neoplasms 93 (18.4%). Indications for BME procedures are shown in Table 1.
In 500 patients (99%), BME was diagnostic or provided useful information for diagnosis. The most common diagnoses among all patients were 110 (21.8%) PCN and 95 (18.8%) myeloproliferative neoplasm (MPN) infiltration cases. Other common diagnoses were 78 cases (15.4%) of non-Hodgkin lymphoma and 55 cases (10.9%) of myelodysplastic syndrome (MDS), and 46 cases (9.1%) of acute leukemia. Among the acute leukemias, 28 had acute myeloid leukemia, and 18 had acute lymphoid leukemia confirmed through flow cytometric immunophenotyping or immunohistochemistry. There were 19 (3.8%) cases of non-hematological disorders, including 18 (3.6%) metastatic deposits and one case of bone marrow tuberculosis granuloma. Of the 18 solid tumor metastases, seven cases had bone marrow involvement of prostate cancer, and six cases had bone marrow involvement of breast cancer. The patient diagnosed with gastric adenocarcinoma had no history of malignancy, and BME was applied to examine pancytopenia. Non-malignant outcomes were observed in 16 cases and comprised 3.2% of the total outcomes, of which thrombocytopenia due to peripheral destruction (immune thrombocytopenia) was the most common in 8 (1.6%) cases. Twenty cases (4%) were classified as normal bone marrow results, and five (1.0%) sample materials were insufficient for a definite opinion. The disease spectrum diagnosed with BME is given in Table 2.
We divided the patients into two groups according to age groups: under 65 years of age and 65 years old and over. Most of the patients diagnosed with myeloproliferative neoplasia and Hodgkin lymphoma were seen in the group under 65 years of age. The majority of patients diagnosed with myelodysplastic syndrome and CLL were seen in 65 and above. The number and percentage of the diagnosis of patients are given in Table 3.
BME is a critical implementation for diagnosing and monitoring hemato-oncological diseases and involves aspiration of the bone marrow cellular component and BMB for obtaining tissue fragments. BMB allows assessment of the marrow’s cellularity, the presence of focal lesions, and establishing the diagnosis of infiltrated bone marrow due to various pathologic conditions such as lymphoma, granulomas, and solid metastatic tumor [6,7]. The procedure also allows the assessment of bone marrow-ablative chemotherapy and monitors the recovery process in patients undergoing bone marrow transplantation [8,9]. BME is also part of the initial staging in patients with the newly diagnosed lymphoproliferative disease and chronic myeloid leukemia. Moreover, BME is essential to determine unexplained anemia, leukopenia, or thrombocytopenia, or the presence of blast or morphologically atypical cells in the peripheral blood smear. Most BMBs are performed on the PSIS in adults. Anterior superior iliac crest or anteromedial face of the tibia are other areas where BME is performed, especially in children. We performed all BMEs on the posterior superior iliac spine. The bone marrow biopsy is associated with anxiety. Reyhaneh Abbaszadeh et al. showed that smelling of lavender aroma is useful to reduce anxiety . With increasing age, the hematopoietic system is modestly affected, and normal aging does not cause a considerable reduction in complete blood count (CBC) parameters [11-13]. Gulati et al. studied 83 patients aged 60 and above who underwent BME, observed a 44.6% prevalence of anemia, and did not find any case of MDS . Likewise, Gaskell et al. showed that in patients aged 65 years and over, the prevalence of anemia was 40% (40–72%) among hospital admissions and 47% (31–50%) in those in nursing homes . Patients 65 years and older are considered elderly patients. We found a 39.6% prevalence of anemia in elderly patients, similar to that reported by Gaskell et al.
Age is a significant risk factor for the development of hematological malignancies. The incidence of lymphoma, PCN, MDS, and MPN increases with age. In both groups, PCN was observed as the most common disease, followed by MPN. According to Palumbo et al., the median age of patients at diagnosis is nearly 66–70 years, with 37% of patients being less than 65 years old . In our results, the number of PCN patients under 65 years of age was higher, although it was not statistically significant. Most cases of MPN are encountered in patients aged 40–60 years. The incidence of polycythemia vera in the United States is nearly 5–17 cases per 1 million population per year. However, the true incidences of essential thrombocythemia and myelofibrosis are unclear . In our study, the evaluation of lymphoma bone marrow involvement constituted 15.6% of the BME indications, of which 14.1% were non-Hodgkin lymphomas, and 1.4% were Hodgkin lymphomas. Most BMEs in lymphoma cases were performed to stage the disease and to establish a treatment program. Michelle Margold et al. demonstrated that BMB is not necessary for the staging of patients presumed to have primary CNS lymphoma . BME procedure was developed with the use of imaging guidance to increase the diagnostic yield . Long et al. has reported a 95% diagnostic yield with an exact pathologic diagnosis of fluorine copy-guided BME administration . Vadlamudi and Sterling reported adequate BME samples in 98.9% of their patients . We had sufficient BME samples in 99% of our patients. On the other hand, many studies have shown that fluorine-18 fluorodeoxyglucose-positron emission tomography (PET/CT) scan is more helpful in evaluating bone marrow involvement, especially in patients with diffuse large B-cell lymphoma [22, 23]. Although the facility of PET-CT is available in our center, BME is routinely performed for disease staging in all lymphoma patients. Widespread use of PET/CT may reduce BME in lymphoma patients but requires more prospective studies to show the advantages of PET/CT scanning over BME for all lymphoma patients.
The incidence of Hodgkin lymphoma shows a bimodal distribution, with the first peak occurring in young adults aged 15–34 years and the second peak in those aged >55 years .
The majority of our Hodgkin lymphoma patients were less than 65 years old; the median age was 40.2 (25–68) years. Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia in adults. In the present study, CLL constituted 3.9% of all patients. This low percentage is because CLL is usually diagnosed based on the evaluation of flow cytometry of the peripheral blood sample.
Our study had some limitations. The study did not include data from the pediatric population. In addition, we did not analyze the results of bone marrow aspiration and complications of the bone marrow procedure.
There is little published literature on the bone marrow profile, especially in geriatric patients. This is the first study, to the best of our knowledge, to evaluate the disease spectrum diagnosed through BMB by age groups in our region. Environmental factors can change the onset and age of the disease. The higher incidence of hematological diseases in patients under 65 years of age can be attributed to more common BME procedures, leading to earlier diagnosis and diagnosis of diseases. With the development of technology, invasive procedures are expected to decrease. These results need to be validated in larger study populations and different ethnic groups.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Wilson DP, Tshabalala WS, Pillay S. Diagnostic outcomes of bone marrow aspirate and trephine biopsies performed at a hospital in KwaZulu-Natal, South Africa. Afr J Lab Med 2020; 9(1): 1028.
2. Bain B. Bone marrow aspiration. J Clin Pathol. 2001; 54(9): 657-63.
3. Bain BJ, Clark DM, Wilkins BS. Bone marrow pathology. Hoboken, New Jersey, U.S.: John Wiley & Sons; 2019.
4. Dapus DO, Damen JG. Diagnostic outcome of bone marrow aspiration in a new centre in Nigeria. Glob Adv Res J Med Med Sci. 2012; 1(7):166–77.
5. Jha A, Sayami G, Adhikari R, Panta A, Jha R. Bone marrow examination in cases of pancytopenia. J Nepal Med Assoc. 2008; 47(169): 12-7.
6. Knowles S, Hoffbrand A. Bone-marrow aspiration and trephine biopsy (1). Br Med J. 1980; 281(6234): 204.
7. Knowles S, Hoffbrand A. Bone-marrow aspiration and trephine biopsy (2). Br Med J 1980; 281(6235): 280.
8. Sale GE, Buckner CD. Pathology of bone marrow in transplant recipients. Hematology/Oncology Clinics. 1988; 2(4): 735-56.
9. Sloane J, Norton J. The pathology of bone marrow transplantation. Histopathology. 1993; 22(3): 201-9.
10. Abbaszadeh R, Tabari F, Asadpour A. The effect of lavender aroma on anxiety of patients having bone marrow biopsy. Asian Pacific journal of cancer prevention: APJCP 2020; 21(3): 771.
11. Travlos GS. Normal structure, function, and histology of the bone marrow. Toxicol Pathol. 2006; 34(5): 548-65.
12. Rothstein G. Disordered hematopoiesis and myelodysplasia in the elderly. J Am Geriatr Soc. 2003; 51(3s): 22-6.
13. Manion EM, Rosenthal NS. Bone marrow biopsies in patients 85 years or older. Am J Clin Pathol. 2008; 130(5): 832-5.
14. Gulati A, Mandal T, Kaushal V, Kaushik R, Thakur S. Bone marrow disease profile in geriatric patients: An institutional experience. Indian J Hematol Blood Transfus. 2018; 34(3): 540-3.
15. Gaskell H, Derry S, Moore RA, McQuay HJ. Prevalence of anaemia in older persons: systematic review. BMC Geriatr. 2008; 8(1): 1-8.
16. Palumbo A, Anderson K. New England Journal of Medicine. NEJM. 2011; 364(11)): 1046-60.
17. Kutti J, Ridell B. Epidemiology of the myeloproliferative disorders: essential thrombocythaemia, polycythaemia vera and idiopathic myelofibrosis. Pathol Biol (Paris). 2001; 49(2): 164-6.
18. Margold M, Seidel S, Kowalski T, Ladigan-Badura S, Baraniskin A, Schroers R, et al. The value of bone marrow biopsy for staging of patients with primary CNS lymphoma. Neuro Oncol. 2021; 23(12): 2076-84.
19. Ellis LD, Jensen WN, Westerman MP. Needle biopsy of bone and marrow: an experience with 1,445 biopsies. Arch Intern Med. 1964; 114(2): 213-21.
20. Long JR, Stensby JD, Wiesner EL, Bryson WN, Hillen TJ, Jennings JW. Efficacy and safety of bone marrow aspiration and biopsy using fluoroscopic guidance and a drill-powered needle: clinical experience from 775 cases. Eur Radiol. 2020; 30(11): 5964-70.
21. Vadlamudi V, Sterling K. Fluoroscopically guided powered bone marrow biopsy in interventional radiology: a safe and efficacious procedure. J Vasc Interv Radiol. 2017; 2(28): S204.
22. Khan AB, Barrington SF, Mikhaeel NG, Hunt AA, Cameron L, Morris T, et al. PET-CT staging of DLBCL accurately identifies and provides new insight into the clinical significance of bone marrow involvement. Blood. 2013; 122(1): 61-7.
23. Berthet L, Cochet A, Kanoun S, Berriolo-Riedinger A, Humbert O, Toubeau M, et al. In newly diagnosed diffuse large B-cell lymphoma, determination of bone marrow involvement with 18F-FDG PET/CT provides better diagnostic performance and prognostic stratification than does biopsy. J Nucl Med. 2013; 54(8): 1244-50.
24. Das P, Ng A, Constine LS, Hodgson DC, Mendenhall NP, Morris DE, et al. ACR Appropriateness Criteria® on Hodgkin’s Lymphoma—Favorable Prognosis Stage I and II. J Am Coll Radiol. 2008; 5(10): 1054-66.
Download attachments: 10.4328:ACAM.21122
Ahmet Seyhanlı, Yazgulu Cansu Ozkan, Sermin Ozkal, Guner Hayri Ozsan, Fatih Demırkan, Inci Alacacıoglu. Evaluation of disease spectrum diagnosed with bone marrow biopsy at a tertiary healthcare center in Turkey. Ann Clin Anal Med 2022;13(7):788-791
Organic or psychosomatic? A cross-sectional study
Süleyman Dönmezdil 1, Eşref Araç 2, Mahir Yeşildal 3, Mehmet Diyadin Güleken 4, Abidin Tüzün 5
1 Department of Experimental Psychology, Artuklu University, Mardin, 2 Department of Internal Medicine, Dicle University Faculty of Medicine, Diyarbakır, 3 Department of Psychiatry, Faculty of Medicine, Üsküdar University, İstanbul, 4 Department of Psychiatry, Gazi Yaşargil Training and Research Hospital, Diyarbakır, 5 Department of General Surgery, University of Health Sciences, Diyarbakır, Turkey
DOI: 10.4328/ACAM.21123 Received: 2022-02-22 Accepted: 2022-05-23 Published Online: 2022-05-27 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):792-796
Corresponding Author: Süleyman Dönmezdil, Department of Psychology, Artuklu University, Mardin, Turkey. E-mail: email@example.com P: +90 507 796 57 00 Corresponding Author ORCID ID: https://orcid.org/0000-0002-7171-1374
Aim: Symptomatic treatments of psychosomatic symptoms are not successful because they cannot solve true etiological causes. To resolve the disorder, it is first necessary to investigate and diagnose the underlying cause and persuade the patient to use the appropriate drugs. In this study, it was aimed to make suggestions in order to identify patients who may have psychiatric symptoms and to prevent unnecessary invasive procedures by scanning psychosomatic symptoms prior to endoscopy indication.
Material and Methods: The Cornell index, Beck depression and Anxiety scales, and the Somatization scale were applied to 140 patients whose EGD procedure was planned. The patients were divided into three groups as normal endoscopic examination, antral gastritis, and other disease diagnoses (erosive gastritis, gastric ulcer, etc.). Beck Depression and Beck Anxiety Inventory scores were statistically lower in other diagnostic groups than in normal endoscopic findings and antral gastritis groups. Also, scores on the somatization scale were significantly higher in normal endoscopic findings and antral gastritis groups compared to other diagnostic groups.
Results: In patients who underwent EGD, the process was found to be more likely to cause normal endoscopic examination as the age decreased. In addition, somatization, Cornell index, anxiety and depression scores were higher at a young age.
The Cornell Medical Index showed a significantly higher sub-score of the strong neurotic structure in the antral gastritis group compared to the other groups. Similarly, there were significantly higher scores for the subscales of depression, irritability-anxiety, fear-startle, psychosomatic symptoms, hypochondriasis, and gastrointestinal disorders in the antral gastritis group compared to other diagnostic groups
Discussion: Our results show that applying the somatization scale or an equivalent screening scale to screen psychiatric symptoms before seeking endoscopic examination, especially in the young population, can provide early treatment and prevent increased treatment costs.
Keywords: Psychosomatic, Esophagogastroduodenoscopy, Somatization, Anxiety, Depression, Gastritis
Somatic symptoms associated with psychiatric disorders have been the subject of many studies [1,3]. Symptomatic treatments for psychosomatic symptoms are not successful because they cannot resolve the true etiological causes. In order to resolve the disorder, it is first necessary to investigate and diagnose the underlying cause and to convince the patient to use appropriate medications. Furthermore, it should not be ignored that there is a possibility that the psychiatric background of a somatic complaint may be rejected by patients.
Somatic symptoms may occur in many psychiatric diagnoses, with a high frequency of somatic gastrointestinal symptoms . Psychiatric disorders associated with gastrointestinal symptoms may include anxiety disorder, depression and somatoform disorders [4,5].
Esophagogastroduodenoscopy (EGD) has been widely used as a diagnostic and therapeutic tool for upper gastrointestinal system diseases . In Turkey, there is a high number of medical interventions because of a health system with easy access to physicians. Excess endoscopic procedures cause labor and financial losses, expose patients to unnecessary interventional procedures, and delay access to treatment for malignancies that require early diagnosis . This can lead to an increase in morbidity and mortality rates in cases that can be solved with a simple procedure.
The literature review performed while designing the research protocol showed that studies on the psychogenic etiology of gastrointestinal complaints mostly have focused on functional dyspepsia, but did not adequately address other psychiatric diagnoses [6,7]. In this study, we aimed to eliminate the gap in the literature by examining the upper gastrointestinal reflections of disorders such as depression, anxiety disorder and somatization.
In our study, we aimed to provide pre-procedural recognition of cases with psychosomatic symptoms, which have a large proportion of EGD procedures, and to raise awareness of gastroenterologists or general surgeons about such symptoms, thus avoiding unnecessary procedures.
Material and Methods
Study population and design
Ethical approval for our study was obtained from the institutional ethics committee of Gazi Yasargil Training and Research Hospital (Protocol number: 102; approval date 22/06/2018). After determining the indication for EGD, written consent was obtained from the patients who came to the endoscopy unit to make an appointment. Then, the psychiatrists in the study applied the scales to the patients. Thus, we tested patients who had not yet undergone EGD before determining the presence of a disease or psychosomatic symptoms, and tried to eliminate possible biases in the test results. Scales were applied to 140 patients who were scheduled for an EGD procedure. In addition, 16 patients who did not undergo EGD or did not complete the tests appropriately were excluded from the assessment.
Our study was the first to investigate the association between upper gastrointestinal diagnoses and common psychiatric disorders such as depression, anxiety disorder and somatization, thus aiming to fill an important gap in this issue.
In our study, we paid attention to the selection of scales with consistent results among themselves. The Cornell index is a large scale used to screen for psychiatric disorders and psychosomatic symptoms. In addition, the Beck depression and anxiety scales provide an idea by measuring the severity of anxiety disorder and depression. In addition, the somatization scale is a scale that shows only the severity of somatic complaints, which was prepared by combining items that scan somatic symptoms in the Minnesota Multifaceted Personality Inventory (MMPI).
Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) software version 23.0 (SPSS, Chicago, Ill., USA). Analysis of categorical data was performed using the Chi-square test. For the analysis of quantitative data, t-test was used in paired groups. However, ANOVA (post hoc Tukey’s test) was used in multiple groups because parametric assumptions were not met. Finally, Pearson’s correlation analysis was used to determine the direction and magnitude of the relationship between two quantitative variables. A p-value of <0.05 was considered statistically significant.
There was no significant difference between the diagnostic groups in terms of sociodemographic data (Table 1).
The Cornell Medical Index showed a significantly higher sub-score of the strong neurotic structure in the antral gastritis group compared to the other groups. Similarly, there were significantly higher scores for the subscales of depression, irritability-anxiety, fear-startle, psychosomatic symptoms, hypochondriasis, and gastrointestinal disorders in the antral gastritis group compared to other diagnostic groups (Table 2).
ANOVA – post hoc Tukey’s test was used. * p <0.05, compared to normal group; ** p <0.05, compared with normal and antral gastritis groups; and *** p <0.01, compared with normal and antral gastritis groups
Of the 124 participants included in our study, 64 were females and 60 were males. The mean age of the patients was 27.81 ± 10.15 years.
Mean age was significantly higher in the group with other diagnoses compared to normal endoscopic findings and antral gastritis groups. Similarly, the age of onset of the disease was statistically higher in the group with other diagnoses compared to normal endoscopic findings and antral gastritis groups.
The scores from Beck Depression and Beck Anxiety Inventory scales were statistically lower in the group with other diagnoses compared to normal endoscopic findings and antral gastritis groups.
In addition, the scores of the somatization scale were also significantly higher in normal endoscopic findings and antral gastritis groups compared to the group with other diagnoses (Table 3).
Pearson’s correlation analysis of the scores obtained from Beck depression and somatization scales showed a statistically significant relationship between the scores on the scales (R: 0.574, p<0.001).
Likewise, Pearson’s correlation analysis of the scores obtained from the Beck anxiety and somatization scale showed that there was a statistically significant relationship between the scores of the scales (R: 0.693, p<0.001).
The somatic repercussions of psychiatric disorders are challenging for physicians from many disciplines in terms of establishing diagnosis and treatment. Lack of understanding whether symptoms are indicative of a psychiatric disorder or an organic cause may result in excessive examinations and symptomatic treatments. Somatic symptoms may occur in most psychiatric disorders, including anxiety disorder, depression and somatization disorder, which have been frequently investigated in studies [8,9].
It has long been known that depression is associated with somatic symptoms and hypochondriac occupations [10,11]. Somatic symptoms associated with depression cause patients to digress from depressive symptoms and deal with their physical complaints, which leads them to refer to non-psychiatric departments. Symptomatic treatments administered by these departments cannot provide a permanent improvement, which may lead to repeated outpatient visits [12,13]. Boven et al. reported that somatic symptoms were associated with depression and anxiety disorder. Prospective studies also found a significant relationship between somatic symptoms and depression and anxiety disorder . Consistent with the literature, our study found significantly higher scores from the depression, anxiety and somatization scales in groups with normal findings or antral gastritis detected by EGD procedure.
The literature review reveals the necessity of questioning the attitudes and recognition levels of physicians against psychiatric disorders. Some studies have shown that psychiatric symptoms are not sufficiently recognized by physicians, with recognition rates ranging from 22 to 80%. It has been reported that physicians may miss psychiatric symptoms, as well as avoid establishing psychiatric diagnoses, which stems from the desire to avoid stigmatizing the patient with a psychiatric diagnosis [14,15]. This may cause patients to seek symptomatic treatment by digressing from the treatment for true etiological cause, which may lead to repeated outpatient visits and thus increases treatment costs .
Abdominal pain and especially epigastric pain, which are frequently reported somatic symptoms, suggest gastritis and other organic causes related to the stomach in internal medicine practice. The EGD procedure, which is an easily accessible method for determining the etiological origin of these symptoms, is often used for the exclusion of other diagnoses and for therapeutic purposes. In our center, 4618 EGD procedures were performed between January 2017 and January 2018.
In Turkey, the general health insurance system is in force and the social security institution covers the fees of the procedures performed in all hospitals affiliated to the ministry of health. The absence of a referral chain to hospitals affiliated to the ministry of health or universities results in the application of patients, who can be treated even in primary care centers, to tertiary hospitals. This may lead to an increase in workload and delayed access to treatment for patients in need of treatment In addition, the increase in workload causes the physician to try to reduce the workload by requesting an excessive number of examinations without following the steps in the therapeutic algorithm. A similar situation applies to magnetic resonance imaging (MRI) studies. One study reported that Turkey is the country with the highest rate of MRI studies among OECD countries, despite the lowest level of allocated resources, which may have been due to the requests of unnecessary examinations .
In Turkey, the income of physicians working in public hospitals consists of a fixed monthly salary and in addition, revolving fund payment calculated by a system called performance system. In the performance system, the income of physicians is calculated on the basis of the number of patients served and the number of specialized procedures and operations. Thus, the revolving fund payment system forces the physician to try to serve more patients and to implement more specialized procedures. Therefore, a high workload can also make it easier for physicians to request an examination. In addition, the physician may choose to request an examination in order to protect himself from legal cases.
In the literature, the mean age of onset of gastrointestinal malignancies was reported to be 40 years or more, whereas our study reported a mean age of 23.3 ± 6.9 years in patients with normal endoscopic findings . It can be predicted that endoscopic examination may be unlikely to give pathological results in young patients. Therefore, detailed screening of psychiatric symptoms in these patients before an invasive procedure may prevent possible unnecessary examinations.
In our study, there were significantly high scores on the scales measuring the severity of anxiety disorder, depression and somatization,
In our study, there were significantly high scores on the scales measuring the severity of anxiety disorder, depression and somatization, which showed that clinicians should not ignore the fact that the EGD procedure is unlikely to provide any evidence in patients with symptoms of the disease. Likewise, a lower mean age in the antral gastritis group compared to the other diagnoses group and statistically significant high scores from the depression, anxiety and somatization scales and the somatic complaints subscale of the Cornell scale support our hypothesis.
It has been reported that 40 to 80% of patients with gastrointestinal symptoms had no pathological findings to explain these symptoms . This suggests a psychosomatic origin of symptoms. The general opinion among physicians is that if there is a psychological etiology, the patient may not benefit from the treatment. In a double-blind randomized controlled trial of 75 patients, Holtmann et al. obtained findings that contradict this idea. They applied the SCL-90 scale to patients and showed that patients with high somatization and anxiety scores benefited more from antacids and other treatments. In fact, this has proven that regular follow-up may relieve symptoms before performing invasive procedures in patients with psychosomatic symptoms. Studies have shown that in most psychological disorders, a regular follow-up of the patient may regress existing symptoms and improve adherence to treatment.
On the other hand, some studies have emphasized the role of immunity in gastric disorders such as gastritis. Considering the studies suggesting the role of inflammatory processes on the etiology of psychiatric diseases, we can suggest a potential common pathogenesis of both gastric and psychiatric disorders, and the coexistence of these two disease groups [20,21].
Our results show that the application of the somatization scale or an equivalent screening scale to screen for psychiatric symptoms prior to the request of endoscopic examination, especially in the young population, may provide early treatment and prevent loss of labor and increased treatment costs. More extensive studies will be able to identify the diagnostic algorithms to be followed before such invasive procedures.
The limitation of our study is that not all patients undergoing the endoscopy procedure have undergone a biopsy examination and therefore diagnoses may have been established based on clinical features and endoscopic images.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Davoodi E, Wen A, Dobson KS, Noorbala AA, Mohammadi A, Farahmand Z. Emotion regulation strategies in depression and somatization disorder. Psychol Rep. 2019;122(6): 2119-36.
2. Wong KMF, Mak ADP, Yuen SY, Leung ONW, Ma DY, Chan Y, et al. . Nature and specificity of altered cognitive functioning in IBS. Neurogastroenterol Motil. 2019; 31(11): e13696.
3. Heidari Z, Keshteli A H, Feizi A, Afshar H, Adibi P. Somatic complaints are significantly associated with chronic uninvestigated dyspepsia and its symptoms: A large cross-sectional population based study. J Neurogastroenterol Motil. 2017; 23(1):80-91.
4. Şengül H, Bulut A, Coşkun S N. Psychological effect of COVID-19 pandemic on university students in Turkey. Ann Clin Anal Med. 2020; 11(6): 609-15.
5. Flaskerud JH. Gastric Ulcers, from Psychosomatic Disease to Infection. Issues in Mental Health Nursing. 2020; 41(11):1047-50.
6. Şimşek G., Gastrointestinal Sistem Endoskopisi (Gastrointestinal System Endoscopy). Türk Cerrahi Derneği/ Turkish Surgery Association. 2016; 1 (1): 75-80
7. Ford AC, Marwaha A, Lim A, Moayyedi P. What is the prevalence of clinically significant endoscopic findings in subjects with dyspepsia? Systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2010; 8(10): 830-7.
8. Anderson G, Berk M, Maes M. Biological phenotypes underpin the physio-somatic symptoms of somatization, depression, and chronic fatigue syndrome. Acta Psychiatrica Scandinavica. 2014; DOI:10.1111/acps.12182.
9. Mallorquí-Bagué N, Bulbena A, Pailhez G, Garfinkel SN, Critchley HD. Mind-body interactions in anxiety and somatic symptoms. Harv Rev Psychiatry. 2016; 24(1):53-60.
10. Lipowski ZJ. Somatization: the concept and its clinical application. Am J Psychiatry. 1988; 145(11): 1358-68.
11. Pontone S, Ridola L, Marianetti M, Pontone P, Petrarca L, Mina C, et al. Endoscopic findings and psychometric abnormalities: what is the relationship in upper endoscopic outpatients. Clin Ter. 2015; 166(6): 238-43.
12. Karvonen JT, Läksy K, Räsänen S. Somatization disorder-an overdiagnosed but underestimated illness. Duodecim; Laaketieteellinen Aikakauskirja. 2016; 132(3): 219-25.
13. Yükselmiş Ö. Perspectives of Patients 65 Years and Above Regarding Family Medicine Applying to Physical Therapy and Rehabilitation Hospital Polyclinics. Tobacco Regulatory Science (TRS). 2021; 6849-6854.
14. Yu NX, Chan JS, Ji X, Wan AH, Ng SM, Yuen L P, et al. Stress and psychosomatic symptoms in Chinese adults with sleep complaints: Mediation effect of self-compassion. Psychol Health Med 2019; 24(2): 241-52.
15. Santarelli L, Rapisarda V, Fago L, Vella F, Ramaci T, Ledda C, et al. Relation between psychosomatic disturbances and job stress in video display unit operators. Work. 2019; 64(2): 303-10.
16. Konnopka A, Schaefert R, Heinrich S, Kaufmann C, Luppa M, Herzog W, et al. Economics of medically unexplained symptoms: a systematic review of the literature. Psychother Psychosom. 2012; 81(5): 265-75.
17. Yiğit A, Erdem R. Sağlık Teknolojisi Değerlendirme: Kavramsal Bir Çerçeve (Health Technology Assessment: A Conceptual Framework). Süleyman Demirel Üniversitesi Sosyal Bilimler Enstitüsü Dergisi/ Suleyman Demirel University Journal of Social Sciences Institute. 2016; (23): 215-49.
18. Rawla P, Barsouk A. Epidemiology of gastric cancer: global trends, risk factors and prevention. Prz Gastroenterol. 2019; 14(1): 26-38.
19. Kani HT, Dural U, Sakalli Kani A, Yanartas O, Kiziltas S, Yilmaz Enc F, et al. Evaluation of depression, anxiety, alexithymia, attachment, social support and somatization in functional dyspepsia. Psychiatry and Clinical Psychopharmacology. 2019; 29(1): 45-51.
20. Kohler O, Krogh J, Mors O, Eriksen Benros M. Inflammation in depression and the potential for anti-inflammatory treatment. Current neuropharmacology. 2016; 14(7): 732-42.
21. Fehér J, Kovács I, Balacco Gabrieli C. Role of gastrointestinal inflammations in the development and treatment of depression. Orvosi Hetilap. 2011; 152(37); 1477-85.
Download attachments: 10.4328:ACAM.21123
Süleyman Dönmezdil, Eşref Araç, Mahir Yeşildal, Mehmet Diyadin Güleken, Abidin Tüzün. Organic or psychosomatic? A cross-sectional study. Ann Clin Anal Med 2022;13(7):792-796
Evaluation of D-dimer and fibrinogen levels in COVID-19 patients
Şeyma Aras, Emine Emektar, Şeref Kerem Çorbacıoğlu, Yunsur Çevik
Department of Emergency Medicine, Ankara Sanatoryum Training and Research Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.21126 Received: 2022-02-24 Accepted: 2022-03-29 Published Online: 2022-03-30 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):797-801
Corresponding Author: Emine Emektar, Ardahan Sokak, Sanatoryum Caddesi, No:25, 06280, Keçiören, Ankara, Turkey. E-mail: firstname.lastname@example.org P: +90 505 556 26 75 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6056-4401
Aim: The aim of this study is to determine D-dimer and fibrinogen levels in COVID-19 patients and to evaluate their correlation with in-hospital mortality.
Material and Methods: Patients aged 18 years and older who applied to the emergency and/or pandemic outpatient clinic of our hospital and were hospitalized and whose COVID-19 PCR test was positive were included. Demographic data, vital and physical examination findings, laboratory values including D-dimer and fibrinogen levels were recorded. P <0.05 was considered statistically significant.
Results: Patients with increased D-dimer value were found to have higher age, higher rate of chronic kidney disease, higher fever and pulse values, lower saturation measurements, longer duration of the complaint, more severe pneumonia, longer hospital stay, greater requirement for mechanical ventilation and intensive care (p<0.05 for all values).
It was observed that the patients with increased fibrinogen were older and the duration of complaints was longer. When the laboratory values of the patients with and without fibrinogen increase were compared, it was determined that neutrophil, CRP and sedimentation values of the patients with increased fibrinogen were lower (p<0.05 for all values).
Discussion: In our study, we demonstrated that D-dimer levels measured at admission and during follow-up were higher in the deceased patients than in the surviving ones. We did not detect any clinical association between admission and follow-up fibrinogen levels and mortality in the deceased patients as compared with the surviving ones.
Keywords: COVID-19, D-dimer, Fibrinogen
COVID-19 is a global pandemic caused by SARS-CoV-2 infection [1, 2]. The number of people infected by SARS-CoV-2 continues to rise on a global scale. Developing novel laboratory tests that would aid the diagnostic and follow-up processes in COVID-19 patients is very important not only for making the diagnosis, but also for distinguishing between severe and non-severe cases, and patients at low and high mortality risk. Mortality and morbidity of the COVID-19 infection have been rising.
Varying degrees of respiratory failure, cardiovascular complications, secondary infections, thromboembolic events, and inflammatory complications may develop in affected patients . The risk of thrombosis increases in the course of COVID-19 [4, 25]. Although the cause of hypercoagulopathy in COVID-19 patients has yet to be fully elucidated, the basic mechanisms first defined by Virchow are considered to be operational . Direct invasion of endothelial cells by the virus, cytokines, mainly Il-6, triggering a systemic inflammatory response, and intravascular catheters widely used for patient follow-up are the main causes of endothelial injury . Elevated factor VIII and fibrinogen levels, prothrombotic microparticles, neutrophil extracellular traps, and hyperviscosity cause hypercoagulopathy. In addition, immobilization during intensive care also increases vascular stasis, independently of the COVID-19 disease [6-8]. A hypercoagulable state, which increases the risk of venous and arterial thromboembolism due to the above-mentioned factors, is termed COVID-19-associated coagulopathy. Despite marked increases in fibrinogen and D-dimer levels, PT (prothrombin time) and aPTT (activated partial thromboplastin time) are normal or slightly prolonged. Platelet count is variable . Excessively elevated D-dimer level is remarkable and associated with poor prognosis. It has been observed that D-dimer levels were significantly higher in patients treated in the intensive care unit than other patients . It was shown that D-dimer could be an early and useful marker that would improve the management of COVID-19 patients . Indication algorithms for the administration of anticoagulant agents in COVID-19 patients are not clear. This situation may cause difficulties in the implementation of the diagnosis, follow-up and treatment procedures of COVID patients. Herein, we aimed to investigate admission and follow-up D-dimer and fibrinogen levels of COVID-19 patients, factors associated with their elevated levels, and their relationship with in-hospital mortality.
Material and Methods
The present study is a retrospective, observational study. It was approved by the local ethics committee (23.02.202, 2012-KAEK-15/2229). Patients aged 18 years or older with a positive COVID-19 PCR test who were hospitalized in Keçiören Training and Research Hospital between 01.08.2020 and 30.11.2020 were enrolled in the study. The demographic data, admission complaints, comorbidities, time of admission, vital and physical examination findings, laboratory studies including D-dimer and fibrinogen levels measured at admission and during follow-up, chest X-Ray/tomographic imaging findings, disease-related thromboembolic (deep vein thrombosis (DVT) and pulmonary embolism) events, if any, and length of hospital stay were recorded for all patients. The patients were grouped as the deceased and surviving patient groups based on their in-hospital mortality status. The patients were additionally grouped by their D-dimer and fibrinogen levels. They were further divided into two groups based on the difference between the admission D-dimer, fibrinogen levels and 5th day D-dimer and fibrinogen levels, as those with elevated levels of the said parameters and those without. Patients with missing data and a negative PCR test were excluded from the study.
Data obtained during the study period and recorded on study forms were analyzed with IBM SPSS 20.0 (Chicago, IL, USA) statistical software package. The Kolmogorov-Smirnov test was used to check if discrete and continuous variables were normally distributed. Descriptive statistics included the median (interquartile range 25-75) for discrete and continuous numerical variables, and number of cases and percentage (%) for categoric variables. Categoric variables were analyzed using the Chi-square test, and continuous variables using the Mann-Whitney U test. Receiver operating characteristic (ROC) analysis was performed for fibrinogen and D-dimer levels, in which the curves’ area under the curve (AUC) values were calculated to distinguish between deceased and surviving patients.
A p-value of less than 0.05 was considered statistically significant for all statistical analyses.
The data of 1997 patients who were enrolled during the study period were analyzed. Five hundred and eighty-six patients were excluded due to a negative PCR test plus 40 patients due to missing data. A total of 1371 patients were enrolled in the study. Of the patients who were enrolled, 53.7% were male (N=736); the median age of the study population was 63 (IQR 52-72) years. The most common comorbidity was hypertension (54.9%). The median length of hospital stay was 7 days (IQR 5-11 days). The in-hospital mortality rate was 10.3% (141). Table 1 shows the demographic data of the study population.
The ROC analysis that was performed to determine a cut-off value for D-dimer level for distinguishing between deceased and surviving patients had an AUC value of 0.695 (95% CI 0.649-0.741; p<0.001) (Figure 1). A D-dimer level of 1475 that was accepted as the best cut-off value to discriminate between deceased and surviving patients had a sensitivity of 42% and a specificity of 89%. There were 1072 patients whose D-dimer level was measured at admission and five days later. The fifth day D-dimer level was higher than the admission D-dimer level in 7.9% of the patients. A comparison of the patients with and without D-dimer elevation indicated that the patients with elevated D-dimer levels had higher median age, higher rate of chronic kidney disease, higher body temperature and pulse rate, lower oxygen saturation, longer duration of symptoms, more severe pneumonia, longer hospital stay, and greater requirement for ventilation and intensive care (p<0.05 for all comparisons) (Table 2).
In 438 patients, fibrinogen levels were measured at admission and five days later. The fifth day fibrinogen level was higher than the admission D-dimer level in 50.5% of the patients. The ROC analysis to determine a cut-off level for fibrinogen to distinguish between deceased and surviving patients had an AUC value of 0.582 (95% CI 0.524-0.641) (Figure 2). A fibrinogen level of 730 that was accepted as the best cut-off value for distinguishing between deceased and surviving patients had a sensitivity of 11.7% and a specificity of 91.5%. As compared with patients without elevated fibrinogen level, those with an elevated fibrinogen level had a higher median age and a longer symptom duration (p<0.05 for both comparisons) (Table 3).
In the COVID-19 pandemic, the number of patients presented to healthcare facilities or hospitals has been increasing, hospital capacities have been exceeded, and in particular, patient requirement for intensive care support has been rising. Thus, there is a growing need for developing early and effective predictors of clinical outcomes in order to risk stratify COVID-19 patients. In the present study, where we investigated how D-dimer and fibrinogen elevation would affect the mortality rate of hospitalized COVID-19 patients, we reached two basic conclusions. Firstly, we determined that deceased patients had higher admission and follow-up D-dimer levels compared with survivors. We also found that patients with D-dimer level elevation were older, had a higher rate of chronic kidney disease, higher body temperature and pulse rate, and lower oxygen saturation. We also demonstrated that these patients presented to the hospital later, had more severe pneumonia, longer hospital stay, and greater need for mechanical ventilation and intensive care. Secondly, when we analyzed our patients’ fibrinogen levels, we revealed that deceased patients had an approximately 2 times higher fibrinogen level than surviving ones. However, although the results of ROC analysis that we performed to determine a cutoff value for fibrinogen that would discriminate between the deceased and surviving patients were statistically significant, it did not yield clinically meaningful results. Even though several studies in the literature have reported that elevated fibrinogen levels were associated with poor prognosis in hospitalized patients, our results were not indicative of a relationship between follow-up fibrinogen levels and mortality in spite of the fact that deceased patients had higher admission fibrinogen levels than survivors.
Data on abnormal coagulation parameters in COVID-19 have first surfaced in reports from China. In a study published in the early period of the pandemic it was reported that patients exhibited a longer bleeding time, 36% of patients had elevated D-dimer and increased inflammatory biomarkers, and 12% had thrombocytopenia . In the first publications, particularly prothrombin time and D-dimer level have come into prominence as the markers of more severe disease . It has been determined that thrombotic events are frequently encountered in patients with COVID-19, which has been shown as a poor prognostic sign in terms of disease severity. In a study on 560 patients from China, an elevated D-dimer level was found in 260 (46.4%) of patients; furthermore, it was shown that as disease severity increased, D-dimer level was elevated proportionally . D-dimer represents the activation of coagulation and fibrinolysis systems . D-dimer test is used clinically to exclude deep vein thrombosis (DVT) and pulmonary embolism (PE) and to confirm disseminated intravascular coagulation [12,13]. Elevated D-dimer levels are not only found in thromboembolic events, but also in physiological states like pregnancy and disease states such as cancer, inflammation, and surgery . A review of D-dimer level in COVID-19 infection concluded that particularly diabetics and patients suffering a venous thromboembolism (VTE) have higher D-dimer level, independently of thromboembolic events [15-17]. Our findings are similar to the previous literature reports. Particularly patients with severe COVID-19 pneumonia and severe COVID-19 infection (evidenced by fever, tachycardia, hypoxia) had higher D-dimer levels. Another study on 138 patients found higher D-dimer levels in 26% of patients that required admission to the intensive care unit. That study also demonstrated that deceased patients had elevated D-dimer levels, progressive lymphopenia, and renal dysfunction. It was also observed by the same authors that D-dimer began to differentiate patients with poor prognosis 5 days after symptom onset . We also found that COVID-19 patients with chronic renal failure (CRF) had higher D-dimer levels. Studies have shown a negative correlation between GFR and D-dimer levels, but no thromboembolic events during a 1-year follow-up of such patients [18,19]. Another study demonstrated that an admission D-dimer level of more than 2.0 µg/mL (four times increase) could effectively predict in-hospital mortality in COVID-19 patients, which suggested that D-dimer could be an early and effective marker for use to improve patient outcomes . We similarly calculated a sensitivity of 42% and a specificity of 89% for a D-dimer cut-off value of 1475 (approximately 3 times normal) to distinguish between deceased and surviving patients. We detected elevated D-dimer levels independent of thromboembolic events in deceased patients.
Fibrinogen is the most abundant coagulation protein in the blood. It has a prominent role in the coagulation cascade and thrombosis. Its primary function is to form fibrin that causes coagulation, but it also actively participates in thrombocyte aggregation [20,21]. In a series of 43 patients by Ranucci et al. fibrinogen level was significantly higher in patients with severe COVID-19 infection . In our fibrinogen level analysis, we found that deceased patients had higher fibrinogen levels at the time of admission. However, our ROC analysis to determine a cutoff value for fibrinogen level for distinguishing between deceased and surviving patients revealed no clinically meaningful result, although the result of the analysis was statistically significant. Although some studies have reported that elevated fibrinogen levels were associated with poor prognosis among hospitalized patients, we could not demonstrate any association between follow-up fibrinogen levels in deceased patients as compared with surviving ones. It was reported that fibrinogen increases in early disease and decreases in the subsequent days [23,24]. We think that this may be due to dynamic behavior of fibrinogen levels in COVID-19 patients.
Our study has some limitations. Firstly, our results cannot be generalized to all centers due to the single-center nature of our study. Secondly, missing or erroneous data may have affected study results because of the retrospective nature of our study. Decisions regarding hospitalization, diagnostic tests, and treatment have shown some variations during the pandemic owing to continuously updated COVID-19 guidelines published by the Ministry of Health of Turkey. Whereas even asymptomatic patients had been hospitalized in the first days after the declaration of the first cases of the disease in the country, the criteria for hospitalization had been changed in subsequent periods. This may have changed our results. Furthermore, COVID-19 patients who had no indication for hospitalization and who had been discharged from the emergency department with outpatient treatment were excluded. This may have affected our study results as well.
In our study, we demonstrated that D-dimer levels measured at admission and during follow-up were higher in deceased patients than surviving ones. We showed that patients with elevated D-dimer levels were older, had higher rates of chronic kidney disease, higher body temperature and pulse rates, lower oxygen saturation, more severe pneumonia, longer hospital stay, and higher requirement for mechanical ventilation and intensive care. We demonstrated that D-dimer elevation occurred independently of thromboembolic complications. Although we also demonstrated that fibrinogen levels were higher in deceased patients, we did not detect any clinical association between admission and follow-up fibrinogen levels and mortality in deceased patients as compared with surviving ones.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-13.
2. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382(18):1708-20.
3. Wendelboe AM, Raskob GE. Global burden of thrombosis: epidemiologic aspects. Circ Res. 2016;118(9):1340–7
4. Fogarty H, Townsend L, Ni Cheallaigh C, Bergin C, Martin-Loeches I, Browne P, et al. COVID19 coagulopathy in Caucasian patients. Brit J Haematol. 2020;189(6):1044–9.
5. Chen R, Sang L, Jiang M, Yang Z, Jia N, Fu W, et al. Longitudinal hematologic and immunologic variations associated with the progression of COVID-19 patients in China. J Allergy Clin Immunol. 2020;146(1):89–100.
6. Teuwen LA, Geldhof V, Pasut A, Carmeliet P. COVID-19: the vasculature unleashed. Nat Rev Immunol. 2020; 20 (7):389-91.
7. Begbie M, Notley C, Tinlin S, Sawyer L, Lillicrap D. The Factor VIII acute phase response requires the participation of NF kappa B and C/EBP. Thromb Haemost. 2000; 84 (2):216-22.
8. Magro C, Mulvey JJ, Berlin D, Nuovo G, Salvatore S, Harp J et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl Res. 2020; 220:1-13.
9. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-9.
10. Zhang L, Yan X, Fan Q, Liu H, Liu X, Liu Z, et al. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost. 2020;18(6):1324-9.
11. Gaffney PJ. Breakdown products of fibrin and fibrinogen: molecular mechanisms and clinical implications. J Clin Pathol. 1980;14:10–7.
12. Halaby R, Popma CJ, Cohen A, Chi G, Zacarkim MR, Romero G, et al. D-Dimer elevation and adverse outcomes. J Thromb Thromboly. 2015;39(1):55–9.
13. Adam SS, Key NS, Greenberg CS. D-dimer antigen: current concepts and future prospects. Blood. 2009;113(13):2878–87.
14. De Monyé W, Sanson BJ, Mac Gillavry MR, Pattynama PM, Büller HR, van den Berg-Huysmans AA, et al. Embolus location affects the sensitivity of a rapid quantitative D-dimer assay in the diagnosis of pulmonary embolism. J Respir Crit Care Med. 2002;165(3):345–8.
15. Rostami M, Mansouritorghabeh H. D-dimer level in COVID-19 infection: a systematic review. Expert Rev Hematol. 2020;13(11):1265-75.
16. Guo W, Li M, Dong Y, Zhou H, Zhang Z, Tian C, et al. Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab Res Rev. 2020; e3319.
17. Yan Y, Yang Y, Wang F, Ren H, Zhang S, Shi X, et al. Clinical characteristics and outcomes of patients with severe covid-19 with diabetes. BMJ Open Diabetes Res Care. 2020;8(1):e001343.
18. Sheikh V, Ahmadpour-Saheb N, Khazaei S. Relationship between D-dimer Levels and the Glomerular Filtration Rate in Patients with Chronic Kidney Disease. Biomedical Research and Therapy. 2021; 8(11): 4695-9.
19. Gubensek J, Lolic M, Ponikvar R, Buturovic-Ponikvar J, D-dimer levels in maintenance hemodialysis patients: high prevalence of positive values also in the group without predisposing diseases. Hemodial Int.. 2016; 20 (2):198-203.
20. Fuss C, Palmaz JC, Sprague EA. Fibrinogen: structure, function, and surface interactions. J Vasc Interv Radiol. 2001;12(6):677-82.
21. Lin SY, Hsieh TF, Wei YS. Mechanical compression affecting the thermal-induced conformational stability and denaturation temperature of human fibrinogen. Int J Biol Macromol. 2005;37(3):127-33.
22. Ranucci M, Ballotta A, Di Dedda U, Baryshnikova E, Dei Poli M, Resta M, et al. The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. J Thromb Haemost. 2020;18(7):1747-51.
23. Tang N, Li D, Wang X. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18 (4):844–7.
24. Osawa I, Okamoto K, Ikeda M, Otani A, Wakimoto Y, Yamashita M, et al. Dynamic changes in fibrinogen and D-dimer levels in COVID-19 patients on nafamostat mesylate. J Thromb Thrombolysis. 2021;51(3):649-56.
Download attachments: 10.4328:ACAM. 21126
Şeyma Aras, Emine Emektar, Şeref Kerem Çorbacıoğlu, Yunsur Çevik. Evaluation of D-dimer and fibrinogen levels in COVID-19 patients. Ann Clin Anal Med 2022;13(7):797-801
The effect of rehabilitation in patients with facioscapulohumeral muscular dystrophy: A prospective clinical study
Department of Physical Therapy and Rehabilitation, Gazi Yaşargil Training and Research Hospital, Diyarbakir, Turkey
DOI: 10.4328/ACAM.21129 Received: 2022-03-01 Accepted: 2022-04-04 Published Online: 2022-04-05 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):802-806
Corresponding Author: Askeri Turken, Elazig Yolu, 10. Km, Uckuyular Mevkii, 21070, Kayapinar, Diyarbakir, Turkey. E-mail: email@example.com P: +90 412 258 00 60 F: +90 412 258 00 50 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0638-8918
Aim: Facioscapulohumeral muscular dystrophy (FSHD) is a rare and slowly progressive disease that causes physical limitations. In our study, it was aimed to reveal the effects of rehabilitation and treatment programs applied in FSHMD patients on activities of daily living and walking.
Material and Methods: A clinical intervention trial was conducted. Data of 33 of the 38 patients diagnosed with FSHD were analyzed. A 20-weeks rehabilitation program composed of exercises (muscle-strengthening, stretching, range of motion, balance, coordination, walking, posture, and breathing), patient and family education, and neuromuscular electrical stimulation. Functional assessments were performed with the Barthel-Index (BI), the functional categories of ambulation (FAC) test, and the Oxford muscle strength grading scale before and after the rehabilitation.
Results: Average age of the participants (±SD) was 30.88±11.43 years, and 81.8% (n=27) were males. All patients had periscapular weakness and wing scapula. There was no prominent difference between flexion and extension and abduction of the two upper limb extremities (p> 0.05). There was a substantial increase in Barthel scores of the patients after rehabilitation (Z= 3,535; p<0.001).
Discussion: The implementation of the rehabilitation program causes an increase in BI scores. It is recommended that training of the society and health personnel will be beneficial. Further studies are needed to provide information about the frequency of this disease in the Turkish population.
Keywords: Rehabilitation, Muscular Dystrophy, Activities of Daily Living, Disability Studies, Genetic Disorders
Facioscapulohumeral muscular dystrophy (FSHD) is a rare and unique muscular dystrophy that initially involves the upper region and gradually spreads to the lower region, except for the extraocular and deltoid muscles . A worldwide prevalence study of FSHD found that it ranged from 2.03 to 6.8 per 100,000 live-born .
FSHD is a progressive disease that makes daily life addictive. This condition, which initially shows involvement in the face, shoulder circumference, and arm muscles close to the shoulders, progresses towards the abdomen and lower extremities over time, the involvement is typically asymmetrical, weakness and atrophy are observed in the affected areas . Symptoms and deformities such as poly-hill, Beevor’s sign, advanced hyperlordosis, Trendelenburg gait, and drop foot occur in the hamstring and posterior calf muscles atrophy .
There is still no specific treatment option for FSHD. In these cases, supportive care and extensive rehabilitation are potentially effective in reducing fatigue, cardiorespiratory and muscle atrophy [5,6], and exercise plays an important potential role in preventing fatigue and limiting muscle atrophy, cardiorespiratory deterioration, and metabolic deterioration. However, few studies of aerobic training [5,7,8] and strength training [6,8] have been conducted in FSHD patients. There is no study evaluating the benefits of rehabilitation programs, daily life, and walking in FSHD patients in Turkey. In these patients, it gradually worsens over the years and weakens the lower extremity muscles, making it difficult to walk, and over time, they depend on a caregiver in daily life.
This study aimed to reveal the effects of rehabilitation and treatment programs in FSHMD patients on activities of daily living and walking.
Material and Methods
Our study was conducted as a prospective study on patients diagnosed with FSHD who came to the Center for Neuromuscular Diseases of the Department of Physical Medicine and Rehabilitation, Gazi Yaşargil Training and Research Hospital, University of Health Sciences. The study protocol was approved by the Local Ethics Committee No:809. Each participant signed an informed consent form per the Declaration of Helsinki. The rehabilitation program started after approval.
A total of 38 patients were diagnosed with FSHD in the Neuromuscular Diseases Center. All individuals diagnosed with FSHD were recommended to participate in the study. Three people who did not agree to participate in the study and 2 patients whose questionnaires were deemed invalid were excluded. The results of 33 participants were analyzed.
In this study, we aimed to evaluate the change in BI and FAC values at the beginning and after the active rehabilitation program in FSDH, a genetic muscle disease, and to see the validity of BI and FAC, which are frequently used in rehabilitation in these patients.
The data were obtained through face-to-face interview using a questionnaire by the researcher. Demographic and clinical information was collected using the sociodemographic data form created by the researchers after reviewing the current literature. The independent variable of the study was the rehabilitation program, and the dependent variables were the extremity muscle strength, Barthel-Index (BI) and Functional Ambulation Classification (FAC) scores of the patients.
Since FSHD physical and neurological manifestations may be different, a personalized rehabilitation program was prepared for each patient, taking into account the individual’s mental, fatigue and participation desire, not exceeding daily 1 hour. The rehabilitation program consisted of 5 days per week for 20 weeks. Ankle orthoses were fitted to patients with ankle dorsiflexion loss and associated walking difficulties.
Functional assessment tools are described below.
As a prospective study, to see the use of BI and FAC in patients with FSDH, to prevent musculoskeletal disorders and neurological losses, and to implement rehabilitation to keep walking and daily life independent.
Barthel’s index of activities of daily living (BI) was first developed by Mahoney and Barthel . The validity and reliability of the Turkish version of the BI were performed by Küçükdeveci et al . BI is a life activity scale consisting of 10 basic parameters commonly used in physical disability. These 10 parameters are feeding, bathing, personal care, dressing, bowel management, bladder management, toilet use, wheelchair use, walking on level ground, and climbing stairs. Each point determines the degree of physical assistance and the amount of time a person needs to perform the independent activity. Points are given to the activities performed by the patient. A score of 100 is considered completely independent, and a score of zero is considered completely dependent.
Functional Ambulation Classification:
The functional categories of ambulation (FAC) test was developed by Holden et al. in 1984 to determine the level of ambulation . FAC is a scale with six categories (0-5); the lowest stage means more addiction. Stages 0 to 3 indicate that the patient is dependent, or stages 4 and 5, in which you are not standing, are independent.
Oxford Muscle Strength Grading Scale:
This is a muscle strength measurement technique. The force exerted by a person against the resistance on the right axis during the movement is scored between zero and 5; 0/5: no muscle strength, 1/5: if gravity is removed, there is only contraction; 2/5: completes the movement when gravity is removed; 3/5: it only completes anti-gravity motion, with no resistance; 4/5: muscle activation against some resistance; 5/5: muscle activation to examiner full resistance, full range of motion .
Those who accepted to participate in the survey were briefed about the research and no identifying information was recorded in the survey. The data collection processes of the participants and the examination were carried out by the same researcher. Error checking was done after the data were entered into the computer.
The data were entered into the computer using SPSS 20.0 software. Descriptive statistics were done to present participant characteristics by summarizing in percentages for categorical variables and as mean ± standard deviations (SD) or median and inter-quartile range (IQR) for numerical variables. Comparison of right and left side muscle strength was made using the Wilcoxon signed-ranks test. Comparison of Barthel and FAC scores before and after rehabilitation was made using the Wilcoxon signed-rank test. A p-value of <0.05 was considered statistically significant.
The study comprised 33 patients with FSHMD. The mean (±SD) age of the participants was 30.88±11.43 years, and 81.8% (n=27) were male. The male/female ratio was 4.5. The mean (±SD) delay between diagnosis and the onset of symptoms was 7.40 ± 8.79 years. The mean value (±SD) of the body mass index (BMI) was 21.40±3.44. Of the patients, 72.7% (n = 27) had a family history of the disease, and parents of 60.6% (n = 20) of the patients had consanguineous marriages. Basic characteristics variables of patients are given in Table 1.
The most common symptoms were periscapular weakness (100.0%; n = 33), winged scapula (100.0%; n = 33), dysphonia (66.7%; n = 23) and facial muscle weakness (63.6%; n = 21), respectively. Two patients were not able to walk (Table 2).
There was no visible difference between the right and left flexion and extension and abduction muscle strengths of the lower and upper limb (p> 0.05), except hip abduction and extension (p<0.05) (Table 3).
There was no prominent difference between the two shoulder flexion, abduction, and extension muscle strengths in patients with and without dysphonia. (p> 0.05).
There was a significant increase in the Barthel scores of the patients after rehabilitation (median= 75.0; IQR= 20.0) compared to before (median=80.0; IQR=15.0) (Wilcoxon Z= 3.535; p<0.001) (Figure 1).
There was no statistically prominent difference between the FAC scores of FSHMD patients before (median= 4.0; IQR=2.0) and after (median=4.0; IQR=1.5) rehabilitation (Z=1.732; p=0.083).
Compared to the values before rehabilitation (median= 70.0; IQR=3.75), Barthel scores of the patients using ankle-foot-orthotics increased significantly after rehabilitation (median= 85.0; IQR=3.75) (Z=2.459; p= 0.014). However, compared to the levels before rehabilitation (median= 3.5; IQR=1.0), there was a borderline significant increase in the FAC scores after rehabilitation (median= 4.0; IQR=0.0) (Z=1.732; p= 0.087).
The majority of FSHMD patients were male. There was approximately 7 years of delay between the onset of the symptoms and the diagnosis. Family history and consanguineous marriages between the parents were common in the patients. The most common symptoms were periscapular weakness, winged scapula, dysphonia, and facial muscle weakness. However, there was an increase in the BI scores after rehabilitation.
Due to ethical concerns, a control group could not be used in the study. Although all potential participants were invited, the study had a relatively low sample size due to the extremely rare nature of the disease. Genealogical analysis, although not among the study objectives, could provide further information about the genetic dimension of the disease
Symptom onset in FSHD patients may occur throughout the entire life span, but it is reported most frequently in the second decade of life [1,13]. The age of onset of symptoms in our study was similar to that reported in the literature. FSHD has less severe progress in females than males and is diagnosed at a more advanced age than in males . This explains why the ratio of men to women is higher in favor of men in our study.
An important problem is that it is diagnosed years after the onset of symptoms. Thus, there is a need for raising awareness about this disease, both at the social and at the health employee level.
Two types of FSHD have been identified that are inherited in an autosomal dominant manner FSHD1 (95% of those affected) and FSHD2. Although both types have different genetic causes, their symptoms and signs are the same. FSHD1 is caused by abnormal expression of the DUX4 gene located in the D4Z4 region of chromosome 4, while in FSHD2, there is a mutation in the D4Z4 region of the SMCHD1 gene . In a study by Wohlgemuth et al., the proportion of symptomatic mutation carriers was 58% . However, the high proportions of consanguineous marriages may have contributed to the high family history in our study.
In preparing for clinical trials and improving clinical care, it is crucial to understand what symptoms are most frequently experienced and essential to patients with FSHD . A study by Hamel et al reported losses mostly in the shoulders or arms (96.9%) and limitations in activities (94.7%), core weakness (93.8%), and fatigue (93.8%) . In the upper extremities, the muscles that fix and hold the scapula the scapular, especially the trapezius and serratus anterior, are frequently involved. This is the result of FSHD with asymmetrical, bilaterally involved scapular blades affecting the BI . Symptoms, such as periscapular weakness, winged scapula, and facial muscle weakness we detected in our study are compatible with the literature. Since facial muscle weakness is not evident at the beginning of FSHD, symptoms of limited lip movements such as keeping eyes open while sleeping, using a straw, and whistling can be seen. Normally, a difference in strength loss is expected between the two extremities. In our cases, it may be due to the patient’s inability to cooperate during the measurement and the lack of sensitivity of the measurement technique. However, if digital myometers were used instead of manual measurement to enable a more precise measurement of muscle strength, a significant observation could be confirmed. Winged scapula can also be seen in other muscle diseases, but they are affected asymmetrically.
In many studies, FSHD has not found any pharmacological evidence that preserves strength and slows muscle loss, and it has been found to be effective in maintaining functional status in terms of scapula fixation, individualized, different-intensity strengthening, aerobic exercises, since the diagnosis . A few studies have worked towards the treatment of physical limitations and fatigue symptoms, aerobic exercise has succeeded in relieving chronic fatigue and increasing physical activity and fitness .
In 2016, at-home clinical trial of exercise therapy for FSHD patients investigated the benefit of combined aerobic and strength programs. The results showed that individuals participating in a 6-month program had significantly improved muscle function without further damage to their diseased tissues . In severe pathological conditions, a physical and rehabilitation program alone may not be sufficient for treatment to correct functional limitations. Therefore, assistive devices can be used to add BI and FAC according to the specific therapeutic needs of each patient. The disease can be partially restored using low ankle-foot-orthoses or knee-ankle-foot orthoses .
When we measured the BI and FAC values on the first and last day of the rehabilitation process, we found a significant positive change in the values of the patients who were taken into active rehabilitation. We applied an ankle orthosis to those with walking potential and severe drop foot. We saw a significant increase in BI and FAC values.
In the evaluation made at the end of the program, it was observed that although there was no significant increase in muscle strength, the proportions of balance loss and falling decreased considerably, and there was an improvement in daily living activities and walking. This was mostly attributed to not motivating the patients, disuse atrophy, and loss of strength. Although we focused more on strengthening, it was seen that when considered on a patient basis, each exercise was effective and beneficial separately.
Since there is no definitive treatment for FSHM, the effectiveness of rehabilitation is expressed in every piece of information, but a standard program has not been established so far. Other scales can be developed to better measure the effectiveness of rehabilitation, and we concluded that the BI and FAC scales are easy to apply and can be used in the rehabilitation program of these patients. Additionally, since the disease is genetically inherited, patients should be directed to genetic counseling for information about the risk of genetic transmission. Since the condition is not known enough both in the community and among the primary health care personnel, it is diagnosed late. Therefore, we believe that training of the society and health personnel will be beneficial. Besides, further studies are needed to provide information about the frequency of this disease in the Turkish population.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Tawil R. Facioscapulohumeral muscular dystrophy. Handb Clin Neurol. 2018;148: 541-8.
2. Statland JM, Tawil R. Facioscapulohumeral Muscular Dystrophy. Continuum: (Minneap Minn). 2016; 22(6):1916–31.
3. Lin XD, He JJ, Lin F, Chen HZ, Xu LQ, Hu W, et al. A “triple trouble” case of facioscapulohumeral muscular dystrophy accompanied by peripheral neuropathy and myoclonic epilepsy. Chin Med J. 2018; 131 (18): 2164-71.
4. Chen TH, Wu YZ, Tseng YH. Early-onset infantile facioscapulohumeral muscular dystrophy: a timely review. Int J Mol Sci. 2020; 21(20):7783.
5. Hamel J, Tawil R. Facioscapulohumeral muscular dystrophy: Update on pathogenesis and future treatments. Neurotherapeutics. 2018;15 (4): 863–71.
6. Bankolé LC, Millet GY, Temesi J, Bachasson D, Ravelojaona M, Wuyam B, et al. Safety and efficacy of a 6-month home-based exercise program in patients with facioscapulohumeral muscular dystrophy A randomized controlled trial. Medicine. 2016; 95(31): 1-10.
7. Andersen G, Prahm KP, Dahlqvist JR, Citirak G, Vissing J. Aerobic training and postexercise protein in facioscapulohumeral muscular dystrophy. Neurology. 2015;85(5):396-403.
8. Faux-Nightingale A, Kulshrestha R, Emery N, Pandyan A, Willis T, Philp F. Upper Limb Rehabilitation in Facioscapulohumeral Muscular Dystrophy: A Patients’ Perspective. Arch Rehabil Res Clin Transl. 2021; 3(4): 100157.
9. Barthel D, Mahoney F. Functional evaluation: The Barthel Index. Md State Med J. 1965;14:61-65.
10. Kucukdeveci AA, Yavuzer G, Tennant A, SuSulfur, Sonel B, ArBrazil. Adaptation of the modified Barthel Index for use in physical medicine and rehabilitation in Turkey. Scand J Rehabil Med. 2000;32(2): 87-92.
11. Holden MK, Gill KM, Magliozzi MR, Nathan J, Piehl-Baker L. Clinical gait assessment in the neurologically impaired. Reliability and meaningfulness. Physical Therapy. 1984;64 (1):35–40.
12. Clarkson HM. Musculoskeletal assessment: joint range of motion and manual muscle strength. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2000.
13. Orrell RW. Facioscapulohumeral dystrophy and scapuloperoneal syndromes. Handb Clin Neurol.2011;101:167-80.
14. Johanna H, Tawil R. Facioscapulohumeral muscular dystrophy: Update on pathogenesis and future treatments. Neurotherapeutics. 2018; 15(4): 863–71.
15. Wohlgemuth M, Lemmers RJ, Jonker M, van der Kooi E, Horlings CG, van Egelen BG, et al. A family-based study into penetrance in facioscapulohumeral muscular dystrophy type 1. Neurology. 2018;91(5):e444–54.
16. Bakker M, Schipper K, Geurts AC, Abma TA. It’s not just physical: a qualitative study regarding the illness experiences of people with facioscapulohumeral muscular dystrophy. Disabil Rehabil. 2017;39(10):978–86.
17. Hamel J, Johnson N, Tawil R, Dilek N, McDermott MP, Heatwhole C. Patient-reported symptoms in facioscapulohumeral muscular dystrophy (PRISM-FSHD). Neurology. 2019;93(12):e1180–92.
18. Mul K, Lassche S, Voermans NC, Padberg GW, Horlings CG, van Engelen BG. What’s in a name? The clinical features of facioscapulohumeral muscular dystrophy. Pract Neurol. 2016;16(3):201–7.
19. Tawil R, Kissel JT, Heatwole C, Pandya S, Gronseth G, Benatar M. Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy. Neurology. 2015; 85(4): 357–64.
20. Lu J, Yao Z, Yang Y, Zhang C, Zhang J, Zhang Y. Management strategies in facioscapulohumeral muscular dystrophy. Intractable Rare Dis Res. 2019;8(1):9–13.
Download attachments: 10.4328:ACAM.21129
Askeri Turken. The effect of rehabilitation in patients with facioscapulohumeral muscular dystrophy: A prospective clinical study. Ann Clin Anal Med 2022;13(7):802-806
Nasogastric tube placement verification with ultrasound by emergency nurses
Birdal Güllüpınar 1, Caner Sağlam 1, Arif Karagöz 2, Shikha Tandon 3, Erden Erol Ünlüer 4
1 Department of Emergency Medicine, Izmir Bozyaka Training and Resarch Hospital, Izmir, Turkey, 2 Department of Emergency Medicine, Izmir Çiğli Training Hospital, Izmir, Turkey, 3 Department of Emergency Medicine, Fortis Hospital, Mohali, India, 4 Department of Emergency Medicine, University of Medical Sciences, Izmir Bozyaka Training and Resarch Hospital, İzmir, Turkey
DOI: 10.4328/ACAM.21180 Received: 2022-04-10 Accepted: 2022-06-07 Published Online: 2022-06-07 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):807-811
Corresponding Author: Birdal Güllüpınar, Department of Emergency Medicine, Izmir Bozyaka Training and Resarch Hospital, Izmir, Turkey. E-mail: firstname.lastname@example.org P: +90 232 250 50 50 / +90 541 940 03 69 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6657-5654
Aim: Nasogastric tube placement is a common procedure. Its insertion can lead to pulmonary complications, perforation, and even death. It is imperative to confirm the placement of the nasogastric tube. Ultrasound is a diagnostic method which can be used to confirm nasogastric tube placement. It has been used successfully not only by physicians but by nurses as well. We aimed to determine the skills of emergency nurses to use the ultrasound for the confirmation of nasogastric tube placement after ultrasound training.
Material and Methods: This study is a single-center, prospective and single-blind study. The study was performed to evaluate the ability of emergency nurses to confirm correct nasogastric tube placement. Six emergency nurses were given theoretical education and hands-on training about ultrasound. They confirmed the location of the nasogastric tube using ultrasound.
Results: A total of 84 patients were included in the study. According to the radiograph, the tube was not in the stomach in two out of 84 patients. While ultrasound verified that the tube was not in the stomach for 5 patients, it detected these two patients. The sensitivity and specificity of ultrasound performed by nurses were 96.34% and 100%, respectively. The area under the curve calculated for the predictive power of the nurses’ ultrasound findings according to the radiography results was found to be 0.982 and statistically significant (p<,0.0001).
Discussion: Ultrasound can be performed by nurses the confirmation of correct nasogastric tube placement. Additionally, ultrasound may not be able to eliminate but significantly reduce the need for radiography.
Keywords: Nasogastric Tube, Enteral Nutrition, Emergency Nurse, Emergency Department, Point-of-care Ultrasound
Nasogastric tube (NGT) placement is a common procedure for diagnosis and treatment in the emergency department (ED) and intensive care unit (ICU). It is most commonly used for gastric decompression, drug administration and enteral nutrition [1,2]. Enteral nutrition is a vital component in the care of critically ill patients . Both NGT placement and enteral feeding are routine practices, generally performed by nurses. In the USA, approximately 1,2 million NGTs are inserted annually for enteral nutrition in adult and pediatric patients . Although NGT insertion is generally seen as a simple uncomplicated procedure, it actually requires skill and expertise . NGT insertion can lead to pulmonary complications (pneumothorax, pneumomediastinum, pneumonia, pulmonary hemorrhage, empyema, hemothorax, bronchopleural fistula), perforation, and even death . Due to these reasons, it is imperative to confirm the placement of the NGT. In critically ill patients who are uncooperative, have anatomical abnormalities and lack a swallowing reflex, the procedure is difficult and hence the risk of complications increases . The misplacement rate of NGT has been reported between 0.3% and 8%, but the exact frequency is tough to estimate .
The recommended methods to confirm NGT position are auscultation, pH measurement, capnography, and radiography . It has been reported that pH measurement does not always give accurate results due to proton pump inhibitors or H2 receptor antagonists being used in the treatment of critical patients commonly [9,10]. It has been shown that the auscultation method, frequently used by nurses, is not safe enough in patients with lung localization . Capnography, on the other hand, may give false results because the NGT is inserted in the mouth or throat. It has also been reported that the capnogram alone does not fully reflect the tube position [12,13]. With these tests having limitations in confirming NGT, radiography remains the gold standard diagnostic method, but it carries a high cost and radiation .
In EDs and ICUs, Ultrasound (US) is a diagnostic method, which can be used to confirm NGT placement as it can be applied at bedside, is easier, faster, inexpensive, and does not expose patient to radiation . In recent years, US has been used successfully not only by physicians but by nurses as well. Based on the available evidence, it is shown that nurses have performed peripheral vascular access under US guidance, detected B lines and pleural effusion in heart failure, volume evaluation in hemodialysis patients [15-17]. To the best of our knowledge, there is no study in which emergency nurses have performed US-guided NGT placement. In this study, we aimed to determine the skills of emergency nurses in using US for the confirmation of NGT placement following US training and later compare the same with radiography.
Material and Methods
This study is a single-center, prospective and single-blind study. The study was carried out in the 2nd level ICU. In our hospital, 2nd level intensive care unit is managed by emergency physicians. The study was approved by Bozyaka Training and Research Hospital ethics committee and was conducted in accordance with the Declaration of Helsinki. Patients who were admitted to the ICU between August 2021 and October 2021 and were 18 years or older with an indication for enteral nutrition were included in the study. Indication for enteral nutrition was determined by the specialist in charge of the ICU. Informed consent was obtained from the patients /relatives. The study was approved by the ethical review board (University of Medical Sciences Izmir Bozyaka Training and Research Hospital – non-interventional clinical trials ethics committee, number: 2021/170 and date:13/10/2021).
Patients under the age of 18, pregnant, those having undergone neck surgery/gastric bypass surgery, with any anatomical deformity, with a history of midface injury and/or skull base fracture, esophageal stenosis or alkaline injury, severe coagulopathy, and/or having an open wound in the area where US had to be applied, and those who did not consent were excluded from the study.
This study was planned in two stages. In the first stage, a training program was conducted to train all emergency nurses. Nurses participating in the study had no previous formal training in confirming NGT placement under US guidance. Within the scope of this training program, 6 nurses with at least 5 years of professional experience were given theoretical information about US-confirmation for NGT application, and training videos for the same were played for 30 minutes. Following this schedule, hands-on training was imparted by an emergency physician carrying more than 20 years of experience in Point-of-Care US. European-accredited ultrasonography courses were organized so as to get used to both the use of US and stomach anatomy in patients who had undergone NGT placement. After the training program, emergency nurses were instructed to perform ten successful NGT placement verifications with US under the supervision of the same physician.
Six emergency nurses working in Bozyaka Training and Research Hospital’s 2nd level ICU, with at least 5 years of experience and voluntarily willing to participate in the study, took part in this study.
NGT length was determined by measuring the distance from the patient’s nose tip to the earlobe tip and then to the xiphoid process and then adding 10 cm to this measurement. The procedure was performed on the patients by selecting the appropriate nostril, lubricating the tip of the tube with 0.9% saline solution, marking the location of the measured tube with hypoallergenic tape, inserting the tube from the selected nostril to the mark, and fixing the tube to the nose. NGT was placed blindly by nurses responsible for the patient’s care. The same type and brand of NGT (Levin® polyurethane, radiopaque) was used in the patients. Tube size used was that of 16 French. After the NGT was placed, the nurse in charge of the study was informed. Mindray® M5 (Mindray Medical Corporation, Shenzhen, China) US machine equipped with a 5 MHz curved array probe was used for US probe placed on the subxiphoid region and then directed towards the left upper abdominal quadrant to visualize the stomach area. To confirm the location of the NGT, 20 cc of air was injected with a 50 cc pine-tipped syringe, and an image of the dynamic hyperechogenic air shadow in the stomach was seen by US. Finally, chest X-ray was taken for all patients. These radiographs were interpreted blindly by two emergency medicine specialists with at least ten years of emergency department experience. Radiography was considered the gold standard for verification of NGT placement.
Collecting the Data
Demographic data of the patients (age, gender, body mass index), vital signs, if they were intubated/not, confirmation of the location of the tube by US and radiography, and related complications were recorded.
A normality analysis of continuous measures was performed by the Kolmogorov–Smirnov analysis, Shapiro–Wilk test, and Q-Q plots. In statistical analysis, evaluation of inter-observer agreement, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy and AUC area calculations were made with SPSS 26th version. In all statistical evaluations, p<0.05 was accepted as the statistical significance limit value, and a 95% confidence interval was used for the mean values of all parameters.
A total of 84 patients (52 malee, 32 females) with a mean age of 69.77±14.31 years were included in the study. Clinical and demographic characteristics of the patients are summarized in Table 1.
According to the radiograph, the tube was not in the stomach in two out of 84 patients. While US verified that the tube was not in stomach for 5 patients, it detected these two patients. In these patients, the tube was folded in the pharynx. The sensitivity and specificity of US performed by nurses were 96.3% and 100%, respectively, PPV was 100% and NPV was 40% (Table 2). In the Kappa agreement analysis for the compatibility of the US results for nurses and radiography results, US findings and radiography results of all nurses were mostly consistent (kappa=0.556)(p=0.000) (Table 3).
The area under the curve (AUC) value calculated in the Receiver Operating Characteristic (ROC) analysis performed for the predictive power of the nurses’ US findings compared to
radiography results was found to be 0.982 and statistically significant (p<0.0001) (Table 2) (Figure 1).
In this study, we compared nurse-performed US with radiography to confirm the location of NGT in patients in ICU. Our results show that nurses can confirm NGT placement using US with high precision after a short training. This study was carried out with 6 nurses with no experience in US. Hence, we concluded that sonographic confirmation of NGT placement should be explored as a valuable skill for non-physicians in the intensive care setting.
Currently, none of the NGT placement verification methods have been proven to be 100% reliable. Although radiography is recommended as the gold standard confirmation method, it is impractical, for confirmation of NGT . Additionally, repeated radiation exposures, long waiting hours, feeding delays, additional costs and misinterpretations are limitations of radiography [8,19]. Since radiography is impractical and has many limitations, it is important to explore new and practical methods for confirming NGT placement [18,20].
US is one of the promising additional verification methods. In recent years, many studies have reported that US provides good diagnostic accuracy and helps confirm NGT location [8,9,14]. Zatelli et al. investigated the diagnostic accuracy of 4-point ultrasonography to confirm NGT location in 114 intubated patients hospitalized in the ICU and reported that US showed 100% sensitivity. However, this study was carried out by an intensive care specialist who was trained by a radiologist . A multicenter, prospective study by Chenaitia et al showed that US had 98.3% sensitivity and 100% specificity in confirming NGT placement in 130 patients intubated in a prehospital setting. In conclusion, they reported that US is an effective and reliable diagnostic method to confirm NGT location in prehospital settings . Atalay et al. found that radiography and sonography showed 100% sensitivity in confirming NGT placement in a prospective study in the pediatric ICU. They also reported that US, performed by a radiologist, is an effective and sensitive diagnostic procedure for confirming NGT location . According to the meta-analysis by Lin et al, the sensitivity of US was 93% and the specificity was 97%, and they reported that US provided a good diagnostic performance in predicting correct NGT placement . In their prospective study, Yıldırım et al. confirmed the position of the nasogastric tube by giving air-water mixture and auscultation with neck ultrasound and subxiphoid ultrasound in patients with indications for NGT placement in the ED. They found the sensitivity of subxiphoid US to be 78.72% and the specificity to be 100%. After the air-water mixture was given from NGT, the sensitivity reached 91.49% and the specificity reached 100%. In addition, positive and negative predictive values were found to be 100% and 33.33%, respectively . Mak and Tam investigated the efficacy of US to confirm NGT placement and the feasibility of using it as a primary level of reference. This method was found to have a sensitivity of 95.45% and a specificity of 100%, and they showed that US performed by nurses can provide good diagnostic imaging to confirm NGT location . Kim et al. conducted a study comparing the effectiveness of auscultation, pH measurement of gastric aspirates, and sonography to confirm NGT placement in unconscious patients in the ED. They found a sensitivity of 86.4%, a specificity of 66.7%, a positive predictive value of 97.4%, and a negative predictive value of 25% in confirming the NGT placement of US. They concluded that confirmation of NGT location with US can reduce complications and unnecessary radiation exposure . In our study, we showed that following a short training, nurses’ confirmation of the NGT location using US had a sensitivity of 96.3% and 100% specificity, 100% positive predictive value and 40% negative predictive value. The results of the US test in this study reflect the findings of other studies in which US has improved the diagnostic accuracy. Accordingly, it has been shown that nurses can also be used to confirm NGT placement in emergency and intensive care conditions.
According to the findings of this study, the high positive predictive value of using US can reduce the number of radiographs and the US image of dynamic fogging after air delivery from the tube may reduce misplacement and complications from misplacement. In this study, US examination appears to be a simple and rapid method for recognizing the correct positioning of the NGT in critically ill patients. This method is faster than traditional x-ray and can be used after a short training period. US is used when radiography is unavailable. Confirmation of NGT location by ultrasonography has the potential to reduce complications, save time, and reduce unnecessary radiation exposure. However, confirmation by chest X-ray is required when ultrasound cannot confirm the localization of the NGT by direct imaging or after a blow of water and air.
A few studies have reported that the failure of US to confirm correct NGT placement is due to gas interposition, and when NGT cannot be visualized in the stomach due to gas interposition, the diagnostic accuracy of dynamic fogging seen in the stomach for correct NGT placement [9,22]. Also, visualization of NGT at the neck is not sufficient to confirm the position of the tube because the tube may bend within the cervical esophagus and may not progress distally. For this purpose, US findings of dynamic fogging were evaluated in order to make US easier and faster for nurses to confirm NGT placement.
One of the limitations of this study was the small sample size. Secondly, US confirmed the correct placement of the NGT, but the reduced need for radiography and the delay between the placement of the NGT and initiation of feeding were not investigated. Finally, prospective randomized studies are required to show how sonographic applications would reduce the need for radiography and the complication rates associated with NGT placement.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Metheny NA, Krieger MM, Healey F, Meert KL. A review of guidelines to distinguish between gastric and pulmonary placement of nasogastric tubes. Heart Lung. 2019; 48(3):226-35.
2. McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig C, et al. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) J Parenter Enteral Nutr. 2016; 40(2):159-211.
3. Koopmann MC, Kudsk KA, Szotkowski MJ, Rees SM. A team-based protocol and electromagnetic technology eliminate feeding tube placement complications. Ann Surg. 2011; 253(2):287-302.
4. Fletcher J. Nutrition: safe practice in adult enteral tube feeding. Br J Nurs. 2011; 20(19):1234-9.
5. Bennetzen LV, Håkonsen SJ, Svenningsen H, Larsen P. Diagnostic accuracy of methods used to verify nasogastric tube position in mechanically ventilated adult patients: a systematic review. JBI Database System Rev Implement Rep. 2015; 13(1):188-223.
6. Yang FH, Lin FY, Hwu YJ. The Feasibility Study of a Revised Standard Care Procedure on the Capacity of Nasogastric Tube Placement Verification Among Critical Care Nurses. J Nurs Res. 2019; 27(4):e31.
7. Pillai JB, Vegas A, Brister S. Thoracic complications of nasogastric tube: review of safe practice. Interact Cardiovasc Thorac Surg. 2005;4(5):429-33.
8. Lin T, Gifford W, Lan Y, Qin, X, Liu X, Wang J, et al. Diagnostic accuracy of ultrasonography for detecting nasogastric tube (NGT) placement in adults: A systematic review and meta analysis. Int J Nurs Stud. 2017; 71:80-8.
9. Kim HM, So BH, Jeong WJ, Choi SM, Park KN. The effectiveness of ultrasonography in verifying the placement of a nasogastric tube in patients with low consciousness at an emergency center. Scand J Trauma Resusc Emerg Med. 2012;20:38.
10. Boeykens K, Steeman E, Duysburgh I. Reliability of pH measurement and the auscultatory method to confirm the position of a nasogastric tube. Int J Nurs Stud. 2014; 51(11):1427–33.
11. Anderson L. Enteral feeding tubes: an overview of nursing care. Br J Nurs. 2019; 28(12):748-54.
12. Elpern EH, Killeen K, Talla E, Perez G, Gurka D. Capnometry and air insufflation for assessing initial placement of gastric tubes. Am J Crit Care. 2007; 16(6):544-50.
13. Ryu JA, Choi K, Yang JH, Lee DS, Suh GY, Jeon K, et al. Clinical usefulness of capnographic monitoring when inserting a feeding tube in critically ill patients: retrospective cohort study. BMC Anesthesiol. 2016; 16(1):122.
14 Vigneau C, Baudel JL, Guidet B, Offenstadt G, Maury E. Sonography as an alternative to radiography for nasogastric feeding tube location. Intensive Care Med. 2005;31(11):1570-72.
15. Edwards C, Jones J. Development and Implementation of an Ultrasound-Guided Peripheral Intravenous Catheter Program for Emergency Nurses. J Emerg Nurs. 2018;44(1):33-6.
16. Swamy V, Brainin P, Biering-Sørensen T, Platz E. Ability of non-physicians to perform and interpret lung ultrasound: A systematic review. Eur J Cardiovasc Nurs. 2019;18(6):474-83.
17. Steinwandel U, Gibson N, Towell A, Rippey JJR, Rosman J. Can a renal nurse assess fluid status using ultrasound on the inferior vena cava? A cross-sectional interrater study. Hemodial Int. 2018;22(2):261-9.
18. Clifford P, Heimall L, Brittingham L, Davis KF. Following the evidence: enteral tube placement and verification in neonates and young children. J Perinat Neonatal Nurs. 2015;29(2):149-E2.
19. Stock A, Gilbertson H, Babl FE. Confirming nasogastric tube position in the emergency department: pH testing is reliable. Pediatr Emerg Care. 2008;24(12):805-9.
20. Taylor SJ. Confirming nasogastric feeding tube position versus the need to feed. Intensive Crit Care Nurs. 2013;29(2):59-69.
21. Zatelli M, Vezzali N. 4-Point ultrasonography to confirm the correct position of the nasogastric tube in 114 critically ill patients. J Ultrasound. 2016;20(1):53-8.
22. Chenaitia H, Brun PM, Querellou E, Leyral J, Bessereau J, Aimé C, et al. Ultrasound to confirm gastric tube placement in prehospital management. Resuscitation. 2012;83(4):447-51.
23. Atalay YO, Aydin R, Ertugrul O, Gul SB, Polat AV, Paksu MS. Does Bedside Sonography Effectively Identify Nasogastric Tube Placements in Pediatric Critical Care Patients? Nutr Clin Pract. 2016;31(6):805-9.
24. Yıldırım Ç, Coşkun S, Gökhan Ş, Pamukçu Günaydın G, Özhasenekler A, Özkula U. Verifying the Placement of Nasogastric Tubes at an Emergency Center: Comparison of Ultrasound with Chest Radiograph. Emerg Med Int. 2018;2018:2370426
25. Mak MY, Tam G. Ultrasonography for nasogastric tube placement verification: an additional reference. Br J Community Nurs. 2020;25(7):328-34.
Download attachments: 10.4328:ACAM.21180
Birdal Güllüpınar, Caner Sağlam, Arif Karagöz, Shikha Tandon, Erden Erol Ünlüer.
Nasogastric tube placement verification with ultrasound by emergency nurses. Ann Clin Anal Med 2022;13(7):807-811
Relationships between pain severity and sleep quality in people with neck pain
Department of Physical Medicine and Rehabilitation, Diyarbakır Dağkapı State Hospital, Diyarbakır, Turkey
DOI: 10.4328/ACAM.21191 Received: 2022-04-19 Accepted: 2022-06-19 Published Online: 2022-06-27 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):812-815
Corresponding Author: Özkan Yükselmiş, Dr. Şeref İnalöz Sokak, 21100, Yenişehir, Diyarbakır. E-mail: email@example.com P: +90 0531 525 39 66 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1996-7030
Aim: Studies have shown that individuals with neck pain experience a severe deterioration in sleep quality, individuals with low sleep quality receive less benefit when they receive neck pain treatment, and decrease in sleep quality increases the symptoms of depression in individuals with severe neck pain.
In the literature, studies on pain and sleep quality in individuals with neck pain have been conducted. However, studies that include all of these factors and determine the relationship between each other are not included. In this context, the aim of our study was to determine the relationship between pain severity and sleep quality in individuals with neck pain.
Material and Methods The study included 89 volunteers aged 18-65 years with complaints of neck pain with a score of 4 and above according to the Neck Disability Index (BDI). The pain intensity of the individuals participating in the study was evaluated with the Visual Analog Scale (VAS), their sleep quality was evaluated with the Pittsburg Sleep Quality Index (PUKI), and their personal information was evaluated with the Personal Information Form.
Results: In our study, it was observed that there was a moderate positive relationship between PUKI and BDI. In our study, a moderate positive correlation was determined between the increase in pain intensity and the deterioration in sleep quality.
Discussion: It was determined that impaired sleep quality could lead to neck disability.
Keywords: Neck Pain, Sleep Quality, Pain Severity
Neck pain is an important health problem that is common in the world. Neck pain causes a decrease in the quality of life and limitation of daily living activities due to the difficulties it creates in physical functions. Neck pain, which has become one of the most important problems of modern society, affects approximately two-thirds of the adult population at some point in their lives. Non-specific neck pain may improve over time. However, 10% may recur or continue .
Neck pain restricts people’s activities of daily living, the quality of life and leads to loss of workforce. People often complain of headaches, limitations and pain during neck joint movements, upper extremity pain and difficulties in upper extremity movements . Studies have shown that individuals experiencing neck pain are psychologically negatively affected . Another factor associated with neck pain was reported as sleep in studies. Sleep has been emphasized as both a cause and a consequence of pain. This bidirectional relationship between sleep and pain has important implications for the clinical management of individuals with neck pain [3-4]. It has been determined that the decrease in sleep quality is seen at high rates in individuals with neck pain, individuals with low sleep quality gain less benefit if they receive treatment for neck pain, and decreased sleep quality increases the symptoms of depression in individuals with severe neck pain, and sleep problems are a risk factor for neck pain .
The presence of thoracic kyphosis was found in studies conducted on individuals with neck pain. In addition to the cervical region, it was determined that there is a relationship between the angles of the thoracic region and neck pain, and it was determined that the increase in thoracic kyphosis was associated with the severity of neck pain and impaired functionality of the neck region. It has been shown that the increase in thoracic kyphosis negatively affects cervical mobility. It has been stated that there is a relationship between thoracic kyphosis and postural changes in the cervical spine, and that thoracic posture should be evaluated in individuals with mechanical neck pain .
Sleep is a vital state of consciousness in which the interaction of the person with the environment is interrupted and may end with physical or sensory stimuli. Each individual’s circadian rhythm may be different, which is also called the biological clock. Sleep in the hierarchy of basic needs may differ for each person. However, sleeping less than seven hours continuously can cause some diseases, as well as an increase in pain sensation and concentration impairment .
In people with chronic pain, complaints such as difficulty in initiating and maintaining sleep, difficulty waking up in the morning, daytime sleepiness, snoring and nightmares are seen. Inadequacies in sleep quality due to chronic pain lead to adverse conditions that affect quality of life such as limitation of activity and functional disability. Up to 50 percent of people diagnosed with insomnia have had chronic pain. At the same time, people with insomnia have a high risk of chronic pain . Human and animal studies have shown that insufficient or interrupted sleep reduces pain-blocking mechanisms. Moreover, restoring good sleep increases the likelihood that persistent pain will pass over time .
It is stated that the decrease in sleep quality has a high prevalence in individuals with neck pain. At the same time, it has been stated that individuals with low sleep quality gain less benefit if they receive treatment for neck pain. In addition, decreased sleep quality has been shown to increase symptoms of depression in individuals with severe neck pain. In a systematic review, it was stated that sleep problems are a risk factor for neck pain .
In the literature, studies on pain and sleep quality in individuals with neck pain have been conducted. However, studies that include all these factors and determine the relationship between each other are not included. In this context, the aim of our study was to determine the relationship between pain severity and sleep quality in individuals with neck pain.
Material and Methods
The study included 89 volunteers aged 18-65 years who applied to Istanbul Aydın University Health Practices and Research Center with the complaint of neck pain between March and May 2021, with a score of 4 and above according to the Neck Disability Index (BDI).
Purpose of the research
The aim of our study was to determine the relationship between pain intensity and sleep quality in individuals with neck pain.
H1: There is a significant relationship between pain severity, disability, thoracic kyphosis, sleep quality and nomophobia in individuals with neck pain.
H2: There is no significant relationship between pain severity, disability, thoracic kyphosis, sleep quality and nomophobia in individuals with neck pain.
Limitations of the research
• Being in the range of 18-65
• Incomplete filling of the questionnaires used in the study
• Individuals with a test score above 4 according to the Neck Disability Index,
• Using drugs that will affect sleep quality
• Applying to Istanbul Aydın University Health Practices and Research Center due to neck pain between March-May 2021
The pain intensity of the individuals participating in the study was evaluated with the Visual Analog Scale (VAS), their sleep quality was evaluated with the Pittsburg Sleep Quality Index (PUKI), and their personal information was evaluated with the Personal Information Form.
Visual analog scale (VAS)
In order to evaluate the severity of pain, one of the individuals who stated that there was no pain at the left end, that is, at the starting point; At the end of the line, they were asked to mark the point showing their pain intensity on the 10 cm long horizontal line where the expressions declaring the most severe pain are included. The marked point was noted in cm .
Pittsburg sleep quality index (PUKI)
It was developed by Buysse et al. in 1989 . Its Turkish validity and reliability were demonstrated by Ağargün et al. in 1996 . The index consists of 24 questions and evaluates the sleep quality of the last month. Nineteen of the 24 questions in the survey were answered by the person; the other 5 questions were answered by the spouse or roommate of the person. These 5 questions were not included in the scoring. The 18 questions of the scale are grouped into 7 components. The components include information about sleep quality, time spent in sleep, medication used for sleep, sleep latency, sleep disorders. The sum of the scores in these components gives the PUKI score, and the total score takes a value between 0 and 21. In our study, the sleep quality of individuals was interpreted as good (0-5 points) or poor (5 and above).
The study protocol was approved by the Diyarbakır Dağkapı State Hospital Ethics Committee (Approval No.: 28 Date: 11 February, 2022).
Eighty-nine volunteers aged 18-65 years who applied to Istanbul Aydın University Health Application and Research Center due to neck pain and had a test score of 4 and above according to BDI were included in the study. Females (n=56) accounted for 62.92 percent of the individuals participating in the research and 37.08 percent were males (n=33). The mean age of the participants whose age range was between 18 and 53 years, was calculated as 28.48 ±8.57 years and the mean Body Mass Index (BMI) was calculated as 23.56±3.84 kg/m2; 62.92 percent of the individuals included in the study were working. While 74.15 percent of individuals were single, 25.85 percent were married; 32.58 percent of the individuals included in the study used cigarettes and 40.35 percent use alcohol (Table 1).
The frequency distribution of the disease histories of the individuals participating in the study is presented in Table 2. Accordingly, 40 participants (45.45%) had a previous surgical operation. The number of individuals with chronic diseases was 24 (27.91 percent). It was observed that 15 individuals (17.24 percent) used a regular drug. Thirty-four (39.08%) of the individuals included in the study were doing regular exercise. In addition, when the daily sitting time of individuals was examined, 40.45 percent of them were 4-6 hours (36 individuals), 24.72 percent were 0-3 hours (22 individuals), 21.35 percent were 7-9 hours (19 individuals) and 13.48 percent spent 10-12 hours (12 individuals) sitting.
The descriptive statistical distribution of the BDI and VAS measurements of the individuals participating in the study was presented. The mean VAS was calculated as 5.16±2.35, the mean BDI as 11.19±5.45, and the mean PUKI as 10.93±3.09.
There was no statistically significant difference in BDI scores according to gender (p>0.05). Age and BMI, which are demographic variables, were statistically significantly different according to the gender of the participants (p<0.05). No statistically significant difference was observed in the comparison of PUKI and VAS measurement values according to gender (p>0.05).
There was moderate positive (r=0.437) correlation between BDI and PUKI; A statistically significant positive correlation (r=0.577) was found between VAS (p<0.05). However, there was no statistically significant relationship between BDI and age, and BDI and BMI scores (p>0.05).
There was moderate positive correlation (r=0.401) between PUKI and VAS; A statistically significant correlation was found between BMI and weak positive (r=0.241) (p<0.05).
In our study the relationship between neck pain, functional disability, pain severity, sleep quality, nomophobia status, and the presence of hyperkyphosis was examined in this study on neck pain, which was determined to reduce daily life and occupational quality and create a financial burden on individuals.
Although debate continues about the age range where neck pain is most common, it has been suggested that the most common age is 45-64, and the age at which it peaks is 50. It has been stated that it is more common in women aged 40 and over. With the exclusion of pathological causes that may cause neck pain, an increase in neck pain as a result of degenerative changes in the neck region with advancing age has been reported . Except for neck pain, it has been determined that women experience more pain than men and go to physiotherapy centers more frequently . However, in our study, it was determined that the individuals experiencing neck pain were males, and the average age of males was higher than that of females. When the average age of our study is examined, it appears to be 28.42 years, which is a younger population. It was commented that different results were obtained with the literature due to the fact that the population was younger, the male population was larger, and the age range of the male population was longer. In a review study, it was stated that there were inconsistent results between nonspecific neck pain and female gender in a younger population aged between 18-29 years, and that more studies should be done to determine the risk factors associated with neck pain .
Neck pain is the most common among mobile device users and neck flexion posture is said to be associated with this problem . It is stated that nomophobic students have text-neck and SMS thumb syndromes and there is a relationship between nomophobia and neck disability .
The bidirectional relationship between pain and sleep problems leads to severe and longer duration of symptoms . It has been stated that decreased sleep quality has a high prevalence in individuals with neck pain, and sleep problems are a risk factor for neck pain . Carmen et al., in their study examining sleep quality in individuals with mechanical neck pain and whiplash-related neck pain, reported that there was a relationship between an increase in the severity of sleep quality disorders and an increase in pain severity, and the cycle between pain and sleep disorders should be considered in the treatment of individuals with neck pain . Scarabottolo et al  evaluated the relationship between low back pain and neck pain and sleep quality in a study on adolescents; 1011 adolescents participated in the study and it was determined that low back pain and neck pain were associated with poor sleep quality. Consistent with the literature, in our study, a moderate positive correlation was determined between the increase in pain intensity and the deterioration in sleep quality. Muñoz-Muñoz et al.  evaluated the relationship between myofascial trigger points, pain, neck disability and sleep quality in individuals with mechanical neck pain, and evaluated sleep quality with PUKI and neck disability levels with BDI, similar to our study. At the end of the study, it was shown that the deterioration in sleep quality was associated with neck disability. In our study, it was observed that there was a moderate positive relationship between PUKI and BDI, and it was determined that impaired sleep quality could lead to neck disability.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Elbinoune I, Amine B, Shyen S, Gueddari S, Abouqal R, Hajjaj-Hassouni N. Chronic neck pain and anxiety-depression: prevalence and associated risk factors. Pan African Medical Journal. 2016; 24:89.
2. Hoy DG, Protani M, De R, Buchbinder R. The epidemiology of neck pain. Best Pract Res Clin Rheumatol. 2010;24(6):783-92.
3. Szeto GPY, Straker L, Raine S. A field comparison of neck and shoulder postures in symptomatic and asymptomatic office workers. Appl Ergon. 2002; 33(1):75-84.
4. Yıldırım C, Sumuer E, Adnan M, Yıldırım S. A growing fear: Prevalence of nomophobia among Turkish college students. Information Development. 2016; 32(5):1-10.
5. Andreucci A, Madrid-Valero J J, Ferreira PH, Ordoñana JR. Sleep quality and chronic neck pain: a cotwin study. J Clin Sleep Med. 2020; 16(5):679–87.
6. Joshi S, Balthillaya G, Neelapala Y. Thoracic posture and mobility in mechanical neck pain population: a review of the literature. Asian Spine J. 2019; 13(5):849–60.
7. Siegel JM. The neurobiology of sleep. Semin Neurol.. 2009; 29(4):277-96.
8. Morin CM, LeBlanc M, Daley M, Gregoire JP, Mérette C. Epidemiology of insomnia: Prevalence, self-help treatments, consultations, and determinants of help-seeking behaviors. Sleep Med. 2006; 7(2):123-30.
9. Long AC, Krishnamurthy V, Palermo TM., Sleep disturbances in school- age children with chronic pain. J Pediatr Psychol. 2008; 33(3):258- 68.
10. Kahl C, Cleland J. Visual analogue scale, numeric pain rating scale and the McGill Pain Questionnaire: an overview of psychometric properties. Physical Therapy Reviews. 2005;10(2):123-8.
11. Buysse DJ, Reynolds CF, Monk TH., Hoch CC, Yeager AL, Kupfer DJ. Quantification of subjective sleep quality in healthy elderly men and women using the Pittsburgh Sleep Quality Index (PSQI). Sleep. 1991; 14(4):331.
12. Agargün MY, Kara H, Anlar O. Pittsburgh uyku kalite indeksinin geçerliliği ve güvenirliği (The validity and reliability of the Pittsburgh sleep quality index). Türk Psikiyatri Dergisi/ Turkish Journal of Psychiatry. 1996; 7:107-15.
13. Ghaderi F, Javanshir K, Jafarabadi MA, Moghadam AN, Arab AM. Chronic neck pain and muscle activation characteristics of the shoulder complex. J Bodyw Mov Ther. 2019;23(4):913-17.
14. O’Leary S, Cagnie B, Reeve A, Jull G, Elliott JM. Is there altered activity of the extensor muscles in chronic mechanical neck pain? A functional magnetic resonance imaging study. Arch Phys Med Rehabil. 2011;92(6):929-34.
15. Jahre H, Grotle M, Smedbråten K, Dunn KM, Øiestad BE. Risk factors for non-specific neck pain in young adults. A systematic review. BMC Musculoskelet Disord. 2020; 21(1). DOI:10.1186/s12891-020-03379-y
16. Xie Y, Szeto G, Dai J. Prevalence and risk factors associated with musculoskeletal complaints among users of mobile handheld devices: A systematic review. Appl Ergon. 2017; 59(Pt A):132–42.
17. Ahmed S, Akter R, Pokhrel N, Samuel AS. Prevalence of text neck syndrome and SMS thumb among smartphone users in college-going students: a cross-sectional survey study. J Public Health (Berl.) 2021; 29:411–16.
18. Husak AJ, Bair MJ. Chronic pain and sleep disturbances: A pragmatic review of their relationships, comorbidities, and treatments. Pain Medicine (Malden, Mass.). 2020; 21 (6):1142-52.
19. Valenza MC, Valenza G, González-Jiménez E, De-la-Llave-Rincón A I, Arroyo- Morales M, Fernández-de-Las-Peñas C. Alteration in sleep quality in patients with mechanical insidious neck pain and whiplash-associated neck pain. Am J Phys Med Rehabil. 2012; 91(7):584–91.
20. Scarabottolo C C, Pinto RZ, Oliveira CB, Tebar WR, Saraiva B, Morelhão PK. et al. Back and neck pain and poor sleep quality in adolescents are associated even after controlling for confounding factors: An epidemiological study. Sleep Sci. 2020; 13(2):107–12.
21. Muñoz-Muñoz S, Muñoz-García MT, Alburquerque-Sendín F, Arroyo-Morales M, Fernández-de-las-Peñas C. Myofascial trigger points, pain, disability, and sleep quality in individuals with mechanical neck pain. J Manipulative Physiol Ther. 2012; 35(8):608–13.
Download attachments: 10.4328:ACAM.21191
Özkan Yükselmiş. Relationships between pain severity and sleep quality in people with neck pain. Ann Clin Anal Med 2022;13(7):812-815
Assessment of inflammatory markers in ulcerative colitis and association with the disease
Ahmed Ramiz Baykan 1, Serkan Cerrah 1, Büşra Karahan 2, Sedat Çiftel 1, Ayetullah Temiz 3, Elmas Kasap 4
1 Gastroenterology, Erzurum Regional Training and Research Hospital, Erzurum, 2 Department of Internal Medicine, Erzurum Regional Training and Research Hospital, Erzurum, 3 Department of General surgery, Regional Training and Research Hospital, Erzurum, 4 Department of Gastroenterology, Celal Bayar University, Manisa, Turkey
DOI: 10.4328/ACAM.21202 Received: 2022-04-21 Accepted: 2022-06-16 Published Online: 2022-06-19 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):816-820
Corresponding Author: Ahmed Ramiz Baykan, Gastroenterology, Erzurum Regional Training and Research Hospital, Erzurum, Turkey. E-mail: firstname.lastname@example.org P: +90 555 506 18 78 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6798-0240
Aim: In daily routine practice, non-invasive tests are needed in addition to symptoms to determine activation in patients with ulcerative colitis (UC). In this study, it was aimed to compare the results of non-invasive tests used frequently at the time of diagnosis of patients diagnosed with UC with endoscopic severity.
Material and Methods: This retrospective cohort study was carried out on 202 patients between 2018 and 2022. The white blood count (WBC), mean platelet volume (MPV), hemoglobin (HB), hematocrit (Hct), C-reactive protein (CRP), albumin, neutrophil-lymphocyte ratio (NLR), CRP-albumin ratio (CAR), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR) of the patients were calculated at the time of diagnosis. The severity of UC was assessed via colonoscopy using the Mayo Endoscopic Subscore (Mayo Score). In addition, patients with active UC were re-evaluated during remission to calculate the predictive values of tests in UC activation and severity.
Results: There was a significant correlation between the Mayo Subscore and CRP (r: 0.34, P < 0.01), WBC (r: 0.23, P = 0.01), HB (r: –0.23, P = 0.01), NLR (r: 0.49, P < 0.01), CAR (r: 0.51, P < 0.01), PLR (r: 0.32, P < 0.01), and LMR (r: –0.34, P < 0.01). The sub-assessment, taking colon involvement into consideration, showed a correlation between the Mayo Subscore and NLR and CAR with pancolitis, left colon involvement, and distal colitis. The highest area under the curve (AUC) value, found in the tests, was with the CAR (0.919). When the CAR cut-off value was taken as 0.11, the sensitivity was 80.2%, and the specificity was 94.4%, indicating UC activation.
Discussion: Inflammatory markers in UC have adequate sensitivity in indicating activation, and they also aid in the identification of severity of involvement in patients.
Keywords: Ulcerative Colitis, CRP-Albumin Ratio, Neutrophil-Lymphocyte Ratio
Ulcerative colitis (UC) is characterized by mucosal inflammation that can exacerbate and remit over time. A recent important development is that the treatment of UC is based on mucosal inflammation rather than symptoms, as it provides better results [1,2]. Symptoms do not represent the presence or severity of mucosal inflammation consistently. In fact, it was revealed that symptoms did not show endoscopic activity in 30% of patients with UC .
Determining the severity of intestinal inflammation in UC is very important for the clinician, and remains a challenging problem at the same time. Although endoscopic methods are the most reliable approach in combination with biopsy, their invasive and expensive nature are the disadvantages of the method. Another significant downside is that endoscopic procedures posed a high risk of transmission during the recent COVID-19 pandemic. As a matter of fact, endoscopic procedures decreased by 95% during this period . Non-invasive tests used at this stage are widely available, and play a key role with their modest accuracy. In this study, it was aimed to determine which marker best predicts intestinal inflammation in patients diagnosed with UC by comparing the results of noninvasive tests at the time of application to our clinic with the results of the subsequent colonoscopic evaluation.
Material and Methods
Study design and patients
The retrospective cohort study was carried out from January 1, 2018 to 2022. Patients over the age of 18 who were diagnosed with UC via colonoscopy, performed after applying to the gastroenterology clinic were included in the study. Patients who had been previously diagnosed with UC and were on medication, those with acute or chronic renal failure, cirrhosis, cancer, or acute or chronic infectious diseases, with a history of immunosuppressive use at the follow-up examination, blood assays and colonoscopy exceeding two weeks were excluded from the study. The control group consisted of patients without comorbidities in a similar age group. Patients included in the study were re-evaluated during clinical remission. Follow-up blood tests were conducted for patients who were in remission and did not use immunosuppressants.
Blood samples of the patients were taken after 8 h of fasting at the time of diagnosis, and at the follow-up examination. The white blood count (WBC), neutrophil, lymphocyte, monocyte, mean platelet volume (MPV), hemoglobin (Hb), hematocrit (Hct), C-reactive protein (CRP), and albumin results were evaluated. The neutrophil-lymphocyte ratio (NLR), CRP-albumin ratio (CAR), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR) were calculated using current results. The severity of UC was assessed via colonoscopy, using the Mayo Endoscopic Subscore (Mayo Subscore).
Accordingly, normal mucosa and inactive disease were rated Mayo 0, and severe disease (spontaneous bleeding, large ulcerations) was rated up to Mayo 3. The involvement of the disease was evaluated in 3 groups, as distal colitis, left colon involvement, and pancolitis.
Endoscopic imaging was carried out using a Fujinon ED-450XT5 device (Minato City, Tokyo, Japan) by 3 experienced gastroenterologists. Biochemical parameters were studied with a Siemens Atellica analyzer (Malvern, PA, USA), and the hemogram was studied with Sysmex xn 9000 device (Kobe, Japan).
This retrospective cohort study was approved by the Ethics Committee of Erzurum Training and Research Hospital in accordance with the Declaration of Helsinki (Ethics Committee approval number: 2021/23-294).
Statistical analysis was performed using SPSS Statistics for Windows 17.0 (SPSS Inc., Chicago, IL, USA). Data were expressed as the mean ± SD or median with range. Categorical parameters were compared using the χ2 or Fisher’s exact test when appropriate, and continuous variables were compared using the student t-test. P < 0.05 was considered statistically significant. The Spearman correlation analysis was used to determine the association of the Mayo Subscore and the inflammation markers. The relationship between the localization of involvement in the colon and the levels of markers was evaluated using ANOVA. The values of the inflammatory markers in predicting activation in patients with inactive UC were evaluated using receiver operating characteristic (ROC) analysis. Optimum cut-off values, sensitivity, specificity, negative predictive values, and positive predictive values were calculated.
The study was carried out on 202 patients, consisting of 114 males and 88 females. The average age was 46.5 ± 13.3 years among male participants, and 42.9 ± 15.8 years among the female participants (P = 0.09). There was a significant difference between the patients with active disease and the control group in terms of the WBC, hemoglobin, platelet, CRP, albumin, NLR, CAR, and PLR. The group of patients in remission and the control group were similar, except for hemoglobin values (P < 0.001) (Table: 1).
A significant correlation between the Mayo Subscore and CRP (r: 0.34, P < 0.01), WBC (r: 0.23, P = 0.01), hemoglobin (r: –0.23, P = 0.01), NLR (r: 0.49, P < 0.01), CAR (r: 0.51, P < 0.01), PLR (r: 0.32, P < 0.01), LMR (r: –0.34, P < 0.01) was found in the Spearman correlation analysis in the patients with UC. As shown in Table 2, the sub-assessment, taking colon involvement into consideration, showed a correlation between the Mayo Subscore and NLR and CAR with pancolitis, left colon involvement, and distal colitis.
When UC involvement localization in the colon and the WBC, CRP, CAR, NLR, PLR levels were compared in the post hoc analysis, the NLR and WBC values were significantly higher in the patients with pancolitis compared to distal colitis involvement (P = 0.01 and P = 0.004, respectively).
The values of the inflammation markers (WBC, NLR, CAR, LMR, PLR) in predicting activation in the patients with inactive UC were evaluated using ROC analysis. As shown in Table 3, the highest area under the curve (AUC) value was also found in CAR (0.919). When the CAR cut-off value was taken as 0.11, the sensitivity was 80.2%, and the specificity was 94.4%, indicating UC activation (Figure 1).
Invasive interventions are often used to detect the activation of the disease in patients with UC. In routine clinical practice, non-invasive and accessible tests are needed to determine activation. There have been numerous studies carried out with various markers that predict the activation of the disease using hemograms and biochemical parameters [5–7]. In this study, it was aimed to assess the effectiveness of commonly used markers in patients diagnosed with UC based on the Mayo Subscore. Consequently, the NLR and CAR were found to be correlated with colon involvement severity in all segments. When the CAR cut-off value was taken as 0.11, the sensitivity was 80.2%, and the specificity was 94.4%, predicting UC activation.
CRP is undoubtedly the most commonly studied inflammatory marker in both Crohn’s disease and UC. CRP is a pentameric acute phase protein with a short half-life that is produced by the liver under the influence of interleukin (IL)-6 and other cytokines upon inflammatory stimulation . Lobaton et al. in their study evaluating activation with the Mayo Subscore, also observed that CRP had a moderate correlation with the Mayo Subscore in patients with UC similar to our study (r: 0.307, P < 0.01). Ishida et al.  noted that there was a better association between CRP and Mayo Subscore (r: 0.54, P < 0.01). When the localizations of involvement were evaluated in this study, no significant association was observed between distal involvement and the CRP values. It was believed that there was no significant association since the Mayo Subscores of the patients with distal colitis were lower, and the involvement affected a limited area when compared to other types of involvement. The severity and toxicity of the disease is correlated with the amount of colonic tissue affected by inflammation in UC . Indeed, it was reported in a study carried out in China  that a higher CRP value was most likely correlated with the presence of extensive colitis (OR: 9.3, 95% CI: 3.30–26.40). Similarly, Ishida et al.  emphasized in their study that high CRP values were associated with disseminated and severe infection.
Chronic inflammation is associated with the higher fractional catabolic speed of albumin, and increases the ejection of albumin from the vascular compartment. Moreover, additional factors such as malnutrition and malabsorption cause reduced albumin levels in patients with UC. Hypoalbuminemia detected at the time of diagnosis is an important parameter indicating the prognosis of UC . The clinical significance of the CAR calculated as CRP divided by albumin has gradually increased after studies showing that it is an independent predictor of mortality in patients with severe sepsis and septic shock. Studies on UC have concluded that it indicated disease activity better when compared to CRP and albumin [11–13]. Furthermore, some studies have shown that the CAR is an important predictor for nonresponse to steroids  and colectomy in patients with UC. Liu et al.  compared the effectiveness of CRP, the erythrocyte sedimentation rate, and CAR in their study with 231 patients in 2021, and emphasized that the most effective result in demonstrating activation in UC patients was with CAR (cut-off value: 0.06, AUC: 0.918, sensitivity: 82.19%, specificity: 95%). Chen et al.  investigated the efficacy of the CAR in 876 patients with inflammatory bowel disease (IBD). They found that the AUC was 0.827, the sensitivity was 67%, and the specificity was 86%, when they took the cut-off value as 0.18 for the CAR in predicting activation in patients with inactive UC. On the other hand, the AUC was 0.919, the sensitivity was 80.2%, and the specificity was 94.4% in this study, where UC activation was assessed using the Mayo Subscore. A study using a different method in predicting activation, but with very similar cut-off values to the current study was carried out by Sayar et al.  Patients with UC were categorized as mild, moderate, and severe, and a CAR level of 0.12 was suggested as the cut-off value for severe disease. The AUC, sensitivity, and specificity at this value were reported as 0.877, 97%, and 79% respectively.
In the studies on the NLR among other parameters considered in predicting activation, the sensitivity varied from 54 to 90%, and specificity from 63% to 91%, with varying cut-off values [7,16,17]. Langley et al.  carried out a systematical review of 62 studies in 2021 that suggested a significant correlation between NLR and endoscopic activity in UC in most studies, which was similar to that herein, while not in Crohn’s disease (no correlation in 4 out of every 5 studies). There are studies that have shown a correlation between the NLR and involvement of the disease [17,18], as well as studies not showing such correlation . In the current study, although not with CRP and the CAR, a significant relationship was observed with endoscopic severity with the NLR, as well as with the size of involvement (P = 0.01, r = 0.298). NLR was also indicated as a predictor  in terms of response to anti-tumor necrosis factor drugs , the risk of post-ileal pouch-anal anastomosis IBD , post-operative hospital stay, and complications. PLR, which is often assessed together for efficacy, has efficacy values similar to the NLR. Although PLR and NLR were found to have similar efficacy in indicating activation, the significant correlation found with the NLR in all of the segments was not found with the PLR when the involvement localization of the endoscopic activity was taken into consideration.
This study had some other limitations in addition to its retrospective nature. Furukowa et al.  found the CAR to be associated with moderate and severe involvement in long-standing disease, but they did not observe a significant correlation in patients with short-term involvement in their study carried out on patients with IBD. We consider the fact that the study population herein consisted of newly diagnosed patients, and the fact that the duration of disease was unknown was another limitation of the study. Being a representation of one region due to being monocentric was another limitation of the study.
Inflammatory markers in UC have adequate sensitivity in indicating activation, and they also aid in the identification of the severity of involvement in patients.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Frøslie KF, Jahnsen J, Moum BA, Vatn MH. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology. 2007;133(2):412–22.
2. Colombel JF, Rutgeerts P, Reinisch W, Esser D, Wang Y, Lang Y, et al. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology. 2011;141(4):1194–201.
3. Regueiro M, Rodemann J, Kip KE, Saul M, Swoger J, Baidoo L, et al. Physician assessment of ulcerative colitis activity correlates poorly with endoscopic disease activity. Inflamm Bowel Dis. 2011;17(4):1008–14.
4. Langley BO, Guedry SE, Goldenberg JZ, Hanes DA, Beardsley JA, Ryan JJ. Inflammatory bowel disease and neutrophil–lymphocyte ratio: A systematic scoping review. J Clin Med. 2021;10(18):4219.
5. Lok KH, Ng CH, Hung HG, Li KF, Li KK, Szeto ML. Correlation of serum biomarkers with clinical severity and mucosal inflammation in Chinese ulcerative colitis patients. J Dig Dis. 2008;9(4):219–24.
6. Khan N, Patel D, Shah Y, Trivedi C, Yang YX. Albumin as a prognostic marker for ulcerative colitis. World J Gastroenterol. 2017;23(45):8008–16.
7. Jeong Y, Jeon SR, Kim HG, Moon JR, Lee TH, Jang JY, et al. The role of platelet to lymphocyte ratio and neutrophil to lymphocyte ratio in ulcerative colitis. Intest Res. 2021;19(1):62–70.
8. Lobatón T, Rodríguez-Moranta F, Lopez A, Sánchez E, Rodríguez-Alonso L, Guardiola J. A new rapid quantitative test for fecal calprotectin predicts endoscopic activity in ulcerative colitis. Inflamm Bowel Dis. 2013; 19(5):1034–42.
9. Ishida N, Higuchi T, Miyazu T, Tamura S, Tani S, Yamade M, et al. C-reactive protein is superior to fecal biomarkers for evaluating colon-wide active inflammation in ulcerative colitis. Sci Rep. 2021; 11(1):12431. DOI: 10.1038/s41598-021-90558-z.
10. Prantera C, Davoli M, Lorenzetti R, Pallone F, Marcheggiano A, Iannoni C, et al. Clinical and laboratory indicators of extent of ulcerative colitis. Serum C-reactive protein helps the most. J Clin Gastroenterol. 1988;10(1):41–5.
11. Chen YH, Wang L, Feng SY, Cai WM, Chen XF, Huang ZM. The Relationship between C-Reactive Protein/Albumin Ratio and Disease Activity in Patients with Inflammatory Bowel Disease. Gastroenterol Res Pract. 2020;2020. DOI: 10.1155/2020/3467419.
12. Sayar S, Kurbuz K, Kahraman R, Caliskan Z, Atalay R, Ozturk O, et al. A practical marker to determining acute severe ulcerative colitis: CRP/albumin ratio. North Clin Istanbul. 2020;7(1):49.
13. Furukawa S, Yagi S, Shiraishi K, Miyake T, Tange K, Hashimoto Y, et al. Effect of disease duration on the association between C-reactive protein-albumin ratio and endoscopic activity in ulcerative colitis. BMC Gastroenterol. 2022; 22(1):39.
14. Gibson DJ, Hartery K, Doherty J, Nolan J, Keegan D, Byrne K, et al. CRP/Albumin Ratio: An Early Predictor of Steroid Responsiveness in Acute Severe Ulcerative Colitis. J Clin Gastroenterol. 2018;52(6):e48–52.
15. Liu A, Lv H, Tan B, Shu H, Yang H, Li J, et al. Accuracy of the highly sensitive C-reactive protein/albumin ratio to determine disease activity in inflammatory bowel disease. Medicine (Baltimore). 2021; 100(14):e25200.
16. Celikbilek M, Dogan S, Ozbakir O, Zararsiz G, Kücük H, Gürsoy S, et al. Neutrophil-Lymphocyte Ratio as a Predictor of Disease Severity in Ulcerative Colitis. J Clin Lab Anal. 2013; 27(1):72–6.
17. Okba AM, Amin MM, Abdelmoaty AS, Ebada HE, Kamel AH, Allam AS, et al. Neutrophil/lymphocyte ratio and lymphocyte/monocyte ratio in ulcerative colitis as non-invasive biomarkers of disease activity and severity. Auto- Immun Highlights. 2019;10(1):4.
18. Zhang MH, Wang H, Wang HG, Wen X, Yang XZ. Effective immune-inﬂammation index for ulcerative colitis and activity assessments. World J Clin Cases. 2021;9(2):334–43.
19. Hanafy AS, Monir MH, Abdel Malak H, Desoky Aiad M. A Simple Noninvasive Score Predicts Disease Activity and Deep Remission in Ulcerative Colitis. Inflamm Intest Dis. 2018;3(1):16–24.
20. Bours P, Vermeijden R, Van De Wiel A. Neutrophil-to-Lymphocyte Ratio as a Predictor of Surgical Complications in Inflammatory Bowel Disease. Gastroenterology. 2011;140:436
21. Qian G, Hongxia D, Jin LI. Neutrophil-lymphocyte ratio at 14th week predicts loss of response to 52-week infliximab therapy in patients with Crohn’s disease. Nan Fang Yi Ke Da Xue Xue Bao. 2020; 40(4):453–8.
22. Nishida Y, Hosomi S, Yamagami H, Fujimoto K, Nakata R, Itani S, et al. Novel prognostic biomarkers of pouchitis after ileal pouch-anal anastomosis for ulcerative colitis: Neutrophil-to-lymphocyte ratio. PLoS One. 2020; 15(10):e0241322.
Download attachments: 10.4328:ACAM.21202
Ahmed Ramiz Baykan, Serkan Cerrah, Büşra Karahan, Sedat Çiftel, Ayetullah Temiz, Elmas Kasap. Assessment of inflammatory markers in ulcerative colitis and association with the disease. Ann Clin Anal Med 2022;13(7):816-820
Inferior vena cava and pulmonary artery diameters for prognosis of Coronavirus disease
Mehmet Altuntaş 1, Mümin Murat Yazıcı 1, Ali Çelik 1, Kemal Panç 2, Nur Hürsoy 2
1 Department of Emergency Medicine, 2 Department of Radiology, Faculty of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
DOI: 10.4328/ACAM.21220 Received: 2022-05-05 Accepted: 2022-06-11 Published Online: 2022-06-22 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):821-825
Corresponding Author: Mehmet Altuntaş, Department of Emergency Medicine, Recep Tayyip Erdoğan University Training and Research Hospital, Rize, Turkey. E-mail: email@example.com P: +90 506 416 14 04 Corresponding Author ORCID ID: https://orcid.org/0000-0001-5624-968X
Aim: In this study, we aimed to analyze the relationship between pulmonary artery (PA) and inferior vena cava (IVC) diameters in non-contrast chest computerized tomography (CT) images of patients with coronavirus disease 2019 (COVID-19) and overall survival.
Material and Methods: This retrospective study consisted of 404 consecutive patients who underwent chest CT after admission to the emergency department between May 1 and June 31, 2021. CT measurements were performed by two radiologists. The prognostic value of PA and IVC diameters, the computerized tomography severity score (CT-SS), quick sequential organ failure assessment (qSOFA), and confusion, urea, respiratory rate, blood pressure, and age ≥65 years (CURB-65) score on overall survival were examined.
Results: The median age of the participants was 62 years (49-72), and 196 (48.5%) were male. Of the 404 patients, 61 died after admission. While main-PA, left-PA, right-PA (p < 0.001) and IVC-transverse (IVC-Tr) (p = 0.045) diameters were larger and statistically significant in the patients who died (AUC; 0.686, 0.722, 0.746, and 0.581, respectively), a statistically significant difference was not detected in terms of IVC anteroposterior diameter (IVC-AP) (p = 0.053) and the IVC-Tr/AP (p = 0.754) ratio. There was a statistical difference in mortality in qSOFA, CURB-65, and CT-SS values (AUC; 0.727, 0.798, and 0.708 p < 0.001, respectively).
Discussion: PA diameters measured from chest CT images at admission (main-PA ≥ 26.5 mm, right-PA ≥ 22.9 mm, and left-PA ≥ 21.6 mm) and the IVC-Tr diameter (≥34.5 mm) can be used as mortality predictors for COVID-19, along with other prognostic scores.
Keywords: Emergency Department, COVID-19, Pulmonary Artery, Inferior Vena Cava, Prognosis
COVID-19, which has affected millions of people and has become a global health problem, is characterized by a wide range of infectious symptoms ranging from mild to severe, including acute respiratory distress syndrome (ARDS) as its primary complication. Six to 20 percent of patients require hospitalization , and the mortality rate among hospitalized patients ranges from 11% to 28% [2,3].
Early and easy identification of patients who may have poor outcomes after hospital admission is important to optimize the use of resources. Various prognostic scores have been developed to determine the high risk of death in patients with community-acquired pneumonia. The pneumonia severity index; confusion, urea, respiratory rate, blood pressure, and age ≥65 years (CURB-65) score; and the quick sequential organ failure assessment (qSOFA) score are well verified as supporting the prognosis of pneumonia . Many scores have proven to be useful tools for determining the prognosis in patients with suspected infection in the emergency department (ED), intensive care units, and at home [5-7]. It is well known that the severity of pulmonary parenchymal involvement in COVID-19 is also associated with a poor prognosis. Non-contrast chest computerized tomography (CT) is a useful tool for the initial evaluation of patients with suspected COVID-19 infection and offers high sensitivity for the diagnosis of the disease . CT severity scores can help classify patient risk and predict short-term outcomes in patients with COVID-19 pneumonia [9, 10].
The pulmonary artery (PA) and the inferior vena cava (IVC) are venous systems that carry deoxygenated blood to the lungs. Reduction of pulmonary compliance in the presence of pneumonia results in severe hypoxemia and ARDS. It is assumed that long-term hypoxemia due to severe pneumonia may result in higher pulmonary vascular resistance and increased diameters in venous system vessels . Widespread alveolar damage, PA thrombosis, and interstitial pneumonia with right ventricular (RV) expansion have been found in autopsies performed on COVID-19 patients . In severe COVID-19 patients undergoing echocardiography, enlargement of the right-hand heart cavities, decreased RV function, and high PA systolic pressures have been identified . While echocardiography is less preferred due to limited resources and technical and practical limitations related to the need to reduce the exposure of health workers to viral load, non-contrast chest CT is widely adopted for COVID-19 pneumonia diagnosis, monitoring, and prognosis . Reference values for IVC and PA diameters, which can be easily measured with chest CT scans, have been determined for healthy people [15,16].
For these reasons, we assumed that PA and IVC diameters would be useful in classifying the risk of COVID-19 patients. We aimed to determine the prognostic estimation of severity scores and IVC and PA diameters in non-contrast chest CT images of COVID-19 patients.
Material and Methods
This was a single-centered, retrospective cohort study. Participants comprised of adult patients whose non-contrast chest CT images had been acquired after admission to the ED between May 1 and June 31, 2021, and were confirmed to have COVID-19 using a polymerase chain reaction test. The study was approved by the local ethics committee (no: 2022/326). Clinical data were demographic characteristics (gender and age), comorbidities (hypertension, diabetes, chronic lung disease, and cardiovascular disease), vital findings, tomography images, blood analysis results, and clinical outcome (survival or death) derived from the hospital information system and ED patient forms. Disease severity scores (i.e. CURB-65, qSOFA, and computerized tomography severity score [CT-SS]) and the diameters of venous system vessels (i.e. IVC and PA) were compared with patient outcomes. Incomplete data on follow-up was considered an exclusion criterion.
Chest CT Scan
All non-contrast chest CT scans were obtained using a 16-detector CT scanner (Toshiba Alexion™; Toshiba Medical Systems Corporation, Nashu, Japan). Measurements were made from 1-mm thick axial images using standard windows (i.e. lung: width 1400 HU, center 450 HU; mediastinum: width 350 HU, center 40 HU).
Chest CT Analysis
The measurements were made by two radiologists with experience in cardiothoracic imaging, who were blind to all clinical data to reduce possible analysis bias and increase the homogeneity and reliability of the data. In addition to identifying any lung involvement parameters (i.e. ground-glass opacities, consolidation, halo sign, inverted halo sign, and pleural effusion), IVC-Tr, IVC-AP, and PA diameter measurements were made. The main PA diameter was measured at its origin, proximal to the branching point. Left-PA and right-PA diameters were measured just after the main PA branching. These points are easy to identify anatomically, which makes them highly repeatable. IVC measurements were performed at the widest level before draining into the right atrium. The measurements are summarized in Figure 1.
The CT-SS was calculated for each of the two hemithoraces taking into account the scope of anatomical involvement as follows: 0 points, no involvement; 1 point, <5% involvement; 2 points, 5–25% involvement; 3 points, 26–50% involvement; 4 points, 51–75% involvement and 5 points, >%75 involvement. The resulting global CT-SS was determined as the sum of each hemithorax score. The presence of related properties, such as ground-glass opacity (GGO), fibrosis, consolidation, subpleural lines, halo sign, inverted halo sign, and pleural effusion, were also defined. The distribution of lung abnormalities was classified as mainly peripheral, central, or both peripheral and central.
All statistical analyses were carried out using a statistics package program (Jamovi Project Computer Software, Version 1.6; Sydney, Australia). Continuous variables with normal distributions were defined by mean and standard deviations, and continuous variables that did not show normal distributions were defined by median and interquartile ranges. Categorical data were shown as frequencies (n) and percentages (%). The Shapiro-Wilk test was used to check whether the data were distributed normally. To compare continuous variables with normal and non-normal distributions, the t-test and the Mann–Whitney U test were used, respectively. A chi-squared test was used to compare the categorical data. For all comparisons, a Type I error was considered to be 5%. To determine the cut-off levels for the main-PA, right-PA, left-PA, IVC-Tr, qSOFA, CURB-65, and CT-SS values for mortality, a receiver operating characteristic (ROC) curve was generated. Finally, sensitivity, specificity, and positive predictive and negative predictive values were calculated for the main-PA, right-PA, left-PA, IVC-Tr, qSOFA, CURB-65, and CT-SS values.
A total of 404 patients were included in the study. The median age was 62 years (49–72), and 48.5% of the patients were male. In-hospital mortality was 15.1% (61 cases), and the median age of those who died was 74 years (68–81). The most common comorbid diseases were hypertension (50.2%), diabetes mellitus (28.2%), and coronary artery disease (17.6%). As expected, the patients who died were the oldest, and they had the most comorbidities. While the presence of GGO and pleural effusion in the CT-SS was statistically significant for mortality, consolidation and halo sign were not significant. The demographics, clinical characteristics, and CT-SS findings are presented in Table 1. While main-PA, left-PA, right-PA, and IVC-Tr diameters were wider and statistically significant in patients who died (AUC; 0.686, 0.722, 0.746, and 0.581, respectively), a statistically significant difference was not detected in terms of the IVC-AP (p = 0.053) diameter and the IVC -Tr/AP (p = 0.754) ratio. Among the vascular diameters, the highest specific measurement was IVC-Tr (79.88%), while the highest sensitive measurement was main-PA (78.69%). All the prognostic scoring systems, namely qSOFA, CURB-65, and CT-SS, had statistical significance for mortality (p < 0.001, AUC; 0.727, 0.798, and 0.708, respectively). The score with the highest specificity was the qSOFA (90.38%), while the most sensitive score was CURB-65 (91.79%). Comparisons of the data and ROC curves of the parameters considered to be prognostic for in-hospital mortality in COVID-19 patients are given in Table 2 and Figure 2.
PA and IVC diameters are two easily obtained and reproducible measurements available from non-contrast chest CTs. Edwards et al.’s investigation of non-contrast chest CT measurements involving 100 normal individuals and 12 pulmonary HT patients showed an average main-PA diameter of 27.2 ± 0.6 mm . The Framingham Heart Study of an asymptomatic community-based population determined that the gender-specific threshold value of main-PA from a non-contrast chest CT was 29 mm for males and 27 mm for females . In another study of non-contrast chest CT scans, the enlarged PA diameter (main-PA ≥ 31 mm) had a specificity of 80–98% and a positive predictive value of 85–98% for pulmonary HT diagnosis, and these patients had a 2–3 times higher risk of mortality than normal patients . Pulmonary vasoconstriction described through low angiotensin II and pulmonary small vessel thrombosis and inflammation in an autopsy series of patients with COVID-19 pneumonia support the pressure change hypothesis of pulmonary arteries . Although the primary aim of the current study was not to determine a limit value as a predictor of mortality in COVID-19 patients, a cut-off value of 26.5 mm for main-PA had a sensitivity of 78.69% and a negative predictive value of 93.26% for mortality. Main-PA, left-PA, and right-PA diameters were wider and statistically significant in patients who died (p < 0.001 and AUC; 0.686, 0.722, and 0.746, respectively).
IVC sizes have previously been suggested as useful predictive markers of adverse cardiopulmonary events and survival [20, 21]. In a study examining the changes in IVC, aorta, and PA diameters in patients with pulmonary embolism, IVC diameters were found to be larger in the pulmonary embolism group than in the control group. (p < 0.001 and IVC diameter; 24 mm and 23 mm, respectively) . Acute cardiac damage is a common complication in COVID-19 patients because they have an increased risk of acute coronary artery disease, cardiogenic shock, pulmonary embolism, and heart failure [12, 23]. In addition, it has been shown that the occurrence of acute cardiac events increases the risk of COVID-19-related death . In an echocardiography study examining findings of RV dysfunction in COVID-19 patients, Li et al. found that the maximum and minimum diameters of IVC increased significantly in critically severe patients compared to healthy subjects (p < 0.01) . In our measurements of IVC, IVC-Tr was slightly significant for mortality (AUC = 0.581, p = 0.045). IVC-Tr had a specificity of
79.88% and a negative predictive value of 87.26% for mortality at a specified cut-off value of 34.50 mm.
In the study cohort, all three prognostic scores, including qSOFA, CURB-65, and CT-SS scores, showed a statistical difference in mortality (p < 0.001, AUC; 0.727, 0.798, and 0.708, respectively). The highest specific score was qSOFA (90.38%), while the most sensitive score was CURB-65 (91.79%) for mortality.
The detection of enlarged PA in non-contrast chest CT may have a potential impact on patient management and treatment. COVID-19 patients can rapidly worsen with RV dysfunction and insufficient oxygenation for ventilation-perfusion incompatibility. In patients with severe pneumonia and dilated PA measurements, alveolar ventilation may be optimized to limit hypoxic vasoconstriction, and prone ventilation may be preferred to minimize positive end-expiratory pressure and hemodynamic effects. Close monitoring of pulmonary vascular resistance should be considered to optimize inotropic support and reduce RV afterload.
The limitation of this study was the lack of right cardiac catheterization or echocardiography patient data. Although echocardiography is a widely used tool to measure PA pressure, the diagnostic accuracy is affected by heart rate, operator experience, and, especially, the presence of significant lung disease. Therefore, it is not routinely applied to all COVID-19 patients. During the active disease, we found an association between PA diameter and COVID-19 prognosis. However, we did not have knowledge of the pre-COVID-19 PA diameter, and we did not follow up on the PA diameter after the disease was treated. The lack of data on the incidence of pulmonary embolism, which can affect the diameter of the PA, was another limitation.
This study demonstrated that PA and IVC diameters, which are easily measured from non-contrast chest CT used for COVID-19 pneumonia assessment during hospital admission, can provide additional prognostic information along with other prognostic scores and assist clinicians with patient management.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Rosenberg ES, Dufort EM, Blog DS, Hall EW, Hoefer D, Backenson BP, et al. COVID-19 Testing, Epidemic Features, Hospital Outcomes, and Household Prevalence, New York State-March 2020. Clin Infect Dis. 2020;71(8):1953–9.
2. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–62.
3. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507–13.
4. Kim MA, Park JS, Lee CW, Choi WI. Pneumonia severity index in viral community-acquired pneumonia in adults. PLoS ONE. 2019;14(3):e0210102.
5. Seymour CW, Liu VX, Iwashyna TJ. Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):762-74.
6. Freund Y, Lemachatti N, Krastinova E, van Laer M, Claessens YE, Avondo A, et al. Prognostic accuracy of sepsis-3 criteria for in-hospital mortality among patients with suspected infection presenting to the emergency department. J Am Med Assoc. 2017;317(3):301–8.
7. April MD, Aguirre J, Tannenbaum LI, Moore T, Pingree A, Thaxton RE, et al. Sepsis Clinical Criteria in Emergency Department Patients Admitted to an Intensive Care Unit: An External Validation Study of Quick Sequential Organ Failure Assessment. J Emerg Med. 2017;52(5):622–31.
8. Xu B, Xing Y, Peng J, Zheng Z, Tang W, Sun Y, et al. Chest CT for detecting COVID-19: a systematic review and meta-analysis of diagnostic accuracy. Eur Radiol. 2020;30(10):5720–7.
9. Revel MP, Parkar AP, Prosch H, Silva M, Sverzellati N, Gleeson F, et al. COVID-19 patients and the radiology department – advice from the European Society of Radiology (ESR) and the European Society of Thoracic Imaging (ESTI). Eur Radiol. 2020;30(9):4903–9.
10. Simpson S, Kay FU, Abbara S, Bhalla S, Chung JH, Chung M, et al. Radiological Society of North America Expert Consensus Statement on Reporting Chest CT Findings Related to COVID-19. Endorsed by the Society of Thoracic Radiology, the American College of Radiology, and RSNA – Secondary Publication. J Thorac Imaging. 2020;35(4):219–27.
11. Yildiz M, Yadigar S, Yildiz BŞ, Aladag NB, Keskin O, Ozer RS, et al. Evaluation of the relationship between COVID-19 pneumonia severity and pulmonary artery diameter measurement. Herz. 2021;46(1):56–62.
12. Fox SE, Akmatbekov A, Harbert JL, Li G, Quincy Brown J, vander Heide RS. Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans. Lancet Respir Med. 2020;8(7):681–6.
13. D’Andrea A, Scarafile R, Riegler L, Liccardo B, Crescibene F, Cocchia R, et al. Right Ventricular Function and Pulmonary Pressures as Independent Predictors of Survival in Patients With COVID-19 Pneumonia. JACC Cardiovasc Imaging. 2020;13(11):2467–8.
14. Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. Correlation of Chest CT and RT-PCR Testing for Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology. 2020;296(2):32–40.
15. Kim JH, Kim WY, Oh J, Kang H, Lim TH, Ko BS. Association of inferior vena cava diameter ratio measured on computed tomography scans with the outcome of patients with septic shock. Medicine. 2020;99(43):e22880.
16. Truong QA, Massaro JM, Rogers IS, Mahabadi AA, Kriegel MF, Fox CS, et al. Reference values for normal pulmonary artery dimensions by noncontrast cardiac computed tomography the framingham heart study. Circ Cardiovasc Imaging. 2012;5(1):147–54.
17. Edwards PD, Bull RK, Coulden R. CT measurement of main pulmonary artery diameter. Br J Radiol. 1998;71(850):1018–20.
18. Truong QA, Bhatia HS, Szymonifka J, Lavender Z, Mhs P, Waxman AB, et al. A Four-Tier Severity Classification System of Pulmonary Artery Metrics on Computed Tomography for the Diagnosis and Prognosis of Pulmonary Hypertension. J Cardiovasc Comput Tomogr. 2019;12(1):60–6.
19. Esposito A, Palmisano A, Toselli M, Vignale D, Cereda A, Rancoita PMV, et al. Chest CT–derived pulmonary artery enlargement at the admission predicts overall survival in COVID-19 patients: insight from 1461 consecutive patients in Italy. Eur Radiol. 2021;31(6):4031–41.
20. Nath J, Vacek JL, Heidenreich PA. A dilated inferior vena cava is a marker of poor survival. Am Heart J. 2006;151(3):730–5.
21. Fukui M, Takamochi K, Suzuki K, Hotta A, Ando K, Matsunaga T, et al. The maximum dimension of the inferior vena cava is a significant predictor of postoperative mortality in lung cancer patients with idiopathic interstitial pneumonia. Surg Today. 2019;49(6):467–73.
22. Gökçen E, Demir B, Savrun A, Çaltekin İ, Yıldırım G, Korkmaz H, et al. Evaluation of Inferior Vena Cava/Abdominal Aorta Diameter Index in Pulmonary Embolism. Eurasian J Emerg Med. 2020;19(2):82-8
23. Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential Effects of Coronaviruses on the Cardiovascular System: A Review. JAMA Cardiol. 2020;5(7):831–40.
24. Guzik TJ, Mohiddin SA, Dimarco A, Patel V, Savvatis K, Marelli-Berg FM, et al. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res. 2020;116(10):1666–87.
25. Li YL, Zheng JB, Jin Y, Tang R, Li M, Xiu CH, et al. Acute right ventricular dysfunction in severe COVID-19 pneumonia. Rev Cardiovasc Med. 2020;21(4):635–41.
Download attachments: 10.4328:ACAM.21220
Mehmet Altuntaş, Mümin Murat Yazıcı, Ali Çelik, Kemal Panç, Nur Hürsoy. Inferior vena cava and pulmonary artery diameters for prognosis of Coronavirus disease. Ann Clin Anal Med 2022;13(7):821-825
Treatment of hydatid liver cyst: Comparison of open and laparoscopic surgery
Ercan Korkut 1, Nurhak Aksungur 1, Necip Altundaş 1, Salih Kara 1, Rıfat Peksöz 1, Mesud Fakirullahoğlu 2, Gürkan Öztürk 1
1 Department of General Surgery, Faculty of Medicine, Atatürk University, 2 Department of General Surgery, Erzurum City Hospital, Erzurum, Turkey
DOI: 10.4328/ACAM.21254 Received: 2022-05-31 Accepted: 2022-06-30 Published Online: 2022-06-30 Printed: 2022-07-01 Ann Clin Anal Med 2022;13(7):826-830
Corresponding Author: Ercan Korkut, Department of General Surgery, Faculty of Medicine, Atatürk University, Erzurum, Turkey. E-mail: firstname.lastname@example.org P: +90 505 562 27 89 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8543-7778
Aim: The aim of this study was to compare parameters that influence patient selection, cyst features, treatment outcomes, morbidity, and death rates in hepatic hydatid disease open versus laparoscopic surgery.
Material and Methods: A total of 660 patients were assessed between 2010 and 2020 who had surgery for a hepatic hydatid cyst diagnosis. The decision for open or laparoscopic surgery was made according to the stage, localization, number, size, and complication features of the cysts observed in the Computerized Tomography (CT) images and the characteristics of patients. The patients were divided into two groups: Open Surgery (Group A; n=607) and Laparoscopic Surgery (Group B; n=53). In terms of morbidity and mortality, characteristics of the cysts, patients, operation type, and treatment outcomes in both groups were compared.
Results: The demographic characteristics of the groups were similar. A total of 1020 cysts were determined in 660 patients. In Groups A and B, the mean number of cysts was 1.59 and 1.03, respectively. The mean duration of surgery in Group A and B was 110 ± 22 minutes and 70±18 minutes, respectively (p> 0.05). The mean hospitalization time in Group A and B was 9.3± 6.5 days and 6.5±1.1 days, respectively (p<0,05). The rate of biliary fistula in Group A and B was 35.5%, and 13.2%, respectively (p<0.05). The rate of other complications was 11.5% in Group A and 3.7% in Group B (p<0.05).
Discussion: Laparoscopic surgery is an effective and safe intervention for cysts in the accessible peripheral segments of the liver.
Keywords: Liver Hydatid Cyst, Laparoscopic Surgery, Open Surgery, Morbidity, Mortality
Despite the developments in the diagnosis and treatment of hydatid cyst disease, it is still a public health problem in the Mediterranean Region, Middle East, South America, and countries like Turkey, where the disease is endemic.
Regarding the treatment of hepatic hydatid cyst disease, albendazole (medical treatment), percutaneous treatment methods, and surgical treatment methods are used. The stage of the cyst, its location in the liver, its diameter, whether it is complicated or not, factors related to the patient, and technical means play an important role in the choice of treatment [1,2].
Studies report that the success rate of albendazole monotherapy was 30% in patients with a cyst smaller than 5 cm. Albendazole monotherapy is recommended for high-morbidity patients, who have disseminated hydatidosis, who are not suitable for percutaneous treatment, and do not want surgery [1,3,4].
Percutaneous treatment is preferred over surgical treatment because it is less invasive intervention, and does not need hospitalization. It is mainly preferred in uncomplicated and unilocular Type 1 and Type 2 cysts according to the Gharbi classification. As a percutaneous treatment, the PAIR (puncture, aspiration, injection, and re-aspiration) technique is used in Type 1 and Type 2 cysts without biliary fistula. In complicated cysts with biliary fistula and multivesicular Type 3 cysts, catheter techniques are preferred within the scope of percutaneous treatment. In suitable patients, the reported success rate of the PAIR technique is between 92% and 100% [5,6].
Surgery is considered a gold standard in all cyst stages and hepatic localizations. Regarding the surgical treatment, conservative methods, in which the content of the cyst is opened and evacuated, and radical methods (pericystectomy, hepatectomy), in which the liver is resected without opening the cyst. Due to bleeding risk, it is recommended that the radical methods should be implemented in health centers, where experienced surgeons and sufficient technical capabilities are available. The most commonly used surgical method is the conservative method [7,8].
The surgical intervention can be carried out with laparoscopic and open techniques. As the hospitalization time is shorter, healing is faster, postoperative morbidities such as wound infection and incisional hernia are rare, laparoscopic surgery became popular in suitable patients . The decision for open or laparoscopic surgery may be changed depending on the stage of the cyst, its location in the liver, its diameter, and whether it is complicated or not.
In this study, our aim was to discuss the factors affecting patient selection, cyst characteristics, treatment outcomes, morbidity, and mortality rates in the open and laparoscopic surgery of hepatic hydatid cysts in light of literature information.
Material and Methods
A total of 660 patients who had undergone surgery due to the diagnosis of hepatic hydatid cyst in the General Surgery Clinic at the Atatürk University Medical Faculty Hospital between January 2010 and December 2020, were evaluated in this retrospective study.
All patients underwent abdominal CT to determine the anatomical location of the cyst and evaluate whether there are cysts in other intrabdominal organs. All cysts were classified according to the Gharbi Classification. In undiagnosed cases, magnetic resonance imaging (MRI) and serological enzyme-linked immunosorbent (ELISA) test were performed.
Pre-operative MRI examination was used in patients with suspected cyst rupture into the biliary tract before surgical intervention. Patients underwent Endoscopic Retrograde Cholangio-Pancreatography (ERCP) according to the results of the MRI examination.
The decision for the preference of open and laparoscopic surgery was made by the team working in the unit of liver transplantation and hepatobiliary surgery according to the type, number, size, localization of the cyst, whether it is complicated or not, the presence of recurrence or not, and whether the patient had previous abdominal surgery or not. Of the 660 patients, 607 (91.9%) underwent open surgery and the remaining 53 patients (8.1%) underwent laparoscopic surgery. The patients were divided into two groups Group A (open surgery) and Group B (laparoscopic surgery). Patients’ data including age, gender, laboratory results, number, type, diameter, localization of the cyst, biliary fistula, ERCP, surgical method, duration of surgery, development of postoperative biliary fistula, cavity abscess, reoperation, hospitalization time, recurrence, morbidity, mortality were obtained from the archived files and information management system of the hospital.
Albendazole treatment (10 mg/kg) was initiated one week before the surgical intervention and continued for two postoperative months.
All patients received 1g of cefazolin sodium prophylaxis 5 minutes before general anesthesia.
The incision sites and trochar entrance sites for laparoscopy were determined according to the location of the hepatic cysts. The content of the cysts was aspirated before cystotomy. Chlorhexidine gluconate (0.04%) (Chx-Glu) was injected into the cysts to inactivate the parasites. During this procedure, compresses soaked in Chx-Glu were used to protect the surrounding tissues from contamination. After 5 minutes of Chx-Glu application, the cyst was opened and its content was aspirated.
The cyst cavity was checked for biliary fistula. Propofol was administered through cystostomy or choledochus to determine the opening of the biliary fistula. Fistulas were repaired with 5-0 prolene stitches.
Unroofing was carried out with the resection of the cyst wall using energy devices. Cholecystectomy was carried out in patients, in whom the cyst wall was adherent to the gallbladder.
Before discharge, all patients underwent CT or USG examination and all drains were removed. Control USG or CT examinations were performed in the postoperative 3rd, 12th, and 24th months.
The study data were analyzed with the Statistical Package for the Social Sciences (SPSS) version 25 software package (SPSS Inc., Chicago, IL, USA). The results were presented in frequency, percentage, median, and intervals. The Mann-Whitney U test was used for the intergroup comparison of the numeric data, and the Fisher Exact Test was used for the categorical variables. P<0.05 was considered statistically significant.
Characteristics of the cysts in patients, who were treated with laparoscopic and open techniques, are summarized in Table 1. Of the 660 patients, 402 were females and 258 were males. The mean age was 38.2 years (18-83 years) and the follow-up period was 42 months (15-110 months). Thirty-three of the patients had recurrent cysts. The total number of cysts was 1020 (1-18) and the mean cyst diameter was 9.1 cm (2-29 cm); 407 of the cysts were inocular Type 1- Type 2; 536 were Type 3 multivesicular, 32 were Type 4, and 45 had a complication/abscessation.
In 53 patients , who had undergone laparoscopic surgery, 55 cysts (1-2) were determined. The mean diameter of the cysts was 8.1 cm (5-14 cm); 43 cysts were unilocular Type 1 and Type 2; 9 were multilocular Type 3, and 3 had a complication/abscessation. The cyst in one patient was recurrent. One patient had a bilobar cyst; 52 patients underwent cystotomy and drainage, and 1 patient pericystectomy. In two patients, the laparoscopic technique switched to the open technique since effective cavity aspiration and control of the spread to the surrounding tissues could not be achieved. The mean duration of surgery was 70 minutes (50-90 minutes).
One patient underwent reoperation on the 3rd day due to bleeding. Seven patients developed biliary fistula (13.2%). The mean hospitalization time was 6.5 days (3-12 days). Recurrence was observed in one patient (1.88%).
Data related to the surgical interventions are presented in Table2.
A total of 965 (1-18) cysts were determined in 607 patients, who underwent open surgery. The mean diameter of the cysts was 9.2 cm (2-29 cm); 364 of them were unilocular Type 1 and Type 2; 527 were multivesicular Type 3; 32 were Type 4, and 42 had complicated cysts. Seventy patients had bilobar cysts; 32 patients had a recurrence; 528 patients underwent conservative cystotomy and tube drainage, 15 patients conservative cystotomy + resection, and 10 patients only pericystectomy + resection. The mean duration of surgery was 110 minutes (65-180 minutes). Eight patients underwent reoperation due to the cavity abscess and one patient due to the stricture in the choledochus; 216 patients developed a biliary fistula (33.7%).
The mean postoperative hospitalization time was 9.3 days (4-59 days). Recurrence was observed in 25 patients (3.74%). Seven patients died.
Postoperative complications observed in our patients are shown in Table 3.
The aim of hepatic hydatid cyst surgery is to eliminate parasites, prevent recurrence, and decrease the complications and morbidity as much as possible.
Regarding the treatment of hepatic hydatid cysts, laparoscopic surgery made a fast entry into the therapeutic field as it does not cause postoperative morbidities, which are common in open surgery. However, hepatic hydatid cyst disease has specific features. The decision for open and laparoscopic treatment is made by taking into consideration the location, type, number, complexity of the cyst, and technical means.
The decision between laparoscopic and open surgery was given during the preoperative period according to the type of the cyst and its location in the liver as observed in the CT images. Of the 660 patients, 607 (91.9%) underwent open surgery, while 53 patients (8.1%) underwent laparoscopic surgery. The characteristics of the cysts in the patients group, which had undergone percutaneous intervention and laparoscopic intervention, were similar. In the last 10 years, 560 of 1220 patients (44.4%), who had applied to our hospital with the diagnosis of hepatic hydatid cyst disease, were treated with a percutaneous approach, and the remaining 660 patients (55.6%) were treated with a surgical approach.
Open surgery was preferred mostly in patients with complicated, bilobar, three or more cysts, multivesicular Type 3 cysts, and recurrences.
In the study by Zaharie F. et al. . it was reported that laparoscopic surgery was a safe and effective approach in all stages of hepatic hydatid cyst. However, while laparoscopic cystotomy and aspiration of Type 1 and Type 2 cysts and removal of the germinative membrane from the abdomen can be performed easily with Endobag, the aspirator is often obstructed during the aspiration of multivesicular Type 3 cysts. This leads to the prolongation of surgery compared to open surgery and contamination of the surrounding tissues. Specially developed aspiration devices with broad lumen are needed, especially for the aspiration of the multilocular Type 3 cysts with little fluid content. Because of this problem, laparoscopy was switched to open surgery in two of our patients and the intervention was completed with open surgery.
Laparoscopic surgery is usually indicated in uncomplicated hepatic cysts and Type 1 and Type 2 cysts with peripheral locations. The cysts with intraparenchymal location, which are not apparent on the liver surface, and cysts located in segment 7, are not suitable for the laparoscopic approach. One patient with an isolated caudate lobe hydatid cyst was successfully treated with conservative laparoscopic cystotomy. However, mostly open surgery in caudate lobe cysts was preferred.
While 634 patients (94%) underwent conservative surgery, 26 patients (6%) underwent liver resection. In 25 of the 26 patients, who had undergone resection, open surgery was preferred, while laparoscopic left lateral hepatectomy was carried out in one patient. Laparoscopic liver resection is a technically difficult intervention, which requires considerable experience.
The rate of cystobiliary fistula is between 5% and 30% in the literature [4,10]. In our study, the rate of the postoperative biliary fistula was 35.6% and 13.2% respectively in open and laparoscopic surgery (the difference was statistically significant; p<0.05). As percutaneous treatment is a common practice in our hospital, surgery is preferred in complicated patients. Therefore, more cystobilar fistulas are seen in patients undergoing surgery. The low rate of biliary fistula in laparoscopic surgery depends on the patient selection.
In the first years of laparoscopic hydatid cyst surgery, there was a concern that the rate of intraperitoneal contamination and recurrence might be higher compared to open surgery [11,12]. Pre- and post-operative albendazole treatment, injection of scolicidal agents, isolation of the cyst from the peritoneal cavity with sponges soaked in a scolicidal agent, and inactivation of the cyst content with scolicidal agents enabled the reduction of this rate [4,13]. We use a 0.4% Chx-Glu solution to prevent the intraperitoneal spread and inactivate the cyst content. Studies have reported that the recurrence rate in hepatic hydatid cyst disease was between 4% and 25% [1,14,15]. Twenty-five of patients with recurrence (n=607; 4.1%) were treated with open surgery and one patient (n=53; 1.8%) with laparoscopic surgery. The reason why the recurrence rate was lower in the laparoscopy group compared to the open surgery group is due to patient selection. At the same time, this shows that liver laparoscopic hydatid cyst surgery is safe for recurrence if surgical technique is observed.
Studies have reported that the complication rate was between 6% and 40% . The rates of the complications such as postoperative surgical site infection, atelectasis, pleural effusion, deep vein thrombosis (DVT), incisional hernia, broncho-alveolar fistula, and the need for reoperation were higher in the open surgery group. Besides biliary fistulas, 108 complications were observed in 72 patients. The rate of complication development was 11%. This rate was 11.5% and 3.7% in open and laparoscopic surgery groups, respectively (p<0.05). When hepatic hydatid cyst is treated with a laparoscopic approach, the following benefits of minimally invasive surgery are observed compared to open surgery: less postoperative pain, shorter hospitalization time, faster return to work life, lower rates of wound infection, and incisional hernia.
The development of cavity infection and abscesses is one of the most important complications and the reason for reoperation. The rate of cavity infection is between 1% and 6.8% in the literature . In our study, cavity infection was encountered in 14 open surgery patients (2.3%). Eighth patients, in whom the cavity infection did not regress, underwent reoperation. The most important factor in the development of cavity infection is the development of postoperative biliary fistula and related long-term catheterization and the development of infection due to ERCP intervention. The higher rate of cavity infection in open surgery compared to laparoscopic surgery can be explained by the more complicated, larger cysts, higher rate of biliary fistula in the open surgery group, and the preference for open surgery in complicated cysts.
When the laparoscopic surgery patients were compared to open surgery patients; the hospital stay, post-operative complications, and biliary fistula rate were found to be lower in the laparoscopic surgery group (P <005). The reason for the shorter hospital stay and lower postoperative complications is that the advantages of minimally invasive surgery are seen in laparoscopic surgery. In addition, the reason that biliary fistula and cavity abscess were more common in the open surgery group was thought to be the fact the complicated cysts of the patients were more common in the open surgery group. The rate of type 3 multivesicular cysts was found to be statistically high in the open surgery group ( p< 0.05). This may have had an effect on the high incidence of recurrences in the open-operated patient group.
In studies, the reported mortality rate after surgical treatment of hydatid cyst disease was between 0% and 3% [14,17]. Seven of the open surgery patients (n=607; 1.15%) died. In 5 of these patients, percutaneous treatment was attempted before surgical intervention. The development of sepsis related to cavity abscess is the most important reason for mortality in hepatic hydatid cysts.
Hepatic hydatid cyst disease has specific characteristics, and each patient should be evaluated individually. Preferring laparoscopy for suitable patients decreases the duration of the hospitalization, and provides faster recovery. Laparoscopy can be performed effectively and safely with better postoperative morbidity rates compared to open surgery.
Scientiﬁc Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Georgiou GK, Lianos GD, Lazaros A, Harissis HV, Mangano A, Dionigi G, et al. Surgical management of hydatid liver disease. Int J Surg. 2015;20:118–22.
2. Bayrak M, Altlntas Y. Current approaches in the surgical treatment of liver hydatid disease: Single center experience. BMC Surg. 2019;19(1):1–10.
3. Sozuer E, Akyuz M, Akbulut S. Open surgery for hepatic hydatid disease. Int Surg. 2014;99(6):764–9.
4. Gomez i Gavara C, López-Andújar R, Belda Ibáñez T, Ramia Ángel JM, Moya Herraiz Á, Orbis Castellanos F, et al. Review of the treatment of liver hydatid cysts. World J Gastroenterol. 2015;21(1):124–31.
5. Akhan O, Erdoğan E, Ciftci TT, Unal E, Karaağaoğlu E, Akinci D. Comparison of the Long-Term Results of Puncture, Aspiration, Injection and Re-aspiration (PAIR) and Catheterization Techniques for the Percutaneous Treatment of CE1 and CE3a Liver Hydatid Cysts: A Prospective Randomized Trial. Cardiovasc Intervent Radiol. 2020;43(7):1034–40.
6. Köroğlu M, Erol B, Gürses C, Türkbey B, Baş CY, Alparslan AŞ, et al. Hepatic cystic echinococcosis: Percutaneous treatment as an outpatient procedure. Asian Pac J Trop Med. 2014;7(3):212–5.
7. Senthilnathan P, Inamdar S, Nalankilli VP, Vijay A, Rajapandian S, Parthsarathi R, et al. Long-term results of hepatic hydatid disease managed using palanivelu hydatid system: Indian experience in tertiary center. Surg Endosc. 2014;28(10):2832–9.
8. Sokouti M, Sadeghi R, Pashazadeh S, Hasan Abadi SE, Sokouti M, Ghojazadeh M, et al. A systematic review and meta-analysis on the treatment of liver hydatid cyst using meta-MUMS tool: Comparing PAIR and laparoscopic procedures. Arch Med Sci. 2019;15(2):284–308.
9. Tuxun T, Aji T, Tai Q wen, Zhang JH, Zhao JM, Cao J, et al. Conventional Versus Laparoscopic Surgery for Hepatic Hydatidosis: A 6-Year Single-Center Experience. J Gastrointest Surg. 2014;18(6):1155–60.
10. Zaharie F, Bartos D, Mocan L, Zaharie R, Iancu C, Tomus C. Open or laparoscopic treatment for hydatid disease of the liver? A 10-year single-institution experience. Surg Endosc. 2013;27(6):2110–6.
11. Dervenis C, Delis S, Avgerinos C, Madariaga J, Milicevic M. Changing concepts in the management of liver hydatid disease. J Gastrointest Surg. 2005;9(6):869–77.
12. Rihani HR, El-nabulsi B, Ziadat AAM. Laparoscopic Approach to liver hydatid cyst. Is it safe ? Jrms. 2004;12(2):69–71.
13. Jerraya H, Khalfallah M, Osman S Ben, Nouira R, Dziri C. Predictive factors of recurrence after surgical treatment for liver hydatid cyst. Surg Endosc. 2015;29(1):86–93.
14. Birnbaum DJ, Hardwigsen J, Barbier L, Bouchiba N, Le Treut YP. Is Hepatic Resection the Best Treatment for Hydatid Cyst? J Gastrointest Surg. 2012;16(11):2086–93.
15. Tagliacozzo S, Miccini M, Bonapasta SA, Gregori M, Tocchi A. Surgical treatment of hydatid disease of the liver: 25 years of experience. Am J Surg. 2011;201(6):797–804.
16. Shrestha SK, Thapa PB, Maharjan DK, Tamang TY. Laparoscopic Approach for Management of Hydatid Cyst of Liver. J Nepal Health Res Counc. 2017;15(35):67–70.
17. Akcan A, Sozuer E, Akyildiz H, Ozturk A, Atalay A, Yilmaz Z. Predisposing factors and surgical outcome of complicated liver hydatid cysts. World J Gastroenterol. 2010;16(24):3040–8.
Download attachments: 10.4328:ACAM.21254
Ercan Korkut, Nurhak Aksungur, Necip Altundaş, Salih Kara, Rıfat Peksöz, Mesud Fakirullahoğlu, Gürkan Öztürk. Treatment of hydatid liver cyst: Comparison of open and laparoscopic surgery. Ann Clin Anal Med 2022;13(7):826-830