April 2023
Evaluation of UCH-L1 and T-Tau as prognostic biomarkers of traumatic brain injury
Ragaa Talaat Darwish 1, Fatma Mohamed Magdy Badr El Dine 1, Asmaa Mohamed Alkafafy 2, Mohamed Nagah Mohamed Ali 1, Saffa Abdelaziz Mohamed Abdelaziz 1
1 Department of Forensic Medicine and Clinical Toxicology, 2 Department of Emergency Medicine, Faculty of Medicine, Alexandria University, Alexandria, Egypt
DOI: 10.4328/ACAM.21446 Received: 2022-10-13 Accepted: 2022-11-14 Published Online: 2022-12-10 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):281-285
Corresponding Author: Mohamed Nagah Mohamed Ali, Champollion Street, Al Mesallah Sharq, Qesm Al Attarin, 21526, Alexandria, Egypt. E-mail: m_mohamad15@alexmed.edu.eg P: +20 100 009 73 75 Corresponding Author ORCID ID: https://orcid.org/0000-0002-8698-8480
This study was approved by the Research Ethics Committee of Alexandria Faculty of Medicine, Alexandria University (Date: 2020-08-22, No: 0201383)
Aim: The current study aimed to evaluate the ability of ubiquitin C-terminal hydrolase L1 (UCH-L1) and total Tau (T-Tau) to predict the need for neurosurgical intervention and neurological outcome in patients with acute mild to moderate traumatic brain injury (TBI).
Material and Methods: Eighty-five patients diagnosed with acute mild to moderate TBI were included in this study. Serum levels of UCH-L1 and T-Tau were measured using enzyme-linked immunosorbent assay (ELISA) technique. Outcome measures were the need for surgical intervention and Glasgow Outcome Scale (GOS), which was evaluated 3 months after the initial trauma. The outcomes were dichotomized into good outcomes (GOS=5) and poor outcomes (GOS<5).
Results: Serum levels of both UCH-L1 and T-Tau were significantly elevated in TBI patients who required neurosurgical intervention and those who had a poor outcome. Receiver operating characteristic (ROC) analysis revealed that UCH-L1 could predict the need for neurosurgical intervention and poor outcome with an accuracy of 82.4% (AUC= 0.872) and 83.5% (AUC= 0.878), respectively. Regarding T-Tau, it could predict the need for surgical intervention and poor outcome with an accuracy of 89.4% (AUC= 0.909) and 90.6% (AUC= 0.916), respectively.
Discussion: Both UCH-L1 and T-Tau can be used for outcome prediction in cases of mild to moderate TBI. However, t-tau could be a better prognostic biomarker of TBI as it was more accurate than UCH-L1.
Keywords: Biomarkers, UCH-L1, T-Tau, Traumatic Brain Injury, Outcome
Introduction
Traumatic brain injury (TBI) is defined as a disruption in the normal function of the brain caused by a sudden trauma to the head. The annual incidence of TBI is estimated at 50 million cases worldwide [1]. Mild traumatic brain injury accounts for 85% of all TBI cases. Although the majority of patients with mild TBI recover completely, clinicians find it difficult to determine who will develop long-term complications [2].
The pathophysiology of TBI is still not fully understood. It is suggested that TBI occurs due to primary impact and secondary effects including neuronal inflammation, disruption of the blood-brain barrier, and metabolic disturbances. These secondary effects are thought to be risk factors for persistent symptoms and poor outcome in TBI patients [3].
The main tools used in the Emergency Department (ED) for TBI diagnosis and outcome prediction are Glasgow Coma Scale (GCS) and head computed tomography (CT). However, GCS is subjective and CT has limited sensitivity to diffuse injuries such as traumatic axonal injury that occur following TBI [4].
Surgical intervention is one of the main treatment options for TBI. It is the most effective treatment for large intracranial hematomas that TBI patients may develop. In addition, it is required if patients with TBI have brain edema and increased intracranial pressure, which is refractory to medical treatment [5].
A biomarker is an objective indicator of a patient’s biological state that can be estimated precisely and consistently [6]. Several biomarkers such as S100 calcium-binding protein B (S100B), glial fibrillary acidic protein (GFAP), and neuron-specific enolase (NSE) have been studied in TBI patients, but there is still controversy between the results of these studies [7, 8]. Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is a low molecular weight stable protein that is involved in axonal transport and removal of misfolded proteins [9]. UCH-L1 is a neuronal biomarker that is leaked from injured neurons and can be detected in the bloodstream [10]. Tau protein is an intracellular axonal protein linked with microtubules that regulates microtubule dynamic stability by phosphorylation. This leads to formation of phosphorylated tau (P-Tau). Following TBI, total Tau (T-Tau) is released and can be found as early as 6 hours [11].
As UCH-L1 and T-Tau are considered promising TBI biomarkers, the current study aimed to evaluate the ability of both biomarkers to predict the need for surgical intervention and neurological outcome in patients with acute mild to moderate TBI.
Material and Methods
1. Study design and patients:
The current study was conducted in the ED of Alexandria Main University Hospital (AMUH), Egypt. The study protocol was approved by the Research Ethics Committee of Alexandria Faculty of Medicine, Alexandria University, Egypt (Approval number: 0201383/08/20, IRB number: 00012098, FWA number: 00018699). Informed consent was obtained from each patient or his/her legally authorized representatives before participating in the study.
The study involved 85 patients, admitted with mild to moderate TBI.
1.1 Inclusion criteria:
(1) Age ≥18 years
(2) History of a blunt closed head trauma followed by loss of consciousness (LOC), amnesia, or vomiting
(3) Initial GCS of 9-15 on admission
(4) Presentation to the ED within 24 hours of the initial trauma
1.2 Exclusion criteria:
(1) History of a neurological disease
(2) Head trauma as a secondary event e.g., after syncope or seizure
(3) The time of injury was unknown
TBI was classified as mild if the patient had a LOC for up to 30 minutes, confusion, or disorientation lasting < 24 hours, an initial GCS of 13–15, or posttraumatic amnesia (PTA) of < 24 hours. On the other hand, TBI was classified as moderate if the patient had a LOC of > 30 minutes but < 24 hours, confusion or disorientation for > 24 hours, an initial GCS of 9–12, or PTA for > 24 hours but < 7 days.
2. Biomarkers measurement:
A venous blood sample (5 ml) was collected from each TBI patient (within 24 hours of the trauma). Sandwich enzyme-linked immunosorbent assay (ELISA) kits supplied by Innova Biotech, Beijing, China (catalog number: In-Hu4136) and Sunred Biotech, Shanghai, China (catalog number: 201-12-4295) were used to measure the levels of UCH-L1 and T-Tau, respectively. The lower limit of quantification was 0.1 ng/ml for UCH-L1 and 1.5 pg/ml for T-Tau according to the manufacturer’s protocol.
3. TBI outcome:
Outcome measures included the need for surgical intervention and neurological outcome.
– Neurosurgical intervention was defined as the need for craniotomy or elevation of a skull fracture [5].
– Neurological outcome was assessed 3 months post-injury using Glasgow Outcome Scale (GOS) during the patient’s follow-up visit to the hospital or by telephone survey with one of the patient’s close relatives. The investigator who conducted the telephone survey was blinded to the laboratory results.
GOS categorizes the outcomes of patients after TBI, as follows [12]:
• Good recovery (GOS =5): resumption of daily life activities
• Moderate disability (GOS =4): disabled but independent from others
• Severe disability (GOS =3): disabled and dependent on others for daily support
• Vegetative state (GOS =2): minimal responsiveness
• Death (GOS =1)
For statistical analysis, the neurological outcome was dichotomized into good outcome (GOS =5) and poor outcome (GOS <5).
4. Statistical analysis:
The sample size required for this study was calculated with PASS software version 20 using independent t-test with an alpha error of 5% and a study power of 80%. This was done using data from a previous study [13].
Statistical analysis was done using IBM SPSS software version 25.0 (Armonk, NY: IBM Corp). The Kolmogorov-Smirnov test was used to determine the distribution of data. The Mann-Whitney test was used to compare between the two groups. Receiver operating characteristic (ROC) curves were generated to assess the performance of UCH-L1 and T-Tau. Acceptable performance was defined as an area under the curve (AUC) of more than 50%, and the best performance was defined as an area of 100%. Cut-off values were obtained from the ROC curves using the Youden index to maximize both sensitivity and specificity.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
1. Characteristics of TBI patients (Table 1):
The study included 85 TBI patients. The majority of them were males (82.4%). The age ranged from 18 to 72 years with a mean of 35.8 years. Vehicle accident was the most common cause of TBI (55.3%).
According to GCS, 81.2% of the study patients had mild TBI (GCS 13-15) while 18.8% had moderate TBI (GCS 9-12). Regarding the clinical manifestations, 24.7% of the patients had vomiting, 21.2% had LOC and vomiting, and 18.8% had LOC and PTA. Intracranial CT lesions as extradural hemorrhage, subdural hemorrhage, cerebral contusion, and subarachnoid hemorrhage were found in 38.8% of all patients.
Surgical intervention was required in nearly 13 % of the study patients. GOS assessed 3 months after the injury showed that 85.9 % of the patients had good outcomes (GOS =5), while the remaining 14.1% had poor outcomes (GOS <5). No deaths (GOS=1) were reported in the study.
2. UCH-L1 and T-Tau results:
2.1 Neurosurgical intervention:
Table 2 compares the UCH-L1 and T-Tau levels in the studied TBI patients who required surgical intervention and those who did not. Regarding UCH-L1 levels, the medians in both groups of patients were 11 and 8 ng/ml, respectively while the medians of T-Tau levels were 140.1 and 57.2 pg/ml, respectively. There was a statistically significant difference between the medians of both biomarkers in the patients who required surgical intervention and those treated medically (p values <0.001).
ROC curves demonstrate that T-Tau (AUC =0.909) outperformed UCH-L1 (AUC =0.872) in distinguishing the patients who required surgical interference from those who did not. The need for neurosurgical intervention was predicted at a cut-off level of UCH-L1 of 9 ng/ml (accuracy 82.4 %, sensitivity 90.9%, specificity 81.1%, negative predictive value (NPV) 98.4%). Regarding T-Tau, the need for surgical intervention was predicted at a cut-off level of 125.7 pg/ml (accuracy 89.4%, sensitivity 81.8%, specificity 90.5%, NPV 97.1%) (Figure 1).
2.2 Neurological outcome:
Table 3 compares UCH-L1 and T-Tau serum levels in the studied TBI patients who had poor outcome (GOS <5) and those who had good one (GOS =5) 3 months post-injury. Regarding UCH-L1 levels, the medians in both groups of patients were 10.75 and 8 ng/ml, respectively while the medians of T-Tau levels were 137.95 and 57.2 pg/ml, respectively. There was a statistically significant difference between the medians of both biomarkers in the patients who had poor outcomes and those who completely recovered (p- values <0.001). ROC curves demonstrate that T-Tau (AUC =0.916) outperformed UCH-L1 (AUC =0.878) in discriminating the patients who had poor outcome from those who completely recovered. A poor outcome was predicted at a cut-off level of UCH-L1 of 9 ng/ml (accuracy 83.5%, sensitivity 91.7%, specificity 82.2%, NPV 98.4%). Regarding T-Tau, poor outcome was predicted at a cut-off level of 125.7 pg/ml (accuracy 90.6%, sensitivity 83.3%, specificity 91.8%, NPV 97.1%) (Figure 2).
Discussion
TBI remains one of the major causes of mortality and disability all over the world. Accurate prediction of outcome in TBI cases is quite difficult because physicians depend on GCS and CT. Both of these tools have limitations; GCS is often inaccurate and may be under or over-estimated, while CT is not sensitive to minute neural and structural changes, which may occur after TBI [4]. Conversely, fluid biomarkers are more accurate and objective tools to assess the severity of TBIs and predict the risk of developing long-term sequelae [14]. However, no biomarker was approved for clinical use except for S-100B [15].
This study was conducted to evaluate the ability of UCH-L1 and T-Tau to predict the need for neurosurgical intervention and 3-months neurological outcome in patients with acute mild to moderate TBI. Those biomarkers were chosen as the pathophysiology of TBI is complex and each biomarker measures a different mechanism of injury; UCH-L1 measures neuronal injury, while T-Tau measures axonal injury [7]. The study was conducted on patients with mild to moderate head trauma due limited sensitivity of GCS and CT imaging as outcome predictors in those patients [16]. Pediatric TBI patients were not enrolled in the study as the pathophysiology of TBI in children is not similar to that in adults due to differences in brain anatomy and physiology [17]. Sandwich ELISA technique was used to measure the serum levels of UCH-L1 and T-Tau as it is reliable, available in many labs and provides highly sensitive and specific results [18]. In addition, it is easy and inexpensive compared to other protein measurement methods such as electrochemical biosensors and Raman spectroscopy [19]. Similarly, sandwich ELISA kits were used in previous studies to measure the concentrations of several biomarkers in TBI patients [20-21].
In the current study, serum levels of UCH-L1 were significantly higher in the patients who required neurosurgical intervention than in those treated medically. In addition, the ability of UCH-L1 to discriminate between patients having and not having surgery was very good (AUC = 0.872). This is in agreement with a study conducted in 2012 by Papa et al who reported that the AUC for UCH-L1 was 0.860 in predicting the need of their study patients for neurosurgical intervention [13].
In the present study, serum levels of UCH-L1 were found to be significantly higher in patients who had poor outcome (GOS <5) than in those who completely recovered (GOS =5). This result is consistent with that of a study conducted in 2016 by Takala et al who measured the serum levels of UCH-L1 in 324 TBI patients and assessed their outcome using GOS or its extended version (GOS-E) [22]. In addition, Mondello et al in 2016 investigated the prognostic value of UCH-L1 in 45 pediatric TBI patients and reported that serum UCH-L1 levels were significantly elevated in patients who had unfavorable outcome [23]. The predictive performance of UCH-L1 for poor outcome in the current study (AUC= 0.878) is similar to that in Mondello et al study (AUC =0.86) and is better than that in Takala et al study (AUC =0.727). In 2022, Korley et al reported that the AUC of UCH-L1 for predicting incomplete recovery 6 months after TBI was 0.610, which is lower than that found in the current study [24]. This difference may be explained by including patients with severe TBI and assessment of neurological outcome 6 months post-TBI in that study.
Regarding T-Tau protein, the study herein revealed that its serum levels were significantly higher in patients who needed surgical interference than in those who did not. Compared to UCH-L1 (AUC= 0.872), the ability of T-Tau (AUC= 0.916) was better for the prediction of neurosurgical intervention in the current study. Concerning the 3-months outcome, T-Tau levels were found to be significantly higher in patients who had poor outcome than in those who had complete recovery. This finding is similar to that of a study performed in 2017 by Rubenstein et al who correlated the plasma levels of T-Tau and P-Tau with the functional outcome in patients with acute and chronic TBI [25]. However, the ability of T-Tau (AUC =0.909) to predict poor outcome, in the present study, was found to be better than that in Rubenstein et al study (AUC =0.770). This variation could be attributed to the utility of a different measurement method by Rubenstein et al who estimated the levels of T-Tau by ultra-high sensitivity laser-based immunoassay multi-arrayed fiberoptics conjugated with rolling circle amplification.
An advantage of this study is the evaluation of the ability of T-Tau protein to predict the need for neurosurgical intervention and neurological outcome in TBI, which have not been adequately studied before. Another advantage is the comparison of the predictive performance for TBI outcome between two biomarkers that measure different mechanisms of injury. The current study points to that both UCH-L1 and T-Tau could be potential prognostic TBI biomarkers. Both biomarkers, especially T-Tau, could be used in clinical practice to help physicians for accurate prediction of TBI outcome. However, further studies with larger sample sizes are recommended to confirm the reliability of UCH-L1 and T-Tau as outcome predictors in patients with acute mild to moderate TBI.
Conclusion
This study revealed that serum levels of UCH-L1 and T-Tau were significantly high in TBI patients who required neurosurgical intervention and in patients who had poor outcome. Measuring the serum levels of UCH-L1 and T-Tau, on admission to the ED, could be used for precise prediction of outcome in patients with acute mild to moderate TBI. However, T-Tau could be a better prognostic TBI biomarker as it was more accurate than UCH-L1.
Acknowledgment
The authors would like to thank the hospital nursing team and laboratory technicians for their assistance in this research.
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.
Funding: None
Conflict of interest
The authors declare no conflict of interest.
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Download attachments: 10.4328.ACAM.21446
Ragaa Talaat Darwish, Fatma Mohamed Magdy Badr El Dine, Asmaa Mohamed Alkafafy, Mohamed Nagah Mohamed Ali, Saffa Abdelaziz Mohamed Abdelaziz.Evaluation of UCH-L1 and T-Tau as prognostic biomarkers of traumatic brain injury. Ann Clin Anal Med 2023;14(4):281-285
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Expiratory muscle training versus incentive spirometry after colorectal surgery
Erhan Kızmaz 1, Süleyman Gürsoy 1, Orçin Telli Atalay 1, Uğur Sungurtekin 2
1 Department of General Rehabilitation, Faculty of Physical Therapy and Rehabilitation, 2 Department of General Surgery, Faculty of Medicine, Pamukkale University, Denizli, Turkey
DOI: 10.4328/ACAM.21451 Received: 2022-10-15 Accepted: 2022-11-22 Published Online: 2022-12-10 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):286-290
Corresponding Author: Erhan Kizmaz, Department of General Rehabilitation, Faculty of Physical Therapy and Rehabilitation, Pamukkale University, 20100, Kinikli, Denizli, Turkey. E-mail: erhankizmaz@hotmail.com P: +90 541 896 66 76 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1973-4146
This study was approved by the Clinical Research Ethics Committee of Pamukkale University Non-Invasive (Date: 2018-07-10, No: 60116787-020/47012)
Aim: The aim of this study was to compare the effects of expiratory muscle training (EMT) and incentive spirometry (IS) after colorectal surgery.
Material and Methods: Twenty-four individuals (13 were males) undergoing colorectal surgery were included. They were randomly divided into two groups. In addition to conventional chest physiotherapy, Group 1 was performed EMT (n=12), Group 2 was performed deep breathing exercises with IS in postoperative period. Respiratory muscle strength, functional capacity, levels of movement and independence, and postoperative pulmonary complications (PPC) were evaluated. Length of stay in hospital (LOS) was recorded.
Results: Respiratory muscle strength, increased in both groups after treatment (p<0.05), but there was no difference between the groups (p>0.05). Functional capacity decreased in both groups, and there was no difference between the groups (p>0.05). PPC did not develop, and the LOS of the groups was similar (p>0.05). Mobility and independence levels improved in both groups at discharge (p<0.05), but there was no difference (p>0.05).
Discussion: IS and EMT in addition to pulmonary rehabilitation improve respiratory muscle strength, have no side effects, and can be easily used in the clinic as alternatives to each other after colorectal surgery.
Keywords: Colorectal Surgery, Respiratory Muscle, Expiratory Muscle Training, Pulmonary Rehabilitation
Introduction
Pulmonary complications are one of the most important causes of postoperative morbidity and mortality. Its incidence after surgery is 6-76%, and it depends on the characteristics of anesthesia, the type of surgery, the condition of the patient before surgery, and the type of complication. In abdominal surgeries, this rate varies between 25-80% [1,2].
Pulmonary rehabilitation is frequently used to prevent postoperative pulmonary complications (PPC). It aims to provide deep inspiration after surgery by using breathing exercises or assistive devices, to achieve a normal breathing pattern, to maintain normal muscle tone and to regulate blood circulation with active participation in exercises and to provide early independent mobility. Secretion clearance accumulated in the airways is ensured by coughing, postural drainage, and manual drainage techniques. Thus, atelectasis is prevented and the risk of infection of the lungs reduces [3].
The surgeries with the highest PPC are thoracic and upper abdominal surgeries. There is a direct correlation between the proximity of the incision to the diaphragm and PPC [4, 5]. It takes two weeks for diaphragmatic functions to return to normal after upper abdominal surgery. Insufficient coughing and postoperative pulmonary restriction and the development of PPC are associated with this process. During abdominal surgery, effective coughing is adversely affected, and secretion clearance is impaired due to the severing of the major abdominal muscles [2]. In colorectal surgeries, the integrity of the rectus abdominis, external obliques, internal obliques, and transversus abdominis muscles, which are forced expiratory muscles, is disrupted using a vertical incision [6]. The strength of these muscles has great importance in increasing the quality of coughing and clearing secretions. Therefore, it is necessary to train the respiratory muscles, especially the expiratory respiratory muscles. Previously, respiratory muscle training (RMT) studies on neuromuscular diseases, chronic obstructive pulmonary disease, pre- and post-thoracic surgery, congestive heart failure and abdominal surgeries have been performed. However, postoperative studies have focused on inspiratory muscle training [7].
The aim of this study was to compare the effects of expiratory muscle training (EMT) and incentive spirometry (IS) in addition to conventional pulmonary rehabilitation after colorectal surgery.
Material and Methods
Twenty-four individuals who underwent colorectal surgery at Pamukkale University General Surgery Department were included in the study. The study protocol was approved by Pamukkale University Non-Invasive Clinical Research Ethics Committee (60116787-020/47012) on 10/07/2018 and registered at Clinicaltrials.gov (Identifier: NCT0529480). All individuals were informed, and consent was obtained. The study was designed as a 1:1 parallel group and randomized controlled trial. Participants were divided into two groups using the sealed envelope method. Treatment and evaluation were performed by two different physiotherapists. The assessing physiotherapist was blind to group allocation. In addition to conventional chest physiotherapy postoperatively, Group 1 underwent EMT (n=12), Group 2 underwent deep breathing exercises with IS (n=12).
Subjects aged 18 years and older, hemodynamically stable, able to walk independently, cooperative, and oriented volunteers were included in the study. Subjects who had any contraindication for chest physiotherapy (unstable cardiovascular disease, severe pulmonary hypertension, corrected severe hypoxemia, exercise desaturation, rib fractures, subcutaneous emphysema, advanced osteoporosis, thrombocytopenia, effort dyspnea and vertigo), any metastases, subjects with severe chronic cardiovascular disease, candidates for organ transplantation, requiring abdominal hernia repair, history of surgery more than one year, or orthopaedic or neurological disease that would prevent independent walking were excluded from the study.
Measurements
The respiratory muscle strength of subjects was evaluated preoperatively, postoperatively and before discharge. Maximum inspiratory pressure (PImax) and maximum expiratory pressure (PEmax) were measured using an additional mouth apparatus attached to the portable spirometer ‘Pony FX Desktop Spirometry’ device [8].
Physical function levels were evaluated with the ‘6 Minute Walk Test’ (6MWT) before surgery and before discharge [9].
The ‘Patient Mobility and Observer Mobility Scale’ (PMOMS), developed by Heye et al. [10], was used to evaluate patient perceptions and objective observations regarding postoperative mobility and independence levels. The global score of ‘patient mobility’ and ‘observer mobility’ was recorded. Evaluation was done in the postoperative and pre-discharge periods.
PPC determination was evaluated with the “Melbourne group scale version-2” in the postoperative period until the patient was discharged [11].
Intervention
Patients who were transferred to the general surgery department after 24 hours of intensive care following surgery were included in the study. On day 2, intervention was started, if the subjects were stable. Preoperatively, the subjects were informed and educated about the postoperative physiotherapy program. Conventional pulmonary physiotherapy (postoperative respiratory control, diaphragmatic breathing, local expansion exercises, bronchial hygiene techniques, effective coughing, posture exercises and early mobilization) was performed once a day by the same physiotherapist until discharge. In addition, EMT was performed with the “Threshold Expiratory Muscle Trainer” (Respironics New Jersey Inc.) device for 3 sets of 10 repetitions, 6 times/per day until discharge in Group 1.
In Group 2, active inspiration was performed with an IS device, 10 repetitions of 3 sets 6 times/per day until discharge. General surgeon, blinded to the groups, decided to discharge.
EMT was performed 5 days a week at 10-30% of the PEmax. The training was continued by increasing 2 cmH2O per day according to the tolerance of the subjects. Participants rested in an upright sitting position for 1-2 minutes after 10 breaths through the Threshold device.
Statistical analysis
Statistical Package for Social Sciences (SPSS, IBM, Armonk, NY, USA) 21.0 program was used for data analysis. The previous study used a large effect size (d= 1.08) for discharge PEmax in independent groups. This effect size was used to calculate sample size; At least 12 individuals were required for each group, with a 95% power and a significance value of 0.05 [11]. In independent group comparisons, when parametric test assumptions are provided, analysis of variance in repeated measures and significance test of the difference between two peers: Friedman and Wilcoxon’s tests were used for nonparametric variables. Significance test of the difference between two means in parametric data was used in independent group comparisons; The Mann-Whitney U test was used for nonparametric data. The difference between qualitative variables was examined by chi-square analysis.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
The flow diagram of the study is shown in Figure 1. Twenty-eight subjects were evaluated in the preoperative period, and 24 patients aged 18 years and older were included in the study. Socio/demographics of the subjects are given in Table 1. There was no significant difference between the two groups at baseline characteristics.
Subjects stayed in the intensive care unit for 1 day after surgery. The surgical characteristics are shown in Table 2.
There was no statistically significant difference between the groups in PImax and PEmax preoperatively, but 2 days after surgery they significantly decreased in both groups. Pre-discharge PImax and PEmax increased significantly in both groups compared to the postoperative period, but no significant difference was observed between the groups (Table 3).
There was no significant difference in preoperative 6MWT distances between the groups. Although the 6MWT distances before discharge decreased significantly in both groups compared to the preoperative period, there was no significant difference between the groups (Table 3).
The mobility and independence levels of the individuals were compared, and no significant difference was found between the two groups in the ‘Patient Mobility Score’
and ‘Observer Mobility Score’ in the postoperative and pre-discharge periods (Table 3).
Any PPC was not observed in both groups. The mean hospital stay was 7.41±2.46 days in the EMT group and 8.33±2.3 days in the IS group. There was no significant difference between the two groups in the length of hospital stay and the percentages of persistence (Table 2).
Discussion
In our study, we compared the effect of expiratory muscle training (EMT) and incentive spirometry (IS) in addition to conventional physiotherapy after colorectal surgery. While there was a significant increase in respiratory muscle strength in both groups compared to the post-operative period, there was no statistically significant difference between the groups. Functional capacity decreased significantly in both groups after colorectal surgery and did not reach the preoperative level at discharge. Although there was a significant increase in the levels of mobility and independence in both groups after the treatment compared to the postoperative period, there was no statistical difference between the groups.
Post-operative PPC did not occur in any of the participants
In the literature, studies on respiratory muscle training focused on inspiratory muscle training. Although there are studies on expiratory muscle training in diseases such as stroke, cardiac surgery, and multiple sclerosis, there is no study that specifically applied expiratory muscle training in colorectal surgeries [13-16]. Onerup et al. [17] applied inspiratory muscle training (IMT) in the preoperative period in colorectal surgery and only informed the subjects about use of PEP device together with respiratory exercises in the postoperative period, but did not apply progressive expiratory muscle training. In our study, EMT was performed progressively according to the measured PEmax and patient tolerance until discharge. In the previous studies on respiratory training, exercise intensity was generally performed by starting with 30-60% of PImax and PEmax values and increasing it daily or weekly [7,16]. In our study, it was started at 10-30% of the PEmax and increased by 2 cmH2O daily. Respiratory muscle training applied in cardiac surgery, neurological diseases and abdominal surgeries has been reported to increase PImax and PEmax [13, 18-20]. In major abdominal surgeries, including colorectal surgeries, RMT was usually limited to IMT only and was performed in the preoperative period. It has been reported as the reason of the previous studies that the inspiration can be made actively by the respiratory muscles, while the expiration can be done passively. As a result of these studies, it was reported that respiratory muscle strength increased after RMT [15,17]. In our study, expiratory muscle training was applied for active expiration and effective coughing, better secretion clearance and less PPC. As a result, expiratory muscles strength improved.
Intensive spirometry is frequently used in clinics after surgery. Previous studies have reported that IS increases respiratory muscle strength after surgery [21,22]. In our study, IS was used in addition to conventional physiotherapy, and it was found that it increased respiratory muscle strength as well as EMT. Our results were similar to previous studies. However, no significant difference was found between the two groups. Based on this result, it can be thought that IS and EMT have similar effects. In addition, this study showed that EMT can significantly increase PImax without the need for inspiratory muscle training.
Functional capacity measured with the 6MWT decreased in both groups and did not reach the preoperative level. Savcı et al. [23] reported that 6MWT distance decreased in the postoperative period compared to the preoperative period in the IS group. When the studies that included RMT were examined, it was focused on the effect of IMT on functional capacity. Studies on EMT after surgery are limited. There is no previous study examining the effect of postoperative EMT on functional capacity. In our study, the reason for the decrease in functional capacity may be the inadequacy of the short-term effects of the trainings during the hospital stay. In addition, it has been reported in the literature that 2/3 of the subjects did not reach their preoperative functional capacity levels even 9 weeks after the abdominal surgery [24]. We think that the surgical operation has a negative effect on the functional capacities of the participants.
The ‘Patient Mobility and Observer Mobility’ scale was used to determine the postoperative independence and mobility levels of the participants. Within the group, observer mobility and patient mobility scores decreased before discharge compared to the postoperative period in both groups. But no significant difference was found between the groups. Gürler and Yılmaz [25] reported that 390 participants were evaluated after surgery and reported that subjects had difficulties in behaviours such as coughing, breathing, getting out of bed, and moving due to pain, and therefore their independence during movement decreased. Savcı et al. [23] reported that after coronary artery bypass graft surgery, the pain decreased in the IS group, Crisafulli et al. [14] reported that the pain decreased in the EMT group compared to the sham group in their study of cardiothoracic surgery. In our study, it was found that the pain felt during the movements of turning in the bed, sitting on the side of the bed, standing up and walking in the hospital room in all participants in the post-surgical period decreased significantly and no PPC were observed. The improvement in movement and independence scores at discharge may be associated with a decrease in pain levels and the absence of PPC. These results are similar to previous studies.
The strength of our study, in which we examined the effectiveness of EMT after colorectal surgery, is that it is one of the few studies in which respiratory muscle training was applied after colorectal surgeries. Most studies provided training in the preoperative period. Contrary to the previous studies that focused on inspiratory muscle training, we applied EMT in postoperative period. Our study was a randomized controlled study. To our knowledge, there is no study in which EMT has been applied after colorectal surgery. Our study is pilot work on this topic. The limitations of the study are that physical therapy is routine and there is no group that was not applied any physical therapy due to ethical reasons. This should be considered when planning further studies.
Conclusion
Expiratory muscle training in addition to conventional chest physiotherapy after colorectal surgery increased respiratory muscle strength, improved mobility, and independence levels, prevented postoperative pulmonary complications, did not affect functional capacity, and did not have any superiority in these parameters compared to the incentive spirometry. We think that both interventions do not have any side effects and can be used as alternatives to each other. We recommend that clinicians add expiratory muscle training to the treatment program after colorectal surgery. We think that more studies are needed due to the limited number of studies on expiratory muscle training after colorectal surgery, and the studies are focused on inspiratory muscle training. Not only respiratory muscle training, but also endurance training should be investigated before and after colorectal surgery. Long-term follow ups will also be advisory.
Acknowledgment
The authors thank all participants who participated in the study for their contribution.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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Erhan Kızmaz, Süleyman Gürsoy, Orçin Telli Atalay, Uğur Sungurtekin. Expiratory muscle training versus incentive spirometry after colorectal surgery. Ann Clin Anal Med 2023;14(4):286-290
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Effect of methylene blue based ultrasound on survival and mitochondrial damage of Leishmania tropica promastigotes
Sercin Ozlem Calıskan 1, Selin Ovalı 2, Husne Ozen 2, Rahsan Ilıkcı Sagkan 3, Didem Bakay Ilhan 4
1 Department of Biophysics, Faculty of Medicine, Usak University, Usak, 2 Student, Faculty of Medicine, Usak University, Usak, 3 Department of Medical Biology, Faculty of Medicine, Usak University, Usak, 4 Department of Biophysics, Faculty of Medicine, Aydin Adnan Menderes University, Aydin, Turkey
DOI: 10.4328/ACAM.21458 Received: 2022-10-20 Accepted: 2022-11-22 Published Online: 2022-12-13 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):291-295
Corresponding Author: Sercin Ozlem Caliskan, Department of Biophysics, Faculty of Medicine, Usak University, 64000, Usak, Turkey. E-mail: srn.ozlem@gmail.com P: +90 536 859 12 22 F: +90 276 221 22 34 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8464-5487
Aim: In photodynamic therapy based on visible light-activated photosensitizers, the tissue penetration of visible light is limited, leading to the need for new treatment approachesSonodynamic therapy (SDT) is a treatment modality derived from photodynamic therapy. SDT is a promising new treatment modality combining sonosensitizer and low-intensity ultrasound. In this study, methylene blue (MB) mediated SDT was used to assess survival and mitochondrial damage in Leishmania tropica (L.tropica) promastigotes.
Material and Methods: L.tropica promastigotes, which were incubated with different concentrations (3.125, 6.25, 12.5, 25 and 50μM) of MB for 1 hour, were exposed to ultrasound (US) at a frequency of 1MHz, 50% duty cycle, 7 min with an intensity of 3 W/cm2. XTT was used to evaluate cell viability and Giemsa staining was used to determine morphological changes. Mitochondria membrane potential (Δψm) was assessed by flow cytometry with JC-1 staining.
Results: With the combination of increasing concentrations of MB and US, L.tropica promastigote viability was found to be decreased compared to the control and US-control group. Giemsa staining findings showed that MB mediated SDT induced several morphological alterations in L.tropica promastigotes typical of apoptosis. The Δψm collapsed significantly when L.tropica promastigotes were treated by US in the presence of MB.
Discussion: US in the presence of MB markedly damaged mitochondrial structure and function and decreased viability of L.tropica promastigotes. Therefore, MB-mediated SDT might be a potential therapeutic modality for L.tropica promastigotes.
Keywords: Leishmania tropica, Methylene Blue, Mitochondria, Sonodynamic Therapy Survival
Introduction
Leishmaniasis is a worldwide parasitic disease caused by an intracellular parasite transmitted to humans by the bite of Phlebotomus and Lutzomyia [1]. Until now, no effective drug or vaccine for the treatment of Leishmaniasis has been reported. Pentavalent antimony compounds as a standard drug have many side effects. There are still a lot of problems in the treatment of Leishmaniasis, such as increasing cases of parasite resistance, side effects caused by drugs [2]. Therefore, alternative anti-leishmanial treatments based on physical mechanisms such as light and ultrasound are being investigated.
Photodynamic therapy (PDT) is the combination with light and a photosensitizer, always offers an attractive methodology against Leishmania infections due to its low cost and non-invasiveness [3,4]. If light is replaced with low-intensity ultrasound to activate sensitizers, a novel physics-driven treatment emerges. This treatment depends on the interaction between sensitizer and low-frequency ultrasonic waves to generate reactive oxygen species (ROS), which are highly cytotoxic to induce apoptosis in nearly all microorganisms [5-7]. The sonosensitizer has no cytotoxic effect alone and exhibits toxic effects when interacting with ultrasound [8].
Methylene blue (MB) is a first-generation photosensitizer that has been researched for nearly 80 years [9]. MB provides perfect penetration in the cell membrane with a minor concentration in lysosomes, mitochondria and DNA due to its benzene ring [10]. Also, these photosensitizers are generally amphipathic planar molecules that contain one intrinsic quaternary nitrogen atom. Due to its cationic property, MB binds strongly to Leishmania spp. Photosensitizers, which have cationic properties improve the electrostatic interaction of cationic compounds by interacting better with L.tropica promastigotes because of the membrane surface negative charge [11]. Studies show that MB-mediated PDT is effective in reducing the viability of L. Promastigotes [12,13]. However, the efficacy of MB-mediated Sonodynamic therapy (SDT) is not yet known. This study aimed to examine the effect of MB-mediated SDT on the survival and mitochondria damage of L. tropica promastigotes.
Material and Methods
Parasites: L. tropica promastigotes were maintained in RPMI-1640 medium supplemented with 200 U/ml of penicillin, 0.2 mg/ml of streptomycin, and 10% fetal calf serum (both from Cegrogen Biotech GmbH, Germany) incubated at 26°C.
Experimental protocols for the study
The study contained four groups:
1. Control group: No MB, no ultrasound;
2. Methylene blue group: Treatment with all MB concentrations alone;
3. Methylene blue mediated SDT group: ultrasound in the presence of MB;
4. Ultrasound group (US-Group): Ultrasound treatment at 1 MHz, with a 50% duty cycle and a 3W/cm2 power intensity for 7 min.
Preparation of sonosensitizer
MB was used as a sonosensitizer. Phosphate buffer solution (PBS) was used as solvent in stock solutions of MB. Stock 200 μM MB solution was prepared as a 1⁄2 serial dilution with RPMI 1640 cell culture solution. Parasites were added to the wells as 1×107 cells and MB concentrations were determined as 50, 25, 12.5, 6.25 and 3.125 μM.
Sonodynamic therapy experimental procedure
Parasites were incubated with 3.125, 6.25, 12.5, 25 and 50μM of methylene blue for one hour and the samples were centrifuged at 1500 rpm for 5 minutes, and subjected to ultrasound at a frequency of 1 MHz, at a distance of 5 cm at an intensity of 3 W/cm2 at 50% duty cycle for 7 min in water [14]. After the ultrasound application, fresh medium was added to the samples and incubated at 26˚C for 18 hours.
Analysis of cell viability of promastigotes of L. tropica by the XTT cell proliferation test
The XTT test was performed to determine the cell viability of the evaluated promastigotes. 100 μL of the parasite culture was added to the control group (no sonosensitizer, no ultrasound), the sonosensitizer group (treated with increasing concentrations of methylene blue), the ultrasound group (1 MHz, 3W/cm2, 50% duty cycle) and the SDT group (treated with methylene blue and 1 MHz, 3W/cm2, 50% duty cycle), and 50 μL of XTT reagent for all the groups analyzed. All absorbance data were acquired at 450 nm using a multimode ELISA reader.
Morphological Analysis by Giemsa staining
Giemsa staining was performed in all groups slides to evaluate morphological alterations. An aliquot with 20 μL from each group was taken and samples were spread onto slides and then air-dried at room temperature. Parasites were fixed with methanol. The parasites were dyed with Giemsa (1:5) for 15 min. Then the samples were washed in running water and allowed to dry. The samples were analyzed in a light microscope.
Mitochondrial Membrane Potential (Δψm) Assay
BD MitoScreen ΔΨm Detection Kit (BD Bioscience, USA), was used for the detection of ∆m alteration by flow cytometry using JC-1 staining according to the manufacturer’s protocol. When the cell is healthy, JC-1 commonly appears as red fluorescence and Δψm value is high.
On the other hand, JC-1 appears as green fluorescence in unhealthy cells and ΔΨm value is low. After being treated with IC50 concentration of the tested MB, samples were centrifuged at 1500 rpm for 5 minutes, and JC-1 working solution was added and incubated for 15 minutes at 26°C. Promastigotes were then washed twice with JC-1 buffer and ΔΨm was determined using the flow cytometer.
Statistical Analysis
The cytotoxic activity and mitochondrial membrane potential alteration of MB and MB-mediated SDT on L.tropica promastigotes were presented and analyzed using one-way ANOVA analysis of variance followed by Tukey post-hoc test via the SPSS 25.0 program. P- value of <0.05 was considered significant.
Results
The cytotoxic activity of MB and MB-mediated SDT on L. tropica promastigotes was calculated using the viability assay to determine the IC50 value of MB. In this study, cytotoxicity of MB-mediated SDT on L.tropica promastigotes by XTT test was determined as 8.623 ± 1.98%, 51.5 ± 5.1%, 62.9± 3.07%, 76.7± 1.35, 80.8± 1.11%, respectively. No effect of MB alone on L. tropica promastigotes was determined. The viability of L.tropica promastigotes is over 73% (Figure 1A-B).
After MB (25 μM) and 50% pulsed 7-minute ultrasound at 1 MHz frequency and at 3W/cm2 intensity, L.tropica promastigote viability was found to be statistically decreased compared to the control group (p<0.001). The observed IC50 of MB-mediated SDT was 25 μM for parasites. In the group with MB-mediated SDT, parasites were detected to be significantly reduced at all concentrations compared to the control group (Figure 1B)
Morphological analysis of Leishmania tropica promastigotes
The morphological analysis of L.tropica promastigotes revealed that the control groups and the ultrasound group showed no morphological changes, maintaining a fusiform appearance, with a single nucleus, kinetoplast, narrow body, and flagellum (Figure 2A and Figure 2G). Alteration of the fusiform shape was observed at the highest MB concentration (50 ψM) (Figure 2B). There was no change in the morphological features of the parasites, except for 50 ψM concentration in the group to which only the MB group was applied (Figure 2C-F). L. tropica promastigotes exhibited morphological alterations such as round and atypical structures after SDT with high concentrations of MB used in the study. After treatments with high concentrations of MB-mediated SDT, L. tropica promastigotes lost their characteristic morphological features such as fusiform shape, nucleus and flagellum, while typical morphological features were determined at the lowest concentrations of MB-mediated SDT (Figure 2H-L).
Evaluation of mitochondrial membrane potential by JC-1 staining
The percentage of cells in the two populations, P3 and P4, was measured as JC-1 fluorescence, which is shown in Figure 3. P3 represents the mitochondrial resting membrane potential and P4 represents the depolarized mitochondrial membrane potential and cells prone to apoptosis. In the control, US control, and MB groups (Figure 3A-C), red fluorescent signals were detected with a higher cell population (93.2%, 91.6%, 70.4%), while green fluorescent signal was observed approximately nine times stronger in the MB-mediated SDT group (46.4%, Figure 3D) than in the control groups (4.6%, 5.6%). It was determined that the ratio of change in mitochondrial membrane potential decreased from 19.5±2.83 to 0.53±0.37 in L.tropica promastigotes treated with MB- mediated SDT at a dose of IC50 (25µM), compared to the controls (Figure 3E). These results were confirmed by demonstrating the change in mitochondrial membrane potential of apoptotic cell death in L.tropica promastigotes of MB-mediated SDT.
Discussion
Methylene blue is the most examined photosensitizer of the phenothiazine class against Leishmania species due to its high singlet oxygen quantum efficiency of around 0.5, absorption band between 550 and 700 nm, and embodies many features of an ideal photosensitizer [15]. Mitochondria have an important effect on cell apoptosis. They are also known as the “powerhouse of the cell” as they produce most of the cell’s source of adenosine triphosphate (ATP) [16,17]. According to various studies, methylene blue is a photosensitizer with a high affinity for mitochondria, due to its hydrophilic/lipophilic nature and the presence of a positive charge. When MB enters the mitochondria, it can be largely retained or accumulated, driven by the mitochondrial membrane potential (ΔΨm). It interacts with nucleic acids, proteins and lipids, modulating their functions [18-20].
Sonodynamic therapy is one of the candidate alternative treatment methods for Leishmaniasis, due to its low cost,, easy of use and non-toxicity. The biological effects of SDT are related to at least one of three different mechanisms, including heat, acoustic cavitation, and mechanical effects. Cavitation was described with microbubbles resulting from pressure changes that occur during the advancement of ultrasound in the tissue fluid [21]. These effects depend on the frequency and intensity of the ultrasound. As a result of the exposure of biological tissues to ultrasound, both structural and functional changes may occur in cells [22].
Basmaciyan et al. suggested the identification of cell death and apoptosis by demonstrating the presence of at least two apoptotic markers in Leishmania. One of the most basic apoptotic markers in Leismania is cell morphology. Regarding morphology, at least two of the five alterations must be present, such as cell shrinkage, cell rolling, preservation of integrity, and changes in the plasma membrane, nuclear fragmentation, and chromatin condensation [23]. This study confirms the findings, as there were also alterations in their morphology with the loss of the shuttle shape and narrow body, as well as the absence of nucleus, kinetoplast and flagella in L. tropica promastigotes.
Another apoptotic marker in Leishmania species is mitochondrial depolarization. The loss of ΔΨm is one of the physiological process associated with programmed cell death and necrosis. Current studies assigned that the decrease of Δψm after PDT is the opening of mitochondrial permeability transition pores [24]. However, the mechanism in SDT is not clear. Caliskan-Ozlem et al. applied curcumin based SDT on L. tropica parasites and identified a reduction in mitochondrial activity with a JC-1 probe [14]. In our study, it was observed that the ΔΨm decreased. The decrease of ΔΨm has shown that it may play a key role in the death of L.tropica promastigotes. These findings confirm the involvement of mitochondria in MB-mediated SDT applied cells. Induction of ΔΨm change showed that MB mediated with SDT, also affected the mitochondria of L.tropica promastigotes.
Caliskan-Ozlem et al. incubated L. tropica rose bengal promastigotes in dark for 1 hour and then exposured ultrasound to the promastigotes. This study group determined that the number of promastigotes was lower than in the control group after rose bengal-mediated SDT (1 MHz frequency, at a distance of 5 cm at an intensity of 2W/cm2). They also confirmed changes in cell morphology by Giemsa staining. This study group stated that atypical cells such as round structures, loss of flagella, nuclei and kinetoplasts were observed after MB-mediated SDT [25]. In our study, it was determined that as the concentration increased after MB-mediated SDT application, cell viability decreased, and there was a significant difference between MB alone and MB-mediated SDT groups in terms of cell viability.
This study has two main limitations. The first limitation is an in vitro study of MB-mediated SDT against L.tropica promastigotes. There are no intracellular amastigotes or experimental animal models. The second limitation is that the reviewed SDT studies differ among themselves, making comparison and rationalization of data uncertain. However, our study also has some strengths. An important contribution will be made to the literature with ultrasound application optimization. Studies of MB-mediated SDT on parasites provide valuable information.
Conclusion
This study confirmed that MB based SDT could remarkably destroy L. tropica promastigotes and highlighted that mitochondria membrane potential depolarization might play an important role in the MB-mediated SDT. Moreover, it showed that MB-mediated SDT could be a potential therapeutic modality that is inexpensive, non-toxic, and non-invasive for treating L. tropica promastigotes.
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
A part of this study was supported by a research grant from the Scientific and Technological Research Council of Turkey-TÜBİTAK (Grant no: 1919B012106402).
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.
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Investigation of pruritus and dermatological quality of life in chronic kidney disease patients
Mukadder Mollaoğlu 1, Esra Başer Akın 1, Ferhan Candan 2
1 Department of Nursing, Faculty of Health Science, 2 Department of Nephrology, Faculty of Medicine, Sivas Cumhuriyet University, Sivas, Turkey
DOI: 10.4328/ACAM.21462 Received: 2022-10-26 Accepted: 2022-12-02 Published Online: 2022-12-15 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):296-300
Corresponding Author: Esra Başer Akin, Department of Nursing, Faculty of Health Science, Sivas Cumhuriyet University, Sivas, Turkey. E-mail: esra_baser568@hotmail.com P: +90 538 478 06 60 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3618-3622
This study was approved by the Ethics Committee of NonInterventional Clinical Investigations (Date: 2020-01-15, No: 2020-01/13)
Aim: This study was carried out to investigate pruritus and dermatological quality of life in all chronic kidney disease (CKD) patients who receive or do not receive renal replacement therapy.
Material and Methods: The cross-sectional study was conducted with 104 CKD patients who volunteered to participate in the study. The data were collected using the Patient Information Form, 5-D Itch Scale and Dermatology Life Quality Index (DLQI).
Results: The total score of the 5-D itch scale of patients receiving hemodialysis (HD) treatment was 8.25 ± 3.69, and the total score of DLQI was 7.25 ± 5.96. The total score on the 5-D itch scale of the patients who did not receive HD treatment was 7.65 ± 3.89 and the total DLQI score was 3.97 ± 4.75. When the correlation between 5 D Itch Scale and DLQI was examined, it was found that patients with itching had a lower dermatological quality of life.
Discussion: Dermatological quality of life is low in patients with pruritus. It has been observed that patients who receive and do not receive dialysis treatment generally experience itching and their dermatological quality of life is low. It has been determined that the dermatological quality of life is better in those receiving hemodialysis treatment. Evaluation is the first step in the prevention and management of pruritus, which is a common symptom in CKD patients. Nurses are required to routinely examine the itching and its causative factors and to take the necessary precautions as they play a primary role.
Keywords: Chronic Kidney Disease, Hemodialysis, Pruritus, Quality of Life
Introduction
Having a serious negative impact on people’s quality of life, end-stage renal disease (ESRD) is a chronic disorder with a rising incidence and high morbidity and mortality rates in the world [1]. Impairment of kidney function causes uraemia, leading to different problems in many organs and systems [2]. Pruritus is a very common complication in patients with chronic kidney disease (CKD) and in hemodialysis patients with ESRD [3]. Pruritus, which is the most common skin symptom in ESRD, is commonly referred to as “uremic pruritus” [4].
The main reason for the occurrence of dermatological symptoms in CKD has been found to be associated with the inability of the kidneys to remove toxic substances from the body, the solutions used in haemodialysis treatment, medications used by patients, and an impaired immune system [5]. It is known that dry skin, allergic reactions, hypersensitivity, and increased blood levels of histamine, parathormone, calcium, and phosphorus are associated with the aggravation of pruritus [6]. As a subjective symptom, the severity of pruritus varies from patient to patient and usually occurs during or after haemodialysis. While pruritus is very difficult to tolerate, resistant to treatment, and impairs sleep in some patients, in others, it can be localized and temporary [7]. Several studies in the literature report that the prevalence of pruritus ranges from 18% to 70% [7,8]. In a study, it has been reported that 5-49% of patients with CKD and 50-90% of hemodialysis patients experience severe pruritus [9].
Physical and psychological effects of pruritus, which is a common and disturbing symptom, are generally neglected. Dermatological symptoms affect a person’s physical health, social life, psychological state, and daily life activities [3]. Although symptoms usually decrease over time, symptom resolution can sometimes take time, and persistent itching can negatively affect the quality of life of patients [10]. As a subjective feeling, pruritus alone is not considered a dangerous condition for the patient; however, it results in physiological changes causing bleeding and the development of skin lesions [11]. The presence of skin lesions, especially in the exposed parts of the body such as hands and face, causes negative psychosociological effects such as embarrassment, distancing from society, and low self-perception [12]. Symptom control in CKD patients requires a multidisciplinary approach. Important responsibility falls especially on nurses for the alleviation and resolution of symptoms [13]. The first step in the prevention and management of pruritus, which is a common symptom in CKD patients, is evaluation. Since nurses take part as the primary caregivers, they should examine factors causing pruritus and take necessary precautions.
This study was planned to examine pruritus and dermatological quality of life in all CKD patients who receive or do not receive renal replacement therapy.
Material and Methods
Design
This study was design as a descriptive correlational and cross-sectional study.
Sampling Size
The research was carried out at the Application and Research Hospital of the Cumhuriyet University. The study population consisted of 104 patients who met the criteria of the study and accepted to participate in the study. The inclusion criteria were: (1) 18 years of age or older, (2) treatment for more than one year, (3) people who have difficulties in seeing, hearing and communicating and (4) willing to participate.
Instruments
Data were collected between January and April 2020 after ethical approval. Research data were collected by the forms described below.
Patient Information Form: Demographic information and data on disease/treatment processes were collected with a questionnaire consisting of 11 questions prepared using the literature.
5-D Itch Scale: In 2010, the 5-D itch scale has been developed by Elman S, et al in English [14]. 5 The 5-D itch scale consists of 8 items in 5 domains as follows: duration, degree, direction, disability, and distribution. The domains of duration, degree, and direction contain 1 item, whereas there are 4 items for determining the disability. The items of 4 domains are assessed by a 5-point Likert scale. The distribution domain includes 16 potential itch areas, including 15 body parts and 1 area with clothing or bandages contact. The total score from the scale ranges from a minimum of 5 (no itching) to a maximum of 25 (itching is of the highest severity). Duration, severity and prognosis and restriction items of the scale were scored from 1 point to 5 points [14]. Turkish validity reliability was done by Ersoy and Akyar [15]. In our study, the Cronbach’s alpha value was found to be 0.94.
Dermatology Life Quality Index (DLQI): In 1994, the DLQI questionnaire was developed by Finlay, et al for assessing HRQoL of general dermatological diseases [16]. Öztürkcan et al. [2006] got the formal permission to validate and use the Turkish version of the DLQI questionnaire [17]. There are 10 questions according to 6 domains: symptoms and feeling, daily activities, leisure, work and school, personal relationships, and treatment. The range of total score is from 0 to 30. High scores indicate a high level of dermatological involvement [16,17]. In our study, the Cronbach’s alpha value was found to be 0.91.
Data Analysis
Data obtained as a result of the research were evaluated using numbers, percentages, mean, standard deviation, T-test, Mann-Whitney U test and One-Way ANOVA test with the SPSS 22.0 version program. The chi-square test was used to compare the two groups, and the ANOVA test was used to determine the difference between the two groups. Correlation was performed to determine the relationship between the scales, and to determine the level of relationship between 5-D itch scale and some features of patients analyzed using linear regression.
Ethical Approval and Consent to Participate
The study was conducted in accordance with the Declaration of Helsinki. Prior to the study, necessary permissions were obtained from the Ethics Committee of NonInterventional Clinical Investigations Ethics Committee (Decision date: 15.01.2020. number: 2020-01/13). Informed consent was obtained from patients.
Results
Information on the sociodemographic characteristics of the patients is given in Table 1. Among the study sample, 52.2% of CKD patients receiving hemodialysis treatment were male, 41.8% were 65 years of age and older, 44.8% were primary school graduates, and 37.3% were housewives. Of the patients who did not receive hemodialysis treatment, 64.9% were men, 35.1% were between the ages of 46-65, 32.4% were illiterate, and 35.1% were housewives and retirees. A statistically significant difference was found between the education and occupation of the patients who received and did not receive hemodialysis treatment (p<0.05). There was no difference between the two groups in terms of other characteristics (p>0.05).
Table 1 shows the findings related to kidney disease and pruritus symptom of the patients. According to the table, 67.6% of the patients who did not receive dialysis treatment were Stage 4. 79.1% of patients receiving hemodialysis treatment and 73% of patients not receiving hemodialysis treatment did not use any medication for itching. Among the participants, 37.3% of patients received hemodialysis treatment and 73% of patients did not receive any treatment other than medication for itching (Table 1).
Comparison of scale scores and total values of the patients are given in Table 2. The total score on the 5-D itch scale of patients receiving HD treatment was 8.25 ± 3.69, and the DLQI total score was 7.25 ± 5.96. The total score on the 5-D itch scale of the patients who did not receive HD treatment was 7.65 ± 3.89 and the total DLQI score was 3.97 ± 4.75. In terms of dermatological quality of life, the average score on the scale in patients receiving HD treatment was found to be statistically significantly higher. According to the data, the mean 5-D Itch scale was found to be 8.03 ± 3.75, and the dermatological quality of life scale was 6.08 ± 5.67. While the severity of dermatological quality of life in patients was high and moderate in 26.9% of those who received hemodialysis treatment, it was found to be mild to severe in 45.9% of those who did not receive hemodialysis treatment. There was no difference between the two groups in terms of DLQI scores. It is seen that the dermatological quality of life of those who do not receive hemodialysis treatment is more intensely affected. According to Table 3, a statistically significant positive correlation was found between 5-D itch scale and DLQI. As itching increases, the rate of adversely affecting the dermatological quality of life increases. When the relationship between the blood values and the scale averages of the patients were examined, a statistically significant relationship was found between the phosphorus, albumin and total protein values and the scale averages. As the value of phosphorus, albumin and total protein increases, itching severity increases and dermatological quality of life decreases.
Discussion
One of the important dermatological symptoms that accompany CKD is pruritus. Pruritus can develop at any stage of the disease in the majority of patients with uremia [18]. Besides the already higher incidence of pruritus in people with ESRD compared to the general population, dialysis treatment further increases this high incidence [18]. According to the results of two comprehensive international epidemiological studies, DOPSS (Dialysis Outcomes and Practice Patterns Study)-I and DOPPS II, the prevalence of uraemic pruritus in CKD patients is reported as 40.6% [19].
This study aimed to examine pruritus and dermatological quality of life in all CKD patients receive or do not receive renal replacement therapy. In our study, the total score on the 5-D itch scale in patients receiving HD treatment was 8.25 ± 3.69 and in those who did not receive HD treatment it was 7.65 ± 3.89 According to these results, it is seen that the pruritus symptom of the patients receiving hemodialysis treatment is more severe and the dermatological quality of life is worse. In the study conducted by Ersoy and Akyar (2019), the mean 5-D itch scale score in hemodialysis patients was found to be 13.97 ± 4.11 [20]. Similar to our findings, another study on hemodialysis patients found the mean itch scale score as 10.9 ± 4.8 [21].
Pruritus of ESRD has a negative impact on people’s performance in several areas of life, disrupting activities, leisure time, school/work life, personal relationships, and treatment [22]. In the present study, the mean score of the dermatological quality of life scale of the patients receiving HD treatment was found to be 7.25 ± 5.96 and for those not receiving hemodialysis treatment the mean score of DLQI was 3.97 ± 4.75. When the impact on the quality of life was examined using the dermatology life quality index scores, 26.9% of the patients who received hemodialysis treatment were highly affected, 45.9% of the patients who did not receive hemodialysis treatment were moderately affected. The studies by Adejumo, Madubuko, Olokor, & Ainaet al., (2019) reported that dermatological quality of life of CKD patients was affected at similar rates, too [12]. Similar to our study, another study conducted on hemodialysis patients found the DLQI scale mean score to be 10.40±6.46 [23]. In our study, these levels of impairment observed in the DLQI scores suggest that pruritus negatively affects functioning in many areas. It is thought that the dermatological quality of life and itching symptoms of the patients receiving hemodialysis treatment are more affected by the products used during the hemodialysis process and the accumulation of waste products in the body due to the complete deterioration of kidney functions. Uraemic pruritus begins 3-6 months after starting hemodialysis. Studies in the literature report that a positive correlation exists between hemodialysis duration and pruritus and that rates of pruritus tend to increase in patients receiving hemodialysis treatment for more than three months [24].
Similar to pruritus in dermatological patients, chronic itch in CKD patients negatively affects the psychosocial and physical condition of patients [22]. Pruritus has been proven to negatively affect performance in daily activities, the use of leisure time, school/work life, and personal relationships, as well as having a negative impact on patient participation in treatment [25]. Similar to other studies, a positive correlation has been found between the 5-D itch scale and the dermatological quality of life [3,24]. Pruritus in CKD patients increases the experienced severity of other symptoms and affects self-esteem negatively. Also, it affects physical performance and activities of daily life [12]. Chronic pruritus causes the individual to feel ugly because of the inflicted wounds on the skin, lesions inflicted in areas of the body that cannot be hidden under clothing, and the frustration of patients caused by the loss of freedom in choosing clothes due to fear of exposing their lesions [24]. Pruritus can disrupt regular sleep and social performance of people and result in depression in advanced stages. Previous studies have reported that increased pruritus severity adversely affects not only the dermatological quality of life but the physical and mental quality of life as well [3,22]. For these reasons, early recognition of pruritus that affects all aspects of life gains importance to provide necessary treatment and care.
Conclusion
In conclusion, it was determined that CKD patients in the sample experienced pruritus and their dermatological quality of life was negatively affected. It was concluded that the severity of itching was higher in patients receiving hemodialysis treatment and the dermatological quality of life was affected more negatively than in the other patient group. It has been proven that the severity of pruritus and the dermatological quality of life of patients affect each other. It has been concluded that patients receiving hemodialysis treatment have a lower dermatological quality of life. Since itching is a common symptom negatively affecting the physical, psychological, and social performance of the person, CKD should be followed up regularly and necessary precautions should be taken. For the alleviation of pruritus, healthcare professionals should carry out regular follow-ups, provide training programs about diet regimens for the correction of clinical parameters, and implement interventions for improving compliance with treatment processes. Pruritus as a complication should be addressed not only for its physiological effects but also for all of its aspects for early diagnosis and treatment. Management of pruritus as a symptom will not only increase the quality of life of patients but also reduce the number of medications used, improve clinical findings, and consequently allow for achieving cost-effectiveness.
The small sample size and the single centre in our study will limit the generalizability of the results.
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.
Funding: None
Conflict of interest
The authors declare no conflicts of interest.
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Mukadder Mollaoğlu, Esra Başer Akın, Ferhan Candan. Investigation of pruritus and dermatological quality of life in chronic kidney disease patients. AAnn Clin Anal Med 2023;14(4):296-300
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Knowledge of the dental healthcare specialists about home bleaching
Waleed Asiri 1, Siraj DAA Khan 2, Saad Masood Al-Qahtani 2, Ghanem Mohammed Alqahtani 3, Saqer Alqarni 4, Mansour H. Alkorbi 2, Salem H. Almutair 2, Nasser A. Almkaeel 2, Khalid Almusabi 2, Aied F. Al-mokhles 2, Gazi Alqahtani 2, Bassam Hassan Al Qahtani 2
1 Department of Restorative Dentistry, Faculty of Dentistry, Najran University, Najran, 2 Department of Preventive Dental Sciences, Faculty of Dentistry, Najran University, Najran, 3 Department of Restorative Dentistry, Armed Forces Hospital, Khamis Mushait, 4 Department of Restorative Dentistry, Khamis Mushite Dental Center, Khamis Mushait, Saudi Arabia
DOI: 10.4328/ACAM.21466 Received: 2022-10-28 Accepted: 2022-11-28 Published Online: 2022-12-10 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):301-305
Corresponding Author: Siraj DAA Khan, Department of Preventive Dental Sciences, Faculty of Dentistry, Najran University, Najran, Saudi Arabia. E-mail: sdkhan@nu.edu.sa P: +966-17542-7960 Corresponding Author ORCID ID: https://orcid.org/0000-0002-7015-2232
This study was approved by the Scientific Ethics Committee of Najran University (Date: 2022-09-11, No: 444-40-9784-DS)
Aim: Cosmetic dentistry is the branch of dentistry that focuses on improving the appearance of the mouth, teeth, gums, and overall smile. Common procedures include home bleaching, veneers, fillings, and implants. Therefore, this study was designed to explore dental healthcare specialists’ knowledge about home bleaching.
Material and Methods: The present cross-sectional study based on a questionnaire was conducted among dental healthcare specialists in March 2022. The survey was conducted by simple random sampling among dental healthcare specialists from different regions of the country by sharing a link to the questionnaire via social media like WhatsApp, Snapchat and Telegram. Collected data were statistically analyzed for the frequency and association of responses.
Results: Among 624 participants, 464 (74.4%) males and 160 (11.9%) were asked about aspects of dental bleaching. Results revealed that some of the individuals in our study benefited after one week of the appropriate application of home bleaching, while some individuals faced health complications such as headache, dizziness, nausea and vomiting etc.
Discussion: Most individuals lack knowledge about appropriate applications of home bleaching. Home bleaching is the most effective remedy for dental treatment as most individuals get benefits after one week of application.
Keywords: Home Bleaching, Headache, Dental Applications, Health Complications
Introduction
Home bleaching involves visiting a dental clinic and acquiring the try for the application of a chemical agent to oxidize the organic pigmentation in the tooth. Nowadays, dental treatment with cosmetics is one of the most common methods because patients want to maintain the appearance of their smiles and general health [1]. Dentistry has seen technological advancements due to patients’ desires to enhance the beauty of their teeth, which is an important component of life satisfaction. According to a UK survey, 28% of people were unhappy with their smile, and out of the 3215 participants, 50 percent had some sort of discoloration [2]. Another research conducted in the UK in 2004 indicated that people’s concern about dental appearance among that teeth color was common. The market for teeth-whitening solutions has grown tremendously over the last few years due to the growing demand for whiter teeth. Currently, the most widely advertised oral care products are those that whiten teeth [3].
Bleaching is a common type of tooth whitening used for the treatment of affected teeth. It is thought to be the least invasive aesthetic procedure for enhancing stained teeth’s appearance [2]. Bleaching can be done in a dental clinic or at home. The most popular methods used for home bleaching nowadays are (i) whitening mouth rinses that combat plaque formation and remove stains; (ii) whitening chewing gums, which are widely enjoyed and accepted by many people as they are a common activity among both adults and children, may therefore be a way to administer local medication into the oral cavity [4]. In addition to increasing saliva flow and removing food particles, surface stains, and plaque, chewing gum-based items are very important and have several advantages of pharmacotherapy (iii). Whitening dental floss has also been developed to reduce stains in the anterior teeth and sub-gingival regions [5].
Teeth discoloration can be intrinsic or extrinsic, depending on the cause. Based on the type of discoloration hydrogen peroxide, sodium tripolyphosphate, sodium hexametaphosphate, and sodium percarbonate are the active components used in the home bleaching solution. Many whitening products also contain carbamide peroxide as an active component [6]. It is a stable compound that disintegrates when it comes into contact with water, releasing H2O2 (10 percent carbamide peroxide, 3 % hydrogen peroxide and 7 % urea) [7]. Dental stains can be inhibited and removed with the help of hydroxy-apatite-bound sodium tripolyphosphate (STPP) because of its inhibition activity on the adsorption of secreted proteins [8].
The current study aimed to explore the knowledge of home bleaching among dental healthcare specialists.
Material and Methods
After getting the ethical clearance from the Scientific Research Ethics Committee (Reference No.:444-40-9784-DS) of Najran University, the study questionnaire was distributed to dental healthcare specialists.
Study sample
The study sample comprised 624 dental professionals and their knowledge of home bleaching and their personal experience were assessed through a questionnaire survey.
Study design
This cross-sectional study was carried out in Saudi Arabia among dental healthcare specialists by sharing a questionnaire link via WhatsApp, Snapchat and Telegram. This questionnaire had specific questions related to knowledge of bleaching.
Statistical analysis
All survey data was transferred from a Google-Sheet to an excel-sheet and then put for further analyses into the Statistical Package for Social Sciences program (version 25, IBM software; Chicago, USA).
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
This study comprised 624 participants, including 464 (74.4%) males and 160 (11.9%) female participants. Among 624 participants, 221 (35.4%) were dental students, 194 (31.1%) were dental interns, 134 (21.5%) were general practitioners and 75 (12%) were specialists. The social and demographic characteristics of participants involved in the current research are shown in Table 1.
Table 2 shows the characteristics of home bleaching among participants, carbamide peroxide was considered the active ingredient in home bleaching by 66 (10.6%) dental students, 55 (8.8%) dental interns, 24 (3.8%) dental practitioners and 17 (2.7%) dental specialists and hydrogen peroxide was chosen by 107 (17.1%) dental students, 101 (16.2%) dental interns, 76 (12.2%) dental practitioners and 38 6.1% dental specialist, while sodium perborate was thought effective ingredient by 34 (5.4%), 2 6(4.2%), 24 (3.8%), 13 (2.1%) dental students, interns, practitioners and specialists, respectively. This response by participants showed a significant p-value. Regarding the damage caused by home bleaching, most of the participants (74.8%) agreed that bleaching does not cause any damage to the old restorations, and a significant number of participants (48.7%) suggested to do composite restoration after 1 week of bleaching.
Table 3 shows the correlation between the experience of home bleaching and speciality, the results revealed that most of the participants (345; 55.3%) used the different types of bleaching but only 30 (4.8%) dental students, 39 (6.3%) dental interns, 35 (5.6%) general dental practitioners and 4 (6%) dental specialists used home bleaching. Among them, 43 (6.9%) dental students, 37 (5.9%) dental interns, 38 (6.1%) general dental practitioners and 14 (2.2%) dental specialists did not face any side effects. Dental sensitivity (31.9%), gingival burn (24.9%) and headache (20.3%) were the commonly faced side effects of the bleaching with a significant P-value (<0.01). Only 76 (12.2%) dental students, 75 (12.0%) dental interns, 75 (12%) general dental practitioners and 47 (7.5%) dental specialists got benefits in their social relationships after the application of home bleaching. However, 155 (24.8%) participants who do bleaching feel the sensitivity of the teeth for more than one week with a significant P-value (<0.01). With the application of home bleaching, effective results were observed in 8 (1.3%) dental students, 5 (0.8%) dental interns, 3 (0.5%) dental practitioners, and 21 (3.4%) dental specialists. A significant number of dental health care professionals (404; 64.7%) advised bleaching to their knowns. Only 48 (7.7%) dental students, 36 (5.8%) dental interns, 15 (2.4%) dental practitioners, and 9 (1.4%) dental specialists thought that home bleaching is the most effective way.
Discussion
A recent randomized clinical study revealed that patients experienced more positive results after the application of 35 % H2O2 as a home bleaching agent, particularly around the upper lateral incisors [9]. Another in vitro investigation examined the color stability after the bleaching and discovered that the bleaching agent affects color stability up to three months after the bleaching [10]. AlOtaibi et al., (2020) conducted a similar study in Saudi Arabia and concluded that most of the participants used home bleaching after getting knowledge from advertisements [11]. Similarly, Moldovan et al., (2022) claimed that over-the-counter bleaching products were used by most of the Romanian population, which is contradictory with our result [12].
Boanfe et al., (2013) showed that home bleaching played a vital role in the degradation of human enamel [12]. They applied home bleaching through gel concentrations of carbamide peroxide (22%) and hydrogen peroxide (35%). Some surfaces had deteriorated that showed the occurrence of enamel erosions. Another in vitro investigation examined the color changes of samples of bleached teeth’s enamel and dentin and mixed enamel and dentin; and discovered that the color was not constant over time in terms of luminosity. They demonstrated that mixed enamel and dentin showed promising results for the enamel of the affected teeth [13].
Another clinical study revealed that home bleaching procedures for three months showed more color change stability over a six-month timeframe than in-office bleaching [14]. Another study by Wiegand et al., (2008) [16] demonstrated that the use of the home bleaching method, using 10% carbamide peroxide gel implemented via a tray was comparable to that acquired with the in-office method that implemented 35% H2O2.
Significance and Awareness of Home bleaching
Researchers who have examined the impact of intensive tooth whitening procedures on dentition and vulnerability to demineralization have paid close attention to the danger of teeth structure damage. According to several of these research studies, severe bleaching procedures can alter the microstructure, surface quality, and enamel crystals’ vulnerability to demineralization [17].
How long will the treatment last? This is a question that patients frequently ask. Because a patient may regularly expose their dentition to foods and drinks known to stain the teeth and would suffer re-staining within a month, it is hard to estimate how long bleaching regimens will last. Nevertheless, it would be safe to expect tooth whitening to last up to one year, provided they are not subjected to chromogens like coffee, cigarette smoke, or red wine.
Conclusion
Most of the individuals in our study have asked about their knowledge of home bleaching and its application during dental treatment. Most individuals lack knowledge about appropriate applications of home bleaching. Home bleaching is the most effective remedy for dental treatment as most individuals have got benefits after one week of application. In contrast, some individuals face health complications including the sensitivity of teeth, gingival burn, headache, etc. This study will help explore knowledge of home beaching and its usage in appropriate ways.
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.
Funding: None
Conflict of interest
The authors declare no conflict of interest.
References
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3. Joiner A. The bleaching of teeth: a review of the literature. J Dent. 2006;34(7):412-9.
4. Carey CM. Tooth whitening: what we now know. J Evid Based Dent Pract. 2014; 14(Suppl.):S70-6.
5. Joshi SB. An overview of vital teeth bleaching. J Interdiscip Dent. 2016; 6(1):3-13.
6. Kwon SR, Wertz PW. Review of the mechanism of tooth whitening. J Esthet Restor Dent. 2015; 27(5)240-57.
7. Kim JH, Kim Y, Shin SJ, Park JW, Jung IY. Tooth discoloration of immature permanent incisor associated with triple antibiotic therapy: a case report. J Endod. 2010; 36(6)1086-1.
8. Lima FG, Rotta TA, Penso S, Meireles SS, Demarco FF. In vitro evaluation of the whitening effect of mouth rinses containing hydrogen peroxide. Braz Oral Res. 2012; 26:269-4.
9. Barabolak R, Hoerman K, Kroll B. Record D. Gum chewing profiles in the US population. Community Dent Oral Epidemiol. 1991;19(2):125-6.
10. Walters PA, Biesbrock AR, Bartizek RD. Benefits of sodium hexametaphosphate-containing chewing gum for extrinsic stain inhibition. J Dent Hyg. 2004;78(4):8.
11. AlOtaibi G, AlMutairi MS, AlShammari MZ, AlJafar M, AlMaraikhi TF. Prevalence and public knowledge regarding tooth bleaching in Saudi Arabia. J Family Med Prim Care. 2020; 9(7):3729-32.
12. Moldovan AM, Popescu V, Ionescu CV, Cuc S, Craciun A, Moldovan M, et al. Various Aspects Involved in the Study of Tooth Bleaching Procedure: A Questionnaire–Based Study. Int J Environ Res Public Health. 2022; 19(7): 3977.
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Waleed Asiri, Siraj DAA Khan, Saad Masood Al-Qahtani, Ghanem Mohammed Alqahtani, Saqer Alqarni, Mansour H. Alkorbi, Salem H. Almutair, Nasser A. Almkaeel, Khalid Almusabi, Aied F. Al-mokhles, Gazi Alqahtani, Bassam Hassan Al Qahtani. Knowledge of the dental healthcare specialists about home bleaching.Ann Clin Anal Med 2023;14(4):301-305
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Incidence of congenital heart disease with consanguinity: 10 years of experience in a single-center
Hüseyin Yılmaz 1, Mehmet Burhan Oflaz 2
1 Department of Pediatrics, Konya City Training and Research Hospital, 2 Department of Pediatrics, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
DOI: 10.4328/ACAM.21468 Received: 2022-11-03 Accepted: 2022-12-24 Published Online: 2023-01-07 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):306-310
Corresponding Author: Hüseyin Yilmaz, Department of Pediatrics, Konya City Training and Research Hospital, Konya, Turkey. E-mail: hoyilmaz42@gmail.com P: +90 533 529 83 63 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9971-9669
This study was approved by the Ethics Committee of Necmettin Erbakan University Meram Faculty of Medicine (Date: 2020-06-19, No: 2020/2612)
Aim: Congenital heart diseases (CHD) are inborn structural and functional anomalies of the heart and its great vessels. It is considered to have a multifactorial origin. This study aims to determine the frequency and types of CHD between siblings in Central Anatolia and investigate consanguineous marriages’ contribution to this undesirable incidence.
Material and Methods: The study included 1916 children admitted to the pediatric cardiology outpatient clinic between 2009-2019. Congenital heart diseases were grouped as uncomplex CHD, complex CHD, heart muscle diseases and other heart conditions.
Results: There were 113 consanguineous parents. No relation was found between the types of consanguineous marriages and CHD incidence. Atrial septal defect (ASD) was the most common heart condition among consanguineous marriages seen in 73 patients. Parents with congenital heart diseases had ASD or Ventricular septal defect( VSD) type septal lesions. There was no relationship between the parents’ consanguinity and the presence of CHD in any sibling (p=0.169). In 300 siblings, CHD was present in both patients. The older sibling having CHD increases the risk for the younger one (p<0.05). Of the patients, 827 had noncomplex cardiac lesions, 13 had complex cardiac lesions, and 136 had other cardiac pathological echocardiographic (ECHO) findings.
Discussion: Families who have a child with pre-existing CHD should be informed about the possibility of CHD recurrence before pregnancy, and these cases should be examined using fetal ECHO in the prenatal period. Those under risk should be followed up and treated in appropriate centers in terms of CHD.
Keywords: Consanguinity, Congenital Heart Defects, Sibling, Twins
Introduction
Congenital heart diseases (CHD) are structural and functional anomalies of the heart and large vessels emerging during embryogenesis in the first trimester. They are the most common anomaly among congenital abnormalities and constitute one-third of all malformations [1,2]. The cause of 80% of congenital heart diseases is still not fully understood. It is accepted to occur due to multifactorial determinants with the common interaction of genetic and environmental variables [3].
Consanguineous marriage increases the risk of babies with anomalies from 2-5% to around two folds [4]. Providing accurate and reliable counseling to families is of great importance for the health of the unborn child [1]. We aimed to determine the frequency and type of CHD among siblings in a set region and to investigate the contribution of consanguineous marriages to this health problem.
Material and Methods
A total of 1916 pediatric patients, 2 from each of the 958 families, who applied to the Pediatric Cardiology outpatient clinic between January 2009 and January 2019 with bruising, murmur, and a family history of heart disease, were included in the study. Since the number of applications for more than two siblings is low, families with more than two siblings were not included in the study. Demographic characteristics, presence of congenital heart disease in the family, consanguinity between the parents, the degree of consanguinity, echocardiographic findings, and diagnoses were extracted from the patient records. The frequency and type of congenital heart disease among siblings, parental consanguinity, and the effect of the presence of CHD in another family member were compared. Echocardiographic evaluation was performed with the GE Vivid S5 instrument using S3-6 sector probes.
Congenital heart defects were categorized into 3 main groups. The first group included those with noncomplex CHD: Conditions without cyanosis patent ductus arteriosus (PDA), ASD, VSD, and their combinations) were included. The second group included those with a complex CHD: Those with pathologies such as Tetralogy of Fallot (TOF), atrioventricular septal defect (AVSD), Ebstein’s anomaly, and transposition of great arteries in which septal, valvular, or great vessels are affected together were included. Finally, the third group consisted of heart muscle and other valve diseases: Bicuspid aorta, mitral valve prolapse (MVP), cardiomyopathy, left ventricular outflow tract stenosis, etc.
The level of consanguinity between the parents was graded according to Thompson [5]. Consanguineous marriages were divided into 3 groups: the marriage of children of same-sex siblings, the marriage of children of different-sex siblings, and the marriage of distant relatives [6].
Approval for this study was obtained from the hospital’s local clinical research ethics committee (2020/2612).Statistical analysis was performed using the SPSS package program (SPSS for Windows, Version 18.0, SPSS Inc., USA). Descriptive statistics were used to classify the data. Categorical data were expressed as percentages. Skewed numerical data was indicated by the median. The Chi-square test was used to compare categorical data between groups, while the Mann-Whitney U test was used to compare numerical data. A p-value of <0.05 was considered significant.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
Between January 2009 and January 2019, 22676 patients underwent ECHO in the pediatric cardiology outpatient clinic. 1916 children from 958 families, who were confirmed to be siblings, were included. Of the siblings, 1536(80.1%) were non twins, 380(19.9%) were twins. The flow chart of the study is given as a diagram (Figure 1).
Nine hundred and seventy-six (51.1%) of them had pathological findings in the ECHO. Of the patients with pathological ECHO findings, 827(84.7%) had noncomplex cardiac lesions, 13(1.3%) had complex cardiac lesions, and 136(13.9%) had other cardiac pathological ECHO findings.
There were 113 (11.8%) consanguineous parents. Of these, 106 (98.8%) were first-degree cousin marriages.When the types of consanguineous marriages were compared, although CHD was numerically higher in marriages between uncle/aunt’s children, there was no statistically significant difference (p>0.05).There was no statistically significant difference between the types of consanguineous marriages concerning the incidence of CHD in the only child of the family or in siblings (p>0.05).
Children of families with consanguineous marriages had 102 noncomplex cardiac lesions, 2 complex cardiac lesions, and 18 valve and heart muscle diseases. These were: 73 ASD cases, 12 ASD/PDA cases, 7 ASD/VSD cases as noncomplex pathologies, and one TOF and one AVSD as complex cardiac lesions (Table 1).
Of the siblings’ families, 23 (2.4%) had CHD. These were noncomplex septal lesions such as ASD/VSD.
CHD was found in one sibling in 676(69.2%) of the sibling cases and in both siblings in 300(31.8%) cases. In these cases, consanguinity was observed between the mother and father in 86 (13%) of those with CHD in one of the siblings and in 36 (22%) of those with CHD in both siblings. Also, There was no relationship between parental consanguinity and the presence of CHD in either or both siblings. (p=0.169). The information on the patients with pathological ECHO findings is schematically summarized in Figure 2
Of the sibling cases with at one sibling with CHD, 516 (76.3%) were normal siblings and 160 (23.7%) were twins. Of the sibling cases with at both siblings with CHD, 166 (55.3%) were normal siblings and 134 (44.7%) were twins When the status of having a normal sibling or a twin were compared, being a twin was riskier in terms of having CHD (p<0.05).
Of the normal sibling cases with a one sibling with CHD, 249(48.3%) were of different sex, and 267(51.7%) were of the same sex. Of the twins, with a one sibling with CHD 64(40.0%) were different sex, while 96 (60.0%)were same-sex. Of the non-twin cases where both siblings had CHD, 83 (50%) were of different sex, while 83(50%) were of the same sex. Of the twins who had CHD in both siblings, 58(43.2%) were of different sex, and 76(56.8%) were of the same sex. There was no relationship between the gender of the older and younger siblings being the same or different sex and the presence of CHD (p=0.941).
In older siblings, ASD was the most common with 266 (27.2%) cases, followed by MVP with 60 (6.3%), and both ASD and PDA in 24 (2.5%).There were complex cardiac lesions in 9 older siblings (0.9%), including 3 AVSD , 2 Ebstein anomaly/ASD, 1 TOF, 1 double inlet left ventricule/AV-VA discordance/VSD, 1 great artery transposition of great arteries/ASD/VSD, and 1 total abnormal pulmonary venous return anomaly/High venosum ASD.
In younger siblings, the most common diagnosis was ASD with 371 (38%) cases, 40 (4.2%) cases of ASD/PDA coexistence, and 36 (3.8%) cases of MVP. There were also 4 (0.4%) patients with complex cardiac lesions in younger siblings. These were 2 atrioventricular septal defects, 1 Tetralogy of Fallot, and 1 case of transposition of the great arteries/ASD/VSD.
ASD, ASD-PDA, MVP, and BAV were observed in two children of 152 families, ten families, six families, and two families, respectively. In addition, VSD, ASD-VSD-PDA, and ASD-BAV were found in 3 families consecutively. The older sibling having CHD poses a risk for the younger sibling to also have CHD (p<0.05). There was no family with complex cardiac lesions in both siblings. These findings are summarized in Table 2.
Discussion
As a result of developing technology and surgical techniques, most patients with congenital heart diseases can survive until reproductive age. Hence, there is a comprehensive and reliable counseling need in terms of CHD heredity [7] . Due to the varying severity of congenital heart disease types, an important factor to consider when counseling families is the estimation of the type of lesion that can recur [8] . It is stated that the risk of recurrence varies between 1% and 3% for different types of heart defects [9] .
Although people with a family history of CHD have an increased risk of also having CHD, mostly only one individual in these families is affected. Thus, the increased risk may not be easily detected in clinical practice [10]. Familial recurrence and the association with some environmental factors support that CHD occurs with polygenic inheritance. In people with genetic predispositions, drugs, environmental factors, and viruses can initiate events and cause cardiac anomalies [11].
It has been reported that recurrence in first-degree relatives is between 2-5%, and these results mathematically fit the model of polygenic transmission [12].
Family Structure in Turkey 2016 survey data indicates that consanguineous marriage is 23% across Turkey, which is 26.7% in Central Anatolia, where our center is located. When these marriages are analyzed according to the type of kinship, it is seen that 28.5% of the individuals who have had consanguineous marriages are married to the children of their father-side aunts/uncles and 20.9% to the children of their mother-side aunts/uncles [13] .
In our study, the rate of consanguineous marriage was 11.8%. The low rate of marriages between relatives may have led to the lower incidence of diseases such as CHD. We think that the relatively low number of CHD patients in our study may be related to this factor of consanguineous marriages.
Ertoy Karagöl et al.were conducted their study in Konya among 651 children having consanguineous parents where most were married to first-degree cousins, reported 16 (3.3%) CHD cases in the relatives, and there was no significant difference in CHD between them and the control group [14].
In the comparison between 1585 non-syndromic CHD cases and 1979 control cases, Chehab G et al., reported that the rate of consanguineous marriage was 19.4% in the CHD group and 14.4% in the control group. Furthermore, some specific heart lesions such as Tetralogy of Fallot, valvular aortic stenosis, and ASD were seen at higher rates in consanguineous marriages, and there was no increase in cardiac malformations such as atrioventricular canal defect and transposition of great arteries with consanguineous marriages [15].
In our study, there was consanguinity in 113 (11.8%) of the 958 families and similar to the study performed by Ertoy Karagöl et al. in the same region, there was no significant difference between the children of related parents and children of non-consanguineous parents regarding CHD (p=0.169) [14].
The increased risk of CHD in siblings descending from parents with CHD is explained by genes, shared environmental factors, or their combined effects. The increased risk may be associated with a single strong risk factor in some families. For other families, it may be the result of familial aggregation of multiple interacting risk factors, each of which carrying a low risk of CHD [16].
The fact that consanguinity did not affect the development of CHD in our study suggests that the genetic predisposition for CHD in this region may be lower and the effect of environmental factors may be less. Relatives of consanguineous parents having no CHD and the previous study in the same region showing similar results support this idea.
Brodwall et al. reported that the risk of CHD among siblings was significantly associated with the presence of CHD in the older sibling, and reported that the risk of CHD in the younger sibling was 411.8 per 10,000 if the older sibling had CHD; if the older sibling did not have CHD, this rate was 112.8 per 10,000 [17]. In the same study, the risk of CHD recurrence was 14.0 in twins of the same sex and 11.9 in twins of different sexes, and this risk increased 10 times in individuals with two older siblings who had CHD. Furthermore, the risk of recurrence between siblings was higher in severe CHD types.
It has been reported that if one of the parents has CHD, the same type of cardiac lesion can be seen in children with a rate of 1/3 or 2/3, and this lesion is more serious in the second and third siblings [18]. In our study, 19 cases with CHD had 3 members of the family with the disease, including both siblings and at least one parent with CHD. These lesions were similar in all family members and were septal lesions such as ASD and VSD.In our study, having CHD in the older sibling was a risk in terms of CHD in the younger sibling (p<0.05). When we compared the status of having a non-twin and having a twin, it was seen that being a twin was riskier in terms of having CHD (p<0.05). In addition, there was no relationship between the gender of the older and younger siblings being the same or different sex and the presence of CHD (p=0.941).In the study performed by Atalay et al., the most common CHD siblings were VSD, ASD, and TOF, and 40% of their siblings had the same type of cardiac lesion [19]. It has been reported that the rate of similar CHD was 71.44% in the children of relatives with consanguinity.
In their study on the risk of CHD among siblings, Brodwall et al. reported that the same type of CHD is 33.3% in twins of the same sex, 20% in twins of different sexes, and 16% among non-twins [17]. Among siblings, similar CHD was detected in 30% and different type of CHD in 54%. Therefore, the increased risk of CHD in siblings may be largely due to the increased risk of having the same type of CHD. However, in this study, unlike ours, the recurrence of septal lesions was less common among siblings. In our study, the most common was ASD, followed by ASD/PDA association in both sibling groups; this being more common in younger siblings. Although VSD is most common in the pediatric age group, the reason why ASD was more common in our study may be that families who are worried bring their children to the pediatric cardiology department in the early period because most families have a history of CHD, and that small ASDs and PDAs are also seen and diagnosed earlier.
In the current literature, we see that the studies are mostly conducted in the general population; there are few studies in which only siblings are evaluated [15]. In the studies conducted in Turkey, the data collection period is mostly short, and they cover a small number of siblings and families. In this respect, our study differs from other investigations in that it took 10 years and included 958 families and 1916 siblings [14,19].
The limitation of our study is covering only the Central Anatolia region. Therefore, these data will not fully reflect the general population. However, the relatively high rate of consanguineous marriage where the study was conducted may affect the evaluation of the effects of consanguinity on CHD. The low rate of consanguinity among the patients in our study may also be considered among the limiting factors.
Conclusion
As a result, the concerns of families with a child with CHD should be taken seriously, and these families should be informed about the possibility of CHD recurrence before pregnancy. Due to the risk of recurrence of CHD in relatives, these cases should be screened for CHD with fetal ECHO in the prenatal period, and high-risk pregnant women with complex CHD should deliver in a center where first interventions can be made after birth.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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Role of echocardiography in guiding fluid therapy in shocked patients with impaired cardiac contractility
Mostafa Gaber 1, Wael Nabil 2, Amr Abdullah 3, Eman Alsharqawy 4, Mina Montasser 1
1 Department of Emergency Medicine, 2 Department of Hepatic and Biliary Surgery, 3 Department of Critical Care Medicine, 4 Department of Cardiology and Angiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
DOI: 10.4328/ACAM.21475 Received: 2022-11-01 Accepted: 2023-01-05 Published Online: 2023-01-25 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):311-314
Corresponding Author: Mostafa Gaber, Department of Emergency Medicine, Faculty of Medicine, Alexandria University, Alexandria, Egypt. E-mail: mostafa.gaber@alexmed.edu.eg P: +20 0105 0607071 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6300-308X
This study was approved by the Ethics Committee of Alexandria University (Date: 2021-05-20, No: 0201517)
Aim: Excessive fluid delivery has harmful effects, such as volume overload and pulmonary and systemic edema, which restrict oxygen transport to different tissues, increasing tissue hypoxia. Therefore, gathering accurate data on the fluid status and intra-cardiac filling pressures in patients with circulatory failure is crucial, particularly in patients who have compromised cardiac function. This study was designed to evaluate the role of echocardiography in guiding fluid therapy in shocked patients with impaired cardiac contractility in the Emergency Department of Alexandria Main University Hospital.
Material and Methods: We enrolled 100 patients who presented with shock and impaired cardiac contractility (ejection fraction < 52%) from August 2021 to July 2022. The baseline left ventricular outflow tract (LVOT) velocity time integral (VTI) and inferior vena cava (IVC) collapsibility index were measured using echocardiography; then, the passive leg raising (PLR) test was performed; and the second LVOT VTI was measured. Fluid challenge using 250-mL normal saline was administered to patients who tolerated the PLR test and did not show signs of volume overload during the PLR test. After fluid challenge, the third LVOT VTI was obtained.
Results: Twenty-one patients were excluded from the fluid challenge step as they did not tolerate the PLR test or they experienced signs of fluid overload (lung congestion) during the PLR test. Using the cutoff value of the IVC collapsibility index >51.85%, the sensitivity, specificity, positive predictive value, and negative predictive value were 75.0%, 80.0%, 82.5%, and 71.8%, respectively. The area under the receiver operating characteristic curve for the IVC collapsibility index for predicting fluid responsiveness was 0.774.
Discussion: The IVC showed major respiratory variations in the responder group compared with that in the other two groups, indicating that the intra-cardiac filling pressures (preload) in the responder group were low and their hearts were working on the steep portion of the Frank–Starling curve.
Keywords: Echocardiography, Contractility, Shock, Fluids
Introduction
Fluid therapy represents a major challenge in managing shocked patients, particularly those who have cardiac dysfunction. When the heart is working on the steep region of the Frank–Starling curve, preload will increase with intravenous (IV) fluids, thus significantly increasing the stroke volume, implying that fluid administration improves cardiac output and oxygen delivery to different tissues [1].
Clinicians cannot depend solely on clinical examination to evaluate the fluid status or responsiveness to fluid therapy [2]. Many studies have illustrated the role of imaging in assessing fluid responsiveness in patients with sepsis, those with septic shock and surgical patients [3, 4]; however, in our study, we only discussed the role of echocardiography in guiding fluid therapy in patients who have impaired cardiac contractility.
This study was designed to evaluate the role of echocardiography in guiding fluid therapy in shocked patients with impaired cardiac contractility in the ED of AMUH.
Material and Methods
Study design and setting
This prospective interventional non-randomized study was conducted in the ED of Alexandria Main University Hospital (AMUH) from August 2021 to July 2022. This study was reviewed and approved by the Ethics Committee of Alexandria University (reference number 0201517). Informed consent was obtained from all patients or next of kin.
Characteristics of participants
We enrolled 100 patients who presented with shock and had impaired cardiac ejection fraction (<52%) (available at: https://www.ncbi.nlm.nih.gov/books/NBK459131/) before receiving any IV fluids, vasopressor, or inotropes. Patients with trauma, unstable arrhythmias, lower limb amputation, prosthetic aortic valves, or pregnant, those on mechanical ventilation, and those aged <18 years were excluded from this study.
Sample Size: Using the Power Analysis and Sample Size (PASS 2020) software (NCSS, LIC, Kaysville, Utah, USA, ness.com/software/pass), the Department of Medical Statistics, Medical Research Institute, Alexandria University calculated the sample size considering 5% significance level and 3% precision using the Z-test [5].
Interventions
This study was conducted by the corresponding author who completed 5 years of training in the use of echocardiography in the ED and attended 100-h dedicated online echocardiography training. Moreover, the author has performed more than 500 reviewed echocardiography examinations before conducting this study.
We performed echocardiographic examination using the Sonoscape S6 portable color Doppler system (Yizhe Building, Yuquan Road. Nanshan, Shenzhen, 518051, Guangdong, China) using a phased array probe (1.9–6 MHZ).
After history taking and ABCDE assessment, performed by the emergency physician in charge of the case, shock was defined as systolic blood pressure of <90 mmHg for >30 min or a shock index (heart rate/systolic blood pressure) of >1 [6], with signs of tissue hypoperfusion, as follows: disturbed level of consciousness, cold clammy skin, oliguria, or serum lactate levels of >2.0 mmol/L [7].
Shocked patients were subjected to echocardiographic examination and were included in the study if they had an EF <52% (by the Simpson method or M-mode). The baseline LVOT VTI (before receiving any IV fluids, vasopressor, or inotropes) was obtained using the apical five-chamber view using pulsed wave Doppler signal from the left ventricular outflow tract, while the patient was supine or in the left lateral position. By tracing the LVOT VTI curve, we obtained the velocity time interval (VTI) [3].
While the patient is in the supine position, IVC scanning was performed through subcostal Window with M-mode. The minimum and maximum diameters were measured using the M-mode, as illustrated in Figure 1.
The collapsibility index was calculated using the following equation: IVC collapsibility index = (IVCmax–IVCmin /IVCmax)-100% [8].
Then, the passive leg raising (PLR) test was performed using the following technique [9]:
• Place the patient in the semi-recumbent position with the head up at 45°.
• Lower the patient’s upper body to the horizontal level and passively raise both legs at 45°.
• The second LVOT VTI was obtained 90 seconds later.
Patients who tolerated the PLR test and did not develop clinical or lung ultrasound signs of fluid overload (lung congestion) were given IV fluid bolus (250-mL normal saline) over 10 min, followed by the measurement of the third LVOT VTI.
Patients who did not tolerate the PLR test or those who developed clinical or lung ultrasound signs of fluid overload (lung congestion) during the PLR test were excluded from the fluid challenge.
The differentiating factor used to allocate patients to groups (non-responders or responders) was the percentage of LVOT VTI variability between the third and baseline VTI values (our gold standard to assess fluid responsiveness).
Patients who showed LVOT VTI variability < 10% were considered non-responders. In contrast, those who showed LVOT VTI variability > 10% were considered fluid responders [10, 11].
Therefore, in this study, we included three groups of patients: non-responders, responders, and those who were excluded from the fluid challenge (third group).
Outcome measures
The outcome measured was the variability in the LVOT VTI to determine fluid responsiveness and how the IVC collapsibility index is correlated with the LVOT VTI variability.
Statistical analysis
Data were fed to the computer and analyzed using Statistical Package for the Social Sciences, version 20.0. (Armonk, NY: IBM Corp). Categorical data were represented as numbers and percentages. Quantitative data were expressed as ranges (minimum and maximum), means with standard deviations, or medians and interquartile ranges (IQRs), as appropriate. The chi-square test was used to compare the three groups. Continuous data were tested for normality of distribution using the Shapiro–Wilk test. For non-normally distributed quantitative variables, the Kruskal–Wallis test was used to compare three groups, followed by a post hoc test (Dunn’s multiple comparisons test) for pairwise comparison between each two groups. Receiver operating characteristic (ROC) curve analysis was performed to predict the performance of the IVC collapsibility index in predicting fluid responsiveness. [12].
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
According to the demographic characteristics of the three studied groups, a male predominance was observed in all groups. In the non-responder group, males accounted for 74.3%, whereas females accounted for 25.7%. In the responder group, males accounted for 52.3%, whereas females accounted for 47.7%. Finally, in the third group, males accounted for 52.4 %, whereas females accounted for 47.6%. The median age of the patients in the non-responder group was 62 years; however, that of those in the responder group and the third group was 64 years. No significant statistical difference in sex or age was observed between the three study groups (Table 1).
Regarding the comparison between the three studied groups according to ejection fraction, the median ejection fraction in the non-responder, responder, and third groups was 37.0%, 34.0%, and 35%, respectively. No significant statistical difference in the ejection fraction was observed between the three study groups.
According to the baseline IVC diameter and respiratory variation, the median minimum IVC diameters in the non-responder, responder, and third groups were 1.7 cm, 1.0 cm, and 1.8 cm, respectively. The median maximum IVC diameter in the non-responder, responder, and third groups was 2.7 cm, 2.1 cm, and 2.5 cm, respectively. The median IVC diameter collapsibility index in the non-responder, responder, and third groups was 26.1%, 55.6%, and 18.2%, respectively. Significant statistical differences in the IVC diameter and its respiratory variation (p < 0.001) were observed between the non-responder and responder groups and between the responder and third groups.
Using the cutoff value of the IVC collapsibility index > 51.85%, the sensitivity, specificity, PPV, and NPV were 75.0%, 80.0%, 82.5%, and 71.8%, respectively, in predicting fluid responsiveness.
In Figure 2, the ROC curve illustrating the diagnostic performance of the IVC collapsibility index in predicting fluid responsiveness, the AUC was 0.774.
Discussion
In this study, 44% of the study cases were fluid responders, and this result was consistent with those reported by Memon AU et al., who found in their observational study that nearly half of the individuals with cardiogenic shock responded to fluid challenge [13].
No significant statistical difference in the recorded clinical parameters was observed between the three study groups, and this result was consistent with the results reported by Hiemstra B et al., who found that the clinical indicators of shock were critical for detecting the presence of shock; however, they did not identify the kind of shock or whether cardiac output was elevated, normal, or decreased [14].
The IVC showed major respiratory variations in the responder group compared with that in the other two groups, indicating that the intra-cardiac filling pressures (preload) in the responder group were low and their hearts were working on the steep portion of the Frank–Starling curve. No significant statistical difference in the ejection fraction was observed between the three study groups, as the responsiveness to fluid therapy depends primarily on intra-cardiac filling pressure (degree of myocardial stretch).
Compared with previous studies, Elsaeed AMR et al. found that the IVC collapsibility index >35% has a sensitivity of 95.8% and specificity of 93.7% for predicting fluid responsiveness in patients with sepsis (available at: https://doi.org/10.1186/s42077-022-00226-1). Nagi AI et al. reported that cutoff value >32% had a sensitivity of 72.41% and specificity of 82.76% for predicting responsiveness to fluid therapy (available at: https://doi.org/10.1186/s42077-021-00194-y). Pereira RM et al. showed that the AUC for the IVC collapsibility index was 0.981 in predicting responsiveness to fluid therapy [4]. Ismail MT et al. discovered that at the cutoff value of 40%, the IVC collapsibility index had a sensitivity and specificity of 93.3% and 70.7%, respectively, with an AUC of 0.908 (95% confidence interval [CI], 0.84–0.975), for predicting fluid responsiveness [15]. Suehiro K reported that respiratory variations of the IVC could reliably predict fluid responsiveness during spontaneous breathing with a pooled sensitivity and pooled specificity of 80% and 79%, respectively, with an AUC of 0.857 [16]. The differences between this study and the aforementioned studies may be because we only examined patients with impaired cardiac contractility who may already have elevated intra-cardiac filling pressures; however, others have examined different types of shock, including septic and hypovolemic shock, which usually respond to the initial fluid bolus.
The use of the IVC collapsibility index in predicting fluid responsiveness may be limited due to diseases in the right side of the heart, such as right-sided heart failure, tricuspid regurgitation, and pulmonary hypertension [17]. Moreover, in patients on mechanical ventilation, the IVC collapsibility is affected by the positive end-expiratory pressure level [18] and intra-abdominal hypertension [19].
Study strength: This study only included patients with shock who had impaired cardiac contractility before providing any fluids or supportive medications, which might have improved the accuracy of the obtained results.
Study limitations: This study was conducted on spontaneously breathing patients only.
Conclusion
The IVC collapsibility index can help clinicians solve the dilemma of fluid therapy in shocked patients with impaired cardiac contractility, thus protecting them from the hazards of unnecessary fluid administration. It is a simple and repeatable test.
Acknowledgment
We thank Dr. Asmaa Ramdan. She is the person who taught me how to hold the echocardiography probe and we would like to thank her assistance while writing this manuscript.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Funding: None
Conflict of interest
The authors declare that they have no conflicts of interest.
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Download attachments: 10.4328.ACAM.21475
Mostafa Gaber, Wael Nabil, Amr Abdullah, Eman Alsharqawy, Mina Montasser. Role of echocardiography in guiding fluid therapy in shocked patients with impaired cardiac contractility. Ann Clin Anal Med 2023;14(4):311-314
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Outcomes and cost-effectiveness of different anesthesia techniques in elderly patients with hip fracture
Gülnihal Gökalp 1, Oğuzhan Gökalp 2, Habip Atalay 3
1 Department of Anesthesiology and Reanimation, Uşak Training and Research Hospital, Uşak, 2 Department of Orthopaedics and Traumatology, Faculty of Medicine, Uşak University, Uşak, 3 Department of Anesthesiology and Reanimation, Faculty of Medicine, Pamukkale University, Denizli, Turkey
DOI: 10.4328/ACAM.21477 Received: 2022-11-02 Accepted: 2022-12-15 Published Online: 2022-12-29 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):315-320
Corresponding Author: Oğuzhan Gökalp, Department of Orthopaedics and Traumatology, Faculty of Medicine, Uşak University, Uşak, Turkey. E-mail: oguzhangokalp@gmail.com P: +90 505 950 32 31 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4062-8559
This study was approved by the Ethics Committee of Pamukkale University, Faculty of Medicine (Date: 2013-03-27, No: 60116787/64)
Aim: This study aimed to determine the optimal type of anesthesia for elderly patients to reduce the need for intensive care, mortality, and costs of operations for hip fractures.
Material and Methods: In this retrospective and cross-sectional study, the records of 204 patients aged 60 years and older who were operated on for hip fracture with neuraxial (107 patients) or general anesthesia (97 patients) at Pamukkale University Hospital. The duration of intensive care stay, duration of hospital stay, mortality, and cost were considered primary endpoints.
Results: All evaluation parameters were evenly distributed between both groups. Among the analyzed parameters, the duration of surgery and the rate of patients requiring >1 unit of blood transfusion were found to be significantly lower in neuraxial anesthesia patients, compared to general anesthesia patients (p=0,001). Intensive care need, duration of intensive care stay and duration of hospital stay, three-month mortality, and cost were found to be significantly lower in the neuraxial anesthesia group, compared to the general anesthesia group (for all p=0.001). Based on logistic regression analysis, age (age 80-89, OR= 2.782, 95% CI= 1.156-6.694; age 90 +, OR= 8.779, CI= 2.056-37.486), general anesthesia (OR = 8.069, 95% CI= 2.778-23.436) and need of intensive care (OR= 5.155, 95% CI= 2.233-11.903) were independent risk factors affecting mortality.
Discussion: The results of our study show that the use of neuraxial anesthesia in geriatric hip fracture surgery has significant advantages, including lower costs and mortality rates compared to general anesthesia.
Keywords: Hip Fractures, Anesthesia Conduction, Anesthesia, Mortality, Cost-Effectiveness
Introduction
Hip fracture is a frequent problem in the elderly population. The predicted number of hip fractures by 2050 is 6.3 million [1]. Approximately 8.4% of patients die within 30 days after hip fracture surgery and 15-30% in the following year [2]. The effect of anesthesia techniques used in elderly patients on outcomes has not yet clarified in the literature. Available scientific evidence that will enable the selection of the most appropriate anesthesia technique in femur fracture surgery to be used is still limited [2].
The costs related to intensive care services are approximately 22% of all hospital expenditures, while intensive care beds constitute only 10% of all hospital beds [3]. Thus, intensive care expenses have an important role in the total cost of surgery-related hospitalizations such as hip fracture treatments. Although the use of neuraxial anesthesia in hip fracture surgery, is shown to result in a reduction in intensive care stay and related costs, the multifactorial reasons for this advantage are not yet all elucidated.
Our primary aim in this study is to compare the impact of anesthesia techniques in hip fracture surgery on postoperative intensive care admission, mortality and cost. Our hypothesis is that local anesthesia is superior to general anesthesia in terms of specified criteria in elderly hip fracture patients. We also wanted to determine the independent effects of variables of the patient and treatment process on mortality.
Material and Methods
This study was approved by the Ethics Committee of Pamukkale University Faculty of Medicine upon the application of the senior author (No: 60116787/64).
In this retrospective cross-sectional study, hospital information management system records and anesthesia intensive care files of 287 patients aged 60 years and older who were operated on with neuraxial or general anesthesia due to hip fracture at Pamukkale University Medical Faculty Hospital were retrospectively analyzed. The choice of anesthetic technique in our study, i.e. general or neuraxial, depended on factors related to both patient consent and the consultation of the anesthesiologist. Both procedures were explained to the patients in detail with advantages and disadvantages, and patient consent was obtained.
Patients were placed in either general anesthesia (GA) or neuraxial anesthesia (NA) group, which included either spinal or epidural anesthesia patients. Patients who met the exclusion criteria were excluded from the study (Figure-1).
Information such as demographic data, history of smoking, ASA risk assessment, Charlson Comorbidity Index (CCI) [4], preoperative laboratory parameters, type of surgery, type of fracture, preoperative intensive care need, duration of operation, use of cement, and amount of intraoperative blood transfusion were obtained from the hospital records. Length of stay in the intensive care unit, duration of hospital stay, mortality, and cost were considered primary endpoints. Mortality rates were assessed at 7 days, 1 month, and 3 months.
Preoperative laboratory parameters were taken from the last lab reports before surgery. Costs were calculated according to the average US dollar rates at the hospitalization date of patients. The cost calculation was made according to the duration of intensive care and hospital stay. Implant costs were subtracted from the total cost because of the variability in the type and cost of implants.
For the statistical analysis of data, the Statistical Package for the Social Sciences (SPSS) 18.0 software was used. The results were assessed with a 95% confidence interval at P <0.05 significance level.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
Out of the 204 patients who met the study criteria, 107 received GA, and 97 NA. The selection of patients is shown in the flow diagram (Figure 1). There were no statistically significant differences between the GA and NA groups, regarding the distribution of age, sex, history of smoking, ASA, CCI, and preoperative laboratory parameters.
The duration of surgery and the rate of patients who needed more than one unit of blood transfusion were found to be statistically significantly lower in the NA patients. Transfer to the intensive care, duration of intensive care, hospital stay, one-month and three-month mortality, and cost (USD) were found to be significantly lower in the NA group (Table 1). Since the ICU length of stay variable was skewed to the right, the analysis was conducted by excluding outliers. Among 107 patients who received GA, 70 were predicted to be transferred to the intensive care unit, and 53 of them ultimately were transferred (53/70, 76%); while of the 97 patients who received NA, 53 were predicted to be transferred to the intensive care, but only 18 were eventually transferred (18/53, 34%) (p<0.05).
The evaluation of all cases showed that, in cases who were transferred to the intensive care unit, some parameters such as ASA III score (I- II or III, 67.6% vs 33.8%), CCI >3 score (<3 or >3, 59.2% vs 26.3%), and need for more than 1 unit of blood transfusion (63.4% vs 27.1%) were found to be statistically significantly higher, preoperative albumin rates were significantly lower and duration of surgery was longer compared to patients who did not go to the intensive care unit (P <0.05).
The evaluation of risk factors affecting mortality showed that some variables, which were considered significant in the univariate analysis (Table 2) were insignificant in the logistic regression analysis. It was confirmed by Collinearity Statistics that there were no multiple linear linkages between independent variables to be included in logistic regression. Age groups, ASA, CCI, type of anesthesia, blood transfusion and intensive care stay variables were included in the Forward Stepwise (Conditional) model. As a result of the analysis, age, GA and need for intensive care were assessed as independent variables for mortality (Table 3). The most common cause of mortality was heart failure.
Clinically, it was thought that the ‘entrance to ICU’ variable might have a mediator role in the effect of ‘Anesthesia type’ on mortality, and mediation analysis was performed. Other variables were excluded from this analysis because they were eliminated in the logistic regression model and the ‘age group’ variable had no effect on the type of anesthesia.
According to the mediation analysis results, the independent variable “anesthesia type” (NA) affects mortality significantly and negatively (β = -2.233 P <0.001 95% CI = 0.040-0.287). ‘Anesthesia type’ (NA) affects the mediator variable “entrance to ICU” statistically significantly and negatively (β = -1.460 P <0.001 95% CI = 0.123-0.439). Similarly, entrance to ICU affects mortality (3 months) statistically significantly and positively (β = 1.941 P <0.001 95% CI = 3.260-14.870). In the last stage of the mediation analysis, it was observed that the effect of anesthesia type on mortality was still significant as in the first model when the entrance to ICU variable was included in the model, but there was a significant decrease in the Beta coefficient (= -1.851 P <0.001 95% CI = 0.057-0.435) (β -2.233 to -1.851). These findings show that the “entrance to ICU” variable has a partial mediator effect in the relationship between anesthesia type and mortality.
Discussion
Hip fracture surgery is a common medical procedure in elderly patients, which can result in high morbidity and mortality due to factors related to the patient and/or surgery [7]. Perioperative mortality and morbidity are affected by the choice of anesthesia method, concomitant diseases, and surgical technique [8].
Anesthesia techniques used in hip fracture surgery have often been compared previously, however, studies that evaluated different anesthesia techniques in terms of both patient results and cost- effectiveness were lacking. Our study focuses on this comparison.
This study has some limitations due to its retrospective design. In addition, the initial design and set-up of the dataset limited the use of ordinal data. Examples of this are the analysis of the Charlson Comorbidity Index values and the need for blood transfusion, both of which are evaluated as binary rather than ordinal data while creating the data set from the patient files. This approach may have reduced the sensitivity of the analysis performed with these two variables.
In the preoperative phase, 53/97 patients who received NA were predicted to be in need of intensive care, while eventually, only 18 needed it. Admission to intensive care, duration of intensive care stay, and duration of hospital stay were found to be significantly lower in the NA group compared to the GA group. Similarly, Kaufmann et al. stated that NA can reduce the postoperative intensive care requirements in high-risk patients who are to undergo hip prosthesis surgery. They also reported that NA reduces the duration of intensive care and hospital stay, and therefore reduces cost [3]. Ahn et al. also found that NA was associated with better outcomes than GA in terms of ICU admission and ventilator care in elderly patients undergoing hip fracture surgery [9]. There are other studies showing that regional anesthesia is associated with a shorter hospital stay compared to GA [10-12].
The decision of anesthesiologists or surgeons on the postoperative destination of these patients probably depends on the initiative of the caregiving physician because of the inadequacy of standard anesthesia intensive care admission guidelines. This relatively subjective decision may be based on the estimation of how well the patient will tolerate the surgical procedure. Patients who receive NA may seem more stable during the operation process, and this can affect the decision of the clinician regarding transfer to the intensive care unit. Additionally, intraoperative blood loss has been reported to be significantly lower in patients who receive NA, therefore, the need for blood transfusion, and probably fluid replacement is also relatively low [13-15]. Since NA has various intraoperative benefits that will affect the general physical status of the patient after surgery, this may affect the decision of the clinician on the need for intensive care.
Our study showed that there was less need for blood transfusion in the NA group, compared to the GA group (Table 2). The recent change in surgical methods and the increase in the rate of closed surgery may have been another factor reducing the need for blood transfusion in our study. Various studies have investigated the relationship between anesthesia techniques and intraoperative blood loss [1,16]. NA was reported to be related to less bleeding in patients with hip fracture surgery [16]. Venous pooling due to sympathetic blockage, vasodilation, and neuraxial blockage reduces the venous return to the heart. However, Urwin et al. showed in their meta-analysis of the data from 3 studies that there was no difference between general and NA in terms of blood transfusion [1].
Hip fractures in the geriatric population create an economic burden on the health system. In our study, a significant reduction was found in the use of intensive care, duration of intensive care stay, and duration of hospital stay, and therefore hospital costs, with the use of NA (Table 2). It has been suggested in a study that length of stay and surgical choice were linearly related to total hospital costs [17]. There are few studies on the economic burden of the type of anesthesia used in intensive care patients. There are some studies showing that neuraxial anesthesia can improve pulmonary outcomes and reduce resources (critical care services, hospital stay) compared to general anesthesia [3,18]. In a study in England, in 2000, the cost per hip fracture patient was calculated as 4760 pounds, whereas in 2008, this number was calculated as 8000 pounds [19].
Our logistic regression analysis showed that older age is an independent risk factor for mortality. Similarly, Mc Leod et al. have reported that the increase in systemic concomitant diseases in older age has an impact on mortality [13].
We found that high CCI risk scores, which indicate multiple medical problems were associated with mortality; 29.8% of the patients with a CCI score above 3 died. However, the CCI score was not found to be an independent risk factor in our logistic regression analysis (Table 3). Souza et al. investigated the use of CCI as a method for estimating 90-day mortality risk in elderly patients hospitalized for hip fracture, and they showed that as the CCI score increased, the mortality risk also increased [15].
In our study, 3-month mortality in ASA III patients (26%) was higher than ASA I and II patients (14%) among the 204 patients. While the difference between these rates was significantly high, ASA physical status scale was not determined to be an independent risk factor for mortality, based on multivariate statistical analysis. Holvik et al. found that those who died within 1 year had a higher ASA score (III, IV) and therefore more comorbid conditions [20]. In this study, the 3-month mortality (short-term mortality) was 25.2% in 107 patients in the GA group. On the other hand, it was found to be significantly lower in the NA group (3.2%). Logistic regression analysis showed that the mortality risk was found to be 8.07 times higher in the GA group compared to the NA group and 5.16 times higher in the group admitted to the ICU. In mediation analysis, it was seen that the effect of “anesthesia type” on mortality was partially through “admittance to intensive care”. Therefore, this situation should be taken into consideration when evaluating odds ratios.
A limited number of studies have reported that postoperative mortality in NA patients is lower than in GA patients [9,14]. Desai et al. found that the use of general anesthesia was associated with a higher risk of mortality during the in-hospital stay compared with regional anesthesia, but this higher risk did not persist after hospital discharge [21]. Chen et al. also reported a similar result, general anesthesia was associated with an increased risk of in-hospital mortality [11]. However, many later studies have shown that, conversely, the type of anesthesia does not affect postoperative mortality [10,12,18].
Gilbert et al. found no significant difference between patients who received spinal or GA in long-term (two-year) mortality and incidence of serious morbidity, in a study with 741 patients operated for acute hip fracture [22] Katušin et al. showed that the mode of anesthesia (general and spinal) had no effect on postoperative mortality and suggested that the patient’s comorbidities should be considered in the selection of anesthesia. [23]. Parker et al. found in their study that after NA, a 1-month mortality decrease is the limit [19]. Hospital mortality (up to 1 month) and short-term mortality (up to 3 months) are lower with spinal anesthesia, but this advantage disappears after 3 months [23]. Rodgers et al. have reported that mortality decreased by 30% with NA in major surgeries, including hip fractures [24].
Conclusion
Overall, the results of our study show that the use of NA in geriatric hip fracture surgery is related to a lower need for blood transfusion, treatment costs, shorter intensive care and hospital stay, and a reduced rate of intensive care necessity. Neuraxial anesthesia was found to reduce mortality by 8.06 times compared to GA. Our findings support the recommendations of the International Consensus on Anesthesia-Related Outcomes after Surgery group as stated “neuraxial anesthesia is recommended for hip arthroplasty given associated outcome benefits; evidence level: moderate-low, strong recommendation” [25].
Longer-term prospective prognosis and cost analysis studies should be conducted to establish criteria for the selection of the appropriate anesthesia type in hip fracture surgery in elderly patients.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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6. Iacobucci D. Mediation analysis and categorical variables: The final frontier. J Consum Psychol. 2012;22(4):582–94.
7. DC Mackey. Physiological effects of regional block. In: Brown DL, editors. Regional Anesthesia and Analgesia, 1st ed. Philadelphia: WB Saunders; 1996. p.397-422.
8. Halachmi S, Katz Y, Meretyk S, Barak M. Perioperative morbidity and mortality in 80 years and older undergoing elective urology surgery – a prospective study. Aging Male. 2008;11(4):162-6.
9. Ahn EJ, Kim H J, Kim K W, Choi H R, Kang H, Bang S R. Comparison of general anaesthesia and regional anaesthesia in terms of mortality and complications in elderly patients with hip fracture: a nationwide population-based study. BMJ Open. 2019;9(9):e029245:1-7.
10. Neuman M D, Rosenbaum P R, Ludwig J M, Zubizarreta J R, Silber J H. Anesthesia Technique, Mortality, and Length of Stay After Hip Fracture Surgery. JAMA. 2014;311(24):2508–17.
11. Chen D X, Yang L, Ding L, Li SY, Qi Y N, Li Q. Perioperative outcomes in geriatric patients undergoing hip fracture surgery with different anesthesia techniques: A systematic review and meta-analysis. Medicine (Baltimore). 2019;98(49):e18220.
12. Nishi T, Maeda T, Imatoh T, Babazono A. Comparison of regional with general anesthesia on mortality and perioperative length of stay in older patients after hip fracture surgery. Int J Qual Health Care. 2019;30;31(9):669-75.
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Gülnihal Gökalp, Oğuzhan Gökalp, Habip Atalay. Outcomes and cost-effectiveness of different anesthesia techniques in elderly patients with hip fracture. Ann Clin Anal Med 2023;14(4):315-320
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Morbidity and mortality results of COVID-19 variant in COVID-19 positive patients treated in the intensive care unit
Ahmet Aydın 1, Erdinç Koca 2, Sevgi Kutlusoy 2, Umut Sabri Kasapoğlu 3
1 Department of Anesthesiology and Reanimation, Faculty of Medicine, Turgut Özal University, Malatya Training and Research Hospital, Malatya, 2 Department of Anesthesiology and Reanimation, Malatya Training and Research Hospital, Malatya, 3 Department of Pulmonary and Critical Care Medicine, Faculty of Medicine, Marmara University, İstanbul, Turkey
DOI: 10.4328/ACAM.21483 Received: 2022-11-06 Accepted: 2022-12-24 Published Online: 2023-01-05 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):321-325
Corresponding Author: Ahmet Aydin, Department of Anesthesiology and Reanimation, Faculty of Medicine, Turgut Özal University, Malatya Training and Research Hospital, Malatya, Turkey. E-mail: ketamin2323@gmail.com P: +90 444 56 34 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1836-2061
This study was approved by the Ethics Committee of alatya Turgut Ozal University School of Medicine (Date: 2021-12-16, No: 2021/109)
Aim: COVID-19 has the potential to affect many systems and organs, resulting in serious clinical symptoms that necessitate admission to the intensive care unit. The purpose of this study was to examine the relationship between CAR, other laboratory findings, comorbidities, and mortality in patients infected with the original SARSCoV-2 or other variants.
Materials and Methods: The data of 368 patients admitted to the intensive care unit with COVID-19 pneumonia between March 2020 and July 2021 were analyzed. These patients were divided into two groups. The first group included [(OC) Original SARSCoV-2 ] COVID-19 infected patients in the first period of the pandemic. The second group [(OV) Other Variants] included patients with COVID-19 infection due to other variants.
Results: The mean age (Mean±SD) in the OC group was 69.79±11.77 years. The mean age of the patients in OC was higher than in the OV group (p=0.001). The most common comorbid disease in both groups was Hypertension (54.1%, 48.8%), followed by diabetes mellitus (DM) (30.2%, 31.6%). The mean age of the survivors in the OC and OV groups was lower (64.53±13.04, 57.85±16.78, p=0.001, p=0.001, respectively). It was observed that albumin and lymphocyte counts were lower in the deceased, while LDH, CRP, Neutrophil, procalcitonin, NLR and CAR were higher (p<0.05).
Discussion: In critically ill COVID-19 patients, high CAR and NLR are good predictors of mortality. In the period when the variants were dominant, the mean age of the patients and the length of stay in the intensive care unit were lower.
Keywords: COVID-19, Variant, CAR, NLR
Introduction
COVID-19 may affect many systems and organs, leading to the emergence of serious clinical symptoms that require admission to the intensive care unit (ICU). The progression of these symptoms may result in acute respiratory distress syndrome (ARDS), multi-organ failure, and shock, which causes an increased risk of mortality [1]. Many risk factors for mortality and severity of clinical symptoms have been demonstrated. Some of these risk factors are age, gender, underlying diseases and genetic factors [2,3].
According to reports, 14% of COVID-19-infected individuals had a severe clinical course, and 5% of all cases were critically ill patients who were received to an intensive care unit [3,4]. The worldwide case mortality rate of COVID-19 is about 1.2% [5]. With the mutations that occurred in the form of the RNA virus SARS-CoV-2, which became dominant in 2020, new variants emerged. In late 2020, alpha, beta, and gamma variants appeared. The delta (B.1.617.2) variant, which emerged in the summer of 2021, became more dominant globally. The resulting variants generally had increased infectivity and were noted to show greater antibody escape [6,7]. Our aim in this study is to examine the clinical course of patients infected with the original SARS-CoV-2 or other variants after admission to the intensive care unit. In addition, it is to examine the Neutrophil/Lymphocyte ratio (NLR), CRP/Albumin ratio (CAR), other laboratory findings, and comorbidities in predicting the risk of mortality.
Material and Methods
Our study was carried out in the 3rd level COVID-19 Intensive Care Unit of Malatya Training and Research Hospital. This study was approved by the Clinical Ethics Committee of Malatya Turgut Ozal University School of Medicine (protocol code: 2021/109). The study was carried out in in line with the Helsinki declaration. The files of 368 patients among the patients hospitalized in the intensive care unit due to COVID-19 pneumonia between March 2020 and July 2021 were scanned. These patients were divided into two groups. The first group [(OC) Original SARSCoV-2] included patients infected with COVID-19 in the first period of the pandemic. The second group [(OV) Other Variants] included patients with COVID-19 infection due to other variants that became dominant due to mutations as of 2021.
Inclusion criteria of the present study includes patients with >18 age years old, confirmed COVID-19 pneumonia patients. Exclusion criteria of the present study includes patients with malignancy, patients with <18 age years old, pregnant patients, suspected COVID-19 patients, non COVID-19 patients.
The following data were collected and analyzed: patients demographic and clinical data, mortality, laboratory findings. All patients was followed up during their ICU stay or until the death in the ICU. Mortality and other data was obtained from the hospital electronical medical record system and patient files.
Statistical anaylsis
The compatibility of the parameters to the normal distribution was evaluated by Kolmogorov-Smirnov and Shapiro Wilks tests. Normal and homogeneously distributed variables are given as mean value±standard deviation, data that does not show normal and homogeneous distribution are given as median (min-max) values, categorical variables are given as numbers and percentages. Student’s t test was used for normally distributed parameters and Mann Whitney U test was used for non-normally distributed data. Chi-square test test were used to compare qualitative data. Significance was evaluated at the p<0.05 level. For statistical analysis, 22 package programs of SPSS (Statistical Package for Social Sciences; SPSS Inc., Chicago) were used.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
A total of 368 critically ill COVID-19 pneumonia patients were admitted to COVID-19 ICU. The mean age (Mean±SD) in the OC group was 69.79±11.77 years. The mean age of the patients in OC was higher than in the OV group (p=0.001). 59.8% (n=220) of the cases included in the study were male. Gender distribution was similar in both groups. The most common comorbid disease in both groups was Hypertension (54.1%, 48.8%), followed by diabetes mellitus (DM) (30.2%, 31.6%). Mortality rates were not statistically significant (OC: 71.7%, OV: 64.6%, p=0.149) (Table 1). In the distribution of comorbidities, obesity, neurological diseases, chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea syndrome (OSAS) were observed at a higher rate in the OC group (p<0.05) (Table 1). The length of stay (LOS) in the intensive care unit was higher in the OC group (median:10, p=0.048) (Table 1).
The mean age of the survivors in the OC and OV groups was lower (64.53±13.04, 57.85±16.78, p=0.001, p=0.001, respectively) (Table 2).
The laboratory data of the cases at the time of admission to the intensive care unit are summarized in Table 2. From laboratory values, D-Dimer level was higher in OV group, CAR, CRP and albumin levels were higher in OC. This result was statistically significant (Table 2).
The comparison of the laboratory values of the surviving and deceased patients in the OC and OV groups is given in Table 3. Ferritin level was not significant in terms of mortality in OC (p=0.116, Table 3). However, it was found to be higher in non-survivors in the OV group (p<0.001, Table 3).
Among the other parameters, albumin and lymphocyte counts were lower in the deceased, and LDH, CRP, Neutrophil, procalcitonin, NLR and CAR were higher (p<0.05), (Table 3).
Discussion
In our study, there was no difference in mortality in patients admitted to the intensive care unit in both periods (original SARSCoV-2-other variants). Gender was similar across the groups. The mean age was found to be higher in the OC group. We found that some laboratory parameters (CAR, CRP) were higher in OC. In comparison of the survivors and those who died, the age was lower in the survivors in both groups. As laboratory findings, lymphocytes and albumin were lower in those who died. Neutrophil, LDH, CRP, PCT, NLR and CAR, NT-proBNP levels were higher in those who died. We think that the mortality of the patients in both groups was similar, especially due to the advanced age of the study population, the excess of comorbidities, and the fact that it consisted of patients in a more severe condition. It has been stated in the literature that especially advanced age is an important indicator of mortality [8]. As age progresses, it is likely to cause an increase in mortality due to the increase in comorbid conditions. In the literature, it has been stated that comorbidities that increase with advanced age are an important factor in increased mortality. Hypertension and DM may increase the risk of mortality in patients with COVID-19 [9,10].
In previous studies, patients infected with the alpha variant were shown to be more contagious, and different opinions were reported on the variants in terms of mortality [7]. In different studies, analyzes have shown that Delta variant infection increases the risk of hospitalization, oxygen demand, admission to the intensive care unit, or death [7,11-13].
Patients in the OC group were older than the OV group. Compared to the first period of the epidemic, we found that the age was lower in this period when variants were dominant and the contagion was thought to increase. In a study conducted during the first months of the epidemic, 116 hospitalized COVID-19 patients had a median age of 58.5 years, and 69% (n:80) of the patients were male. The most common co-morbidities were hypertension (38.8%) in 45 people and DM (16.4%) in 19 people. Severe cases were older than non-severe cases (median, 64 years–56 years, respectively) [14]. Due to the severe clinical course of Covid-19, many studies have been carried out in the literature because it may be useful to detect laboratory findings related to mortality. As laboratory abnormalities, NT-proBNP, neutrophil count, procalcitonin, c-reactive protein, D-dimer and lactate dehydrogenase were found to be high and lymphocyte count was low in severe cases [14]. Similar laboratory abnormalities have been shown in other studies as in our findings [8-10,15-18]. In addition, although the D-Dimer level was found to be higher in the OV group in our study, it was found to be similar in mortality. In another analysis performed on COVID-19 patients over 60 years of age, the rate of severe pneumonia was found to be 71.05% (n:27). Serum aspartate aminotransferase, CRP, serum procalcitonin, D-Dimer and BNP levels were found to be higher in these patients [16]. The findings of our study support this information.
In a delta-dominated study, the median duration of stay in the intensive care unit of 23 patients was 11 days, 70% (n:16) patients were male and the median age was 53 years. Seven patients (30%) had hypertension, and 14 patients (60%) had diabetes mellitus (DM). Laboratory abnormalities were similar. Of the 23 patients, 13 (57%) required invasive oxygenation, and 8 (62%) of these patients died. Nine of 23 patients (39%) died during the follow-up period [15]. In a different study, people aged 65 and older had a higher COVID-19 mortality rate than those aged 55-64 [17].
In one of the studies on critically ill patients, it is stated that 65.4% (n:647) of 990 patients needed mechanical ventilation and 60.4% of the patients who needed MV may have died. Again, in the same study, it is mentioned that 67.17% of all critically ill patients are dead [19]. In another, ICU mortality was 50%, and 57% in patients who were connected to MV [20]. In a systematic review, the overall ICU mortality was found to be 32.3% [21]. When the duration of ICU stay of the patients was examined, it was seen in an analysis that the average ICU stay of 5 studies was 9 days. In another study, it was found that while it was 20.6 days in the first wave, it decreased to 16 days in the third wave [22,23]. The presence of similar results in our study also supports these results. Similarly, we found that the mean age of the patients was lower in the period when other variants were dominant. Mortality rates in the groups (OC, OV) were 71.7% and 64.6%, respectively. The mortality rate was higher in the OC group with older age. Age-related mortality rates were statistically significant in both groups, and those who did not survive were older. In addition, our mortality rate does not represent the rate among all patients admitted to the intensive care unit. This rate represents only a certain number of patient population included in the study. In our study, the LOS in the intensive care unit was longer in the OC group and the median was 10 days, while it was 7 days in the OV group.
Low albumin levels have been related with poor prognosis in patients with COVID-19. In severe cases of COVID-19, it has been reported that an elevated CRP level can be used to identify serious cases in the early period. In addition, the presence of hypoalbuminemia at admission in COVID-19 cases can predict the course of the disease independently of other indicators [8,9,16]. In our study, Albumin level was lower in the OV group and was associated with higher mortality. We found the CRP level to be higher in the OC group and the CRP level was significant in terms of mortality in both groups.
The high CAR and NLR levels can be used to differentiate the severity of COVID-19. It has been shown that high CAR is related with high mortality and can be used as an risk factor. In addition, it has been reported that high CAR is an important prognostic factor in predicting disease progression and mortality in hypertensive COVID-19 patients [3,8,9,16,23,24]. It has been shown in many studies that NLR is higher in critically ill patients [25]. The data in our study showed that CAR and NLR were similar in OC and OV, but were higher in critically ill patients and were significant in mortality.
Our study has some limitations. First, the study is a single-center retrospective study consisting of more severely ill patients admitted to the intensive care unit only. Second, the patients in the study did not include all patients hospitalized in the intensive care unit due to COVID-19. Third, patients’ original virus and variant differentiation was made periodically.
Conclusion
In seriously ill COVID-19 patients, high CAR and NLR are predictors of mortality. The mortality rates in OC and OV were similar. The patients in the OV group had a lower mean age and lenght of stay in the intensive care unit.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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Effect of boron-based gel on postpartum episiotomy wound healing in primiparous pregnant women
Derya Kanza Gul 1, Yeliz Mercan 2
1 Department of Gynecology and Obstetrics, Faculty of Medicine, Istanbul Medipol University, Istanbul, 2 Department of Health Management, Faculty of Health Sciences, Kirklareli University, Kirklareli, Turkey
DOI: 10.4328/ACAM.21492 Received: 2022-11-12 Accepted: 2023-01-05 Published Online: 2023-01-11 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):326-331
Corresponding Author: Derya Kanza Gül, Department of Gynecology and Obstetrics, Faculty of Medicine, Istanbul Medipol University, Istanbul, Turkey. E-mail: deryakanza@yahoo.com P: +90 532 700 70 39 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8879-9299
This study was approved by the Clinical Research Ethics Committee of Istanbul Medipol University (Date: 2020-04-16, No: 10840098-604.01.01-E.14176)
Aim: The present study aimed to determine the effects of boron-based gel on episiotomy wound healing and episiotomy pain in primiparous women.
Material and Methods: This case-time control design, which is one of the hybrid designs included 450 primiparous women who had a normal delivery with episiotomy at Private Nisa Hospital between January 2019 and March 2020. The participants were grouped as 150 women who used the Boron-Based Gel on the postpartum episiotomy site (cases-1), 150 women who used Beta Chlorhexidine Gel (cases-2), and 150 women who refused treatment or did not use any topical gel (controls). Wound healing status was evaluated on days 2, 5-7, and 10-14 after birth along with Redness, Edema, Ecchymosis, Discharge with Approximation (REEDA) Scale, and the pain levels felt in the episiotomy area were evaluated using the Visual Analog Scale (VAS).
Results: No statistically significant differences were detected between the three groups in terms of age and other variables (p>0.05). The mean scores of VAS and REEDA on days 2, 5-7, and 10-14 after birth were significantly different in the Boron-Based Gel Group compared to Chlorhexidine Gel and control group (p<0.001).
Discussion: It was found that the use of Boron-Based Gel increased episiotomy wound healing and reduced pain at significant levels.
Keywords: Boron-Based Gel, Chlorhexidine Gel, Episiotomy, Wound Healing, Primiparity
Introduction
An episiotomy is a surgical incision made in the bulbocavernosus muscle in the second stage of the labor to facilitate labor, prevent unwanted tears, and preserve the perineal tonus [1-3]. In a study that was conducted in Turkey, the rate of episiotomy was reported to be 93.3% in primiparous women, and 30.2% in multipara women, and it was shown that the frequencies varied between 50.4% and 88.6% in primiparous and/or multiparous women [4].
An episiotomy may cause pain on the first day in 97% of primiparous women and the first seven days in 71% [5]. Episiotomy infection is one of the most serious postpartum complications occurring with fever, pain, and purulent discharge [1,6]. In a systematic review, the incidence of perineal trauma wound infection related to birth was found to be between 0.1% and 23.6% [6]. Many pharmacological and non-pharmacological methods (hot and cold showers, using dry heat with rays, lavender, aloe Vera, chamomile, green tea, etc.) are used to accelerate the healing of the wound site in the episiotomy area [1,7,8,9].
Boron, which is a very stable element, plays regulatory roles in the cell membrane and various enzymatic systems with its anti-inflammatory, antimicrobial, antioxidant, epithelializing, and angiogenesis-enhancing effects [10,12]. Although the wound healing effects of boron compounds were shown previously in vivo and in vitro [12], no study investigated its effectiveness on episiotomy wound-healing.
The purpose of the present study was to evaluate the effectiveness of boron-based gel or chlorhexidine-based gel application on episiotomy wound healing in primiparous women who had a normal delivery.
Material and Methods
Study design
The case-time control design, which is one of the hybrid designs, was used in the study. This study was conducted in Istanbul Private Nisa Hospital. To conduct the study, the Clinical Research Ethics Committee of Istanbul Medipol University approved the study.
Study population
The records of women who were hospitalized in the Obstetrics and Gynecology Service applying to the postpartum polyclinic between January, 2019, and March, 2020, were analyzed retrospectively in the study. As a general hospital protocol, some pharmacological drugs (cream, ointment, gels, etc.) that have effects on wound healing after episiotomy are prescribed/ordered. Women who used Boron-Based Gel or Chlorhexidine Gel or did not use/apply any topical gel, had a normal birth, primiparous, and registered in digital media were evaluated in the study. Four hundred and fifty patients who met the criteria were retrospectively reviewed. One hundred and fifty women who used Boron-Based Gel on the postpartum episiotomy area were named as the cases-1, 150 women who used Chlorhexidine Gel on the episiotomy area as the cases-2, and 150 women who did not use any topical gel as the control group.
Inclusion criteria
According to the inclusion criteria of the study, primiparous women who had spontaneous labor at 37-42 weeks, normal delivery, single fetus, mediolateral episiotomy, and second-degree perineal laceration were included in the study.
Exclusion criteria
Those who had cesarean deliveries, manual placenta removal, third and fourth-degree perineal tears, long-term (>18 hours) rupture of membrane, abnormal postpartum hemorrhage or hematoma, irregular use of gels according to instructions, or developing side effects due to gels, those who had a history of disease disabling wound healing or those who used certain drugs, chronic systemic disease, those with history of genital warts, those with symptomatic vaginitis, those using antibiotics after episiotomy, and those who had a history of perineal reconstructive surgery were not included in the study.
The data were obtained retrospectively from hospital records in the present study. The REEDA and VAS Scale, which can be used and recorded in the hospital upon the request of the physician, were used in the study.
The REEDA Scale
The REEDA Scale, which indicates perineal wound healing, was developed by Davidson in 1974 [13]. Recovery was evaluated according to Redness, Edema, Ecchymosis, Discharge, Approximation in the perineal region with this scale. The sum of the scores obtained on the scale evaluated by giving points between 0 and 3 makes up the REEDA score. The lowest score is 0, and the highest score is 15. The highest score indicates the most serious perineal trauma [14].
Visual analog scale
The Visual Analog Scale (VAS) was originally developed and used by Bond and Pilowsky. In the VAS, which is evaluated with a 10 cm scale, “no pain” is graded with “0” points, and “the worst pain imaginable” is rated with “10” points. High scores indicate increased pain severity [15].
Procedures
The treatment ordered by the physician was applied during the postpartum hospital stay. Wound healing status was evaluated during the discharge from the hospital on days 2, 5-7, and 10-14 after birth. Mothers were called for the evaluation of weight, bilirubin, and hearing tests, and puerperal women were also invited to the obstetrics clinic for the follow-up of the episiotomy wound. For these reasons, the healing of the episiotomy wound of puerperal women who applied to the obstetrics clinic of the hospital was evaluated with the REEDA score, and the episiotomy pain was evaluated with the VAS score.
The creams, ointments, or gels recommended being applied on the episiotomy area after birth are in the form of applying these for 1 cm to the episiotomy (sutures) area after the perineal area is washed and dried under proper conditions as of the first day after birth twice a day for 10 days. This procedure was explained to the puerperal women by physicians or clinical nurses in detail.
Pharmacological drug forms used
Antimicrobial Boron-Based Gel and gel-containing Beta Chlorhexidine are generally used in hospital protocols.
Boron-based gel: The Boron-Based Gel is in the composition of a carbopol gel containing 2% Chlorhexidine, Sodium pentaborate pentahydrate (NaB), Poloxamer F68, and F127. NaB is an active ingredient involved in wound-healing and inhibits microbial growth in scar tissue along with Chlorhexidine [16].
Beta chlorhexidine: Chlorhexidine Gel contains 2% Chlorhexidine as the active ingredient, and is an effective antimicrobial
Statical analysis
Descriptive statistics such as numbers (n), percentages (%), mean values, Standard Deviation (SD), median values, and Inter Quartile Range (IQR) were used in the analysis of the data. The conformity of the data to the normal distribution was tested with the Shapiro-Wilk Test. The differences between the groups were checked with the Kruskal-Wallis Test, and when significant differences were detected, Dunn’s Test was used to check the differences between the two groups. The statistical significance level was taken as p < 0.05. The data were analyzed with the SPSS 22.0 Statistical Package Program.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
The statistical characteristics of the Boron-Based Gel, Chlorhexidine Gel, and control group are shown in Table 1. No significant differenceswere detected between the groups (p > 0.05).
The assessment of the Boron-Based Gel Group, Chlorhexidine Gel Group, and control group in terms of REEDA score is given in Table 2. The Boron-Based Gel Group was found to be different from the Chlorhexidine Gel and control group at statistically significant levels on day 2, days 5-7 and 10 in terms of pain (p <0.001).
Significant differences were determined between the groups on days 2, 5-7, and 10-14 in terms of redness (p <0.01). Statistical differences were detected between the Boron-Based Gel Group and the Chlorhexidine Gel Group on day 2 (p=0.003), and between the Boron-Based Gel Group and the control group (p=0.005); however, no significant differences were detected between the Chlorhexidine Gel Group and the control group (p=0.418). Statistical differences were detected between the Boron-Based Gel Group and Chlorhexidine Gel Group (p<0.001) on days 5-7 and 10-14, and between Boron-Based Gel Group and control group (p<0.001); however, no statistical differences were detected between the Chlorhexidine Gel Group and the control group (p>0.05) (the results are not shown in the tables).
No statistically significant differences were detected between the groups in terms of ecchymosis on the 2nd day after birth (p=0.337); however, significant differences were detected between the groups on days 5-7, and 10-14 (p <0.001). Statistically significant differences were detected between the Boron-Based Gel Group and the Chlorhexidine Gel Group on days 5-7 (p<0.001) and between the Boron-Based Gel Group and the control group (p=0.009); however, there was a borderline significant difference was detected between the Chlorhexidine Gel Group and the control group (p=0.050). Statistically significant differences were detected between the Boron-Based Gel Group and Chlorhexidine Gel Group (p<0.001) on days 10-14, and the Boron-Based Gel Group and the control group (p<0.001); however, no significant differences were detected between the Chlorhexidine Gel Group and the control group (p>0.05) (the results are not shown in the tables).
In terms of edema, significant differences were detected between the groups on days 2, 5-7, and 10-14 after birth (p <0.001). Statistically significant differences were detected between the Boron-Based Gel Group and the Chlorhexidine Gel Group on day 2 (p=0.004); between the Boron-Based Gel Group and the control group (p<0.001); between the Boron-Based Gel Group and the Chlorhexidine Gel Group on days 5-7 and 10-14 (p<0.001); and between the Boron-Based Gel Group and the control group (p<0.001). However, no significant differences were detected between the Chlorhexidine Gel Group and the control group on days 2, 5-7, and 10-14 (p>0.05) (the results are not shown in the tables).
In terms of dehiscence, significant differences were detected between the groups on days 2, 5-7, and 10-14 after birth (p <0.001). The Boron-Based Gel Group was different from the control group at statistically significant levels on days 2, 5-7, and 10-14 (p<0.001), and the chlorhexidine Gel Group was different from the control group at statistically significant levels (p<0.001). It was found that the Boron-Based Gel Group was different from the Chlorhexidine Gel Group at statistically significant levels on days 5-7 (p=0.038). However, no statistical differences were detected between the Boron-Based Gel Group and the Chlorhexidine Gel Group on days 2 and 10-14 (p>0.05) (the results are not shown in the tables).
In terms of the discharge status, a significant difference was found between the groups on days 2, 5-7, and 10-14 after birth (p<0.001). Statistically significant differences were detected between the Boron-Based Gel Group and the Chlorhexidine Gel Group (p<0.001), and between the Boron-Based Gel Group and the control group (p<0.001). However, no significant differences were detected between the Chlorhexidine Gel Group and the control group on days 2, 5-7, and 10-14 (p>0.05) (the results are not shown in the tables).
The comparison of the REEDA Scores in the Boron-Based Gel Group, Chlorhexidine Gel Group, and control group on days 2, 5-7, and 10-14 is shown in Table 3. Statistically significant differences were detected between the groups in terms of REEDA scores on the 2nd, 7th, and 10th days (p <0.001). Statistically significant differences were detected between the Boron-Based Gel Group and the Chlorhexidine Gel Group on days 2, 5-7, and 10-14 (p<0.001), and between the Boron-Based Gel Group and the control group (p<0.001). However, no significant differences were detected between the chlorhexidine gel group and the control group on days 2, 5-7, and 10-14 (p>0.05) (the results are not shown in the tables).
Discussion
The present study is the first in this field to investigate the effectiveness of Boron-Based Gel on episiotomy pain and wound-healing. The NaB in the Boron-Based Gel that was used in the study is the active ingredient involved in wound-healing and has antimicrobial effects together with chlorhexidine [16]. According to this study, better episiotomy healing and lower levels of pain were detected in patients who used Boron-Based Gel on the episiotomy area when compared to patients who used only chlorhexidine gel and the control group.
When the participants that were included in the study were examined in terms of socio-demographic and obstetric characteristics, no significant differences were detected between the groups. These results, which show that the evaluation was made under similar conditions, were similar to the results of other studies that examined episiotomy pain and healing of the episiotomy site [9,17].
When the literature was reviewed, a limited number of in-vivo and in-vitro studies were found on the effects of boron on wound-healing [16,18,19]. .Fibroblasts synthesize the extracellular matrix and collagen in animal connective tissue and play a critical role in wound-healing. In in-vitro studies using human fibroblasts, Boron was found to improve the extracellular matrix cycle by facilitating the activity of enzymes such as elastase, trypsin, collagenase, and alkaline phosphatase that are found in fibroblasts [10,11].
In their animal study, Demirci et al. found that the gel form that was obtained by combining Boron with some active biological polymers affected the healing of second-degree burn wounds positively in rats and showed antimicrobial activity against bacteria, yeast, and fungi [16]. In another study, Boron-Based Gel was applied in radiation-induced dermatitis in rats and it was found that it alleviated dermatitis by reducing the mRNA expression levels of Bcl-2-associated X proteins [20].
When human studies on were examined, Blech et al. found that the wound-healing was three times faster after applying a 3% Boric Acid solution to the wound site in 31 patients who had deep wound infection in the intensive care unit, and the wound healing was three times faster in those treated with Boric Acid when compared to the patients receiving traditional antiseptic, and that these patients returned to a normal care unit approximately three times faster (mean: 20 and 55 days, respectively) [21]. In another study, Boron-Based Gel was used in the treatment of diabetic foot ulcers, which is one of the chronic complications of diabetes and is highly resistant to treatment in case of infection, and it was shown to be effective in wound-healing [22]. In the study that was conducted by Aysan et al. with 47 women who had breast cancer, they investigated the curative effects of boron in dermatitis developed by radiotherapy and applied Boron-Based Gel and gel-containing Vaseline to the breast skin four times a day after the day the radiotherapy started. They found faster and better healing in the breast skin of women who used Boron-Based Gel compared to the placebo (Vaseline) group, and emphasized that this was because of the antioxidant and wound-healing effects of boron [19]. In the present study, similar to the study by Aysan et al [19], according to the REEDA score results in which episiotomy wound-healing and pain were evaluated, and according to VAS, it was found that the wound-healing was quite good and the level of pain in the episiotomy area was quite low in participants who used the Boron-Based Gel compared to the participants in the chlorhexidine gel and control group. It can be considered that this occurred because the Boron-Based Gel has effects of accelerating episiotomy healing by increasing anti-inflammatory, antimicrobial, epithelialization, and angiogenesis properties.
Limitations
One of the limitations of the study was that all the factors that affected wound healing, such as nutritional status and physical activity levels of the subjects, could not be controlled because the study had a retrospective design. The application of scales by different people in episiotomy evaluation may have caused information bias.
Study strengths
To the best of our knowledge, this is the first study in this field conducted on the effectiveness of the Boron-Based Gel on episiotomy pain and wound-healing. No side effects were reported by the participants in the three groups
Conclusions
It was determined in the present study that the use of Boron-Based Gel on the postpartum episiotomy site in primiparous patients accelerated episiotomy wound-healing and reduced pain. For this reason, the use of Boron-Based Gel on the episiotomy area can be an effective treatment.
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.
Funding: None
Conflict of interest
The authors declare no conflict of interest.
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Derya Kanza Gul, Yeliz Mercan. Effect of boron-based gel on postpartum episiotomy wound healing in primiparous pregnant women. Ann Clin Anal Med 2023;14(4):326-331
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Is there a relationship between diabetic retinopathy and vitamin D?
Zuhat Onur Usalp
Department of Ophthalmology,Balıkesir Atatürk City Hospital, Balıkesir, Turkey
DOI: 10.4328/ACAM.21498 Received: 2022-11-13 Accepted: 2022-12-15 Published Online: 2022-12-26 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):332-335
Corresponding Author: Zuhat Onur Usalp, Department of Ophthalmology, Balıkesir Atatürk City Hospital, Balıkesir, Turkey. E-mail: zzusalp@gmail.com P: +90 507 238 95 56 Corresponding Author ORCID ID: https://orcid.org/0000-0001-5247-6391
This study was approved by the Ethics Committee of Balıkesir University Faculty of Medicine (Date: 2021-12-22, No: BAÜN/2021/279)
Aim: In this study, we aimed to investigate the relationship between vitamin D and diabetic retinopathy by comparing clinical features and serum vitamin D levels of patients with and without diabetic retinopathy.
Material and Methods: The study is retrospective observational, and data were obtained by scanning the data file of patients diagnosed with Type 2 diabetes mellitus and undergoing fundus examination. A p-value < 0.05 was considered significant in all results.
Results: The mean age of patients with diabetic retinopathy (n=40) included in the study was 58.9±7.8 years, and the mean age of patients without diabetic retinopathy (n=40) was 58.5 ±5.2 years. In the diabetic retinopathy group, duration of diabetes ([19.0 ± 7.5] vs. [10.8 ± 7.2], p<0.001), serum glucose level ([218.9 ± 80.9] vs [142.7 ± 44.9], p<0.001), HbA1c level ([10.1 ± 2.1] vs. [7.2 ± 1.4], p<0.001) and total cholesterol level ([203.4 ± 41.2] vs [182.1 ± 37.1], p=0.009) were higher. However, serum 25[OH]D level was lower ([12.8 ± 4.2] vs [19.9 ± 11.2], p=0.011). In univariate regression analyzes, low vitamin D level (OR:0.889, CI[0.802 – 0.987], p=0.027) was determined as a possible independent risk factor for diabetic retinopathy.
Discussion: In our study, we found that low vitamin D levels were associated with an increased risk of diabetic retinopathy. Vitamin D deficiency may be one of the underlying causes of diabetic retinopathy, and we believe that prospective comprehensive studies will shed light on this issue.
Keywords: Vitamin D Deficiency, Diabetes Mellitus, Diabetic Retinopathy
Introduction
The prevalence of diabetic retinopathy (DRP) has reached approximately 93 million people worldwide and is one of the most important causes of premature visual loss [1]. Factors such as factors the duration of diabetes, hemoglobin A1c (HbA1c) level and hypertension lie in the etiology of DRP and their treatment provides modest improvement in retinopathy [2].
The development of retinal pathology, which includes neovascularization as a result of neural and retinal vascular dysfunction, is thought to be multifaceted. For this reason, various studies involving vitamins and minerals have investigated whether there is a relationship with DRP. 25-hydroxyvitamin D (25[OH]D) deficiency has been shown to be associated not only with DRP but also with other diseases [3,4,5]. In studies investigating the relationship between vitamin D deficiency and DRP, vitamin D receptor (VDR)-dependent calcium-binding proteins have been isolated from the human retina, especially from the photoreceptor layer of the cones [6]. In those expressing VDR in retinoblastoma tissue, Vitamin D supplementation reduced tumor growth and caused apoptosis in retinoblastoma cells [7]. 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is closely associated with and reversed the regulation of Vascular Endothelial Growth Factor (VEGF) in experimental models, but also hypoxia is hypothesized to be associated with tissue hypoxia [8].
In this study, we aimed to investigate the relationship between vitamin D and diabetic retinopathy by comparing the clinical features and serum vitamin D levels of patients with and without diabetic retinopathy.
Material and Methods
The study was retrospective, and data were obtained by scanning the files of the patients who were diagnosed with Type 2 diabetes mellitus and had fundus examination. Diabetes mellitus was diagnosed according to the guidelines of the American Diabetes Association (ADA) (fasting blood glucose ≥126 mg/dL, 2-hour plasma glucose level ≥200 mg/dL in oral glucose tolerance test) [9]. Body mass index (BMI) was obtained by dividing kilograms by the square of height (weight, kg/height,m2). Demographic clinical characteristics of the patients were obtained from the hospital data recording environment.
Best-corrected visual acuity (BCVA) was documented using the logMAR scale. All patients underwent detailed fundoscopic examination using stereoscopic slit-lamp biomicroscopy and indirect ophthalmoscopy. All patients underwent digital fundus photography and fluorescein angiography. Diagnosis and classification of patients with diabetic retinopathy were made in accordance with the guidelines of the study group (ETDRS) for the early treatment of diabetic retinopathy in Type-2 DM [10].
Venous blood samples were obtained from the right or left antecubital vein after at least 8 hours of fasting. The level of glycosylated hemoglobin was measured with a standard protocol using an autoanalyzer. Serum 25[OH]D level was measured by the chemiluminescent microparticle immunoassay method (Thermo Scientific, HPLC, Ultimate LPG-3400SD, Thermo Fisher Scientific).
Exclusion criteria
Those who had any systemic disease other than diabetes affecting the retina, a history of cardiovascular disease, kidney failure, chronic liver disease, cancer, calcium metabolism disorder, or taking vitamin D therapy for osteoporosis were excluded from the study.
Ethics Committee Approval
Ethics Committee Approval was obtained from the local ethics committee of the Faculty of Medicine (Decision number: BAÜN/2021/279, date: 22.12.2021).
Statistical analyzes
The obtained data were recorded in the statistical program of SPSS version 20.0 (Statistical Package for Social Sciences, Inc., Chicago, IL, USA). The suitability of data for a normal distribution was evaluated with the Kolmogorov-Smirnov test. Numerical variables with normal distribution were expressed as mean ± standard deviation, and categorical variables were expressed as percent (%). The student’s t-test was used to compare normally distributed data between the two groups, and the Chi-square test was used to compare categorical variables. Univariate and multivariate logistic regression analyzes were used to determine independent predictors of diabetic retinopathy. A p-value of < 0.05 was considered significant in all results.
Results
The mean age of patients with diabetic retinopathy (n=40) included in the study was 58.9 ± 7.8 years, and the mean age of patients without diabetic retinopathy (n=40) was 58.5 ± 5.2 years. There was no difference between the two groups in terms of gender, BMI, and frequency of hypertension.
In the diabetic retinopathy group, duration of diabetes ([19.0 ± 7.5] vs. [10.8 ± 7.2] years, p<0.001), serum glucose level ([218.9 ± 80.9] vs [142.7 ± 44.9] mg/dL, p<0.001), HbA1c level ([10.1 ± 2.1] vs. [7.2 ± 1.4], p<0.001) and total cholesterol level ([203.4 ± 41.2] vs [182.1 ± 37.1] mg/dL, p=0.009) were higher. However, serum 25[OH]D level was lower ([12.8 ± 4.2] vs [19.9 ± 11.2] ng/mL, p=0.011), (Table 1, Figure 1).
In univariate regression analyses performed to detect risk factors associated with diabetic retinopathy, duration of diabetes (Odds ratio [OR]: 1.167, 95% Confidence interval [CI] [1.089 – 1.251], p<0.001), serum glucose level (OR:1.020) , 95% CI [1.011 – 1.030], p<0.001), HbA1c level (OR:2.452, 95% CI [1.728 – 3.480], p<0.001), total cholesterol (OR:1.014, 95% CI [1.003 – 1.025) ], p=0.011) and vitamin D level (OR:0.889, [0.802 – 0.987], p=0.027) were found to be possible independent risk factors. There is no significant difference was observed between these parameters in multivariate analysis (Table 2).
Discussion
In our study, while the duration of diabetes, serum glucose level, HbA1c level and total cholesterol level were high in patients with diabetic retinopathy, vitamin D level was found to be quite low, and low vitamin D was found to be a possible independent risk factor for diabetic retinopathy.
Vitamin D is a multifunctional hormone with the active metabolite 1,25-dihydroxyvitamin D3. Insulin hormone synthesis and secretion are impaired at low vitamin D levels [11]. Vitamin D also has anti-inflammatory and anti-angiogenic properties [12]. In the presence of high glucose levels, inflammation, oxidative stress increases VEGF and ICAM release [12]. Angiogenesis begins to increase in retinal endothelial cells and the ground is prepared for DRP [12]. Vitamin D plays an important role in diabetic retinopathy due to its angiogenesis and anti-inflammatory properties. In in vivo and in vitro animal studies, it has been shown that vitamin D inhibits VEGF, induces endothelial cell apoptosis, and inhibits signalling pathways required for angiogenesis in patients with retinopathy [13,14].
Nadri et al. divided 72 diabetic patients into 3 groups. They found that mean vitamin D levels were 23.3 ng/mL in those without retinopathy, 18.10 ng/mL in those without proliferative diabetic retinopathy, and 14.1 ng/mL in those with proliferative diabetic retinopathy also, they found that statistically, serum vitamin D level was lower in patients with proliferative diabetic retinopathy and it was closely related to the severity of retinopathy [15].
According to Yuan et al. in their meta-analysis, they found that the risk of DRP increased by up to 60% in those with vitamin D deficiency compared to those without it [16]. In this study, they found that vitamin D deficiency was an important risk factor for proliferative diabetic retinopathy, even after necessary adjustments for age, gender, duration of diabetes, and HbA1c level [16].
Patrick et al. in their study, which included 1790 patients, found that as the severity of diabetic retinopathy increased, the rate of vitamin D deficiency increased. However, in the regression analyses, they could not reveal this relationship statistically [17].
Afarid et al. found that serum vitamin D levels of 30 diabetic retinopathy patients and 60 diabetic patients without diabetic retinopathy were generally low (25(OH)D <20 ng/mL) [18]. However, vitamin D levels were found to be quite low in patients with retinopathy compared to those without retinopathy [18].
In our study, in accordance with the literature, vitamin D levels were found to be lower in patients with diabetic retinopathy than in patients without retinopathy (mean 12.8 ng/mL). Unlike in our study, diabetes duration, HbA1c, serum glucose and total cholesterol levels were also found to be higher in patients with diabetic retinopathy. In addition, in the regression analyses, it was seen that the high of these parameters and the low level of vitamin D were significantly associated with diabetic retinopathy.
Although the number of publications showing the relationship between vitamin D deficiency and diabetic retinopathy is considerable, some publications do not find a relationship between these two conditions, and the issue is open to discussion. In the study of Alam et al. in which 657 diabetic patients were recruited, they found similar vitamin D levels in comparison between groups with and without diabetic retinopathy. In this study, similar to our study, diabetes year, glycemic control and lipid levels were found to be associated with diabetic retinopathy [19].
Limitation
Our study was a single-center study and the number of patients was limited. Since it was a retrospective study, patients were not followed up for adverse events. Determining the relationship between diabetic retinopathy and poor in-hospital and long-term outcomes would have contributed to our study.
Conclusion
In our study, we found that low vitamin D levels were associated with an increased risk of diabetic retinopathy. We found that diabetic retinopathy was also associated with high glucose and lipid values. Vitamin D deficiency may be one of the underlying causes of diabetic retinopathy, and we think that it would be appropriate to measure vitamin D levels as much as possible in these patients. We believe that prospective studies with a larger number of patients will contribute to this issue.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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2. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J,Cohen R, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. The Lancet. 2010;376(9739):419-30.
3. Dziedzic, EA, Gasior, JS, Pawlowski M, Wodejko-Kucharska B, Saniewski T, Marcisz A, et al. Vitamin D level is associated with severity of coronary artery atherosclerosis and incidence of acute coronary syndromes in non-diabetic cardiac patients. Arch Med Sci. 2019;15(2):359-68.
4. Muris, AH, Smolders, J, Rolf L, Thewissen M, Hupperts R, Damoiseaux J, et al. SOLARIUM study group. Immune regulatory effects of high dose vitamin D3 supplementation in a randomized controlled trial in relapsing-remitting multiple patients receiving IFNB: the SOLARIUM study. J Neuroimmunol. 2016;300:47-56.
5. Usalp S, Kemal H, Yüksek B, Yaman B, Günsel A, Edebal O, et al. Is there any link between vitamin D deficiency and vasovagal syncope? J Arrhythm. 2020;36(2):371-6.
6. Chan HN, Zhang XJ, Ling XT, Bui CHT, Wang YM, Ip P, et al. Vitamin D and Ocular Disease: A systematic Review. Int J Mol Sci. 2022;23(8):4226.
7. Caban M, Lewandowska U. Vitamin D receptor, calcitriol analogues and their link with ocular disease. Nutrients. 2022;14(11):2353.
8. Cardus A, Panizo S, Encinas M, Dolcet X, Gallego C, Aldea M, et al. 1,25-dihydroxyvitamin D3 regulates VEGF production through a vitamin D response element in the VEGF promoter. Atherosclerosis. 2009;204(1):85-9.
9. American Diabetes Association. 2.Classification and Diagnosis of Diabetes: Standards of medical care in diabetes-2021. Diabetes Care. 2021;44(1):15-33.
10. No authors listed. Grading diabetic retinopathy from stereoscopic colour fundus photographs – An Extension of the Modified Airlie House classification. ETDRS Report Number 10. Early Treatment Diabetic Retinopathy Study Research Group. Ophtalmology. 2020;127(4S):99-119.
11. Luo BA, Gao F, Qin LL. The association between vitamin D deficiency and diabetic retinopathy in type 2 diabetes: a meta-analysis of observational studies. Nutrients. 2017;9(3):307.
12. Ben-Shoshan M, Amir S, Dang DT, Dang LH, Weisman Y, Mabbjeesh NJ. 1 alpha, 25-dihydroxyvitamin D3 (calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells. Mol Cancer Ther. 2007;6(4):1433-9.
13. Lazzara F, Longo AM, Giurdanella G, Lupo G, Platania, Rossi S, et al. Vitamin D3 preserves blood retinal barrier integrity in an in vitro model of diabetic retinopathy. Front Pharmacol. 2022;13:971164.
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16. Yuan J, Zhou JB, Zhao W, Zhang RH, Cai YH, Shu LP, et al. Could Vitamin D be Associated with Proliferative Diabetic Retinopathy? Evidence from Pooling Studies. Horm Metab Res. 2019;51(11):729-34.
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Changes in objective dry eye diagnostic tests after upper eyelid blepharoplasty
Emrah Mat 1, Emin Serbülent Güçlü 2
1 Department of Ophthalmology, Private Egepol Hospital, İzmir, 2 Department of Ophthalmology, Mersin City Hospital, Mersin, Turkey
DOI: 10.4328/ACAM.21501 Received: 2022-11-18 Accepted: 2023-01-05 Published Online: 2023-01-12 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):336-339
Corresponding Author: Emrah Mat, Department of Ophthalmology, Private Egepol Hospital, Bornova, İzmir, Turkey. E-mail: dremrahmat@yahoo.com P: +90 505 292 68 29 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1454-7731
This study was approved by the Ethics Committee of Bakircay University Training and Research Hospital (Date: 2022-07-29, No: 673)
Aim: In this study, we aimed tto evaluate the effect of upper eyelid blepharoplasty performed by removing the orbicular strip in patients with only functional visual complaints on objective dry eye tests.
Material and Methods: In our ophthalmology clinic, this retrospective study included 46 eyes of 23 individuals who underwent upper eyelid blepharoplasty for grade 3 lateral dermatochalasis with associated visual complaints between October 2021 and June 2022. Schirmer test and tear break-up time (BUT) were measured preoperatively and postoperatively at three months in all individuals. In addition, the effects of upper eyelid blepharoplasty on objective dry eye tests (Schirmer test and BUT) were evaluated.
Results: The mean value of the preoperative Schirmer’s test was 17.3 mm, while the postoperative 3rd-month measurements were 17.42 mm. In addition, the preoperative BUT measurements of our patients were 11.43 seconds, while the postoperative 3rd-month measurements were 11.38 seconds (p:0.268).
Discussion: Upper eyelid blepharoplasty performed by removing the orbicular muscle strip in grade 3 dermatochalasis patients with only functional visual complaints may not affect objective dry eye tests in the postoperatively third month.
Keywords: Upper Eyelid Blepharoplasty, Schirmer Test, Dry Eye Test, Dry Eye
Introduction
Dermatochalasis is a redundant eyelid skin that may compose a “hooding” impact, possibly influencing and narrowing the visual field [1]. Upper eyelid dermatochalasis is primarily associated with the aging process, genetic factors, and effects of ultraviolet exposure. Because of the anatomic and functional changes, patients experience visual field narrowing and cosmetic concerns [2,3]. Therefore, upper eyelid blepharoplasty is one of the most common cosmetic procedures that improve the esthetic appearance and functional visual field [1]. Also, upper eyelid blepharoplasty is performed to repair the aesthetic view of the periorbital area and improve visual field narrowing. This procedure is usually carried out under local anesthesia. It includes the removal of redundant skin, orbital fat, and commonly the removal of a different amount of orbicularis oculi muscle strip. This surgery has considerably increased patients’ quality of life through improved visual function and cosmetic appearance [4,5].
Upper eyelid blepharoplasty achieves satisfactory esthetic outcomes; however, performing upper eyelid blepharoplasty can cause the development or aggravation of dry eye (DE) symptoms in some individuals, reported ranging from 0% to 26.5% in some studies [6,7]. The development of dry eye after upper eyelid blepharoplasty is associated with various factors, for example, temporary postoperative lagophthalmos [7]. Although after upper eyelid blepharoplasty DE is a relatively uncommon and temporary complication, the intensity of DE symptoms could affect life quality [8,9]. However, some patients may develop permanent, chronic DE syndrome, severely affecting their mental and physical situation. Also, quality-of-life studies have demonstrated that DE may affect visual acuity [4]. The development of DE after upper eyelid blepharoplasty is associated with various situations, including temporary postoperative transient lagophthalmos is the most common one. Also, in a few patients, DE can become permanent, continuing well beyond the period of any transient postoperative lagophthalmos or even in its beginning absence [7]. The exact cause of postoperative DE is still uncertain; a better understanding is needed. Since upper eyelid blepharoplasty procedure frequently involves resectioning the orbicularis oculi muscle strip (responsible for eyelid closure), some studies hypothesize that the change of blink forces might be a trigger factor for DE. Alternations in upper eyelid anatomy and motion dynamics could be attributed to the development of DE following upper eyelid blepharoplasty [6,7,10].
Alternations in eyelid structure and motion dynamics could be featured in the development of DE following upper eyelid blepharoplasty. The other opinion is that postoperative DE triggered by upper eyelid blepharoplasty is related to the decrease of tear film stability. Some possible mechanisms contributing to this idea have been suggested: the unstable distribution of tear film caused by the alternation in the interplay between the ocular surface and the upper eyelid [7,11,14]
To the best of our knowledge, several studies on the development of DE after blepharoplasty can be found in the literature [6,7,13]. However, we have yet to find a study that analyzed the effect of blepharoplasty performed for only visual complaints on objective dry eye tests. Upper eyelid blepharoplasty can be associated with DE since the function of the orbicularis oculi muscle can influence the tear film stability. The present study aims to evaluate the effect of upper eyelid blepharoplasty performed by removing the orbicular strip in patients with only functional visual complaints on objective dry eye tests.
Material and Methods
The present study included 23 (21 females, 2 males) patients who underwent upper eyelid blepharoplasty for visual complaints between October 2021 and June 2022. Electronic medical records of the Egepol Hospital Ophthalmology Clinic were reviewed to identify all patients who underwent upper eyelid blepharoplasty for uncomplicated dermatochalasis. In addition, we reviewed files retrospectively; after three months, 23 patients (mean age 57.5 years, range 51–67) were evaluated. All patients had grade 3 lateral severe dermatochalasis according to Silva’s new classification and only with coexisting visual complaints [15]. The present study was carried out with the permission of the Bakircay University Training and Research Hospital, Clinical Researches Ethics Committee (Date: 29.07.2022, Decision No: 673). All procedures were carried out in accordance with the ethical rules and the principles of the Declaration of Helsinki. Written consent was obtained from the patient participating in this study for the use of her photograph.
Before the surgery, the individuals underwent a complete ophthalmologic examination, including biomicroscopic examination, fundus examination, and best-corrected visual acuity. In addition, all patients underwent the tear break up time [BUT] test and Schirmer’s test measurements before the operation and again 3 months after surgery. The Schirmer test was performed without using topical anesthesia. Schirmer test strips (Akschirmer-India) were placed on the outer 1/3 of the lower eyelid. At the end of the fifth minute, values of 10 mm and above were considered normal [16]. After the Schirmer test, sterile fluorescein strips (Fluoro Touch-India) were placed on the lower eyelid fornix for BUT measurements. The patients were asked to blink three times and then look straight without blinking in the dye on the cornea under biomicroscopic examination at x10 magnification with a cobalt blue filter [17]. The time between the last blink and the first dry spot was measured. This measurement was repeated three times, the average of these three measurements was taken, and values of 10 seconds and above were considered normal [18].
The exclusion criteria included neuromuscular abnormalities, a history of ocular surgery and previous eyelid surgery within four months, contact lens wear, or ocular/eyelid diseases such as lagophthalmos, glaucoma, acute inflammation or infection, Sjögren’s syndrome, Stevens-Johnson syndrome, and thyroid eye disease. Also, patients with grade 1-2 lateral dermatochalasis with concomitant cosmetic complaints or visual complaints incomplete and grade 3 lateral dermatochalasis coexisting cosmetic complaints were excluded from the study.
The bilateral upper eyelid crease was marked as the lower border of the skin tissue to be excised, approximately 8-9 mm above the upper lid margin. As its upper edge is about 10 mm below the lower part of the eyebrow, a pinch test was performed with forceps to avoid excessive resection. Local anesthesia with 1-2 ml of 0.5% lidocaine with 1:100.000 epinephrine was applied to both eyelids. The incision was made with a 15-blade scalpel, and the excess skin was dissected from the underlying tissue with the help of curved tissue scissors. Afterward, approximately 5-6 mm wide orbicular tissue was removed with scissors. Hemostasis was achieved using electrocautery. The skin incision was closed with a continuous intradermal nonabsorbable suture (nylon 7/0).
All results were statistically analyzed using SPSS software (version 21.0, IBM Corp, Armonk, NY, USA). The statistical analysis for the differences between preoperative and postoperative BUT and the Schirmer test was conducted using the mean value of both eyes of the individuals. For statistical analysis, the Wilcoxon rank test was used. A p-value of 0.01 or less was considered statistically significant.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
The present study included 46 eyes of 23 patients who underwent bilateral upper eyelid blepharoplasty for grade 3 dermatochalasis coexisting visual complaints in our clinic between October 2021 and June 2022. The mean age of patients (21 females, 2 males) was 57.5 years (range 51–67). Preoperative and postoperative third-month photographs of a typical patient who underwent upper eyelid blepharoplasty are presented in Figure 1.
The assessment of the individuals’ Schirmer’s test results showed that, preoperatively, the mean measurement was 15.90±2.05 mm, whereas, postoperatively, the mean measure was 15.64±1.92 mm in the third month. The Schirmer’s test measurements in the third postoperative month were lower than all the preoperative measurements. But this was not statistically significant (Table 1).
The assessment of the individuals’ BUT results showed that the preoperative measure was 16.40±2.80 seconds. Postoperatively, it was 15.95±3.05 seconds in the third month. Accordingly, it was observed that no significant differences were observed at the third-month visit compared to the preoperative measurements (Table 1).
Discussion
With the effect of aging and gravity, dermatochalasis develops due to the relaxation of the subcutaneous tissue along with the eyelid skin. Dermatochalasis develops when the eyelid skin and subcutaneous tissue lose their elasticity due to aging and gravity. Excess skin, loose subcutaneous tissue, and adipose tissue due to aging make people to look older and more tired than they are. Blepharoplasty is a treatment method with high patient satisfaction and surgical success. For this reason, blepharoplasty has become the most frequently applied facial plastic surgery. During upper eyelid blepharoplasty, excess skin, orbital fat, and/or orbicular muscle are resected. Changes in the upper lid anatomy may lead to altered objective dry eye test results and dry eye development after upper eyelid blepharoplasty. The incidence of dry eye after upper eyelid blepharoplasty varies between 0-12.9% in some studies [6,7].
Black et al. [19] defined a transient decrease in eyelid sensation after upper eyelid blepharoplasty and attributed this reduction to trigeminal nerve injury during surgery. Besides direct nerve injury, the corneal surface sensation can also be reduced because of inflammation. Decreased ocular surface sensation results in reduced tear production [14,15]. In a previous research assessing tear production and ocular surface sensation in individuals who underwent upper eyelid blepharoplasty, Kim et al.[25] demonstrated that ocular surface sensation was decreased in the postoperative first week and turned back to preoperative results after the first month. We considered that the Schirmer test, which is associated with tears production, and BUT that assesses tear film stability, might have been temporarily decreased, especially in the early postoperative period, as a result of reduced blinking reflex, inadequate blinking, and temporary meibomian gland dysfunction caused by postoperative inflammation and preoperative local anesthetics. Opposite to other studies, they followed a rise in Schirmer test measurements in the first month. Yan et al.[21] also demonstrated increased Schirmer tests and BUT results in the first week after upper eyelid blepharoplasty. It is usually thought that aesthetic upper eyelid blepharoplasty, mainly resecting the orbicularis oculi muscle, might alter the balance of eyelid closure, tear distribution, and tear pumping, causing a reduced tear secretion and blink rate [14,22]. Kim et al. [20] showed a significant increase in the Schirmer test after one month postoperatively in 11 individuals. They showed no significant difference in tear production after one day postoperatively, but found increased tear production in the first postoperative month. These findings differed from the present study, but the present study had a longer follow-up period. Lima et al.[23] evaluated preoperatively and three months postoperatively rose bengal staining, BUT, Schirmer’s test, dry eye symptoms in 29 individuals after upper eyelid blepharoplasty procedure. Their outcome was similar to the present study, with no difference in BUT between the preoperative period and the third month after surgery. Opposite to the present study, the authors observed significant differences in Schirmer’s test measurements at postoperative assessment. Aksu et al.[24] determined no considerable change in postoperative Schirmer test results after a levator surgery. The statistically significant reduction in the upper eyelid blepharoplasty group proposes a mechanism connected with the orbicularis oculi muscle. They suggested that Orbicularis strip resection is thought to weaken the orbicularis oculi muscle, decrease the blinking reflex arc, and reduce ocular sensation and tear production due to injury to trigeminal nerve branches in a reduction in basal and reflex tear secretion. These findings do not support our results. In the present study, we demonstrated a decrease in the Schirmer test and BUT test results, but this was not statistically significant. We evaluated objective dry eye tests postoperatively for three months in the present study. This suggested that orbicular muscle healing, functional improvement, and all inflammatory process could be completed after three months. Regeneration of orbicularis oculi muscle by 4–6 months postoperatively could permit improvement of normal blink function. After selectively devastating the orbicularis muscle in rabbits, Wirtschafter et al. [25] demonstrated complete healing of the orbicularis at six months. The present study showed that after upper eyelid blepharoplasty, orbicularis oculi function about tear production and tear film dynamics could reach enough effect postoperatively in the 3rd month.
As retrospective research, the present study has some limitations. The number of individuals included in the present study was limited. Other limitations are short follow-up time and few parameters. In addition, there are different surgical techniques that determine the width of the orbicularis oculi muscle resection to be performed. Another limitation of the present study is the absence of histological parameters concerning dry eye, corneal and conjunctival surface alternation. Therefore, there is a need for a long-term follow-up period and prospective controlled studies in large patient series to achieve a concurrence concerning the amount of optimal orbicularis oculi muscle resection and histological parameters that would change objective dry eye tests and disclosure of the mechanisms that may reason dry eye.
Conclusion
In conclusion, to the best of our knowledge, this is the first study that evaluated the effect of upper eyelid blepharoplasty performed by removing the orbicular strip in patients with only functional visual complaints on objective dry eye tests. The present study showed that upper eyelid blepharoplasty performed by removing the orbicular muscle strip in grade 3 lateral dermatochalasis patients with only functional visual complaints might not affect objective dry eye tests in the postoperatively third month.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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The relationship between systemic immune-inflammation index and length of hospitalization in acute pancreatitis
İbrahim Halil Yasak 1, Mustafa Yılmaz 2
1 Department of Emergency Medicine, Faculty of Medicine, Harran University, Şanlıurfa, 2 Department of Emergency Medicine, Faculty of Medicine, Fırat University, Elazıg, Turkey
DOI: 10.4328/ACAM.21511 Received: 2022-11-21 Accepted: 2022-12-24 Published Online: 2022-12-29 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):340-344
Corresponding Author: İbrahim Halil Yasak, Department of Emergency Medicine, Faculty of Medicine, Harran University, 63300, Sanliurfa, Turkey. E-mail: dr_ihy@hotmail.com P: +90 414 344 44 44 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6399-7755
This study was approved by the Ethics Committee of Harran University Faculty of Medicine (Date: 2022-09-05, No: HRÜ/22.17.13)
Aim: To determine the relationship of the systemic immune-inflammatory index (SII) in acute pancreatitis (AP) with disease severity and length of stay in hospital.
Material and Methods: This retrospective study was conducted in the Emergency Department over a 3-year period. The basic and laboratory data were examined from the electronic patient records system of 100 patients who were hospitalised because of pancreatitis.
Results: Evaluation was made of 100 patients, comprising 71 females and 29 males, with mild AP determined in 67 and severe AP in 33. The SII and neutrophil-lymphocyte ratio (NLR) values were determined to be significantly higher in the severe AP group (p=0.001, p=0.014, respectively). A statistically significant correlation was determined between the SII and the Glasgow (Imrie) score (r=0.430, p<0.001). According to the Glasgow (Imrie) criteria, the SII was determined to have sensitivity in the differentiation of severe AP. The SII, C-reactive protein level, and Glasgow (Imrie) criteria were determined to be independent predictors of length of stay in hospital.
Discussions: The SII was determined to be effective in predicting disease severity and length of stay in hospital in AP patients.
Keywords: Acute Pancreatitis, Inflammation, Systemic Immune-Inflammation Index, Hospitalization
Introduction
Acute pancreatitis is a common inflammatory disease of the exocrine pancreas, with symptoms ranging from severe abdominal pain to pancreas necrosis. It can cause permanent organ failure and multiple organ dysfunction and has a mortality rate of 1-5% [1]. At the molecular level, the triggers of acute pancreatitis cause damage to the pancreatic acinar and ductal cells by disrupting the intracellular calcium signal. In acute biliary pancreatitis, high pressure occurs as a result of gallstone obstruction of the ampulla vaterin, and with this high pressure, bile enters the pancreatic canal [2].
Multiple cytokines, primarily tumour necrosis factor-α, and interleukins-1α, 1β, 6, and 18, mediate a strong proinflammatory immune response, exacerbate the initial pancreas damage, and through lymphatic and systemic circulation pathways, inflammatory responses pass to the liver, lungs, heart, kidneys, and gastrointestinal system. This situation progressing in acute pancreatitis causes systemic inflammatory response syndrome [3, 4]. Therefore, studies have been conducted on macrophage-related inflammatory response and neutrophil infiltration associated with acute pancreatitis [5]. The inflammatory response can be determined with the levels of neutrophils, lymphocytes, thrombocytes, and acute phase proteins.
In the determination of the severity of acute pancreatitis, scoring systems are used such as the Acute Physiology and Chronic Health Evaluation II (APACHE-II), the Ranson Criteria or Modified Glasgow Acute Pancreatitis Severity Score (Glasgow Imrie Score) for mortality, and the Atlanta Classification for systemic inflammatory response syndrome. The current guidelines recommend observation of the presence of systemic inflammatory response syndrome or organ failure for a minimum of 48 hours from the time of hospital admission for the prediction of the course of disease severity [6, 7]. Therefore, the scoring systems suitable for use at the time of presentation in the Emergency Department (ED) are limited. Previous studies have determined that the Atlanta and Glasgow (Imrie) scoring systems can be used on presentation at ED [8]. Recently, the systemic immune-inflammation index (SII), which is a combined tool, has been used to obtain prognostic information in patients with various malignant tumours [9, 10]. There are also more recent studies showing that the SII can be used in pancreas cancers and in the early determination of the severity of acute pancreatitis [11, 12].
The aim of this study was to determine the effect of the SII on a change in disease severity according to the Glasgow (Imrie) criteria and the duration of hospitalization in patients diagnosed with acute pancreatitis in the ED.
Material and Methods
Approval for this retrospective study was granted by the Local Ethics Committee. The basic and laboratory data in the electronic patient records system were examined of 100 patients (71 females, 29 males) diagnosed and hospitalised with a diagnosis of acute pancreatitis made in the ED over a 3-year period. The diagnosis of acute pancreatitis was made from the presence of two of three criteria: (1) abdominal pain consistent with pancreatitis, (2) serum amylase or lipase ≥2-fold more than the normal upper limit, (3) findings consistent with pancreatitis on computed tomography (CT) or magnetic resonance imaging (MRI) [7]. The Glasgow (Imrie) criteria were used in the determination of the severity of AP (13]. The Glasgow Imrie score is formed of 8 criteria, each scored with 1 point. A score of ≥3 is evaluated as severe AP [14].
The patients included in the study were aged >18 years and were diagnosed with acute pancreatitis according to the diagnostic criteria. Patients were excluded from the study if they were aged <18 years, if they refused treatment and hospitalization despite the medical recommendation, or if they had a history of chronic hematological disease.
Laboratory measurements:
The neutrophil-lymphocyte ratio (NLR) and SII were calculated from the laboratory results: NLR = neutrophil count /lymphocyte count, and SII = thrombocyte count x NLR [15].
White blood cell (3.7–10.1 10e3/μL), hemoglobin (12–18 g/dL), hematocrit (35%–53.7%), platelet (142–424 103/μl), lymphocyte (1.09-2.99 103/μL), neutrophil (1.63-6.96 103/μL), monocytes (0.24-0.79 103/μL), eosinophil (0.03-0.44 103/μL), mean platelet volume (6.8-10.8 fL), and red blood cell distribution width (11.8-15.8%)counts were determined with the Alinity HQ device (Abbott, USA). The levels of serum glucose (74–106 mg/dL), urea (19–50 mg/dL), creatinine (0.55–1.02 mg/dL), aspartate aminotransferase (13-40 U/L), alanine aminotransferase (7-40 U/L), bilirubin (0.3-1.2 mg/dl), albumin (3.2 – 5 g/dL), calcium (8.7-10.4 mg/dl), lactate dehydrogenase (120-246 U/L), amylase(30-118 U/L), lipase(12-53 U/L), and C-reactive protein (0-0.05) were measured using conventional laboratory methods on Atellica Solution (Siemens Healthineers, Germany). Activated partial thromboplastin time (22-36 sec), prothrombin time (10.5-15.5 sec), and International Normalized Ratio (0.8-1.2 INR) values were determined using the Sysmex CS-2000i device (Siemens Healthineers, Germany).
Statistical analysis
Data were analyzed using SPSS 21.0 (IBM Corporation, Armonk, NY, USA) and University licensed Microsoft Excel packaged software. Numerical data were expressed as median and interquartile range (IQR) values and qualitative data as number (n) and percentage (%). The conformity of continuous variables to normal distribution was determined using the Shapiro–Wilk normality test. In the comparisons of two independent groups, the Mann Whitney U-test was applied and in the comparisons of categorical data, the Chi-square test. Spearman correlation ananlysis was performed to determine correlations. ROC analysis was applied to evaluate the use of SII in the differentiation of severe and non-severe AP. The ROC curve analysis results were presented as % specificity and % sensitivity [area under the ROC curve (AUC), p-value, and 95% confidence interval (CI)]. In the determination of factors affecting the length of stay in hospital, linear logistic regression analysis was used. A value of p < 0.05 was considered statistically significant.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
Evaluation was made of 100 patients, comprising 71 females and 29 males, with mild AP determined in 67 and severe AP in 33. The SII and NLR values were determined to be significantly higher in the severe AP group (p=0.001, p=0.014, respectively). The basic and biochemical data of patients with non-severe AP (0-2) and severe AP (≥3) according to Glasgow (Imrie) criteria are presented in table 1 and hematology data in table 2.
A statistically significant positive correlation was determined between the SII and the Glasgow (Imrie) score (r=0.430, p<0.001). When a cutoff value of 2178.33 was taken in the ROC analysis, the use of SII in the differentiation of non-severe AP (0-2) and severe AP (≥3) according to the Glasgow (Imrie) criteria, had 72.73% sensitivity and 58.21% specificity (Figure 1).
According to the results of the linear logistic regression analysis, the SII, CRP, and Glasgow (Imrie) criteria were determined to be correlated with the length of stay in hospital (Table 3).
Discussion
The results of this study demonstrated that as the severity of acute pancreatitis increased, so the SII significantly increased, and the use of the SII in the differentiation for severe pancreatitis was determined to have 72.73% sensitivity and 58.21% specificity. A correlation was also determined between the SII and length of stay in hospital.
Although the pathophysiology underlying the effect of locally occurring damage in AP on the systemic inflammatory response is not fully known, neutrophils, monocytes, macrophages, and lymphocytes have been determined to have a very important role in the progression of immune system diseases [16]. Previous studies have based the definition of severe AP on organ failure, and it has been reported that patients with organ failure ongoing for more than 48 hours have a greater risk of mortality. Moreover, there is a period of significant inflammatory response (SIRS) before organ failure and this shows that the patient is at very high risk of organ failure [17]. Generally, the majority of patients (80-85%) have a mild form of the disease which is self-limiting and has a mortality rate <1-3%, but approximately 20% of patients have a moderate or severe AP attack, for which the mortality rate increases to 13-35%. Therefore, the early identification of severe AP or predicting that there could be severe AP is of critical importance to further reduce complications and mortality [17].
Although many biomarkers have been examined as early predictors of AP severity, there is no practical, consistent, or accurate laboratory test to predict disease severity in patients with AP [17, 18]. The need for at least 48 hours of observation to determine organ failure and systemic inflammatory response limits the use of these scoring systems in the ED. Therefore, studies of biochemical markers to determine AP severity are ongoing. The recently defined SII, which is a combined tool to provide prognostic information in patients with different malignant tumours, has been used in studies [9, 10]. The SII is a simple, low-cost, objective index, which better reflects the balance between the inflammatory and immune responses of the host than all the other systemic inflammation scores. Wu J. et al. reported that the SII increased in ankylosing spondylitis, which is an inflammatory disease of unknown etiology, and as it increased more in periods of disease activity than in periods of remission, it could be used as a biomarker in the observation of disease activity [19]. In another study by Yorulmaz et al., it was reported that SII could be an independent prognostic marker for patients with psoriasis and psoriatic arthritis [20]. It has also been reported that in addition to SII being affected in chronic inflammatory disease and cancer, the SII is affected in acute inflammation conditions [21].
There are several studies in literature that have investigated hematological parameters in AP, which is an inflammatory process. In recent years, the relationship has been investigated of new inflammatory markers to predict the severity of pancreatitis such as the NLR and platelet-lymphocyte ratio (PLR) with prognosis and severity in AP (22). NLR was found to have 58.33% sensitivity and 73.73% specificity in the determination of AP and organ failure in a study by Liu G. et al., and was therefore said to be a marker with prognostic value in AP [22]. Similarly, Zhou et al. reported that NLR, PLR, red blood cell distribution width (RDW) and blood urea nitrogen (BUN) values were good markers for the prediction of AP severity and prognosis [23].
In severe pancreatitis, IL-1, IL-6, IL-8, TNFα, thrombocyte activating factor (PAF), and various cytokines in the circulation can activate chemotaxis, neutophils, monocytes, lymphocytes and thrombocytes [24]. The SII, which is obtained by multiplying the NLR and PLT values, and has been determined to significantly increase in several cancers, has been reported to be important in pancreas cancers.
Bittoni et al. reported that increased SII was a negative prognostic factor independently of others for both overall survival and progression-free survival in advanced pancreatic ductal adenocarcinoma patients treated with first-stage chemotherapy [25]. Liu X et al. reported that SII was more sensitive and specific than NLR and PLR in predicting acute pancreatitis severity and in differentiating AP patients into two groups of moderate and severe according to the Atlanta classification of acute pancreatitis. In that study, SII was determined to have 92.9% sensitivity and 87.7% specificity in the differentiation of moderate and severe AP [12]. In the current study, when the AP patients were separated into two groups of severe (≥3 points) and non-severe according to the Glasgow (Imrie) criteria, SII was found to have 72.73% sensitivity and 58.21% specificity in this differentiation. In addition, the SII was determined to be an independent factor for length of stay in hospital.
Conclusions
The results of this study demonstrated that the SII could be predictive in the determination of disease severity in AP patients, and was one of the independent factors in the duration of hospitalization of patients.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission
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Download attachments: 10.4328.ACAM.21511
İbrahim Halil Yasak, Mustafa Yılmaz. The relationship between systemic immune-inflammation index and length of hospitalization in acute pancreatitis. AAnn Clin Anal Med 2023;14(4):340-344
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Should we rely on electrolyte values measured by venous blood gas analysis in children with critical illness?
Sefika Bardak 1, Emel Berksoy 1, Gülşah Demir 1, Alper Çiçek 1, Şule Demir 2, Elif Yiğit 3, Pelin Elibol 4, Tuğçe Nalbant 5, Gamze Gökalp 5
1 Department of Pediatric Emergency, University of Health Sciences, Tepecik Research and Training Hospital, Izmir, 2 Department of Pediatric Emergency, Maternity and Children’s Diseases Hospital, Aydin, 3 Department of Pediatrics, University of Health Sciences, Tepecik Research and Training Hospital, Izmir, 4 Department of Pediatric Emergency, Faculty of Medicine, University of Ege, Izmir, 5 Department of Pediatric Emergency, University of Katip Çelebi, Tepecik Research and Training Hospital, Izmir, Turkey
DOI: 10.4328/ACAM.21515 Received: 2022-11-28 Accepted: 2022-12-31 Published Online: 2023-01-05 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):345-349
Corresponding Author: Emel Berksoy, Department of Pediatric Emergency, University of Health Sciences, Tepecik Research and Training Hospital, Izmir, Turkey. E-mail: emelberksoy@hotmail.com P: +90 505 252 06 55 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6831-1353
This study was approved by the Clinical Research Ethics Committee of University of Health Sciences, Tepecik Training and Research Hospital (Date: 2020-09-14, No: 2020/11-43)
Aim: In this study, we aimed to compare venous blood gas analysis and auto-analyzers for obtaining levels for sodium, potassium, and glucose in critically ill patients and to investigate the correlation between results.
Material and Methods: Sodium, potassium, and glucose values obtained by two methods simultaneously were evaluated separately for three groups’ pH status: acidosis, normal pH, and alkalosis.
Results: A total of 198 paired measurements were recruited. A statistically significant difference was found between blood gas analyzer and auto-analyzer methods in terms of sodium (136.78 ± 10.553 mmol/l; 136.78 ± 6.686 mmol/l), potassium (4.307 ± 0.881 mmol/l; 4.529 ± 0.902 mmol/l), and glucose (182.89 ± 83.39 mg/dl; 163.44 ± 99.108 mg/dl) (p < 0.05). A Bland-Altman plot of difference suggested that all agreements between venous blood gas analysis and auto-analyzer were good (the latter measure was considered the standard).
Discussion: Differences between electrolytes and glucose values obtained with both techniques vary according to the pH state.
Keywords: Biochemistry, Blood Gas Analysis, Critical Care, Electrolyte, Glucose
Introduction
Among the routine laboratory measurements in pediatric emergency departments, glucose, sodium, and potassium are the primary and necessary parameters in the management of critical patients requiring rapid intervention [1-3]. Although laboratory assessments (auto-analyzer method) are conventional and reliable, waiting for results in life-threatening situations such as shock can worsen the outcome [4]. In such cases, blood gas analysis (BGA) is an alternative method used to obtain test results in a few minutes. Utilization of direct ion-selective electrode technology with BGA offers important advantages such as evaluating acid-base status with a small blood sample, as well as providing electrolyte levels [5, 6]. Despite all these advantages, the majority of clinicians do not rely on electrolyte values determined by BGA in patient management [7, 8].
There are studies in the literature, which are mostly conducted on adult patients that evaluate the reliability of BGA in terms of sodium, potassium, and glucose measurement, but the results are inconsistent [5, 9-14]. Critical patient distinction was not made in most studies evaluating the reliability of electrolyte and glucose values obtained with BGA [8, 9, 11, 15]. Studies conducted on critically ill patients are insufficient [5,16]. For this reason, it has become necessary to compare electrolyte measurements obtained with BGA with those obtained with the auto-analyzer (AA) and to show consistency between them in critical child patient management.
Critical illness and/or critical injury are defined as diseases and/or injuries that reduce or potentially reduce oxygen delivery to the tissues [17]. Blood gas analysis is one of the first-step laboratory assessments in critically ill patients because it enables the evaluation of acid-base balance, oxygenation, and ventilation.
In this study, we aimed to compare sodium, potassium, and glucose levels obtained by venous BGA and AA in critically ill patients and to investigate the correlation between results. We also wanted to find out whether changes in acid-base balance cause any difference between the results obtained with these two techniques.
Material and Methods
A retrospective, observational, and cross-sectional study was conducted in the pediatric emergency clinic of a tertiary care hospital with 170,000 average annual admissions. Patients (0–18 years of age) with critical illness and unstable vital signs in the pediatric emergency room between January 2016 and December 2019 were included. Measurements using BGA and AA were studied with blood samples taken simultaneously from the peripheral venous route, and the results were obtained from patient files and hospital information system records. Patients with respiratory, circulatory, and/or neurological disorders and abnormal vital signs were included in the study.
Patient age, gender, admission diagnosis, venous blood gas parameters (pH, sodium, potassium, and glucose), AA measurements (sodium, potassium, and glucose), and disposition data (intensive-care-hospital inward admission, exitus, emergency observation) were recorded. Patients with incomplete data, or who had received intravenous fluid or any treatment before blood was drawn, or whose blood samples were not taken simultaneously, or whose vital signs were stable were excluded from the study.
Venous blood gas samples were taken into a heparinized injector (dry, containing 72 IU / 2 ml Lithium heparin) and studied within 2 minutes with a daily calibrated device (ABL800 FLEX; Radiometer Medical ApS, Copenhagen, Denmark) in a pediatric emergency room. All blood samples taken from critically ill patients were delivered to the pediatric emergency department laboratory within 5 minutes by the service personnel. Venous blood samples were taken into a serum separator tube and electrolyte results were obtained within 60–90 minutes via the AA (AU680; Beckman Coulter, Indianapolis, Indiana).
Simultaneous BGA and AA measurement values were evaluated separately for three groups as acidosis (pH < 7.35), normal pH (pH = 7.35–7.45), and alkalosis (pH > 7.45).
Statistical Analysis
Descriptive statistics for variables were specified as mean, standard deviation, median, minimum value, maximum value, and percentage. Homogeneity of variances, which is one of the prerequisites of parametric tests, was checked with Levene’s test, and normality assumption was evaluated with the Shapiro-Wilk test. Differences between three and more groups were compared with one-way analysis of variance and Tukey HSD [honestly significant difference] test when parametric test prerequisites were met, and the Kruskal-Wallis analysis and Bonferroni-Dunn test when not provided. The Pearson correlation coefficient was calculated for each parameter: between 0.30 and 0.70 was considered a moderate correlation, and between 0.71 and 0.99 a strong correlation. In comparison, laboratory measurement results were determined as the gold standard. The consistency between measurement techniques was evaluated with the Bland-Altman chart (mean and 95% Limits of Agreement = LoA). Data were evaluated via SPPS 20 (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.) and p < 0.05 was considered significant.
Ethical Approval
Ethics Committee approval for the study was obtained. Since our study was conducted retrospectively, informed consent was not obtained from the patients.
Results
In total, 198 children (125 males, 73 females) with a mean age of 41.06 ± 57.67 months (range: 0.2 –218.9) were recruited. Electrolyte measurement values were recorded in all patients with BGA and AA. While glucose measurements were available in all patients with an AA, measurements could only be obtained in 27 (13.6%) patients via BGA. Demographic data and clinical characteristics of the patients are shown in Table 1.
When classifying the study group according to acid-base balance, it was found that 110 (55.6%) patients were in the normal pH group, 80 (40.4%) patients were in the acidosis group, and 8 (4%) patients were in the alkalosis group.
There was a moderate correlation in terms of sodium (r = 0,59; p = 0.001) and a strong correlation in terms of potassium (r = 0.76; p = 0.001) and glucose (r = 0.88; p = 0.001) between the two measurement techniques (Tables 2, 3).
When the differences were evaluated according to pH groups, linear positive correlation was found with r values of 0.45 for sodium, 0.76 for potassium, 0.88 for glucose in the normal pH group between the two measurement techniques (p < 0.05). Linear positive correlation was found in the acidosis and alkalosis groups for both sodium and potassium (p < 0.05) (Tables 2, 3).
Tables 2, 3 also compare the mean values of all measurements by BGA and AA of all three pH groups. Sodium values determined by BGA in the acidosis group were statistically more significant other pH levels (p < 0.05). This statistical difference was not detected in the measurements examined by AA (Table 2). It was determined that the potassium measurement was not affected by different pH conditions in both measurement techniques (Table 2). While glucose levels obtained via BGA were not affected by pH levels, a statistical difference was found between all three pH groups for AA measurements (p < 0.05) (Table 3).
When evaluating the agreement between the two methods with Bland-Altman, 95% LoA was -16.6–16.6 (mean 0.0) for sodium, -1.0–1.4 (mean 0.2) for potassium and -83.7–69.8 (mean -7.0) for glucose (Figure 1).
Discussion
Rapid evaluation of electrolytes is very important in making decisions quickly, regulating fluid and medical treatments in management of critically ill children, and is often lifesaving. Blood gas analysis is one of the indispensable examinations in pediatric emergency services in management of critically ill children, especially in infants, due to its important advantages, such as working with minimal blood samples, giving fast results in electrolyte values, and not being affected by serum proteins [18, 19]. As shown in many studies, it is understood that the differences between the electrolyte values obtained from BGA and AA are due to the chemical reaction differences between these two techniques and BGA working with whole blood and AA with serum.
In the United States Clinical Laboratory Improvement Amendment (US CLIA), differences of ± 0.5 mmol/L in potassium levels, ± 4 mmol/L in sodium levels, and ± 6 mg/dL in glucose levels can be accepted with standard calibration [5, 20].
This study shows that there is a significant difference between sodium, potassium, and glucose measurements obtained with BGA and AA, including all pH groups. It is remarkable that sodium levels were found to be significantly higher with BGA than AA measurements, especially in the acidosis group. However, there are studies in the literature showing that the electrolyte levels obtained with BGA were found to be lower compared to AA [6, 16]. It is thought that this difference may be due to the dilution of additional heparin or due to heparin binding to electrolytes [5, 6]. On the other hand, we think that using a dry heparin injector causes sodium levels to be higher in BGA compared to AA. In addition, higher potassium levels in AA measurements may be due to the centrifugation of blood samples or delayed analysis.
There are studies in the literature evaluating the reliability of electrolyte and glucose levels obtained with BGA [5, 8, 9, 11, 13-15, 21-24]. However, the results of these studies vary. In the study conducted by Altunok et al. [11] in adult patients a strong correlation between sodium and potassium and a moderate correlation between glucose levels were found between these analysis methods. However, it was reported that the difference was not acceptable limits for any parameter. Similar to our study, patients were compared according to their pH status, but unlike our results, it was concluded that the measurements did not differ according to their pH status [11].
With the Bland-Altman plot, we observed a good agreement between the two measurement techniques in terms of sodium and potassium levels, since the mean difference is at acceptable levels and the scatter plots are in the agreement range.
When the agreement was evaluated according to pH groups, it was found that sodium values were better in the acidosis group and the potassium values in the alkalosis group. In terms of glucose values, it was determined that there was an agreement in the acidosis group compared to the normal pH group, with findings suggesting that the total group was not consistent. Since glucose levels can be measured in only one patient and other parameters in eight patients in the alkalosis group, we think that a clear interpretation cannot be made about compliance and reliability. While glucose level could be measured in 198 patients with laboratory measurement, glucose level could be measured in only 27 patients in BGA. Therefore, it would not be appropriate to comment on glucose levels in general and especially in the alkalosis group.
Laboratory tests are evaluated after clinical evaluation and necessary vital interventions in pediatric emergency departments. First interventions should be decided according to the clinical findings of the patient. We think it would be appropriate that verification of abnormal values in BGA with an AA confirmation should not be required if the BGA results correlate with clinical findings.
Limitations
The most important limitation of our study is that it was conducted in a single center and is retrospective. An insufficient number of patients in the alkalosis group to evaluate patients according to their pH status, as well as the low number of glucose results obtained by BGA, constitute limitations in terms of interpretation. Nevertheless, the strength of this study is that this is the first study to compare electrolytes measurements between venous BGA and AA for different pH status in a population of critically ill children. Larger population and multicenter studies investigating the reliability of measurements with BGA in the management of critically ill children are needed.
Conclusion
Our results confirm that sodium levels measured via venous BGA were statistically significantly higher in patients with acidosis, whereas potassium levels do not differ according to pH conditions in both methods. While potassium levels measured via venous BGA can be trusted, care should be exercised in critically ill patients, as sodium values may differ by pH conditions. Eventually electrolyte values should be confirmed with laboratory analysis, if possible, when sodium levels are not compatible with clinical findings.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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Sefika Bardak, Emel Berksoy, Gülşah Demir, Alper Çiçek, Şule Demir, Elif Yiğit, Pelin Elibol, Tuğçe Nalbant, Gamze Gökalp. Should we rely on electrolyte values measured by venous blood gas analysis in children with critical illness? Ann Clin Anal Med 2023;14(4):345-349
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Spine ultrasound evaluation in occult spinal dysraphism: A 5-year retrospective observation
Özlem Erdede 1, Kutlay Gür 1, Emek Uyur 2, Özden Us Özcan 3, Rabia Gönül Sezer Yamanel 1
1 Department of Pediatrics, 2 Department of Pediatric Neurology, 3 Department of Radiology, University of Health Sciences, Zeynep Kamil Maternity and Children’s Disease Training and Research Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.21520 Received: 2022-12-04 Accepted: 2023-01-20 Published Online: 2023-02-02 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):350-353
Corresponding Author: Özlem Erdede, Department of Pediatrics, University of Health Sciences, Zeynep Kamil Maternity and Children’s Disease Training and Research Hospital, 34668, Üsküdar, Istanbul, Turkey. E-mail: ozlem@erdede.com.tr P: +90 532 650 21 45 Corresponding Author ORCID ID: https://orcid.org/0000-0002-5490-5361
This study was approved by the Ethics Committee of University of Health Sciences, Zeynep Kamil Maternity and Children’s Disease Training and Research Hospital (Date: 2022-09-11, No: 121)
Aim: Spine ultrasound scans are commonly used in neonates and infants with sacral dimples to rule out associated congenital malformations. In this study, we aimed to evaluate the type and frequency of spinal dysraphisms in patients examined by superficial spine ultrasound, which is used in screening vertebral and spinal anomalies.
Material and Methods: We retrospectively reviewed the presence of suspicious lumbosacral skin manifestations and Spine ultrasound findings in our pediatric clinic over a 4-year period (June 2015-December 2019). The patients’ natal histories, comorbidities, sacral physical examination findings, and spine ultrasound scans were evaluated from the medical records.
Results: Among n=1854 spine ultrasounds, n=1708 were included in the study. On physical examination, there were 56.5% sacral dimples, 19.1% bifurcations, 18.7% sacral hair growth, 3.5% hemangiomas or discolorations, 1.5% sacral sinus, 0.5% skin tag, and 0.1% sacral asymmetry. Multiple examination findings were present in 6.3% of the patients. In spine ultrasounds, most reports had normal (90.2%) or variants of normal findings (8.5%). 7.6% (n=130) filar cysts and 0.5%(n=9) terminal ventricles were reported. The number of patients with pathological findings in spinal ultrasound results was n=23 (1.3%). Tethered cord was reported in 0.6% (n=10), syringomyelia in 0.5% (n=8), diastomyelia in 0.1% (n=2), and solid mass in 0.1% (n=2) and sacral agenesis in 1 patient.
Discussion: In healthy infants with sacral dimples, the risk of major spinal dysraphism is exceedingly minimal. Spinal ultrasonographic scanning is a simple and safe tool for patients with suspected spinal dysraphism and sacral skin findings. Clinical suspicion is still of primary importance in recognizing conditions such as tethered cord syndrome, which are rare but can contribute significantly when diagnosed early.
Keywords: Infant, Occult Spinal Dysraphism, Spine Ultrasound
Introduction
Occult Spinal Dysraphism (OSD) means incomplete closure of midline structures and anomalous improvement of the caudal cell mass at some point of embryogenesis. Its frequency varies depending on ethnicity, geography, and gender [1].
Some skin findings in the lumbosacral region may accompany OSD; these are hemangiomas, increased hair growth (hypertrichosis), skin folds (skin tag), sacral dimple, dermal sinus, subcutaneous mass, curvature in the gluteal cleft, aplasia cutis [2]. Lumbosacral cutaneous manifestations (LsCMs) are seen in 51% to 100% of children with OSDs [3,4]. The relationship between simple sacral dimples and tethered cord syndrome or other spine anomalies is not well understood. One type of OSD, tethered cord syndrome is associated with congenital malformations and some cutaneous stigmata, may cause neurological, urological, and orthopedic sequelae [5]. Examination of the child with further investigation allows to to establish whether the visual abnormalities can be completely distinguished via visual examination [6]. Before developing neurological findings in these patients, early diagnosis of OSD for early surgical intervention recognition is essential [7]. Ultrasound and magnetic resonance imaging are the preferred imaging modalities for spine examinations in newborns up to 3 months of age [8]. Ulrasound is a safe, non-invasive imaging modality that does not require sedation. It does not use radiation, and parents widely accept its results. Consequently, this procedure is well established to investigate the spinal cord and canal in pregnancy and newborns to recognize spinal abnormalities. Ultrasound imaging method is an effective screening tool for the presence of a tethered cord, with a sensitivity of 96% and a specificity of 96% [9,10].
In this study, we discuss the identification of lumbosacral cutaneous manifestations that predict OSD. We retrospectively analyzed 1854 spine ultrasounds performed in our hospital between 01 June 2015 and 30 June 2019 and evaluated 1708 cases with skin findings in terms of OSD and compared them with the literature.
Material and Methods
We reviewed 1854 cases with suspicious skin findings at the lumbar spinal region and spine ultrasounds performed in Zeynep Kamil Maternity and Child Health and Diseases Hospital retrospectively from June 2015 through December 2019. One thousand seven hundred and eight cases were included in the study and evaluated from the electronic data of the hospital. The ultrasound findings of the patients who underwent the first ultrasound within three months after their birth were analyzed. Ultrasound of the lumbar spine is generally not performed at our institutions after three months due to ossification of the posterior elements of the spine by this age.
Data collection and flowchart are presented in Figure 1.
Cases Inclusion criteria:
1. 0-3 months age
2. Suspicious skin findings in terms of OSD
3. A superficial ultrasonographic imaging of the spinal region was performed
Criteria for exclusion of cases from the study:
1. Age older than three months
2. No superficial ultrasonographic imaging of the spinal region
3. Previously diagnosed with other medical conditions such as neurological diseases, congenital abnormalities, syndromes.
4. Grossly observed anal anomalies and multiple deformities.
Gestational age, gender, and skin findings in the spinal region detected on physical examination were recorded.
After superficial ultrasonography for further examination, all patients with abnormal spine ultrasound results were referred to a pediatric neurosurgeon, who determined whether a lumbar MRI was necessary.
This retrospective chart review study involving human participants was conducted in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The local Ethics Committee approved this study (no: 121, date: November 09, 2022).
Statistical analysis
Windows-based SPSS 26.0 analysis program was used for statistical analysis. Normality of the data was examined with the Kolmogorov-Smirnov test. In the evaluation of the data, descriptive statistics were used for demographic data. Mean ± standard deviation and median (min-max values calculated for variables) were determined by measuring within the counted variables (%), and frequency values were calculated. The chi-square test was used to compare the qualitative data. p <0.05 was considered to indicate statistical significance.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
From June 2015 to December 2019, 1854 cases who applied to our hospital with the complaint of skin findings or who had suspicious skin findings during the examination were retrospectively reviewed. One hundred fifty of 1854 cases older than three months or with incorrect ultrasound requests were not included in the study. The flow diagram for enrollment was drawn in Figure 1. Of the 1708 patients included in the study, 51.1% were boys, and 48.9% were girls. The mean gestational age was 263±16.4 days, and birth weight was 3149.5 ±567.7 gr. The median age at admission was 28 (0-90) days (Table 1). The main reasons for admission were routine well-child visits (53.5% (n=909)) and hip dislocation screening (29.7% (n=505)). Only 16.7% (n=284) of the patients had active complaints. Of these complaints, 25.3% (n=72) were related to spinal dysraphism. On physical examination, there were 56.5% sacral dimples, 19.1% bifurcations, 18.7% sacral hair growth, 3.5% hemangiomas or discolorations, 1.5% sacral sinus, 0.5% skin tag, and 0.1% sacral asymmetry (Figure 1). Multiple examination findings were present in 6.3% of the patients. In spinal USGs, most reports had normal (90.2%) or a variant of normal (8.5%) findings. 7.6% (n=130) filar cysts and 0.5% (n=9) terminal ventricles were reported. The number of patients with pathological findings in spinal USG results was n=22 (1.3%). Tethered cord was reported in 0.6% (n=10), syringomyelia in 0.5% (n=8), diastomyelia in 0.1% (n=2), and solid mass in 0.1% (n=2) of patients, sacral agenesis in 1 patient. No statistical significance was found between gender (p=0.343), low birth weight (p=0.262), preterm birth (p=0.051), presence of multiple examination findings (p=0.313), and spinal pathologies. All patients (n=22) with tethered cord, syringomyelia, diastomyelia, and suspected mass were referred to neurosurgery. It was seen that 16.9% of the patients with a variant of normal findings were referred to neurosurgery.
Discussion
Although there is no consensus on imaging in the literature, it is important to determine whether even a single patient can be performed surgical correction. Although occult spinal dysraphism’s frequency varies in different studies, the fact that patients who cannot be diagnosed early may experience urological, neurological and, orthopedic sequelae and meningitis in the future shows the importance of imaging. In the lumbosacral region of an infant, a wide spectrum of cutaneous findings may be observed, with varying degrees of suspicion for OSD. In the scientific literature, 80% of patients diagnosed with tethered cord syndrome have evidence of midline cutaneous lesions over the lumbosacral spine [4,11].
Shields LB et al. reported in their study that, due to the risk of specific lumbosacral cutaneous manifestations with occult spinal dysraphism, all lumbosacral cutaneous manifestations in patients with a suspected spinal dysraphism should be investigated using a spine ultrasound [12].
Features considered high-risk for OSD include dimpling and mass in the lumbar region, large pedunculated lesions, raised hemangiomas, dermal sinus tract, subcutaneous lipoma, and caudal appendage. Low-risk features include a flat hemangioma, non-midline lesion (such as a forked gluteal cleft), coccygeal pit, or simple sacral dimple [11,13]. In our study, the most common skin finding was sacral dimple (56.5% ). Kriss et al. defined ‘atypic sacral dimples as more than 5 mm in depth and 2.5 cm in height from the anus, requiring imagining, and found the frequency of sacral dimples to be 74% in their study [14]. We saw that a spinal abnormality was detected in only 14 patients (1,2%) with sacral dimples, and referred to neurosurgery. In the literature review, the general opinion is that further investigation is unnecessary for an isolated sacral dimple. Kucera NJ et al. reported that in asymptomatic infants with an isolated sacral dimple, the risk of spinal malformations is exceedingly low. From their large cohort of asymptomatic children with simple sacral dimples, only 0.13% led to surgery [15]. Albert GW reported that sacral dimples do not indicate a spinal cord malformation and that a spine ultrasound should not be performed on neonates with simple sacral dimples. The review found that the incidence of spinal abnormalities in children with simple sacral dimples (3.4% was very close to that of children without sacral dimples (4.8%) [16]. Hypertrichosis is commonly observed with other cutaneous manifestations of OSD, which indicate an underlying spinal defect. The association of increased hair growth in the sacral region with diastematomyelia is known [17]. McGovern et al. [18] reported a hair growth rate of 4% over 216 cases, and a hair growth rate of 14% in the cases with 144 skin findings was found in a study by Henriques et al. In both studies, diastematomyelia was not accompanied by hair growth [19].
In our study, hair growth was found in 18.7 %, and 3 (0,94 %) patients had spinal abnormalities.
The presence of more than one skin finding is considered more significant in terms of OSD. In the literature, McGovern et al. have shown that OSD detection of the presence of multiple skin findings was six times more significant than a single skin finding [18].
A review of 54 cases of congenital midline lumbosacral cutaneous lesions observed by a pediatric dermatologist, detected OSD in 11 of 18 patients with two or more different skin lesions [20].
The most common complex skin manifestations are associated with sacral dimples and hair growth [2,18]. In our study, the frequency of complex skin findings was 0,31%, and the most common complex finding was sacral dimple and hair growth; none of these cases had OSD.
A spine ultrasound is a simple, inexpensive, and noninvasive screening tool for detecting OSD of the vertebrae in infants less than three months old when the bones have not yet been fully ossified [8]. A patient with an abnormal or equivocal spine, or one that was limited due to ossification of the spine, should undergo magnetic resonance imaging (MRI). The MRI is the most sensitive imaging modality for detecting osteosclerosis in infants. However, its use comes with several drawbacks: it entails the need for general anesthesia, which has its own risks and costs more than other methods; it is more difficult to obtain; availability may be limited, and infants’ heartbeats can generate motion that can complicate image acquisition [21]. Shields LB. et al. [12] recommended if a patient is younger than three months, undergo the US; if the patient is older than six months, MRI without contrast; and if a patient meets the criteria for neurosurgery, they recommend referral to pediatric neurosurgery. In our study, we reviewed the patients’ spine ultrasound findings for three months and, showed that all patients with pathological findings were referred to pediatric neurosurgery. According to Irani et al. [22] filar cysts occurred at a frequency of 11.8 %, and the short-term outcomes were not significantly different from those of normal controls. Neonatal filar cysts found isolated on lumbar ultrasound can be considered normal variants, despite the fact that little is known about how and why filar cysts exist. In our study, the incidence of filar cysts was 7.6%. However, interestingly, it was seen that 16.9% of the patients with a variety of normal findings were referred to neurosurgery. A neonatal spine ultrasound can demonstrate several spinal variants. Common spinal cord variants include ventriculus terminalis, filar cyst, thickened filum terminale and a fibrous tract from the coccyx [23]. These should be known to the sonographer and clinician not to cause unnecessary additional imaging or stress for parents or guardians.
Limitation
The limitations of this study were that it was a retrospective, single-institutional study. Secondly, we need to find out the follow-up of children with pathological USG findings. Future prospective studies should be conducted to evaluate long-term clinical outcomes. Third, because of the retrospective nature of this study, medical records were insufficient, and we could not classify the sacral dimples. Because of the retrospective nature of this study, the authors were unable to examine the children’s sacral dimples, without determining whether the sacral dimple was simple in nature or complex.
Conclusion
Although OSD is rare, it is a common disease group that causes permanent sequelae when undiagnosed. Early detection with some skin findings is possible. In this regard, an exceptionally detailed physical examination of newborn babies becomes essential. Ultrasonography is an inexpensive and noninvasive imaging method. Evaluation of patients having suspicious skin lesions with ultrasonography will guide clinicians. The risk of major spinal dysraphism is exceedingly minimal in healthy infants with sacral dimples.
Routine physical examination of the lumbar region for cutaneous manifestations of OSD is imperative to confirm prompt treatment and avoid potentially devastating repercussions.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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Levels of STING in rheumatoid arthritis
Özge Kızılırmak 1, Firdevs Ulutaş 1, Hülya Aybek 2, Veli Çobankara 1
1 Department of Internal Medicine, 2 Department of Biochemistry, Faculty of Medicine, Pamukkale University, Denizli, Turkey
DOI: 10.4328/ACAM.21526 Received: 2022-11-29 Accepted: 2023-01-20 Published Online: 2023-01-25 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):354-357
Corresponding Author: Firdevs Ulutaş, Department of Internal Medicine, Faculty of Medicine, Pamukkale University, Denizli, Turkey. E-mail: firdevsulutas1014@gmail.com P: +90 530 094 46 32 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8441-5219
This study was approved by the Ethics Committee of Pamukkale University (Date: 2016-12-27, No: 23)
Aim: STING (stimulator of Type-I Interferon genes) is a transmembrane carrier protein that is responsible for the transduction of (deoxyribonucleic acid) DNA-triggered signals. In this study, we aimed to investigate the serum level of STING and its prognostic value related to the disease activity in patients with rheumatoid arthritis (RA).
Material and Methods: We enrolled 80 patients with RA, and age-, gender- and body mass index (BMI)- matched 80 healthy individuals. Serum levels of STING were investigated using enzyme-linked immunosorbent assay kits. The SPSS (Statistical Package for the Social Sciences) program (IBM, Armonk, NY, USA) was used for statistical analysis of the data. Descriptive statistics were expressed as mean ± standard deviation or median (minimum-maximum) for discrete and continuous numerical variables, and the number of cases and (%) for categorical variables. Cross-table statistics were used to compare categorical variables (Chi-square, Fisher). Comparisons between multiple groups were made with Post Hoc Tukey analysis. Results were defined as p<0.05 statistical significance.
Results: Neutrophilia, higher values of erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) and lower hemoglobin values were detected in the RA group (Neutrophil: 4.54 ± 1.71×109/L, CRP: 1.03 ± 1.30 mg/dL, ESR: 30.27 ± 18.1 mm/h, and Hgb: 12.88 ± 1.50 g/dL; p values: 0.013, 0.001, 0.001 and 0.029, respectively). The mean level of serum STING was 3422.75 ± 398,92 pg/mL in the RA group, whereas 3548.70 ± 126,03 pg/mL in the control group. Male patients and patients with higher ESR and CRP values had higher STING levels compared with female patients, and patients with lower ESR and CRP values (p-values: 0.044, 0.006 and 0.046, respectively).
Discussion: Serum STING levels were similar in RA patients and healthy controls. Additional knowledge related to the STING pathway will be beneficial for the development of new immunotherapeutic strategies in many inflammatory diseases such as RA.
Keywords: STING, Rheumatoid Arthritis, Inflammation, Autoimmunity, Type-I Interferon
Introduction
STING (stimulator of Type-I Interferon genes) is a transmembrane carrier protein encoded by Transmembrane protein 173 (TMEM173) that plays a role in innate immunity. Human STING is 379 amino acids in length. STING is localized in the endoplasmic reticulum (ER) of numerous cell types such as macrophages and dendritic cells, as well as endothelial and epithelial cells. This ER-related signaling molecule is involved in the control of transcription of many host defense genes such as interferon (IFN) and pro-inflammatory cytokines, following the detection and recognition of cyclic dinucleotides (CDNs) or aberrant (deoxyribonucleic acid) DNA molecules in the cell cytoplasm [1]. STING has three functional domains: the cytoplasmic C-terminal tail (342-379 amino acids), the central globular domain (155-341 amino acids), and four N-terminal transmembrane motifs (1-154 amino acids) that present STING to the ER and receive signals. STING is responsible for the transduction of DNA-triggered signals.
Examples of the sources of DNA that induce the formation of CDNs include the genomes of pathogens such as Herpes simplex virus type 1 (HSV-1). In addition, some bacteria can secrete CDNs when they infect the host. Recent studies have shown that self-DNA that comes out of the nucleus of the host cell during cell division and/or as a result of DNA damage is also the potent activator of the STING pathway. It has been shown that such DNA molecules may be responsible for autoinflammatory diseases such as systemic lupus erythematosus (SLE) or Aicardi–Goiteres syndrome (AGS), or inflammation-associated cancer [2]. Many DNA viruses such as adenovirus, vaccinia virus, papillomavirus, and/or bacterial infections (such as listeria monocytogenes or mycobacterium tuberculosis) and/or parasites (malaria) have been reported to trigger STING-dependent processes. Type-I interferon (Type-I IFN) activation occurs as a result of STING overexpression and induces nuclear factor-kappa B (NF-kB) and Type-I IFN regulatory factor 3 (IRF3) [3]. In addition, there are opposite mechanisms in the body to prevent self-DNA from initiating host defense through DNA sensors. TREX1 likely inhibits the activation of STING signals by intrinsic self-DNA. DNase II has the function of preventing STING in phagocytes. These DNases are indirect negative regulators of the STING pathway, and when these DNases are defective, basal and continuous STING activity and then inflammatory diseases occur [4].
Rheumatoid arthritis is one of the autoimmune rheumatic diseases. Therefore, examining the effects of the STING pathway in autoimmune diseases may contribute to the elucidation of the etiopathogenesis of RA. In this study, we aimed to investigate serum levels of STING, and its prognostic value related to the disease activity in RA patients.
Material and Methods
Study design and Data collection
The study was designed by following local ethical rules (date: 27/12/2016 and no: 23) and the Helsinki Declarations. Written- and informed- consent form was obtained from all participants.
We enrolled 80 patients with RA who fulfilled the American College of Rheumatology (ACR) classification criteria [5], and age-, gender- and body mass index (BMI)- matched 80 healthy individuals. All patients were diagnosed by the same rheumatology team, between June 2017 and November 2017. Disease activity score 28-ESR (DAS28-ESR) was calculated as: (0.56 x √number of tender joints) + (0.28 x √number of swollen joints) + (0.70 x ESR) + (0.014 x visual pain scale) [6]. Demographic characteristics and laboratory parameters at diagnosis were noted for each participant. Venous blood samples were collected at 8.00-10.00 am after 12 hours of fasting, and all samples were centrifuged and stored at -80 degrees. Serum levels of STING were investigated using enzyme-linked immunosorbent assay (ELISA) kits.
Inclusion and Exclusion criteria
Inclusion criteria were defined as: having RA and/ or being a volunteer for the control group.
Exclusion criteria were defined as: smoking, having at least one of the following diseases such as hypertension, diabetes mellitus, coronary arterial disease, cardiac valve disease, and/ or having abnormal thyroid functions, abnormal renal and/or hepatic function tests, recent infectious disease in the last three months, having active solid organ and/or hematologic malignancies.
Statistical analysis
The Statistical Package for the Social Sciences (version 21.0 of the SPSS, IBM, Armonk, NY, USA) program was used for statistical analysis of the data in the study. Descriptive statistics were expressed as mean ± standard deviation or median (minimum-maximum) for discrete and continuous numerical variables, and number (n) of cases and (%) for categorical variables. Cross-table statistics were used to compare categorical variables (Chi-square, Fisher). Normally distributed parametric data were compared with Student’s t-test and ANOVA, and non-parametric data that did not conform to normal distribution were compared with the Mann-Whitney U and the Kruskal-Wallis tests. Comparisons between multiple groups were made with Post Hoc Tukey analysis. Results were defined as p<0.05 statistical significance.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
The mean age was 46.43 ± 12.8 years for the whole study group (distribution range: 18-67 years), and one hundred, twenty-one (n=121, 75.6%) patients were female. The vast majority of individuals in both groups were female (n=61, 76.3% in the RA group; n=60, 75% in the control group). Both groups were similar in terms of age, gender and body mass index (BMI) (p>0.05). The mean value of DAS28-ESR was 3.29 ± 0.68 among RA patients (distribution range: 2.4-4.8). Laboratory parameters at diagnosis including complete blood count, acute phase reactants and serum uric acid are shown in Table 1. As expected, neutrophilia, higher values of ESR and c-reactive protein (CRP), and lower hemoglobin values were detected in the RA group (Neutrophil: 4.54 ± 1.71×109/L, CRP: 1.03 ± 1.30 mg/dL, ESR: 30.27 ± 18.1 mm/h, and Hgb: 12.88 ± 1.50 g/dL; p values: 0.013, 0.001, 0.001 and 0.029 respectively). Twenty-six (n=26, 32.5%) RA patients had positive anti-nuclear antibody (ANA), whereas 60 (75%) RA patients with positive rheumatoid factor (RF), and 51 (63.7%) RA patients with positive anti-citrullinated protein (anti-CCP). A vast majority of patients were on treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). The three most commonly used drugs were methotrexate, glucocorticoids and antimalarials, respectively.
The mean level of serum STING was 3422.75 ± 398,92 pg/mL in the RA group, whereas 3548.70 ± 126,03 pg/mL in the control group. There was no statistical difference between the groups. Male patients and patients with higher ESR and CRP values had higher STING levels compared with female patients, and patients with lower ESR and CRP values (p-values: 0.044, 0.006, and 0.046, respectively) (Table 2). In addition, there was a positive correlation between RF positivity and serum STING levels in RA patients (r=294, p=0.008) (Table 3).
Discussion
We conducted the study to reveal the possible role of the STING pathway in the pathogenesis of RA. RA has multiple complex immunogenetic mechanisms in the underlying pathogenesis. Our data demonstrate similar levels of serum STING both of the RA patients and healthy controls. However, this does not mean that STING is not involved in the pathogenesis of RA. Recently, the main cytokine tumor necrosis factor-alpha (TNF-α) has been shown to trigger the cyclic guanosine monophosphate-AMP synthase (cGAS) related- STING pathway in RA [7]. Triptolide has also been shown as a new immunosuppressant and anti-inflammatory agent in RA. It plays a role in the down-regulation of the cGAS and STING protein and reduces the levels of proinflammatory cytokines such as interleukin-1beta (IL-1β), interleukin 6 (IL-6), and TNF-α [8].
Recent studies have shown that overactivation of the STING pathway as a result of overexpression of self-DNA molecules originating from possible necrotic or inappropriately apoptotic cells plays an important role in the pathogenesis of autoimmunity, not only in RA [9]. Many variable mutations in the innate immune signaling are also culprit factors in inflammatory vasculopathy and a variety of interferonopathies [10]. As an example, TREX1 acts as a negative regulator for STING, and TREX1 mutations have been reported to occur in inflammatory diseases such as SLE [11].
SLE is one of the most investigated autoimmune diseases in association with STING. The role of the STING pathway has been discussed by many researchers. Kato Y et al. observed a high type- I IFN activity induced by the cytosolic DNA-sensitive STING pathway in SLE patients [12]. Similarly, Wang J et al reported the hyperactive cGAS related-STING pathway in SLE patients, and they showed that type- I IFN overproduction occurs in connection with the contribution of the Interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) gene in this overactivation [13]. Konig N et al. found traces of STING mutation in 5 patients with chilblain lupus erythematosus, a rare inflammatory form of chronic cutaneous lupus erythematosus with uncertain pathogenesis, and they blamed the functional anomaly of the STING pathway in the pathogenesis of the disease [14].
The effect of the STING-dependent pathway has also been proven using specific bifunctional autoantibodies. It has been shown not only in SLE, but also in the development of ANA-mediated inflammatory arthritis. Pawaria S et al. noticed that autoreactive B cell activation could not be achieved in double-knockout (DNase II−/−, Ifnar1−/−) mice due to deficiency of Toll-like receptor 9 (TLR9) activation [15]. Similarly, Baum R et al. investigated inflammation in another study in triple knockout mice with STING or melanoma 2 (AIM2) defects. Mice with AIM2 defect induced a limited inflammatory response against accumulated endosomal self-DNA, while mice with STING defect showed regression of inflammation in the joints. Thus, the researchers showed that the cytosolic and endosomal nucleic acid-sensitive pathways are TLR7/9-dependent, and autoantibody production is disrupted in any defect, thus they play an active role in the formation of the disease [16].
In fact, the effect of the STING signaling pathway has been demonstrated not only in inflammatory processes. Baum R et al. also proved the necessity of the intact STING pathway in bone formation. Thus, researchers have demonstrated the pathogenic role of disruptions in the STING pathway in bone anomalies observed in autoimmune diseases [17]. Besides, Hartlova et al. worked with patients diagnosed with ataxia-telangiectasia (AT). AT protein kinase gene (ATM gene) is involved in the DNA repair mechanism. In the presence of a genetic defect, unrepaired DNA residues trigger type- I IFN and cause a serious increase in viral and bacterial responses, and at the same time, the DNA fragments accumulated in the cytoplasm activate the DNA-sensitive STING pathway, thereby activating the TLR-1 [18]. Liu Y et al. detected an autosomal dominant mutation in the TMEM173 gene in 6 children with infant-onset systemic and/or organ-specific inflammation and vasculopathy. Also, ESR and CRP which are indices of systemic inflammation, have also been reported to be elevated in these children who were defined as STING-associated vasculopathy with onset in infancy (SAVI) [19]. Similarly, although there was no statistically significant difference in serum STING levels between the RA group and the control group, high sedimentation rate (> 30 mm/s) and high CRP (> 0.50 mg) /dl) values were related to higher serum STING levels in our study. A statistically significant positive correlation was also found between mean serum STING levels and serum RF values in patients with RA (p=0.008, r=294). This situation may be explained by the relationship between hyper inflammation- and autoimmunity-related mechanisms and serum STING levels, as expected.
There are few limitations in thisstudy. First, the number of study groups is relatively small for cytokine and/or gene trials. Secondly, concurrent evaluation of serum STING levels and related-gene polymorphisms can provide more accurate knowledge. Also, further studies could compare more homogeneous patient groups with only differences in disease activity scores (mild or severe disease).
Conclusion
Serum STING levels were similar in RA patients and in healthy controls. Additional knowledge related to STING pathway will be beneficial for the development of new immunotherapeutic targets in many inflammatory diseases such as RA. It could be useful to compare the results of our study with the findings of future studies with larger sample groups.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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Download attachments: 10.4328.ACAM.21526
Özge Kızılırmak, Firdevs Ulutaş, Hülya Aybek, Veli Çobankara. Levels of STING in rheumatoid arthritis. Ann Clin Anal Med 2023;14(4):354-357
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Effect of implant-abutment connections with peri-implant bone defect models under removal torque force: A 3D finite element analysis
Ahu Uraz Çörekci 1, Sila Cagri Isler 2, Janset Şengül 3, Berceste Guler 4, Yücel Özdemir 5, Deniz Ozbay 2
1 Department of Periodontology, Faculty of Dentistry, Izmir Democracy University, Izmir, 2 Department of Periodontology, Faculty of Dentistry, Gazi University, Ankara, 3 Department of Periodontology, Ankara Memorial Hospital, Ankara, 4 Department of Periodontology, Faculty of Dentistry, Kütahya Health Sciences University, Kütahya, 5 Department of Private Practice, Istanbul, Turkey
DOI: 10.4328/ACAM.21527 Received: 2022-11-30 Accepted: 2023-01-05 Published Online: 2023-01-24 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):358-364
Corresponding Author: Ahu Uraz Çörekçi, Department of Periodontology, Faculty of Dentistry, Izmir Demokrasi University, Konak, Izmir, Turkey. E-mail: ahu.urazcorekci@idu.edu.tr P: +90 232 260 10 01 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6281-6855
Aim: Peri-implant complications can result in a process that includes implant removal and is related to anatomical conditions, implant design, remaining peri-implant bone and defect type, and bone quality. The aim of this study was to assess how different implant geometries and thread designs in different peri-implant bone defect types under a removal torque value could affect the stress distributions in the implants and surrounding bone employing finite element analysis (FEA).
Material and Methods: Four different designs (Type-I: external hexagonal-cylindrical; Type-II: internal hexagonal-root form; Type-III: internal conical-cylindrical; Type-IV: Internal conical-root form) placed in the maxillary and mandibular posterior region with D2 and D3 type bone with three peri-implant bone defect models or as a control, fully osseointegrated dental implants were evaluated using the 3D-FEA method. The application of a reverse torque force of 10 Ncm to implants has been examined by comparing the stress distributions of the maximum principle and the minimum principle.
Results: The stress transmitted to the cortical bone in the neck region was found to be higher than to the cancellous bone. Circular-type bone defects had an increasing trend for stress values towards the apical region. Type II and Type IV implants demonstrated the highest von Mises stress values in peri-implant defect models, especially on buccal sites.
Discussion: In the presence of horizontal and circular bone defects, the implant surface reached higher stress values in 2/3 coronal sites remarkably for the root-form implants during implant removal. Reaching high-stress values in the buccal area has marked the critical importance of buccal bone preservation during implant removal procedures.
Keywords: Dental Implants, Removal Torque, Peri-Implantitis, Finite Element Analysis, Abutment Connection
Introduction
Peri-implantitis is defined as an inflammatuar disease of functionally loaded dental implants and characterized by inflammation of the mucosa and subsequent progressive supporting bone loss that may eventually lead to a complete loss of osseointegration [1].
Implant removal may also be demonstrated if the implants are immobile, but the fixture is broken, misplaced, infected or has advanced peri-implantitis. In these cases, the implant may remain osseointegrated, and removal of the implants may cause damage to the surrounding tissues, leading to eventual loss of valuable soft and hard tissue volume [2]. Although various techniques and their combinations have been reported to explant a failed dental implant, the selection of the appropriate removal technique should be addressed based on factors including anatomical conditions, implant design, bone quality, and the amount of bone remaining around the implant [1,3]. Determination of the most appropriate minimally invasive technique is critical for preserving the available bone and gingival tissues at the site, where the implant has been removed [4].
Considering the application of optimal reverse torque force without any damage to the surrounding bone during the removal of an implant, the effect of implant geometry and thread designs in different types of peri-implant bone loss is of great clinical relevance. The distribution and stress magnitude on the implant and peri-implant bone surrounding in different clinical situations can be evaluated by means of finite element analysis (FEA), which provides comprehensive predictions of complex implant-bone system relations depending on the accuracy in modeling the implant and bone structure design [5,6].
The aim of the present study was to assess how different implant geometries and thread designs in different peri-implant bone defect types under removal torque could affect the stress distributions in the implants and surrounding bone employing FEA.
Material and Methods
Four different implant designs placed in the maxillary and mandibular posterior region with D2 and D3 type bone [7] with different types of defects or without a bone defect were evaluated using the 3D FEA method. For this purpose, a total of 32 models were obtained by creating three different peri-implant bone defect shapes around each implant and a control group without defects. Von Mises stress, maximum principle and minimum principal stress distributions formed in the cortical and cancellous bone around the implant on the implant surface by applying a 10 Ncm reverse torque force on the implants in these models were examined by FEA, and the stress distributions were compared.
The implant and implant-abutment connection designs were defined as follows:
• Implant Type I: Cylindrical body, square-thread, bone-level, external connection (external hexagon), length 10.5 mm, 4mm ø (External [Maestro] Dental Implants, BioHorizons, Birmingham, AL, USA.),
• Implant Type II: Root-form, tapered body, buttress thread, bone-level, internal connection (internal hexagon), length 10.5 mm, 3.8 mm ø (Laser-Lok Tapered Internal, BioHorizons Implant System),
• Implant type III: Cylindrical body, micro-macro V-shaped thread, bone-level, internal conical connection, length 11 mm, 4 mm ø, (Microcone, Medentika, Medentika GmbH, Hügelsheim, Germany),
• Implant type IV: Root-form, tapered body, V-shaped micro-threaded in coronal portion and macro-threaded in apical portion, bone-level, internal conical connection, length 11 mm, 4.3 mm ø, (Quattrocone, Medentika Implant System).
Four peri-implant bone defect models were determined based on the classification by Schwarz et al. (2010) [8].
• Type A: Loss of 50% of the buccal bone–vertical dehiscence (Class Ic)
• Type B: Loss of 50% -horizontal dehiscence (Class II)
• Type C: Loss of 50% peri-implant region, a circumferential component of the defect (Class Ie)
• Type D: No bone loss, completely osseointegrated.
Maxilla, mandible, and implants and their components were scanned using a smart optics scanner (Activity 880, Smart Optics, Sensortechnik GmbH, Bochum, Germany). Cone beam computerized tomography images were transferred to a 3-D reconstruction software (3D-Doctor; Able Software Corp, Lexington, MA) and were converted into Hounsfield units with the ‘Interactive Segmentation’ method to determine the bone tissue. The models were placed in the correct coordinates in 3D space in Rhinoceros 4.0 and VRMesh (VirtualGrid Inc, Bellevue City WA, USA) software and the modeling process was completed. Then, they were transferred to Algor Fempro (ALGOR, Inc. 150 Beta Drive Pittsburgh, PA 15238-2932 USA) software in stl format to make them ready for analysis.
The models were meshed with modeling software. In the meshing process, the models are formed from elements with 10 nodes (brick type) as much as possible. In the regions close to the center of structures in models, elements with fewer nodes are used to complete the structure when necessary. The vertical and narrow regions in the models, which facilitate the analysis process, were made regular by removing linear elements.
A 10 Ncm counter-clockwise force was applied to remove the implants. The material properties used in the models were homogeneous, isotropic and linear elastic. The strength capacity of the cortical bone was accepted as 121-135 MPa for maximum principle (tensile) stresses, between 167-205 MPa for minimum principle (compression) forces, and as maximum 20 MPa for cancellous bone. The amount of force required for the resistance capacities of the stress values to be obtained in the analysis of the models accepted as linear elastic was calculated with a proportional increase.
The maximum principle, minimum principle and von Mises stresses and their distributions were calculated resulting from the application of CTRT. The values obtained from these circumferential measurements were compared by determining 4 reference points (mesial, buccal, distal, lingual/palatal) around each implant and were marked as the maximum and minimum stresses.
The stress distribution was depicted into colorimetric scales in order to allow the comparison of the differences among study models.
Results
When evaluating the stress values of the Type I implant in the mandible according to the peri-implant defect types, the highest von Mises stress value was exhibited in the circular defect model in 2/3 coronal part of the implant (5.88 MPa). The highest stress value observed in the neck region for this implant type was in the buccal model as in the maxilla. Type II implant showed a markedly higher stress value in the 2/3 coronal part of the implant in the circular defect model compared to the other models (20.02 MPa). Another high-stress value was seen in the 2/3 region of the implant in horizontal defect (26.44 MPa). The highest stress values in Type III and Type IV implants were observed in circular defects in 2/3 coronal region of the implants and horizontal defects in 1/3 coronal region of the implants, respectively.
Regarding the maxilla, for all the types of implants, in the presence of a buccal defect, both in the neck and apical regions of the implant, cancellous and cortical bone, the highest stress values were observed in the palatal aspects. In the horizontal defects, the highest values were also identified in the palatinal
aspects of the neck regions for the implant surface, and cancellous and cortical bone, while in the apical region of all sites of interest, mesial aspects showed the highest stress values for Type I implant. For Type IV implant, in the horizontal and circular defects, buccal aspects showed the highest stress for all sites in the neck region and palatal aspects had the highest values in the apical region. In the control models, in the neck regions of the implant surface, cancellous and cortical bone, the highest stress values were seen in the buccal aspects. (Figure 2 and Figure 3) In both horizontal and circular type defects, the maximum stress values were observed in palatal surface of Type II implant in the apical region (20.03 MPa, and 4.76 MPa). Among all the control models, the highest stress was seen in the buccal aspect of Type IV implants in the apical region (9.33 MPa). (Table 1)
When evaluating the mandibular models, in the presence of buccal defect, the highest stress values were exhibited in the mesial aspects of implant surface, cancellous and cortical bone in the neck region, while lingual sites presented the highest values for all sites in the apical region for Type I and II implants. For the Type I implants, in horizontal defects, the highest stresses were found in the buccal and distal aspects for the neck and apical regions, respectively. Whereas the highest stresses were observed in Type II implants in the opposite areas compared to Type I implants. For the Type III implants, in both buccal and horizontal defects, lingual aspects had the highest stresses for all sites of interest. For the Type IV implants, the highest stresses were found in the mesial and lingual aspects for the neck and apical regions, respectively. The lowest stress values of the mandible were observed in the cancellous bone in the presence of horizontal defect, while it was seen in the cortical bone in the presence of circular defect (Table 2).
Discussion
High torque applications are known to cause excessive compression of bone, inhibition of microcirculation, microdamage, the spread of programmed cell death over a wider area, prolongation of the inflammatory phase, delayed healing, and peri-implant marginal bone loss [9,10]. The present study demonstrated that the bone with D3 density modeled as the upper jaw has more intense and higher stress values compared to the bone with D2 density modeled as the lower jaw. Considering the values on the implant surface and surrounding cortical and cancellous bone together, the stress transmitted to the cortical bone in the neck region was found to be higher than cancellous bone. However, in the models where the implants are in contact with both the cortical and cancellous bone, the stresses were seen to distribute more regularly, while the stress values increased much more in the models where the implants are only in contact with the cancellous bone, especially in the maxilla models with circular-type defects. Besides, in the apical region, the stresses on the surface of the Type II and Type IV implants are greater than the other areas, especially in the palatal aspects. A study has reported the stress distributions in cortical and cancellous bone caused by bone resorption progressing from the marginal area of the implants towards the apical using finite element stress analysis [11]. In parallel with the present study findings, a study has demonstrated higher stress in the cortical bone than in the trabecular bone for narrow diameter implants placed in maxillary and mandibular models and the stress concentrations were showed at the top threads in the coronal third of the implants and the cortical bone-implant interface [12]. On the other hand, Lemos et al. (2021) stated that a progressive increase in peri-implant marginal bone loss was associated with higher stress concentrations in the bone tissue in the coronal and apical regions of the implants [13]. A study has examined the effect of the stress caused by occlusal forces in the presence of horizontal bone loss at different levels on peri-implant bone using three-dimensional FEA and found that as the amount of cortical bone decreased, the stress on implant surface increased [14]. Furthermore, in cases where the horizontal bone loss is seen exceeds 25% of the implant length, it has been shown that the stress on the implant surface reaches a level that could not compensate for functional forces [14]. In our study, it was observed that in horizontal and circular bone defect models, where 50% of the implant length is lost, the stress on the implant surface reached higher values, especially in root form tapered implants.
The present study exhibited that Type II implants mostly demonstrated the highest von Mises stress values compared to the other types of implants in the presence of maxillary peri-implant defects. However, the maximum value of stress was identified for Type IV in 2/3 coronal site, which was the area containing to the first BIC, in the presence of circular peri-implant defects among all the maxillary models. Moreover, in the control model without bone loss, the greatest stress was seen for the Type IV implant at the buccal aspect in the neck area. These findings marked that root-form tapered implant body with buttress thread or V-shaped thread indicated higher stress concentrations on the implant surface and surrounding bone compared to implants having cylindrical implant body in maxilla. One explanation for this finding may be that those conical tapered implants are more stabile increasing bone-implant contact during insertion through applying pressure on the cortical bone [15,16]. A study has indicated that the conical implants exhibited higher von Mises and maximum principal stresses in the peri-implant bone tissue in non-linear groups, while in linear groups the cylindrical implants showed greater stress compared to conical implants [15]. In the present study, in the presence of a horizontal defect, it should be considered that the high stress value in the remaining bone after removal of a conical tapered implant may not have a favourable healing potential to allow immediate implant placement [17]. Furthermore, reaching high stress values in the buccal area has marked the critical importance of buccal bone preservation during implant removal procedures.
The study has reported that the continuous increase in the dimension of the thread geometry and in the BIC area was associated with higher stress magnitude in the surrounding bone [18]. In that study, the highest stress value was demonstrated for the root-form tapered implant having a double-lead V-shape thread compared with other models presenting a tapered implant with micro-thread in the collar area, reverse buttress thread in the middle area. In both the maxilla and mandible, higher stress value in cortical bone was observed for the root-form, tapered body implant with buttress thread compared to the other implant types. Implant-abutment connection design is another critical factor influencing stress distributions on the implant surface and the surrounding bone under axial, oblique, and rotational forces. It has been suggested that internal connection implants presented lower stress concentrations than external connection implants in the absence of bone loss around the implants [13]. It has also been highlighted that, since the main factor in stress transmission is considered to be loss of peri-implant bone, the effect of other influencing factors such as implant-abutment connection might be considered ineffective. This may be the reason why the loss of support around the implant compromises the stability of the implant-abutment interface, thus negating the effect of another external variable. In line with this, the present study indicated that higher stress was observed for internal-abutment connection implants compared to external connection in the models with peri-implant bone loss. On the contrary, in models without bone loss, external connection implants showed higher stresses on both the implant surface and cortical bone in the mandible with D2 bone type, but not for the models in the maxilla.
Conclusion
• Higher stress was observed for internal-abutment connection implants compared to external connection in the models with peri-implant bone loss.
• Increased high stress values in the buccal area have marked the critical importance of buccal bone preservation during implant removal procedures.
• Cortical bone can show the maximum stress in the neck region of the implants with peri-implant bone loss compared to cancellous bone under a removal torque value.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
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2. Anitua E, Piñas L, Begoña L, Alkhraisat MH. Prognosis of Dental Implants Immediately Placed in Sockets Affected by Peri-implantitis: A Retrospective Pilot Study. Int J Periodontics Restorative Dent. 2017;37(5):713-9.
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13. Lemos CAA, Verri FR, Noritomi PY, Kemmoku DT, Souza Batista VE, Cruz RS, et al. Effect of bone quality and bone loss level around internal and external connection implants: A finite element analysis study. J Prosthet Dent. 2021;125(1):137.e1-e10.
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15. Dos Santos MBF, Meloto GDO, Bacchi A, Correr-Sobrinho L. Stress distribution in cylindrical and conical implants under rotational micromovement with different boundary conditions and bone properties: 3-D FEA. Comput Methods Biomech Biomed Engin 2017;20(8):893-900.
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Ahu Uraz Çörekci, Sila Cagri Isler, Janset Şengül, Berceste Guler, Yücel Özdemir, Deniz Ozbay. Effect of implant-abutment connections with peri-implant bone defect models under removal torque force: A 3D finite element analysis. nn Clin Anal Med 2023;14(4):358-364
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Our clinical experiences in patients with de novo and secondary metastatic breast cancers
Halil İbrahim Taşcı 1, Selman Alkan 2, Alper Varman 2
1 Department of General Surgery, Karaman Training and Research Hospital, Karaman, 2 Department of General Surgery, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
DOI: 10.4328/ACAM.21541 Received: 2022-12-06 Accepted: 2023-01-20 Published Online: 2023-01-25 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):365-370
Corresponding Author: Halil İbrahim Taşcı, Department of General Surgery, Karaman Training and Research Hospital, Karaman, Turkey. E-mail: okcu6528@gmail.com P: +90 505 481 04 45 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2269-4798
This study was approved by the Clinical Research Ethics Committee of Karamanoğlu Mehmet Bey University (Date: 2022-08-31, No: 08/03)
Aim: While breast cancer may be de novo, that is, metastatic at the time of diagnosis, a local tumor at initial diagnosis may metastasize to other regions over the course of treatment and follow-up. This study aimed to reveal the clinical, pathological, and survival differences in patients with de novo metastatic and secondary metastatic breast cancer who were followed up and treated in our clinic, and to investigate factors that may have an effect on survival.
Material and Methods: The data of female patients who were diagnosed with metastatic breast cancer, treated, and followed up in our clinic between January 2000 and May 2021 were retrospectively analyzed. Patients were divided into two groups: the de novo metastatic disease group (Group 1) and the secondary metastatic disease group (Group 2). Clinical and pathological data of the groups were analyzed.
Results: Patients with de novo metastatic disease most commonly had bone metastases. But in the secondary metastatic disease group, the most common metastasis type was multiorgan metastases. The rate of triple negativity was significantly lower in Group 1. When the groups were analyzed in terms of survival, the median time was 77 ± 10.89 months in the de novo metastatic group and 66 ± 10.15 months in the secondary metastatic group (p=0.05).
Discussion: Our study demonstrated that de novo metastatic breast cancers had a better prognosis than secondary metastatic breast cancers even though they tend to metastasize early.
Keywords: Breast Cancer, De Novo, Metastasis, Survival
Introduction
Breast cancer is the most common type of cancer in women. Around 1.7 million new cases of breast cancer are diagnosed each year, and 520,000 patients die from breast cancer [1]. Moreover, the incidence of breast cancer is rising every year, and it has been predicted that the annual number of cases will reach 3.2 million by 2050 [2]. While breast cancer may be de novo, that is, metastatic at the time of diagnosis, a local tumor at initial diagnosis may metastasize to other regions over the course of treatment and follow-up [3]. Nearly 30% of node-negative patients with local breast cancer at initial diagnosis and 70% of node-positive patients develop distant metastasis during follow-up and treatment [4].
Thanks to advances in treatment methods and extensive screening programs, mortality rates of breast cancer have decreased by 25-38% [1]. However, it has been observed that screening programs implemented in a similar way for breast cancer have not significantly decreased the incidence of de novo metastatic breast cancer [5]. The prognosis and clinical course of patients with metastatic breast cancer may vary depending on patient and tumor characteristics. Although there are palliative treatment options after the occurrence of distant metastasis, it is believed that the patient loses the chance of curative treatment [4].
This study aimed to reveal clinical, pathological, and survival differences in patients with de novo metastatic and secondary metastatic breast cancer who were followed up and treated in our clinic, and to investigate factors that may have an effect on survival.
Material and Methods
This study was approved by the Karamanoğlu Mehmet Bey University Clinical Research Ethics Committee (Date: 31.08.2022, Decision No: 08/03). The data of female patients who were diagnosed with metastatic breast cancer, treated and followed up in our clinics between January 2000 and May 2021 were retrospectively analyzed. Patients were divided into two groups: the de novo metastatic disease group that included patients with metastatic disease at initial diagnosis (Group 1, n=113) and the secondary metastatic disease group that included patients who developed distant metastasis during their follow-up after the treatment of the primary tumor (Group 2, n=178). Male patients, patients with primary tumors other than breast carcinoma, those who died from causes other than breast cancer, and those who could not be regularly followed up for various reasons were not included in the study.
Demographic data, metastasizing organs, surgical and/or medical treatments, clinical and histopathological findings of the tumor, mortality rates, and overall survival of the patients who met the study criteria and were included in the study were evaluated. In terms of these data, the differences between Group 1 and Group 2 and the variables that may have an effect on overall survival were statistically analyzed. For calculating the follow-up times used in the analysis of the intergroup difference in survival, the follow-up period after the diagnosis was taken into account for Group 1, while the follow-up period after the development of metastatic disease was taken into account for Group 2.
Statistical Analysis
The analyses in the study were carried out using the SPSS software package version 21.0. The level of error was set at p<0.05 in all analyses. The normality of data distribution was checked using the Kolmogorov-Smirnov test. Frequency table results were given for categorical variables and descriptive measures for numerical variables (mean±standard deviation (SD) or median (min-max) in non-parametric cases). Student’s t-test or Mann-Whitney U test was used for the comparison of the two groups. The Chi-square analysis was used to test whether categorical variables were related to each other or not. Overall survival and disease-free survival were calculated using the Kaplan-Meier method. The Log-Rank test was used to evaluate whether there was a difference between the groups in terms of survival times. Risk factors that may have an effect on survival were analyzed with Cox’s proportional hazards model.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
Comparative basic demographic and clinical data of the patients included in the study are summarized in Table 1. The analysis of the data of 113 de novo metastatic and 178 secondary metastatic breast cancer patients who met the study criteria showed a mean age of 52.21±13.43 in Group 1 and 48.37±12.94 in Group 2. Tru-cut biopsy was the most commonly used biopsy technique in both groups. This was followed by excisional and fine-needle biopsy techniques, respectively. There was no statistically significant difference between the groups in terms of the biopsy techniques used (p=0.75). The most common histological type was infiltrative ductal carcinoma in 77.9% (n=88) of the patients in the de novo metastatic disease group and 81.5% (n=145) of the patients in the other group, followed by infiltrative lobular carcinoma and mixed type (has features of both infiltrative ductal and infiltrative lobular carcinoma) in both groups (Figure 1). The groups were statistically similar in terms of histopathological types (p=0.57). The histopathological features of the tumors of the groups are summarized in Table 2. The evaluation for tumor size revealed a median tumor size of 3.5 (range, 1-10) cm in Group 1 and 3.5 (range, 0.8-12) cm in Group 2 (p=0.52). T stage of 40 (35.4%) patients and N stage of 53 (46.9%) patients in the de novo metastatic disease group could not be evaluated. In Group 1, the most common T stage was T2 (26.5%), followed by T4 (15.9%), T3 (13.3%), and T1 (8.8%) tumors, while in Group 2, 97 (54.5%) patients had T2 tumors, followed by T3 (28.7%), T1 (8.4%), and T4 (6.2%) tumors. In terms of lymph node involvement, the most common N stage in Group 1 was N3 (17.7%), followed by N1 (16.8%), N2 (10.6%), and N0 (8%), while the most common N stage in Group 2 was N1 (30.3%), followed by N2 (23.6%), N0 (23%) and N3 (19.7%) tumors. The comparison of the groups by sites of metastasis showed a statistically significant difference (p=0.002) (Figure 2).
The incidence of lymphovascular and perineural invasion on histopathological examination was similar in both groups (52.3% (n=34) and 38.9% (n=65), respectively, p=0.06). Seventy-four percent (n=54) of the patients in Group 1 and 58.2% (n=89) of the patients in Group 2 had grade 2 tumors (p=0.018). The groups were similar in terms of estrogen and Cerb-B2 receptor positivity (p=0.057 and p=0.44, respectively). In terms of progesterone receptor positivity, the rate of positive patients was significantly higher in Group 1 (63.9% (n=62) and 46% (n=64), respectively, p=0.007). While the groups were similar in terms of triple positivity (33% (n=32) and 23.2% (n=32), respectively, p=0.09), the rate of triple negativity was significantly lower in Group 1 (4.1% (n=4) and 15.1% (n=21), respectively, p=0.007).
Surgical and/or medical treatment methods of the patients are summarized in Table 3. Of the patients in Group 1, 45.1% (n=51) did not undergo any surgical intervention, while 49.6% (n= 56) underwent modified radical mastectomy. In Group 2, 89.3% (n=159) of the patients underwent modified radical mastectomy and 7.3% (n=13) underwent breast-conserving surgery. In terms of chemotherapy the groups had a statistically significant difference in the rates of not receiving chemotherapy and receiving palliative, adjuvant, and neoadjuvant chemotherapy (p<0.001). Furthermore, the rate of hormone therapy was statistically significantly higher in Group 2 ( p=0.04). There was no difference between the groups in terms of Herceptin treatment (p=0.42). There was a significant difference between the groups in terms of radiotherapy (p<0.001).
The median follow-up time was 27 (range, 4-92) months in the de novo metastatic disease group, while it was 54 (range, 6-240) months in Group 2. The follow-up time of Group 2 was statistically significantly longer (p<0.001). The comparison of the post-metastasis follow-up times revealed a statistically significantly longer follow-up time in the de novo metastatic disease group (27 (range 4-92) and 16 (range, 1-108) months, respectively, p<0.001). During the follow-up period, 23 (20.4%) patients in Group 1 and 44 (24.7%) in Group 2 died. Although the mortality rate was lower in Group 1, there was no statistically significant difference in mortality rates between the groups (p=0.38).
Overall survival and disease-free survival were calculated using the Kaplan-Meier method. Figure 3 illustrates the overall survival charts for both groups. In the secondary metastatic disease group, the rate of five-year disease-free survival was 89±2.4% months and the disease-free survival of 75% was 48±8.13 months. In this group, the rate of five-year overall survival was 90.5±2.3% and the overall survival of 75% was 72±8.49 months. The overall survival analysis performed by considering the post-metastasis follow-up time of the second group and the follow-up time of the first group showed a median time of 77±10.89 months in the de novo metastatic disease group and 66±10.15 months in the secondary metastatic disease group. The survival rate of 75% was attained at 62±16.12 months in Group 1 and 37±5.14 months in Group 2. Whether there was a difference between the groups in terms of overall survival was evaluated with the Log-Rank test, which showed a statistical difference between the two groups (longer overall survival in Group 1) (p=0.05).
Risk factors that may affect survival were analyzed with Cox’s proportional hazards model. Accordingly, being in Group 1 or Group 2 did not have a statistically significant effect on overall survival (p=0.054). Of other variables for which a Cox regression analysis was carried out with a single variable, factors such as age, presence of any comorbid disease, laterality, quadrant of involvement, multicentric involvement, histological type of the tumor, T stage and N stage of the tumor, histological grade, estrogen receptor positivity, progesterone receptor positivity, Cerb-B2 positivity, and having received chemotherapy, Herceptin treatment, and radiotherapy or not were found to have no effect on mortality (p>0.05). Not receiving hormonal therapy (HR=2.13, 95% CI=1.29–3.52, p=0.003) was found to be associated with increased mortality.
Discussion
Despite the more frequent use of screening methods, the incidence of de novo metastatic breast cancer is increasing day by day [6]. In spite of this increase in incidence, studies on both de novo and secondary metastatic breast cancer have shown significant improvements in the survival of patients in both groups over time thanks to new therapeutic agents and advancements in care [7].
Some studies have shown more frequent hormone receptor positivity, a higher rate of nodal involvement, and better survival outcomes in de novo metastatic breast cancers than in secondary metastatic breast cancer [1,8]. The results of our study also showed a statistically significantly higher rate of progesterone receptor positivity in the de novo metastatic disease group (p=0.007). Although the groups were similar in terms of estrogen receptor positivity and Cerb-B2 positivity (p=0.057 and p=0.44, respectively).
In addition to publications reporting similar characteristics for both patient groups in terms of prognosis independent of disease-free survival, there are also some reports suggesting better prognosis for patients with de novo metastatic disease who receive systemic chemotherapy [9,10]. Some hypotheses have been proposed regarding the better prognosis for those with de novo metastasis. One of these is that the removal of the primary tumor diagnosed in the early stage with surgery, which is performed as a step of treatment, will cause the disease to become more aggressive in case of a possible metastasis compared to those with de novo metastases [7]. Contrary to these studies, there are also publications reporting a positive effect of local surgical treatments of the primary tumor on the survival of patients with de novo stage 4 tumors [11, 12]. Another hypothesis regarding the survival difference between the groups is that drug resistance may have developed due to previous chemotherapeutic treatment in patients with recurrent disease and the treatment response may therefore be worse than in those with de novo metastasis [7].
Tumor histology has a very important role in guiding treatment and prognosis in advanced breast cancers. A study by Seltzer et al. showed a higher rate of hormone receptor and C-erb B2 positivity in patients with de novo metastatic disease compared to those with secondary metastatic disease [1]. In this way, the chance of hormonal therapy and targeted therapy, and consequently survival time of patients can be increased. In patients with secondary metastatic disease, the tumor histologically tends to be triple-negative for hormone receptors [13]. In our study, the rate of triple negativity was significantly higher in Group 2 (p=0.007). This leads to a more aggressive course of the tumor and a shorter survival time.
There are also other proposed hypotheses regarding the better prognosis of patients with de novo metastatic tumors compared to those with secondary metastases. One of these is that mutations of PTEN, a tumor suppressor gene, in patients with de novo metastatic disease do not adversely affect the prognosis of the disease, while mutations of tumors in the secondary metastatic group may affect the prognosis very adversely [14]. Furthermore, depending on the histological characteristics of the tumor, patients with de novo metastatic disease may have a more suppressed immune response, more active steroid biosynthesis, and a higher chance of hormone therapy compared to those with secondary metastases, and these tumors may be more sensitive to drugs targeting the cytoskeleton such as taxanes, which are commonly used in advanced breast cancers [10, 15].
Some prognostic factors have been identified in patients with metastatic breast cancer. A study reported that age at diagnosis, site of metastasis, and hormone receptor status were independent prognostic factors for survival after the development of the first metastatic recurrence [16]. The same study stated that these prognostic factors also apply to de novo metastatic disease [16]. In addition to these, another relevant study found that factors such as an early age during metastasis, Caucasian race, hormone receptor positivity, absence of lymphovascular invasion, low-grade tumors, and absence of internal organ metastasis were prognostic factors that positively affect survival [7]. The same study reported that disease-free survival was also an important prognostic determinant in patients with secondary metastatic disease [7]. In our study, many parameters that may have an effect on mortality were analyzed, and only not receiving hormone therapy was associated with increased mortality (HR=2.13, 95% CI=1.29–3.52, p=0.003).
Despite the frequent use of screening methods, the absence of a decline in the incidence of de novo metastatic breast cancer has been attributed to several reasons. One of these is that the tumor may metastasize at imaging intervals since it has the potential to grow very rapidly and metastasize at an early stage. Another reason is the insufficiently effective use of screening methods in societies with underdeveloped socioeconomic and educational levels [5,17].
Our study has some inevitable limitations. These include an insufficient level of evidence because of the retrospective design of the study, collection of the data from patient records and operative notes, and the lack of objective examination findings.
Conclusion
In conclusion, our study demonstrated that de novo metastatic breast cancers had a better prognosis than secondary metastatic breast cancers even though they histologically tend to metastasize early. All these results give rise to the question: “Is de novo metastatic breast cancer a different clinical manifestation?”. Studies aimed at answering this question may lead to the emergence of new treatment strategies, thus improving the prognosis of metastatic breast cancers.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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9. Lobbezoo DJ, van Kampen RJ, Voogd AC, Dercksen MW, van den Berkmortel F, Smilde TJ, et al. Prognosis of metastatic breast cancer: are there differences between patients with de novo and recurrent metastatic breast cancer? Br J Cancer. 2015;112(9):1445-1.
10. Shen T, Gao C, Zhang K, Siegal GP, Wei S. Prognostic outcomes in advanced breast cancer: the metastasis-free interval is important. Hum Pathol. 2017;70:70-6.
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The effect of Helicobacter pylori eradication treatment with amoxicillin, gemifloxacin and rabeprazole on inflammatory parameters
Guner Kilic, Gulce Ecem Kilic, Adnan Özkahraman, Sevki Konur, Ramazan Dertli, Yusuf Kayar
Department of Internal Medicine, Van Education and Research Hospital, Van, Turkey
DOI: 10.4328/ACAM.21547 Received: 2022-12-13 Accepted: 2023-02-02 Published Online: 2022-02-22 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):371-374
Corresponding Author: Guner Kilic, Department of Internal Medicine, Van Education and Research Hospital, 65100, Van, Turkey. E-mail: gunerrkilic@gmail.com P: +90 532 316 84 21 F: +90 432 217 56 00 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6799-3391
This study was approved by the Ethics Committee of Van Training and Research Hospital (Date: 2022-10-10, No: 2022/22-03)
Aim: Inflammation of the gastric mucosa caused by H. pylori is usually chronic and lasts a lifetime. This permanent colonization results in the mucosal expression of chemotactic factors that attract neutrophils and mononuclear cells. Despite the known production of proinflammatory cytokines in stomach mucosa and infiltration of inflammatory cells, there are few studies in the literature related to the effects of these and changes after treatment. The aim of this study was to evaluate patients determined with H.pylori positivity endoscopically and histopathologically, and to investigate the change in inflammatory parameters after successful eradication treatment with gemifloxacin, amoxicillin and rabeprazole.
Material and Methods: This study included 126 patients who presented with dyspeptic complaints between April 2022 and September 2022, who were determined as HP-positive from stomach tissue biopsies taken under upper gastrointestinal system (GIS) endoscopy in the Gastroenterology Endoscopy Unit, and were then determined with successful eradication following the treatment given. Demographic data (age, gender) of all the patients were documented. Blood samples were taken for analysis before the treatment and after successful HP eradication treatment.
Results: The patients consisted of 72 (57.1%) females and 54 (42.9%) males with a mean age of 40.7±13.8 years (range, 18-65 years). Statistically significant differences were determined in the comparisons of the inflammatory parameters before and after treatment in patients with successful H.pylori eradication.
Discussion: Although H.pylori seems to be a local infection, persistent inflammation results in long-term gastric and extra-gastric effects. A reduction in inflammatory parameters with successful eradication reduces the long-term effects that can develop.
Keywords: H.Pylori, Eradication, Inflammatory, Parameters
Introduction
Helicobacter pylori (H.pylori) is a gram-negative bacteria that affects more than half of the world’s population. These are pathogenic bacteria closely associated with chronic gastritis, stomach ulcers, stomach adenocancer and stomach lymphoma (mucosa-related lymphoid tissue lymphoma). H.pylori positivity has been shown to vary according to different factors such as age, geographic region, living conditions, and socioeconomic status [1, 2]. The prevalence of H.pylori infections has been estimated to be 85-95% in developing countries and approximately 30-50% in developed countries [3, 4].
The stomach mucosa inflammation caused by this bacteria is generally chronic and lasts throughout life [5]. This permanent colonization results in the mucosal expression of chemotactic factors that attract neutrophils and mononuclear cells [6, 7]. Cytokines produced from IL-8 play a role in the activation and uptake of neutrophils in the stomach mucosa, and extensive biological effects of IL-6 in mononuclear cells are known, including macrophage activation and lymphocyte differentiation [8, 9]. Despite the known production of proinflammatory cytokines in stomach mucosa and infiltration of inflammatory cells, there are few studies in the literature related to their effects and changes after treatment [8].
Although long-term gastric and extra-gastric effects of H.pylori has been shown, there are few studies showing a change in the inflammatory parameters of these effects. Therefore, the aim of this study was to evaluate patients determined with H.pylori positivity endoscopically and histopathologically, and to investigate the change in inflammatory parameters after successful eradication treatment with gemifloxacin, amoxicillin and rabeprazole.
Material and Methods
Patient Selection
This retrospective, observational study included 126 patients who presented with dyspeptic complaints between April 2022 and September 2022, who were determined as HP-positive from stomach tissue biopsies taken under upper gastrointestinal system (GIS) endoscopy in the Gastroenterology Endoscopy Unit, and were then determined with successful eradication following the treatment given. The patients were aged 18-65 years, presented with dyspeptic complaints, gave permission for upper GIS endoscopy to be performed, had not previously received any treatment for H.pylori eradication, and provided informed consent for voluntary participation in the study.
The study exclusion criteria were defined as use of antibiotics and/or proton pump inhibitors (PPI) up to one month before the study, irregular or incomplete use of the HP eradication treatment, failure of HP eradication, a history of acute or chronic disease that could affect inflammatory markers, or not willing to participate in the study. Demographic data (age, gender) of all the patients were documented. Blood samples were taken for analysis before the treatment and after successful HP eradication treatment.
Endoscopic evaluation
The endoscopic examination of the patients was made in the Endoscopy Unit of our hospital using a Fujinon EG530WR endoscopy device. Verbal and written informed consent was obtained from the patient before the endoscopy procedure. After a 6-hour fasting period, local pharyngeal xylocaine anesthesia was administered, then sedation was applied with 0.1mg/kg midazolam and 1mg/kg ketamine. During the endoscopy procedure, first the oesophagus, and then the stomach together with the duodenum were examined in detail. Biopsies were taken from the antrum and corpus for examination of the presence of HP.
Histopathological evaluation
The biopsies taken endoscopically from the antrum and corpus were sent to the pathology laboratory in 10% formaldehyde. Following routine tissue processing, the tissue samples were embedded in paraffin blocks. Sections were cut at a thickness of 5 microns, then routinely stained with hematoxylin-eosin (HE) and evaluated under light microscopy. To evaluate the presence of H.pylori, staining was applied with modified Giemsa. Biopsies were reported according to the updated Sydney classification (inflammation, activation, dysplasia, intestinal metaplasia, atrophy, and H.pylori density) [10].
Laboratory analysis
Complete blood counts [neutrophil count, lymphocyte count, platelet counts] were analyzed using an XN-1000 analyzer (USA). CRP, ferritin, and fibrinogen levels were analyzed using a Roche Hitachi Cobas 501 analyzer (Switzerland). Erythrocyte sedimentation rates were measured automatically using the Biosed 100 (Italy) device in blood sample tubes. NLR was calculated by division of neutrophil counts to lymphocyte counts. PLR was calculated by dividing platelet counts to lymphocyte counts.
HP eradication treatment
All the patients were administered Amoxicillin (1000 mg twice a day) + Gemifloxacin (320 mg once a day) + Esomeprazole (40 mg twice a day) treatment for 7 days. One month after the end of the treatment, HP eradication was evaluated in all patients by examining HP antigen in the faeces [11].
Statistical analysis
The data obtained in the study were analyzed statistically using SPSS vn. 24.0 software (Statistical Package for the Social Sciences). Continuous variables were reported as mean ± standard deviation values and categorical variables as number (n) and percentage (%). Conformity of the data to the normal distribution was assessed with a histogram and the Kolmogorov-Smirnov test. Comparisons were made using the Paired Samples t-test and the Independent Samples t-test, as appropriate. A p- value <0.05 was accepted as statistically significant.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
We evaluated 126 patients who were endoscopically and histopathologically determined to be positive for H.pylori, who were treated, and obtained successful eradication. The patients consisted of 72 (57.1%) females and 54 (42.9%) males with a mean age of 40.7±13.8 years (range, 18-65 years).
Statistically significant differences were determined in the comparisons of the inflammatory parameters before and after treatment in patients with successful H.pylori eradication. Following treatment, a statistically significant decrease was determined in the leukocyte level (7.40±1.68 vs. 6.42±1.59), neutrophil level (5.18±1.17 vs. 4.38±1.11), NLR (4.6±1.4 vs. 3.5±1.3), PLR (245.2±74.1 vs. 199.6±60.3), thrombocyte level (261.1±58.4 vs. 233.4±58.5), CRP level (2.75±0.3 vs. 1.77±0.1), sedimentation level (12.6±5.2 vs. 8.9±3.1), ferritin level (40.7±21.6 vs. 30.9±16.7) and fibrinogen level (359.7±72.7 vs. 297.6±52.2), and a statistically significant increase was determined in the lymphocyte level (1.11±0.25 vs. 1.22±0.31) (p<0.001) (Table 1).
Discussion
Although H.pylori infection can be seen in all regions of the world, colonization rates vary significantly according to geographical regions. Higher rates have been reported in developing countries than in developed countries [12]. In almost all infected individuals, chronic gastritis develops associated with long-term colonisation, but clinical findings occur in only a small proportion of colonized individuals. Variable outcomes of H. pylori infection from person-to-person are most probably due to factors such as strain-specific bacteria components, inflammatory responses that develop associated with the genetic variations of individuals or ultimately, environmental factors affecting the interaction between the pathogen and the host [13].
This infection, which affects more than half of the global population, is chronic and lives for decades in the stomach of the host, and can cause serious problems such as several changes in cells and subclinical inflammation lasting a lifetime. Pathogenesis has been associated with various virulence factors such as flagella, lipopolysaccharides (LPS), vacuolation toxin (VacA) and cytotoxin-associated gene pathogenicity island (cagPAI). In connection with these factors, changes are seen such as changes in the host gene expression, infection-related cell proliferation, loss of polarity in epithelial cells, deterioration of cell-cell links, and decreased stomach acid expression [14].
Extra-gastric findings associated with inflammation developing due to H.pylori infection have been determined in previous studies, and these findings have been shown to decrease with eradication treatment. In a study by Kohda et al., it was reported that following eradication treatment, thrombocyte counts increased significantly in patients with idiopathic thrombocytopenic purpura (ITP) [15]. Similarly, Zentilin et al. showed that with H.pylori eradication in rheumatoid arthritis patients, the disease activity significantly decreased over 2 years in the H.pylori -negative group [15]. The results of the current study showed that eradication treatment resulted in a regression of inflammation that had developed associated with H.pylori infection. Although this inflammation seems to be a local inflammation, previous studies have shown that there are extra-gastric effects [16]. Even if inflammatory parameters examined before H.pylori eradication treatment are in the normal range, reduction of long-term inflammation in the stomach prevents the development of diseases such as stomach/duodenal ulcer, adenocancer, and lymphoma.
This study had some strengths and limitations. Strong aspects of the study include that the study was prospective in design and therefore, the results were more accurate and reliable as all acute and chronic diseases which could affect inflammatory parameters were excluded, that the presence of H.pylori was investigated endoscopically and histopathologically, and a new treatment regimen was used of amoxicillin+gemifloxacin+esomeprazole. The relatively low number of patients can be considered a limitation of our study.
Conclusion
Although H.pylori seems to be a local infection, persistent inflammation results in long-term gastric and extra-gastric effects. A reduction in inflammatory parameters with successful eradication reduces the long-term effects that can develop. The treatment of amoxicillin+gemifloxacin+esomeprazole used in the patients with indication in this study was seen to effectively reduce the inflammatory parameters.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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2. Konur S, Surmeli N, Bilgili MA, Dertli R, Kayar Y. Is There a Relationship Between Helicobacter Pylori Eradication and Blood Group? Eastern Journal of Medicine. 2020;25(3):422-6.
3. Burucoa C, Axon A. Epidemiology of Helicobacter pylori infection. Helicobacter. 2017;22 (Suppl. 1). DOI: 10.1111/hel.12403.
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7. Perkins A, Tudorica DA, Amieva MR, Remington SJ, Guillemin K. Helicobacter pylori senses bleach (HOCl) as a chemoattractant using a cytosolic chemoreceptor. PLoS Biol. 2019;17(8):e3000395.
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16. Tsay FW, Hsu PI. H. pylori infection and extra-gastroduodenal diseases. J Biomed Sci. 2018;25(1):65.
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Guner Kilic, Gulce Ecem Kilic, Adnan Özkahraman, Sevki Konur, Ramazan Dertli, Yusuf Kayar. The effect of Helicobacter pylori eradication treatment with amoxicillin, gemifloxacin and rabeprazole on inflammatory parameters. Ann Clin Anal Med 2023;14(4):371-374
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The effect of circumcision on voiding functions in healthy children
Mehmet Ali Narsat 1, Rıdvan Özbek 2, Şahin Paşalı 2
1 Department of Pediatric Surgery, 2 Department of Urology, Faculty of Medicine, Kastamonu University, Kastamonu, Turkey
DOI: 10.4328/ACAM.21553 Received: 2022-12-15 Accepted: 2023-01-25 Published Online: 2023-02-02 Printed: 2023-04-01 Ann Clin Anal Med 2023;14(4):375-378
Corresponding Author: Mehmet Ali Narsat, Department of Pediatric Surgery, Faculty of Medicine, Kastamonu University, Kastamonu Training and Research Hospital, Kastamonu, Turkey. E-mail: malinarsat@gmail.com P: +90 507 716 64 71 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6496-1965
This study was approved by the Ethics Committee of Kastamonu Training and Research Hospital (Date: 2022-11-02, No: KEAK-2022-101)
Aim: In this study, we aimed to assess whether the circumcision procedure in healthy children without any clinical problems or complaints after circumcision makes a difference in voiding functions.
Material and Methods: The sample group of 90 people was formed, consisting of three groups of thirty people, whose demographic characteristics were statistically the same, were provided. The patients were divided into 3 groups of thirty people in each: those circumcised while wearing diapers, circumcised at school age, and uncircumcised patients. Urine volume, voiding time, maximum voiding rate and mean voiding rate values were recorded and evaluated.
Results: The mean urination volume in the volunteer group was 323.9±30.8 ml. The mean flow rate was 9.0±1.3 ml/s, mean Qmax was 19.1±1.3 ml/s. The mean voiding time in the volunteer group was 36.4±6.2. In the Kruskal-Wallis test, it was observed that the urination volume was different between the groups (p=0.028).
Discussion: In conclusion, circumcision, done while using a diaper, was seen to increase the voiding volume in our volunteer population. Apart from this finding, there was no significant difference in urinary function between circumcisions performed when diapers are used or in diaper-free time and uncircumcision.
Keywords: Circumcision, Pediatric, Uroflowmetry, Voiding Functions
Introduction
Circumcision is one of the most common surgeries performed on boys [1]. Circumcision may be performed for medical, traditional, religious and cultural reasons [2-4]. In some societies, the rate of male circumcision accounts for 99% [5].
As in any surgical procedure, during circumcision, complications such as early bleeding and infection may occur [1, 6, 7]. Glans injuries, urethral injuries and glans or penile amputations are among the complications reported in the literature [1, 6, 7]. One of the most common complications is urethral meatal stenosis and web formation [6].
Urethral meatal stenoses are also seen in uncircumcised patients [6]. However, their frequency increases in circumcised patients [8]. It has been shown that the frequency of meatal stenoses in patients circumcised in the neonatal period, increases even more [8].
Patients with significant meatal stenosis are admitted to the hospital with clinical complaints. In particular, urethral meatal strictures that do not change voiding thickness and pattern are often considered normal among patients. There are many studies on patients with meatal stenosis [1, 6, 8].
It is worth examining whether circumcision, which is such a commonly performed procedure, has other consequences besides the known complications. There is a limited number of studies on the changes that circumcision produces in patients without clinical complaints. Typically, these are studies on sexual functions and cosmetic outcomes or studies comparing circumcised and uncircumcised patients in the community [9–13]. An epidemiological study from Denmark furthered the view on the consequences of circumcision, concluding that the incidence of autism increases 2.3-fold in patients circumcised before the age of 2 years [14].
In the study, we did not aim to assess the complications of circumcision, we aimed to assess whether the circumcision procedure and circumcision performed with or without the use of a diaper in healthy children without any clinical problems or complaints after circumcision make a difference in voiding functions.
Material and Methods
After the approval of the local Ethics Committee (protocol code KEAK-2022-101 and date of approval: 2 November 2022), the volunteer population was informed about the study. The 620 participants who agreed to participate in the study were assessed for eligibility. Seventy-eight participants with previous urinary system surgeries, significant urinary system problems, active or recurrent complaints related to the urinary system, motor mental function disorders, whose age and weight did not fit the study group, or whose urethral meatal vertical length was less than 5 millimeters were excluded from the study. Of the remaining participants, the sample group of 90 people was formed, consisting of three groups of thirty people, whose demographic characteristics were statistically the same, so that statistically 0.5 effect power, 0.05 alpha value and 95% power were provided.
The study group consisted of 10-year-old boys with a body mass index between 19-24, who had been circumcised at least 24 months ago or were uncircumcised. The study group was standardized for age and body mass index. All patients underwent urogenital examination. Patients in the study group did not have meatal stenoses and external urethral webs with or without a clinical presentation.
The patients were divided into 3 groups of thirty people in each: those circumcised while wearing diapers, circumcised at school age, and uncircumcised patients.
The voiding patterns of the patients were measured with a uroflowmetry device under the supervision of a pediatric surgeon or a urologist. During the voiding of uncircumcised patients, the foreskin was retracted and the urethral meatus was fully opened. Urine volume (V), voiding time (t), maximum voiding rate (Qmax) and mean voiding rate (Qavr) values were recorded by making two measurements in which they urinated at least 250cc.
Statistics
IBM SPSS program version 26 was used for all statistical operations. Descriptive data were presented as numerical value ratio, percentage, mean, median, minimum, maximum and standard deviation values. The Chi-square test was used to compare qualitative variables. Since the groups were composed of thirty volunteers and normality could not be achieved for all of the variables in the Shapiro-Wilk test and histogram evaluations, the Kruskal-Wallis test was used in the analysis of quantitative data. The significance level was accepted as p<0.05 in all statistical evaluations.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
All volunteers were selected from 10-year-old children. There was no statistical difference in terms of height, weight and body mass indexes (p>0.05). The mean urination volume in the volunteer group was 323.9±30.8 ml. The mean flow rate was 9.0±1.3 ml/s, mean Qmax was 19.1±1.3 ml/s. The mean voiding time in the volunteer group was 36.4±6.2. Values according to volunteer groups are given in Table 1.
In the Kruskal Wallis Test, it was observed that the urination volume was different between the groups (p=0.028). There was no difference in Qmax, Qavr and voiding times (Table 2).
There were no volunteers with staccato flow patterns in the evaluated flow patterns. Fourteen volunteers had a flat flow pattern (Table 3).
No numerical disorder was detected in voiding functions in any of the volunteers.
Discussion
The benefits and harms of circumcision, which has been practiced since ancient times, are still being discussed in the 21st century [1,2,15]. Since these discussions have not been concluded yet, the physiological effects remain in the background. According to the recommendations made by the American Academy of Pediatrics as a result of current studies and meta-analyses, the benefits of circumcision are seen in terms of individuals and society [16].
The effects of such a frequent procedure on normal physiology have been little studied. Considering this point in our study, we excluded the complications of circumcision and evaluated voiding functions in healthy volunteers. When comparing uroflowmetry results before and after circumcision, it was observed that circumcision increased the maximum flow rate and mean flow rate [17]. However, this study evaluated the same patients before and after circumcision [17]. In our comparison with different volunteers, there was no difference in flow rates. In the study by Sancar and Egemen, in the evaluation before and after circumcision, it was not indicated whether foreskin patency was achieved [17].
We think that the difference in the pre- and post-circumcision flow is due to the measurements made after the foreskin patency was achieved in our study. Especially in young children, the foreskin in front of the urethral meatus will change the flow evaluations as a secondary obstruction.
In addition, we saw that diaper use, which we determined as the dependent variable, did not change the current values. In a study that included approximately 1700 circumcised children from our country, it was shown that the diaper did not increase the number of complications [18]. There is no significant difference between circumcisions performed at the age when diapers are used and circumcisions performed at a later age.
We detected a flat voiding pattern in 14 patients who looked completely healthy. We had no volunteers with staccato or intermittent urination. We did not find a significant difference in the distribution of patients with flat voiding patterns to groups, therefore we do not think that circumcision or circumcision time is effective in this situation. Similarly, in the meta-analysis by Morris et al., they found no difference between the circumcision procedure and voiding patterns [6].
Urine volumes were statistically different between the groups in our study. Urine volume can be affected by many factors. However, we think that the greater bladder capacity of the volunteers who were circumcised at an early age may result from the elongation in epithelialization due to the pH changes during the diaper use period.
In our study, no difference was observed between circumcised and uncircumcised patients in terms of voiding functions. Our important conclusion here is that circumcision does not have a negative effect. In addition to the positive effects known in the current literature, the absence of a negative effect that we could show reveals that there is no obstacle in terms of voiding functions in the application of circumcision [4,19–21].
The exclusion of complications and patients with urinary system problems is a limitation of our study. Contrary to the belief that circumcision should not be performed on children due to possible complications, especially advocated in anti-circumcision articles, conducting similar studies on fully randomized controlled groups will reveal stronger scientific results.
Conclusion
In conclusion, circumcision, done while using a diaper, was seen to increase the voiding volume in our volunteer population. Apart from this finding, there was no significant difference in urinary function between circumcisions performed when diapers are used or in diaper-free time and uncircumcision.
Acknowledgment
The authors thank the managers and staff of Kastamonu University and Kastamonu Training and Research Hospital.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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