Supplement 2 2021
Sonography and computed tomography in aortic aneurysms: Radiological approach to a public health problem
Mehmet Ercüment Döğen
Department of Radiology, Mersin City Training and Research Hospital, Mersin, Turkey
DOI: 10.4328/ACAM.20392 Received: 2020-11-03 Accepted: 2020-12-01 Published Online: 2020-12-13 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S126-130
Corresponding Author: Mehmet Ercüment Döğen, Mersin City Training and Research Hospital, Department of Radiology, Mersin, Turkey. E-mail: ercumentdogen@yahoo.com GSM: +90 506 5341161 P: +90 324 2251000 F: +90 324 2251017 Corresponding Author ORCID ID: https://orcid.org/0000-0002-5414-2771
Aim: Aortic aneurysms and their complications are among serious public health problems which are still subject of scientific researches. In this study, we aimed to present sonography (US) and contrast-enhanced computed tomography (CT) findings in patients who were referred to the radiology department with various complaints such as abdominal pain, severe chest pain, with the preliminary diagnosis of aortic aneurysm. We also aimed to determine the mean diameters of the aneurysms, and to demonstrate the type and frequency of their complications.
Material and Methods: Overall, 46 patients (30 males, 16 females) with a mean age of 67.6 years were included in the study. The locations and types of aneu- rysms, the types and frequency of their complications were determined, and the diameters of the aneurysms were obtained. Numerical values were given as mean values, percentages and n = n1/total number.
Results: In the present study, 2.1% (n = 1/46) of the patients had a saccular type aneurysm while 89.1% (n = 41/46) had the fusiform type aneurysms and 8.6% (n = 4/46) had aortic dissection. Of these patients, 52.1% (n = 24/46) had an abdominal aortic aneurysm (AAA), 36.9% (n = 17/46) had a thoracic aortic aneurysm (TAA), and 8.6% (n = 4/46) had aortic dissection.
Discussion: Sonography and CT scans should be the first-line methods for the diagnosis of aortic aneurysms and their complications, which are important public health problems.
Keywords: Aneurysm; Sonography; Tomography; Aorta
Introduction
An aneurysm is generally defined as a 50% increase in the normal diameter of a blood vessel [1]. Abdominal aortic aneurysm (AAA) is defined as a focal enlargement >3 cm in the sonography literature [2]. For adults aged>50 years, the aortic diameter is 12-19 mm in women and 14-21 mm in men [3]. The AAA prevalence is 1.4% in the general population; 6% in individuals aged <80 years and 6-20% in those with atherosclerotic disease [4]. It is more prevalent among men than women (male to female ratio: 5-9: 1) [1-4]. The AAA is often seen in adults aged >60 years [5]. The AAA rupture is the thirteenth most common cause of death in the United States (US) [2]. A Thoracic aortic aneurysm (TAA) can be associated with hypertension, coronary artery disease, and AAA [6-8]. The TAA is the most common vascular cause of mediastinal mass lesions [5-8]. Direct radiography, aortography, ultrasound (US), multi-slices computed tomography (CT), and magnetic resonance (MR) imaging are used in the diagnosis of AAA and TAA [9, 10]. In an aortic aneurysm, an important public health issue, the localization, diameter and complications of the aneurysm affect mortality and morbidity. In this study, we aimed to present sonography and contrast-enhanced CT scan findings in cases with AAA, and contrast-enhanced CT scan findings in cases with TAA and to detect aneurysm diameters, and type and frequency of complications in the whole study population.
Material and Methods
This retrospective, cross-sectional study included 46 cases (30 men and 16 women, mean age: 67.6 years; age range: 34-86 years) who were referred from the emergency department for initial diagnosis of thoracic/abdominal aortic aneurysm/ dissection with complaints including severe or chest pain associated with tearing sensation and/or hypotensive shock and/or findings such as pulsatile abdominal mass between 2015 and 2018. In addition, we excluded 21 cases referred with the above-mentioned complaints, findings and initial diagnoses, in which pathologies other than aortic aneurysm were detected on sonography and/or CT scan. AAA was diagnosed by sonography and CT scan in 8.6% (n=4/46), whereas by sonography alone in 6.5% (n=3/46) and only by CT scan in 36.9% of cases (n=17/46). The CT scan was used in the diagnosis of TAA in 39.1% of cases (n=18/46). The diagnosis of aortic dissection was made by CT scan. The sonography was performed using a 3.5-3.75 MHz convex probe. CT scans were performed with intravenous contrast material infusion. In addition to axial CT sections, multi-planar reformatted (MPR) CT images and 3-D angiographic images were reconstructed for diagnosis. The localization, types, complications and frequency of aneurysms were identified, and the mean aneurysm diameter was calculated. Numerical variables were presented as mean, percent and n=n1/total. All patients gave written informed consent before imaging studies. The study was conducted in accordance with the tenets of the Helsinki Declaration.
Results
There were saccular aneurysms in 2.1% (n=1/46) (Figure 1) and fusiform aneurysms in 89.1% (n=41/46), while aortic dissection was detected in 8.6% (n=4/46) of the patients.
Among patients with aneurysm, there was AAA in 52.1% (n=24/46) and TAA in 36.9% (n=17/46). The mean aortic diameter was 62±14 mm in AAA and 81±1.0 in TAA. Suprarenal localization and bilateral acute renal artery occlusion were detected in 2 cases (4.3%) with aortic dissection; of AAAs, 30.4% (14/46) were suprarenal. Unilateral or bilateral iliac artery involvement was observed in 13.0% (6/46) of cases with AAA. There was ascending aorta involvement alone in 23.9% (n=11/46) and ascending plus descending aorta involvement in 13.0% (n=6/46) of the cases with TAA. Mural thrombus at varying degrees was detected in all cases with AAA. Retroperitoneal bleeding and intraperitoneal fluid due to extravasation/rupture were observed as a complication in 8.6% (4/46) of AAA cases. Aortocaval fistula was detected in 2.1% (n=1/46) and pleural fluid in 2.1% (1/46) (Figure 2) of patients.
Among the cases with aortic dissection, there was DeBakey type I aortic dissection (Stanford type A) in 25% (n=1/4) (Figure 3a), DeBakey type II aortic dissection (Stanford type A) in 50% (n=2/4) (Figure 3b) and DeBakey type III aortic dissection (Stanford type B) in 25% (n=1/4) (Figure 3c). Pericardial tamponade and bilateral pleural fluid were observed in one of the cases with (Stanford type A) DeBakey type II dissection, whereas right aortic arc in the other. In (Stanford type A) DeBakey type III dissection, it was seen that the left renal artery originated from the aortic lumen, while the right renal artery from the pseudo-lumen.
Discussion
Atherosclerosis is the most common etiological factor in the development of aortic aneurysms (73-90%) [4]. In true aneurysms, permanent dilatation is observed, involving all layers with an intact vessel wall [3]. Fusiform aneurysm is the most common form (80%) where dilatation surrounds the aorta, while aneurismal dilatation is observed at one site of the aortic wall in the saccular aneurysm [1-3]. In this study, aneurysms wereclassifiedasfusiformin97.6%andsaccularin2.3%of the cases.
The growth rate in aortic aneurysms with a diameter of 3-6 cm is 3.9 mm per year [2, 3]. Bincari et al. found that the mean growth rate in aneurysms with a diameter of 25-40 mm was 2.2 mm per year after 10 years of sonographic follow-up in 41 patients with small AAA [4].
The AAAs can be seen with visceral and renal artery aneurysms, isolated iliac and femoral artery aneurysms, Celiac trunk/ superior mesenteric artery occlusion, renal artery stenosis, inferior mesenteric artery occlusion and lumbar artery occlusion at varying proportions [11]. Thus, radiological evaluations should clarify whether there is an involvement in the above- mentioned arteries, or whether involvement is infra-renal or suprarenal regarding aortic clamping; and left renal vein trajectory (whether retroaortic or not).
Infra-renal involvement is observed in 91-95% of AAAs, 66- 70 of which extend to the iliac arteries [7-12]. In this study, 82.3% of AAAs were infra-renal, which is in agreement with the literature. However, it was found that the iliac artery extension rate (35.2%) was inconsistent with the literature. As a complication, retroperitoneal bleeding and intraperitoneal fluid due to extravasation/rupture were observed in 8.6% of cases with AAA. In addition, rare complications of aortocaval fistula and pleural rupture were successfully demonstrated by CT scan. In AAAs, the increased size of the areas limited by mural calcifications on direct radiographs can provide information about the size of the lesion. In eligible patients, the accuracy rate for measurement of aneurysm size using sonography is above 98% [6, 13]. Sonography is a choice of the imaging modality to monitor an increase in AAA size since it is an inexpensive, readily available and non-invasive tool. However, sonographic images are suboptimal in obese patients and those with excessive intra-abdominal gas. Sonography cannot show periaortic disease reliably; in addition, it is unable to detect proximal and distal extensions of the aneurysm in all patients. Thus, sonography cannot provide the information required for the preoperative assessment in patients undergoing elective aneurysm repair, although it may be helpful in acute settings [14]. Moreover, due to availability of multi-slices CT scan within seconds, contrast-enhanced CT scan, which can provide detailed information without data loss regarding all complications and extensions of aneurysms, has become the first choice without wasting time for sonography in emergency settings. However, sonography remains to be an imaging modality that can be applied rapidly, when needed, in centers having problems with the rapid use and interpretation of CT scans with appropriate specifications. In a study on cases with AAA, Vardulaki et al. reported that sonographic screening and periodical sonography assessment could decrease AAA-related mortality by 21% at 10- year follow-up [6]. The authors suggested that abdominal aortic diameter>60 mm, an increase by >10 mm per year in aneurysm diameter, and iliac artery aneurysm development (diameter≥30 mm) are sufficient for elective surgery, while abdominal aortic aneurysm diameter of 30-44 mm requires annual rescreening, and 45-59 mm requires rescreening at intervals of 3 months. Bianca et al. reported that the growth rate is low in small AAAs and that these aneurysms are occasionally life-threatening, emphasizing the importance of continuous sonographic monitoring [5]. In a case series of 101 AAA patients, Candio et al. performed sonographic screening before elective surgery and reported that there were slight differences between aneurysm diameter measured with sonography and those measured during surgery (0.5 cm on average); sonography accurately detected supra-, juxta- and infra-renal localizations; most iliac artery aneurysms could be demonstrated by sonography, suggesting that sonography is reliable for the preoperative assessment of AAA, and CT scan is indicated when juxta-renal or suprarenal aneurysms are suspected on sonography or when sonography is inconclusive. Based on sonographic data in our study, we think that sonography is not as helpful as suggested in the above-mentioned studies, and the finding that only 60% of cases with a retroaortic left renal vein can be detected with sonography alone reveals the need for preoperative contrast- enhanced CT. Since it is extremely important to demonstrate vascular variants such as retroaortic left renal vein or other abnormalities before AAA surgery in order to prevent bleeding during aortic surgery [8].
DSA, aortography, can be used in the diagnosis of AAA and TAA. However, the overall aneurysm diameter can be underestimated on aortography, since only the intact lumen can be observed on aortography. In addition, a false-negative result is possible if the pseudo-lumen is thrombosed or if the intimal flap is observed as non-phase [15-17]. Most aneurysms harbor thrombus. Aortography is an invasive, expensive modality requiring substantial amounts of contrast-material infusion [1, 18]. Currently, CT plus CTA provides the vast majority of the data that can be obtained with aortography, and additional data regarding surrounding tissues and complications due to its cross-sectional nature. Thus, aortography for aneurysm is rather performed in the context of therapeutic interventions such as endovascular stent-graft procedures today [9, 19].
MR imaging and MR angiography are used to diagnose aneurysms at all levels of the aorta with high sensitivity and specificity. Since contrast-enhanced CT scans provided all the data required for preoperative assessment and follow-up in our study, no MR imaging or MR angiography was performed in the emergency settings.
Hypertension is the most important risk factor for the onset of aortic dissection (60-90%) [3]. A dissection may accompany an aneurysm, or aorta with near-normal size can be observed in AAA and TAA. Aortic dissection develops within fusiform aneurysm in 28% of cases, and no dissection occurs in aneurysm with diameter <5 cm [1-3]. Major complications include aortic rupture, mesenteric ischemia or infarction, acute renal failure due to renal artery occlusion, and lower extremity ischemia in abdominal aortic dissection [19]. Anatomically, thoracic aortic dissection is classified using two classification systems, namely
DeBakey and Stanford. In the DeBakey system, dissection is classified into three types. Both the ascending and descending aorta are involved in DeBakey type I, while ascending aorta alone is involved in DeBakey type II, and descending aorta alone in DeBakey type III [9-14]. In the Stanford system, dissection is classified into two types. In Stanford type A, only the ascending aorta and only the first 4 cm of the aortic knob are involved. Seventy percent of dissections are of type A, which has a higher mortality due to the risk for tamponade, acute aortic failure, and dissection of coronary arteries or brachiocephalic arteries [9, 4]. The Stanford type B dissection begins from the distal to the origin or left subclavian artery and involves the descending aorta but not the ascending aorta [9, 14]. These have a more benign course as they do not involve aortic branches [9]. In our study, one of the cases with dissection was classified as DeBakey type I (Stanford type A), while two were classified as DeBakey type II (Stanford type A), and one case as DeBakey type III (Stanford type B). Pericardial tamponade and bilateral pleural fluid were detected in one case with DeBakey type II (Stanford type A) aortic dissection, while right aortic arc in another. In the patient with DeBakey type III (Stanford type A) dissection, it was shown that the left renal artery originated from the aortic lumen, while the right renal artery from the pseudo-lumen,
In our study, major limitation is the lack of long-term follow-up data. We could not monitor the annual growth rate. Another limitation is the small sample size. Although we thought that sonography should be performed following CT scans in all cases for comparison, it was not possible due to the clinical presentations of the cases and emergency settings. However, our data were beneficial regarding whether sonography or CT scan can be used preferentially, indicating the diagnostic importance and priority of CT scan.
Conclusions
Sonography and CT are choices of imaging modality in the diagnosis of aortic aneurysms and complications, which are important public health issues, particularly in the emergency settings.
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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Opinions and attitudes of the local people towards family planning: Nyala/Sudan example
Metin Ocak 1, 3, Elif Esra Özmen 2, 3
1 Department of Emergency Medicine, Gazi State Hospital Emergency Clinic, Samsun, Turkey, 2 Department of Oral and Maxillofasial Surgery, Kahramanmaraş Oral and Dental Health Hospital, Kahramanmaraş, Turkey, 3 Nyala Sudan-Turkish Training and Research Hospital, Nyala, Sudan
DOI: 10.4328/ACAM.20396 Received: 2020-11-10 Accepted: 2020-12-09 Published Online: 2020-12-20 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S131-137
Corresponding Author: Metin Ocak, Samsun Gazi State Hospital Emergency Clinic, Samsun, Turkey. E-mail: mdmocak@gmail.com P: +90 5061255010 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9978-0216
Aim: Family planning (FP) is an application that enables individuals to avoid unplanned pregnancy, arrange the time between pregnancies, and have a baby anytime they want and the childless individuals to have a baby. The purpose of the study is to identify the opinions and attitudes of married male and females in the Nyala region in Sudan towards FP methods and shed light on the actions to be taken on this matter.
Material and Methods: This cross-sectional, analytical questionnaire study was conducted on married males and females in the Nyala region in Sudan.
Results: Two hundred and nine people in total participated in the study. In the study, there were 168 people (80.38%) who think that family planning is neces- sary. The reasons that are mostly stated for this (132 people 79.04%) are economic. Thirty-nine (95.12%) of those who do not believe in the necessity of family planning stated their religious belief as the reason. There were 120 people (57.42%) in the study that utilize family planning.
Discussion: It is concluded that males and females in the Nyala region have insufficient knowledge about modern FP methods, and the utilization rate of FP methods is too low.
Keywords: Family health; Public health; Family planning; Contraception; Women’s health
Introduction
Family planning (FP) is an application that enables individuals to avoid unplanned pregnancy, arrange the time between pregnancies, and have a baby anytime they want, and childless individuals to have a baby. FP methods prevent superfecundity, which affects maternal and infant health negatively and contribute significantly to the protection and improvement of community health as well as maternal and child health [1]. As rapid population growth negatively affects the national economy, FP also contributes to this field [2]. Postpartum family planning also helps prevent short interbirth intervals, high-risk and unwanted pregnancies, and reduces the risk of maternal mortality. Therefore, it is regarded as a component of maternal health [3].
Individuals’ knowledge about FP methods and the accessibility to FP methods have a significant influence on their decision as to whether they use contraception methods and their choice of method. In developing countries, high birth rate is the leading cause of maternal mortality [4]. Thus, the provision of FP services efficiently contributes to both maternal and child health and community health [5,6].
Previous study has found that 62% of women of childbearing age use contraception methods. Although the use of contraceptives is pretty common, it has been reported that 49% of all pregnancies in the United States of America in 2001 were unwanted pregnancies and 42% of those pregnancies were terminated by means of abortion, which is one of the most common surgical procedures among women of childbearing age in the USA [7]. Likewise, a recent CDC (Center for Disease Control and Prevention) report indicates that 64.9% of women of childbearing age use contraceptives [8].
In developing countries, around 137 million women who want to avoid pregnancy do not use any family planning method. Around 80 million out of 210 million pregnancies every year are unplanned. Around 42 million pregnant women want to terminate their unplanned pregnancy. In Sudan, the contraceptive prevalence rate (CPR) is 7.7%. The reasons behind this low prevalence rate are low admission rate, failure to access FP services and fear of the side effects of FP methods [9].
According to the data of Sudan Statistical Institution (Central Bureau of Statistics) for the year 2018, the population of Sudan is 39,280,000 and 3,583,000 of the population lives in South Darfur state, the capital of which is Nyala. Also, there are 955,000 women of childbearing age (ages 15-49) in South Darfur state. The literacy rate of males in the region is 80%, and the literacy rate of females is 53%. The mortality rate of children under the age of 5 is 71.9/1000, the mortality rate of the babies is 52.6/1000. The fertility rate in the region was reported to be 6.9 (available at: http://cbs.gov.sd// resources/uploads/files/ ). According to the Sudan Household Health Survey (Federal Ministry of Health, Central Bureau of Statistics. Sudan Household Health Survey. Khartoum; 2010), the Maternal Mortality Rate (MMR) is about 750 per 100,000 Sudanese population. In addition, the annual income per capita is 2370 American Dollars according to the data of the World Health Organization. According to the same data, in Sudan, annual health care spending per capita is 283 American Dollars. The health care spending in Sudan constitutes 8.4% of gross national income (available at: https://www.who.int/countries/ sdn/en/).
Family planning services in Sudan started in 1965 and were included in Basic Health System in 1985; nevertheless, the utilization rate of these services in 2012 is still below 9%, which is the lowest level in the Eastern Mediterranean Region (EMR). The reduction of MMR for some countries in EMR, such as Sudan, is still below 25% [10]. Considering all these sociodemographic and health data of Sudan, learning and using FP methods are crucial. For healthcare professionals to be able to provide an efficient FP service, individuals’ utilization rate of and beliefs on FP methods must be determined and quality education and consultancy services that they need to develop a positive attitude towards the use of FP methods must be provided.
This study aims to identify the opinions and attitudes of married males and females in the Nyala region in Sudan towards FP methods and to shed light on the actions to be taken in this regard.
Material and Methods
This cross-sectional analytical questionnaire study was conducted on married males and females in the Nyala region in Sudan. A total of 209 people participated in the study. First, or the study, the authors prepared a questionnaire consisting of 8 questions, which also contains the socio-economic and demographical data of the participants. Then, this questionnaire was translated into Arabic by translators who know Turkish and Arabic. Participants were randomly chosen out of the patients and patient relatives who applied to Nyala Sudan-Turkish Training and Research Hospital. The participants/their spouses who are of childbearing age were included in the study. With the help of translators, the study was explained to the participants in clear and understandable language, and those who agreed to participate in the study were asked to fill in the questionnaire upon their approval. The data were translated into Turkish by the translators after the questionnaires were filled in. The permissions necessary for this study were obtained from the Nyala Sudan-Turkish Training and Research Hospital. The expenses (Translation fee, stationery expenses, etc.) for the study were covered by the researchers.
The data was uploaded to Microsoft Excel 2016 and statistical analyses were performed by means of the program SPSS version 17.0. The conformity of the variables to the normal distribution was analyzed using histogram charts and the Kolmogorov- Smirnov test. Mean and standard deviation, and median values were used in the presentation of descriptive analyses. Categorical variables were compared using Pearson’s Chi- square Test. The Mann-Whitney U test was used for evaluation of nonnormal (nonparametric) variables between two groups; The Kruskal-Wallis Test was used for evaluation of them among more than two groups. Spearman’ Correlation Test was utilized in the analysis of the measurable data. The cases with p-value below 0.05 were considered statistically significant results.
Results
A total of 209 participants participated in the study; 102 (%48.8) were male and 107(%51.2) were female. Educational status of the participants was as follows orphanage (4.31%), primary school (57.89%), high school (57.89%) and university (10.53%). It was determined that 78.95% of the participants, had economic status below the average, 18.66%, had average economic status and 2.4% above the average. Among the participants, 44.98% (n=94) wanted more than 6 children, while only 30.14% (n=63) of them wanted less than 5 children. The mean age of the participants was 36.81 (±8.62); the mean marriage period was 9.44 (±7.19) years. The mean number of children of the participants was 5.11 (±3.57); the mean number of their siblings was 6.58 (±6.37).
There were 168 people (80.38%) who believed in the necessity of family planning. The reasons that are mostly stated for this (132 (79.04%) people) are economic. Thirty-nine (95.12%) of those who don’t believe in the necessity of family planning, stated their religious belief for this. Twenty-nine (70.73%) of those who do not believe in the necessity of family planning stated that they made this decision based on their opinions. There were 120 people (57.42%) who utilize family planning. There were 66 people who prefer long-term breastfeeding as a method of family planning and 104 people who prefer safe period follow-up. Two hundred and three people think that the coil reduces sexual intercourse; 206 people think that the males who had tubal ligation surgery do not receive sexual pleasure; 201 people think that the females who had tubal ligation surgery do not receive sexual pleasure; 200 people think that use of family planning method by unmarried people does not make sense; 23 people think that birth control techniques reduce virility; 199 people think that AIDS can be reduced by birth control techniques; 202 people think that cervical and penile cancer can be prevented by birth control techniques (Table 1). One hundred sixty-six people (79.43%) think that the family planning apparatus and mentality protect people from infections; 31 people (14.83%) think that they protect from unhealthy pregnancies. Those who want more than six children are older than the others (p<0,001).
There is a linear correlation between the age, marriage period, number of spouses, number of pregnancies, and number of children of the participants (p<0.001, r=0.764; p<0.001, r=0.522; p<0.001, r=0.640; p<0.001, r=0.618).
The number of males who get a college education is lower than that of females. The number of males who believe that family planning is necessary is lower than that of females. The utilization rate of family planning methods is lower in males compared to females. The number of males who do not use any of contraception, such as contraceptive pills, tubal ligation, and RIA method, is higher than that of females (Table 2).
Those who utilize family planning methods have fewer children (Table 3). Those who have heard about the long-term breastfeeding method and do not use it have more children than those who use it continuously (p=0.013). Additionally, those who heard of the safe period follow-up method and do not use it have more children than those who use it continuously (p<0.001). There was no statistical difference between the number of children among those who have never heard of other family planning methods, those who have heard but did not apply them, those who used them in the past, and those who currently use them (p>0.005).
The rate of people who are university graduates and whose economic condition is below average was lower than that of others (p<0.001). The rate of people who are primary education graduates and want to have more than six children was higher than that of others (p<0.001). The rate of people who consider family planning necessary because of economic reasons was higher than that of people who graduated from orphanage (p=0.023). The rate of people who are university graduates and do not consider family planning necessary because of their religious beliefs was lower than that of others (p<0.001). The rate of people who graduated from orphanage and utilize family planning methods was the highest among others (p<0.001). The rate of people whose economic condition is above average and want to have equal numbers of boys and girls was lower than that of others (p<0.001). The rate of people whose economic condition was below average and who utilize family planning methods was lower than that of others (p<0.001). The rate of people who utilize family planning methods among those who believe that family planning is necessary was higher than that of others (p<0.001). The rate of people who continuously use long-term breastfeeding and safe period follow-up methods among those who believe that family planning is necessary was lower than that of people who do not believe in the necessity of family planning (p<0.001).
Discussion
The study shows that only 2.87% (n=6) of the males and females who participated in the study use modern contraception methods, 54.5% (n=114) use traditional methods. This rate is far below the world average. According to the data of WHO for the year 2019, 44% of women around the world use modern contraception methods, while only 4% of women use traditional methods ( available at: https://www.un.org/ en/development/desa/population/publications/pdf/family/ ContraceptiveUseByMethodDataBooklet2019.pdf). Although many previous studies have reported that around 50% of women in Sudan use modern contraception methods, the rate in this study is far too below that rate [10]. We consider that this is caused by socio-cultural, political, economic, and educational differences in Darfur state.
The utilization rate of FP methods is affected by various factors, such as geographical availability, restrictive religious and cultural norms, affordability, opinions and perceptions on FP, socio-cultural conditions, educational level, healthcare access, insufficient and poor quality FP services [11,12]. Most of the participants in this study believe in the necessity of FP (80.38%). The reasons for this are mostly stated (79.04%) as economic. A great majority (95.12%) of those who do not believe in the necessity of family planning stated their religious belief as the reason. Despite the large number of people who believe in the necessity of FP, misinformation on FP methods may be one of the reasons for the low utilization rate of FP. For example, 203 people think that coil reduces sexual intercourse; 206 people think that the males who had tubal ligation surgery do not receive sexual pleasure; 201 people think that the females who had tubal ligation surgery do nt receive sexual pleasure; 23 people think that birth control techniques reduce virility. The individuals who hold these opinions may avoid using FP methods.
Another factor that affects the decision on the use of FP services is related to the unequal balance of power between males and females. Traditionally, males generally play a significant role in the crucial decisions on the reproductive health of women. However, FP specialists assume that males are less interested in reproductive health and they mostly focus on women [13]. Therefore, there is a limited number of studies on FP in literature that deals with the attitudes and behaviors of males. One of these studies showed that most of the male students at Venda University in South Africa have negative attitudes and behaviors towards contraceptives [14]. This study may contribute to the literature as a study that analyses the attitudes and behaviors of both males and females. While 66.6% of the male participants believe in the necessity of FP, 93.4% of the female participants hold this opinion. Besides, 82.3% of the males care about their own opinions, only around 14.3 of the females care about their own opinions. The rate of people that have never heard of FP methods is rather high in both males and females. All these data indicate that there is a substantial need to enlighten the people in this region about FP and males should also be included in the process of enlightenment. A previous study in Khartoum/Sudan showed that the use of FP by women who participated in an innovative family planning intervention program has increased significantly [10]. As is known, many therapeutic health services are provided in the Darfur region with the support of the United Nations (UN). Based on this study, we hold the opinion that this region should also be supported in terms of FP services along with therapeutic services.
J.C. Caldwell and P. Caldwell reported that social culture in African countries necessitates the preservation of high fertility rates in the region. In many African societies, it is forbidden to avoid having any children. Thus, high fertility is approved by various communities and religious leaders. Age, settlement (urban or rural), education, and socio-economic status of women affect the utilization rate and choice of family planning methods [15]. In this study, 97.06% of those who do not believe in the necessity of family planning stated their religious belief as a reason. It was also found that age, marriage period, number of spouses, number of pregnancies and number of children of the participants are in linear correlation. The rate of people who want to have more than six children among primary school graduates is higher than among others. The rate of people who state their religious belief as a reason for not believing in the necessity of family planning among university graduates is lower than among others. Contrary to expectations, the utilization rate of family planning methods is the highest among orphanage graduates. The utilization rate of family planning methods is lower among those whose economic conditions are below average than among others.
The data in this study and the literature show that various factors affect the rate of FP use by people. Proper FP services must be provided; training must be provided on FP in socio- cultural and religious education; and males must also be included in all FP processes so that people in the Darfur region can use FP methods efficiently and properly. This will give rise to healthier mothers, healthier babies and thus healthier societies.
Limitations
One of the limitations of the study is that the participants were chosen only out of the patients and patients’ relatives who applied to Nyala Sudan-Turkish Training and Research Hospital. We could not reach the camps and villages in poor socio-cultural and economic conditions for security reasons.
Conclusion
It is concluded that the males and females in the Nyala region have insufficient knowledge about modern FP methods and there is a great deal of misinformation about FP methods. In addition, the study found that religious belief is highly effective in considering FP unnecessary. All these reasons, along with various factors such as socio-cultural, educational, and economic factors, etc. have led to a very low utilization rates of modern FP methods. We consider that people in this region should be supported in terms of FP services as well as therapeutic health services.
Acknowledgment
We thank associate professor of family medicine Onur Öztürk his support.
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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4. Erenel AŞ, Kavlak T, Bingöl B. Kadınların doğum sonrası altı ay sonunda aile planlaması yöntemi kullanma durumu (The status of women using family planning method at the end of six months after birth). Van Tıp Dergisi/ Van Medical Journal. 2011;18(2):68-76.
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Metin Ocak, Elif Esra Özmen. Opinions and attitudes of the local people towards family planning: Nyala/Sudan example. Ann Clin Anal Med 2021;12(Suppl 2): S131-137
Citations in Google Scholar: Google Scholar
Clinical reliability and cost analysis of using petroleum jelly creams versus water-based gels for urethral catheterization
Mehmet Caniklioğlu, Ünal Öztekin, Sercan Sarı, Volkan Selmi, Emin Gürtan, Levent Işıkay
Department of Urology, Yozgat Bozok University, Faculty of Medicine, Yozgat, Turkey
DOI: 10.4328/ACAM.20397 Received: 2020-11-11 Accepted: 2020-12-13 Published Online: 2020-12-28 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S138-141
Corresponding Author: Mehmet Caniklioğlu, Yozgat Bozok University, Faculty of Medicine, Urology Department, Atatürk Yolu, Yozgat, Turkey. E-mail: dr.mehmetcaniklioglu@gmail.com P: +90 5362915732 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2216-5677
Aim: Lubricants applied to the urethra prior to using the urethral catheter increase patient comfort and ease of operation. Different combinations of water- based lubricants are widely used in medicine. Combinations of fusidic acid and petroleum jelly creams and ointments are also used in the clinical routine for lubrication. In this study, we compared the use of a lidocaine gel (Cathejell®) and fusidic acid (Stafine®) cream containing petroleum jelly in urethral catheter- ization in terms of pain, cost and success rates.
Material and Methods: A total of 99 male patients who admitted to our clinic and were directed for urethral catheterization were included in the study. The pa- tients were divided into two groups. Group 1 consisted of 36 patients who underwent urethral catheterizations after application of a cream containing fusidic acid (Stafine® cream 15gr) to the urethral meatus. In Group 2 (n=39), urethral catheterization was performed by squeezing lidocaine gel (Cathejell® lubricant gel, 12.5 g, single-use) to the urethra. Complications, visual analog scale scores, and weight of the medication spent were recorded.
Results: While the visual analog scale score in Group 1 was 3 (0-8), this value was 1 (0-4) in Group 2. No complications were observed in any of the patients. A cost analysis revealed that while fusidic acid (Stafine®) cream brought a cost of 0.27 $ per patient, the cost of lidocaine-containing gel (Cathejell®) was seven times higher.
Discussion: Although patients feel more pain, petroleum jelly based creams are safe and more economical to use in urethral catheterization of uncomplicated patients.
Keywords: Lidocaine; Lubricants; Fusidic acid; Petroleum jelly; Urethral catheterization; Visual analog scale; Cost
Introduction
Insertion of urethral catheters is a procedure frequently performed in all hospitals. Urethral gels and creams are used to facilitate the insertion, provide ease of operation, and increase patient comfort [1]. Lubrication primarily protects the urethra from trauma and thus from the risk of development of stenosis. The use of 6 ml of lubricant in females and 11 ml in males has been shown to be sufficient for successful insertion of urethral catheters [1,2]. Although it has been reported that preventing traumas also decreases infections that may develop secondary to microtraumas and disruption of the integrity of the biofilm, information on this subject is insufficient [3–5]. Besides several procedures in urology, lubricants containing lidocaine can significantly reduce pain during the advancement of the catheter in the urethra, which is the most painful stage of urethral catheterization [6,7].
The lubricants currently offered in the market are generally in the form of water-based gels. This may be due to the fact that, unlike oil and petroleum-based lubricants, water-based gels do not interact with latex materials commonly used in medicine [8, 9]. Pure water-based gels, water-based gels with lidocaine, chlorhexidine, and lidocaine + chlorhexidine have been used in urethral catheter application for many years [12]. Apart from these, ear-nose-throat physicians have used solid petroleum jelly, water-based gels, and antibiotic-containing creams and ointments during Foley applications for epistaxis [13]. However, despite claims of some medical web pages, there is actually no data regarding the use of most of them in urology (available at: https://www.blowoutmedical.com/lubricant.html). Unfortunately, non-sterile liquids or solid petroleum jelly have been routinely used in the past and some antibiotic creams and ointments are still used now from time to time. Lidocaine-containing gels are disposable and costly. On the other hand, antibiotic ointments and creams are less costly when calculated per patient and can be used to place catheters in dozens of patients. In this study, we aimed to compare a water-based polyacrylamide gel containing lidocaine and a petroleum jelly- based cream containing fusidic acid as lubricants during urethral catheterization in terms of cost, pain, and success of the procedure. The reader should be aware of the fact that this study does not aim to compare an antibiotic with a local anesthetic. We only used routine and widespread pharmaceutical products in this study.
Material and Methods
Ethics committee approval (2017-KAEK-189_2020.05.28_05) was obtained from the local ethics committee for data screening and analysis. A total of 99 male patients who underwent urethral catheterization in our outpatient clinic between January 1 and March 31, 2020, were included in the study. In this case-control study, the patients’ data were obtained retrospectively from the outpatient records. Seventy-five patients who had indication for bladder catheterization (vesical globe, intermittent catheterization, urine tracking, bleeding) were included in the study. For standardization of the catheter diameter, only patients who underwent catheterizations with a 16F flat-tipped Foley catheter were evaluated. Group 1 consisted of 36 patients who underwent catheterization after a cream containing fusidic acid (Stafine® cream 15 g) was applied to the urethral meatus. Meanwhile, Group 2 consisted of 39 patients in whom urethral catheterization was performed by squeezing lidocaine gel (Cathejell® lubricant gel, 12.5 g single-use) to the urethra. As the waiting time is given as 5-10 minutes before the catheter insertion, the daily routine of our clinic, it is always waited for 5 minutes for the anesthetic effect of Cathejell® in. Patients with urethral stenosis, chronic catheter use, neurological disease, neurogenic bladder diagnosis, diabetic neuropathy, psychiatric illness, drug use, patients undergoing chronic pain treatment, and patients under the age of 18 years were excluded from the study. Moreover, patients in whom the initial catheterization attempt was unsuccessful and required additional manipulations were excluded from the study.
In Group 1, the used amount of Stafine® per patient was calculated after the tube ended. We divided the tubes’ total Stafine amount (15 g) to the number of patients who had undergone catheterization using that tube. The cost per patient for Group 1 was calculated by multiplication the amount per patient and the dollar ($) currency at the date on which our hospital had bought the medical devices. The cost per patient for Group 2 was taken as the cost of a single Cathejell® product on the same date mentioned above.
The presence of any complications (unsuccessful attempt, hematuria or urethrorrhagia, rupture in the urethral wall, infection, urethral stricture, allergic reactions) developed during and after the procedure was investigated. The results of the visual analog scale (VAS), which is routinely used in our clinic to assess pain after interventional procedures, were also evaluated.
Statistical analyzes in the study were performed using the SPSS Statistics for Windows, v25.0 program (IBM Corp. Released 2017. Armonk, NY). The distributions were examined with the Kolmogorov-Smirnov test. The Mann-Whitney U test was used for non-parametrically distributed data, while the Chi-square test was used for categorical data. The statistical significance was accepted as p <0.05.
Results
The mean age in Group 1 (n=36) and Group 2 (n = 39) was 70.31 ± 10.55 and 68.11 ± 13.72 years, respectively. There was no significant difference between the groups in terms of age (p = 0.52). Group 1 had significantly higher median VAS scores compared to Group 2 [3 (0-8) vs 1 (0-4), p <0.001] (Table 1).
No complications were seen in any of the patients.
The cost analysis was performed for both procedures. Outpatient clinic supply receipt records were used to calculate the cost of the material used. It was determined that Cathejell® lidocaine gel was used at a rate of 12.5 g per patient, while for Stafine® that rate was 1.66 g per patient. Based on the pricing information obtained from the hospital pharmacy, Stafine®’s cost was 0.27 $ per patient, while Cathejell®’s cost was seven- fold higher.
Discussion
Multiple studies have evaluated lubricants containing local anesthetics in terms of pain scores. Chung et al. compared the lubricants containing lignocaine with water-based lubricants and found that lignocaine lubricants resulted in better pain management [12]. On the other hand, Tanabe et al. argued that neither catheter type nor lubricant type had any effect on pain scores during urethral catheterization [13]. Due to the lack of consensus on this subject, it is suggested that the use of standard lubricants is sufficient, except for patients with a history of urethral stricture [14]. However, when it comes to pain, it is also important to use the lubricant correctly in accordance with the recommendations of the manufacturer and to give enough time for the local anesthetic to take effect [14,15].
Despite this confusion in the literature, the use of lidocaine- containing lubricants has become the standard in clinical practice [4,14]. However, some medical centers warn of potential problems with the use of these materials. First of all, some studies cautioned about the systemic effects of lidocaine (NHS, Southern Health. Urinary Catheter Care Guidelines v5 SH CP 123., 2020.). In addition, although lidocaine-containing lubricants are effective in increasing patient comfort, their disadvantage is that they are quite expensive.
The data on the role of lubricants in the development of catheter-related infections are not consistent yet [3]. Some studies have reported that chlorhexidine added to lubricants to reduce catheter-related infections may cause allergic reactions in some patients [16].
In our study, we evaluated a gel containing lidocaine and a cream containing the antibiotic fusidic acid in terms of infection, complications, and pain. None of the patients had any complications, including infection. It is known that manipulation and technique are important when inserting the catheter [3]. Although there are no studies comparing water-based gels to petroleum jelly in terms of ease of operation, it can be thought that water-based gels can provide superior processing convenience due to their thicker consistency than petroleum jelly. However, in this study, we did not evaluate ease of operation, which is a subjective parameter. In terms of infection, since fusidic acid is an antibiotic, it can be thought that it should be superior to a gel without antibiotics. However, as stated in the literature, the aseptic technique alone can give very good results [1,3]. In this study, we also used aseptic techniques and did not observe any catheter-related infections even in patients that had undergone catheterization with water-based gels.
We also found that the VAS scores of patients using fusidic acid containing Stafine® were statistically higher than those using lidocaine gel Cathejell®. Our results were in line with other studies in the literature that had emphasized the superiority of lidocaine-containing gels in terms of pain control [7,10,12]. It should not be forgotten that enough time should be given after application of lidocaine gel for this effect to occur, and the main issue in studies that did not detect differences between various lubricants in terms of pain scores is perhaps due to non-compliance with the manufacturer’s instructions for waiting times [1,13]. Although there was a significant difference in our study between those who used lidocaine gel and creams containing fusidic acid, no significant difference was observed in terms of clinical presentation of pain. Although the median VAS score in Group 1 was 3 (0-8), no significant clinical complaints were observed in the patients.
Creams containing fusidic acid also include petroleum jelly, glycerol and paraffin. Glycerol and paraffin are already included in many drugs applied to the mucosa or skin surface. On the other hand, there is no clear information on the application of petroleum jelly other than its topical use. It is mentioned in many package inserts and nursing guidelines as a suggestion that petroleum jelly should not be used in urethral catheterization (available at: https://www.nationwidechildrens.org/family- resources-education/health-wellness-and-safety-resources/ helping-hands/catheterization-self-clean-intermittent-male). However, this is due to possible damage to the Foley catheter rather than to the body [9]. In 2004, Gaspar-Sobrinho FP et al. reported that petroleum jelly caused the Foley catheter balloons to rupture, but did not cause any degeneration in latex catheters [11]. Gels for topical use such as petroleum jelly are not considered harmful when refined according to the European Union standards and when polycyclic aromatic hydrocarbons that are associated with cancer are removed from their structure [17,18]. Medical petroleum gels are produced this way and are safely used in medical practice on the skin surface and nasal mucosa [11,19].
Although the price comparison of such a study may be altered due to several factors such as the economics of the countries, production rates, taxes, supply and demand equilibrium, the bidding process of that product, etc., we showed that lidocaine containing gel is sevenfold (1.6 $ per patient) costly than petroleum jelly in our hospital. This amount might seem small per patient; however, catheterization is a procedure which is performed very often in our hospital. Therefore, the cost of catheterization soars to large amounts.
To date, there have been no studies comparing petroleum jelly with polyacrylamide water-based lubricants. In this study, we demonstrated that fusidic acid creams containing petroleum jelly can be used easily and safely in urethral catheterization. Moreover, the use of such creams reduces the cost per patient up to 7 times (Table 1).
Limitations of the study include retrospective design and lack of long-term results due to the short study period. Also, localness is an important limitation for this study.
Conclusions
In this study, we have shown that a cream containing petroleum jelly combined with medical fusidic acid can be safely applied to the urethral mucosa. They do not have a negative effect on the urinary mucosa in the early period.
Lidocaine-containing gels provide better pain control than fusidic acid creams in urethral catheterization. However, there were no pain-related significant clinical complaints in either of the groups. The use of these two lubricants in urinary catheterizations was compared for the first time, and no complications or infections were observed in any of the patients. Creams containing petroleum jelly reduce the cost per patient up to 7 times. Therefore, we believe that the use of petroleum jelly based gels in urethral catheterization of uncomplicated patients is safe and economical, although patients feel more pain.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: 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.20397
Mehmet Caniklioğlu, Ünal Öztekin, Sercan Sarı, Volkan Selmi, Emin Gürtan, Levent Işıkay. Clinical reliability and cost analysis of using petroleum jelly creams versus water-based gels for urethral catheterization. Ann Clin Anal Med 2021;12(Suppl 2): S138-141
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Percutaneous cholecystostomy for management of acute cholecystitis in severely ill patients
Oğuzhan Özdemir 1, Volkan Kızılgöz 2, Türkhun Çetin 2, Doğan Gönüllü 3
1 Department of Radiology, VM Medical Park Ankara Hospital, Ankara, 2 Department of Radiology, Kafkas University, Faculty of Medicine, Kars, 3 Department of General Surgery, Kafkas University, Faculty of Medicine, Kars, Turkey
DOI: 10.4328/ACAM.20399 Received: 2020-11-12 Accepted: 2020-12-11 Published Online: 2020-12-21 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S142-148
Corresponding Author: Volkan Kızılgöz, Kafkas University, Faculty of Medicine, Department of Radiology, Kars, Turkey. E-mail: volkankizilgoz@gmail.com P: +90 5057994013 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3450-711X
Aim: In this study, we aimed to determine the therapeutic efficacy of percutaneous cholecystostomy (PC) in critically ill patients with an APACHE II score greater than or equal to 12 in the management of acute cholecystitis (AC) compared to conservative treatment.
Material and Methods: Clinical data from January 2007 to June 2020 of 132 and 125 patients managed by PC and conservative treatment, respectively, were retrospectively analyzed. Medical records of patient demographics, comorbidities, indications for PC catheter placement, complications, alterations in labora- tory parameters (white blood cell (WBC) count, C-reactive protein (CRP) value) and APACHE II scores, and clinical outcomes during follow-up were retrieved from our hospital database for this case-control study.
Results: After PC, a statistically significant decrease in WBC counts, CRP values and APACHE II scores was found in the study group compared to the control group (p <0.022). Additionally, the admission to follow-up ratio of WBC counts, CRP values and APACHE II scores was significantly higher in the study group than in the control group (p <0.001). Following PC, WBC counts, CRP values and APACHE II scores decreased significantly over time (p <0.001). After the PC procedure, catheter indwelling time ranged from 1 to 45 days. Except for one patient who died within a few hours following intervention, no major complica- tions related to PC were observed. Out of 132 patients, 29 minor complications were noted.
Discussion: In critically ill, high-risk patients, PC compared to conservative treatment was found to be a safe and efficient salvage therapy for the manage- ment of AC.
Keywords: Acute cholecystitis; Cholecystostomy; Interventional radiology; Ultrasonography; APACHE II; Intensive care units
Introduction
Acute cholecystitis (AC) is one of the most common emergency applications to general surgery services. Treatment options for AC include open or laparoscopic cholecystectomy (LC). It has been reported that emergency cholecystectomy, delayed or interval LC, following conservative management with antibiotic therapy and supportive care for AC, is associated with high morbidity and mortality rates in critically ill patients with significant comorbidities; in addition, they are considered potentially high-risk for surgery [1]. These patients are also prone to the progression of disease to empyema, gangrene, perforation, and abscess formation with conservative treatment [1]. It has also been reported that patients in intensive care units (ICUs) are especially prone to AC, and their clinical outcome is generally sepsis. AC has high morbidity and mortality in these patients, largely because of delays in diagnosis [2].
In patients with AC, percutaneous cholecystostomy (PC) has been promoted as an alternative to surgery in many studies; however, no consensus has been reached yet on the need for delayed or interval cholecystectomy [3]. PC was performed only when an extensive clinical, laboratory and radiological search did not reveal other sources for sepsis outside the gallbladder. An ultrasound (US) guided PC for therapeutic purposes was first reported in 1979 [4]. The first report of PC for the management of AC was given in 1980 [5]. PC has been used as a relatively safe and efficient intervention for the treatment of AC in high- risk, critically ill patients with serious comorbidities and in elderly patients, circumventing general anesthesia necessary for laparoscopic or open cholecystectomy [1].
The present retrospective study aimed to assess the safety and therapeutic efficacy of PC for AC in critically ill high-risk patients with comorbid diseases compared with conservative management. To our knowledge, this study involved the largest study population, most of whom were critically ill elderly already hospitalized in ICUs and services with an Acute Physiology and Chronic Health Evaluation II (APACHE II) score greater than or equal to 12.
Material and Methods
Patient population
Clinical records from January 2007 to June 2020 of surgically high-risk patients with clinical, laboratory and radiological findings of AC and an APACHE II score greater than or equal to 12 were analyzed retrospectively. Patients were randomly assigned into two groups: (1) the study group (n = 132) who underwent PC, and (2) the control group (n = 125) who was managed with conservative treatment. All patients were critically ill, had significant comorbid disease with varying degrees of septic findings, and were considered high-risk patients for surgery. These patients were referred to the interventional radiology department for PC.
The majority of the patients were being followed in ICUs and services because of other comorbid diseases and a small number of them were ambulatory. All ambulatory patients were hospitalized following AC diagnosis. ICU patients had unexplained sepsis and, after a complete clinical, laboratory and radiological evaluation, exhibited no source of sepsis outside the gallbladder. After a collaborative discussion between the surgeon, the intensive care specialist and the interventional radiologist, the final decision by consensus was reached regarding the treatment options (i.e., PC or conservative treatment). When extensive clinical, laboratory and radiological search did not identify any other source of sepsis outside the gallbladder, PC was performed. Additionally, patients whose PC procedure technically failed were included in the control group receiving only conservative treatment.
Patients who were pregnant or under the age of 18, and patients without comorbid disease and an APACHE II score under 12, were excluded from the study. Also patients whose at least one-month follow-up clinical data were not available in the archives were excluded.
When we consider the patient distribution with regard to the comorbidities, in the study group, there were 107 patients with multisystem disease, 103 patients with debilitation, 89 patients with cardiovascular disease, 74 patients with pulmonary disease, 71 patients with malignancy, 41 patients with neurological disease, 39 patients with diabetes mellitus, 34 patients with chronic renal disease, 21 patients with chronic liver disease, 16 patients with hematologic disease, 13 patients with deep vein thrombosis, 9 patients with immunosuppression, 6 patients with trauma, and 5 patients with morbid obesity. In the control group, there were 93 patients with multisystem disease, 96 patients with debilitation, 77 patients with cardiovascular disease, 69 patients with pulmonary disease, 65 patients with malignancy, 33 patients with neurological disease, 28 patients with diabetes mellitus, 30 patients with chronic renal disease, 13 patients with chronic liver disease, 11 patients with hematologic disease, 8 patients with deep vein thrombosis, 4 patients with immunosuppression, 3 patients with trauma and 2 patients with morbid obesity.
There were no patients with grade I score according to the Tokyo guidelines 2018 (TG18) for the severity of acute cholecystitis, however, there were 72 patients with grade II, 60 patients with grade III score in the study group and 67 patients with grade II, 58 patients with grade III score in the control group according to the TG18 classification.
Considering the gallbladder ultrasonography findings of patients, wall thickening was reported in 118 patients, pericholecystic fluid in 103 patients, hydrops in 89 of patients, sludge in 79 patients and calculi in 67 patients. In the control group, 109 patients with wall thickening, 88 patients with pericholecystic fluid, 80 patients with the hydropic gallbladder, 72 patients with sludge in the gallbladder lumen and 59 patients with calculi were observed during the ultrasonographic examination.
Cholangiogram performed for 117 (88,6%) patients revealed a stone in the gallbladder in 64 (54,7%) patients, a stone in the cystic duct in 26 (22,2%) patients, patent cystic duct in 70 (59,8%) patients, obstructed cystic duct in 47 (40,1%) patients, choledocolithiasis in 11 (9,4%) patients.
The institutional review board approved this study, and the ethics committee waived the need for informed consent from each patient due to the retrospective nature of the investigation. Diagnosis of AC and follow-up
Ultrasonography criteria for AC were as follows: (1) gallbladder wall thickness greater than three mm, (2) hydrops of the gallbladder, (3) US Murphy’s sign, (4) stone or sludge formation, (5) the presence of pericholecystic fluid, and (6) positive US Murphy’s sign. For AC diagnosis, at least two criteria for each patient were needed. Cholecystitis severity grading was performed according to the Tokyo Guidelines criteria of 2018 (TG18) [6].
All patients had significant comorbidities and were considered high-risk for surgery. The APACHE II clinical scoring system was applied to each patient’s clinical status both on admission and at follow-up. Those with a score greater than or equal to 12 were considered surgically high-risk patients [7].
Laboratory tests used for diagnosis and follow-up were white blood cell (WBC) counts, C-reactive protein (CRP) values, and total bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. The results of admission and follow-up WBC counts, CRP levels and APACHE II scores were recorded.
WBC count, CRP value and APACHE II score obtained at admission, twenty-fourth hour and forty-eighth hour were represented by WBC 1, CRP 1, and APACHE 1; WBC 2, CRP 2, and APACHE 2; and WBC 3, CRP 3, and APACHE 3, respectively. Management and PC technique
All patients had already been started on broad-spectrum antibiotics and metronidazole when referred to the department of interventional radiology. All PC interventions were performed by one experienced interventional radiologist. All PC procedures were performed at the bedside in the ICU patients and some service patients. PC was performed via transperitoneal (n = 98) and transhepatic (n = 34) routes under US guidance. Pigtail drainage catheters of either 8 Fr (n = 95) or 10 Fr (n = 37) were routinely used. Catheters were placed using the Seldinger technique. After insertion of the needle, a bile sample was obtained and sent for culture. After an 18G Chiba needle puncture to the fundus of the gallbladder under US guidance, a 0.035 guidewire with a three mm j-tip was inserted, then the tract was dilated with 7–9 Fr dilators, followed by catheter placement. When possible, after puncture guidewire insertion, tract dilatation and catheter placement were performed under fluoroscopy. However, in a significant number of patients, fluoroscopy was not possible, mostly in ICU patients; for them, the entire procedure was carried out only under US guidance. When the catheter loop was visualized either ultrasonographically or fluoroscopically in the gallbladder lumen (Figure 1), PC was considered technically successful. The catheter was anchored to the skin with stitches, placed on gravity drainage and irrigated daily with 10 ml of sterile saline to prevent occlusion. Whenever possible (after resolution of septic findings), cholangiography was performed in the next days. Following catheter placement, drainage was allowed for at least two to three weeks for tract maturation, depending on the route of catheter insertion (i.e. transhepatic or transperitoneal).
Statistical analysis
All statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS 13.0 Statistical Software, SPSS Inc., Chicago, IL, USA) and the MedCalc package MedCalc Statistical Software version 16.8 (MedCalc Software bvba, Ostend, Belgium). The means and ranges for age, CRP levels, WBC counts, WBC ratios 1-2, CRP ratios 1-2 and APACHE II scores were calculated for the study and control groups. To show deviation from the normal distribution, the Kolmogorov- Smirnov test was used. Within each treatment period, changes in serum CRP levels, WBC counts and APACHE II scores were assessed using the Friedman test followed by post-hoc tests. The changes in WBC and CRP ratio 1-2 in the ICU, services, and ambulatory patients in the study and control groups were compared with the Mann-Whitney U test. A p-value less than 0.05 was considered statistically significant.
Results
All patients were high-risk surgical patients with findings of AC and APACHE II scores greater than or equal to 12. There was no statistically significant difference between the patient and control groups for TG18 scores (p = 0.512).
This study included only 132 technically successful PC patients and compared them to those who received only conservative treatment. Among the 132 PC patients, 62 (46.9%) were male and 70 (53%) were female. Among the 125 controls, 53 (42.4%) were male and 69 (57.6%) were female. The age range for the study and control groups was 47–102 (mean: 74.8 ± 10.2) and 50–98 (mean: 73.7 ± 10.5), respectively. There was no significant difference in the ages between the patient and the control group (p = 0.052).
Among the study and control groups, 121 (91.6%) [64 (48.4%) in ICU and 57 (43.1%) in-service] and 111 (88.8%) [75 (60%) in ICU, 36 (28.8%) in-service] were already hospitalized, while 11 (8.3%), and 14 (11.2%) were ambulatory, respectively. All ambulatory patients were hospitalized after the intervention. Patients in the study and control groups had symptoms and laboratory findings of AC, ranging from one to 13 days (mean: 4.5 days ± 2.3) and one to 11 days (mean: 4.3 ± 2.5), respectively. For the study and control groups, the mean duration of findings of AC was 4.5 days (range: 1–13 days ± 2.3) and 4.3 days (range: 1–11 days ± 2.5), respectively. The overall mean catheter indwelling time after PC ranged from one to 75 days (mean: 41.7 days ±15.4), while it ranged from one to 75 days (mean: 46.1 days ± 16.6) for ICU patients (p = 0.051). In regards to the catheter insertion approach, the catheter indwelling time ranged from one to 73 days (mean: 44.1 days ± 16.2) and six to 75 days (mean: 45 days ± 16.9) for transperitoneal and transhepatic routes, respectively (p = 0.053). Due to choledocholithiasis during follow-up, 11 patients in the study group and six patients in the control group underwent endoscopic retrograde cholangiopancreatography (ERCP). LC was performed in 20 of the 132 patients in the study group, over a period of two to eight months (mean 4.6 months ± 1.6). On the other hand, 16 of 125 patients in the control group underwent LC within three to nine months (mean: 5.6 months ± 1.6).
In addition to PC, all patients received antibiotics. The mean interval from diagnosis of AC to PC was 2.3 days. One patient died due to massive intra-abdominal bleeding within a few hours after the PC procedure. In the rest (n = 131), no attributable mortality or major complications were observed. Except for temporary and moderate pain, no significant periprocedural complication was observed in those patients. Minor bleeding was noted in nine patients (6%). Thirteen patients (9.8%) developed simple skin infections at the catheter site.
In seven patients (5.3%), biliary peritonitis, which resolved within a few days, was observed. Catheter dislodgement was noted in 13 patients (9.8%) during the follow-up. In nine of them, there was no need for recatheterization because the septic findings had already resolved. In the remaining four, recatheterization was performed because of the ongoing septic findings. In 97 (73.4%) patients, bile aspirated at the time of catheter placement was culture positive. Escherichia coli was the most frequently cultured pathogen (53.6%). After PC, cholangiography could be performed in a total of 117 patients (88.6%) within over a period of one to six days (mean: 3.7 days ± 1.5).
On admission, there was no significant difference between WBC counts, CRP values and APACHE II scores in the study and control groups (p> 0.413). Following PC, WBC counts, CRP values and APACHE II scores decreased significantly over time (p <0.001), as shown in Figure 3. Moreover, after PC, a statistically significant decrease was found in WBC-2, WBC-3 counts and CRP-2, CRP-3 values of the study group compared to the control group (p <0.022). Additionally, the WBC ratio 1-2 and the CRP ratio 1-2 were significantly higher in the study group than the control group (p <0.001; Table 1).
Table 2 shows the changes in APACHE II scores at admission and 48-hour follow-up for both groups. Table 3 and Figure 3 show a one-month follow-up for both groups. One patient died due to massive bleeding within a few hours after PC. In the control group, 21 patients (16.8%) developed serious complications (nine perforations, three empyemas, three gangrenous cholecystitis, and six abscesses) related to AC. Ten of 13 total deaths in the control group were due to septic shock related to these complications, while the rest were due to underlying comorbid diseases. None of the patients in the study group faced complications related to AC. During this period, eight patients in the study group died from severe comorbid diseases not related to the PC procedure. At the end of the one-month follow-up period, 102 patients (77.7%) of the study group and 74 patients (59.2%) of the control group were discharged from the hospital.
When classifying the patients according to the place of hospitalization, (1) ICU patients showed a significant increase in WBC ratio 1-2 and CRP ratio 1-2 (p <0.026), (2) service patients showed a significant increase in WBC ratio 1-2 (p <0.012) and an insignificant difference in CRP ratio 1-2 (p >0.073), and (3) those who were ambulatory at admission showed an insignificant difference (p >0.501) when comparing the the study and control groups, respectively. In all three categories, the APACHE ratio 1-2 significantly increased in the study group compared to the control group (p <0.001).
In terms of analyzing the 13-year accessible recorded data, the mean time frame that was possible for obtaining data ranged from one to 12 months (mean: 4.5 months ± 2.1) and one to eleven months (mean: 4.4 months ± 2.3), respectively, for the study and control groups. In the study group, LC was performed in 20 of the 132 patients in the period from two to eight months (mean 4.6 months ± 1.6). On the other hand, in the control group, 16 of 125 patients underwent LC between three and nine months (mean: 5.6 months ± 1.6). All patients who underwent LC had gallbladder stones.
Recurrent cholecystitis rates were 6.8% (n = 9) and 16% (n = 20) for the study and control groups, respectively. Among these patients, admission calculous AC rates of 88.8% (n = 8) and 85% (n = 17) were noted in these respective groups. Six of them underwent a second PC intervention. The overall long-term mortality rates during this time frame until study conclusion were 26.5% (n = 35) and 30.4% (n = 38) for the study and control groups, respectively.
Discussion
This is the largest review, to our knowledge, analyzing the efficacy and safety of PC compared to conservative management of AC in patients with APACHE II scores greater than or equal to 12. In addition, this study seems to be unique in having the largest ICU population. It has been reported that ICU patients have an increased risk of AC and are prone to high morbidity and mortality because of diagnostic difficulties [8]. In recent years, interval cholecystectomy has come to the fore as a preferable option after medical treatment [9] in high- risk patients with AC. However, previous reports have shown that some comorbid patients with AC who were managed conservatively may be at risk for complications such as empyema, gangrene, and perforation [8], as shown by our conservative patient group (n= 21). The Tokyo Guidelines 2018 (TG18) recommend PC as an alternative for such patients [9]. Hatzidakis et al. [10] carried out the sole randomized study comparing PC with conservative management in high-risk patients (APACHE II score ≥ 12) with AC. The authors stated that in the early follow-up period, PC did not reduce mortality in high-risk patients over conservative management in AC (18% vs 13%).
However, our overall mortality rates for the study and control groups at one-month early follow-up were 6.8% (n = 9) and 10.4% (n = 13), respectively, showing PC as an efficient intervention for managing AC in high-risk critically ill patients. The transhepatic approach is the most commonly used access in PC [11]. Many reports suggest that this method is safer than a transperitoneal approach, with a lower risk of bowel injury and bile peritonitis, but with higher rates of complications such as hepatic bleeding and hemobiliary fistula [11–15]. In our study, in contrast to to the literature, the access route was mostly transperitoneal. Comparable to some other studies [16], we did not face any major complications related to the transperitoneal approach. The optimal duration of catheter indwelling times is still being debated in the literature. Moreover, it has been reported that catheter removal decisions are generally based on subjective clinical evidence rather than hard evidence [1]. Okan et al. [8] suggested that before catheter removal, the drainage tract should be mature enough to prevent bile leakage, the patient should be asymptomatic, and cystic duct patency should be confirmed by cholangiography. One report stated that for mature tract development, two and three weeks are required for transhepatic and transperitoneal approach, respectively [17]. In the present study, cholangiography could be performed in 88.6% of patients, after PC, with a mean of 3.7 days. However, our catheter removal decision was mainly based on clinical status, as well as a minimum two- and three-week catheterization period, for transhepatic and transperitoneal approaches, respectively, and a symptom-free period of three days after catheter clamping, in consideration of tract maturation. In the literature, it was stated that the ideal catheter maintenance time is when tract consolidation is revealed on tractography [17]. In the largest series, by Bundy et al. [11], the mean indwelling catheter time was reported to be 89 days, far longer than our study. They concluded that the long time might be a reflection of the increased frequency of cholecystoscopy with stone removal performed at their institution. Let us remind that none of our patients underwent such an intervention at our institutions. In the present study, with regard to the catheter insertion approach, a mean of 44.1 and 45 days of catheter stay was found for the transperitoneal and transhepatic routes, respectively. These results were found to be statistically insignificant (p >0.05). Hatjidakis et al. reported a longer catheter stay in the transperitoneal compared to the transhepatic route [17]. For comparison, we found that the catheter stay time for the transhepatic route was slightly longer than for the transperitoneal route.
In the present study, 89.3% of the study and 70.4% of the control group showed clinical improvement with a mean of three days. In contrast, results from the study by Hatzidakis et al. showed 86 and 87% clinical improvement rates for the PC and conservative groups, respectively, showing that PC has no advantage over conservative treatment [17]. In other studies by Bundy et al. [11] and McKay et al. [16], 100 and 85% respective clinical improvement rates were found for PC. However, the main disadvantage of these studies was the absence of a conservatively managed control group.
In the 13-year retrospective analysis period, the possible mean time frame for obtaining data was 4.5 and 4.4 months for the study and control groups, respectively. The present study revealed an overall long-term follow-up mortality rate of 26.5% (n = 35) and 30.4% (n = 38), for these respective groups. In one of the largest series studied by Bundy et al., the mortality rate was 6.8% during the seven-year period from catheter placement. In another study, it was 35.8% for 10-year follow-up [18]. However, when reviewing these studies, we could not find information regarding the mean time frame of data availability in hospital records during the study periods. Our long-term mortality rate was higher than in the Bundy et al. study. We think the possible factors for this are as follows: (1) The mean age of our PC group was 74.8, while it was 67 for the aforementioned study; (2) 56.8% of our patients had an APACHE score over 15; and (3) 54% of our patients were in an ICU on admission. The study by Bundy et al. also lacks TG18 grading for AC severity as well as APACHE II or ASA scoring systems for evaluating general clinical status. Thus, we could not evaluate the objective clinical status of their patients compared to the present study. Another weakness of these studies is the absence of one-month mortality rates, which might show the possible early effects of PC intervention in high-risk critically ill patients with AC.
This study has several limitations. During the 13-year time frame, some data loss may have occurred in hospital archives due to the large amount of clinical data and the long timespan, which might have affected our results. Another important point is that we did not perform a comparison with the high-risk, critically ill patients who underwent cholecystectomy during the same time frame. However, this could cause selection bias, as pointed out by McKay et al. [16]. They also reported that it is unclear whether it would be advantageous or not if that group of patients underwent cholecystectomy. It has also been reported that immediate PL as a definitive treatment method might be superior to PC, because of the high rate of recurrent AC symptoms after PC [19]. Lastly, we did not analyze the cost- effectiveness in relation to the study and control groups. Conclusions
PC, compared to conservative treatment, was found to be a safe and efficient way of managing AC in high-risk critically ill patients, especially those in an ICU. We recommend PC as the initial treatment of choice for this specific group of patients. We would also like to suggest that PC may be a definitive treatment option for acalculous AC in this group of patients. Additionally, we also recommend the transperitoneal approach as an easily performed, safe, and efficient method for PC.
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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Oğuzhan Özdemir, Volkan Kızılgöz, Türkhun Çetin, Doğan Gönüllü. Percutaneous cholecystostomy for management of acute cholecystitis in severely ill patients. Ann Clin Anal Med 2021;12(Suppl 2): S142-148
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Thiol/Disulfide homeostasis in childhood chronic kidney disease
Fatma Yazılıtaş 1, Fatma Zehra Oztek Celebi 2, Sare Gülfem Özlü 1, Mehmet Bülbül 1, Evrim Kargın Çakıcı 1, Fehime Kara Eroğlu 1, Gökçe Can 1, Tülin Güngör 1, Özcan Erel 3, Murat Alışık 3, Özlem Aydoğ 1
1 Department of Pediatric Nephrology, Saglik Bilimleri University, Dr Sami Ulus Maternity and Child Health and Diseases Training and Research Hospital, 2 Department of Pediatrics and Adolescent Medicine, Saglik Bilimleri University, Dr Sami Ulus Maternity and Child Health and Diseases Training and Research Hospital, 3 Department of Biochemistry, Yıldırım Beyazıt University Medical School, Ankara, Turkey
DOI: 10.4328/ACAM.20400 Received: 2020-11-12 Accepted: 2020-12-13 Published Online: 2021-01-01 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S149-154
Corresponding Author: Fatma Yazılıtaş, Saglik Bilimleri University, Dr Sami Ulus Maternity and Child Health and Diseases Training and Research Hospital, MD, Department of Pediatric Nephrology, Babür Caddesi No:44 Altındağ, Ankara, Turkey. E-mail: meryemesra@yahoo.com GSM: +90 505 710 4672 P: +90 312 305 62 57 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6483-8978
Aim: The pathogenesis of chronic kidney disease (CKD) remains unknown, but an imbalance between the oxidant and antioxidant defense systems may be a potent trigger of adverse effects in chronic kidney disease (CKD) patients. Measuring thiols in plasma offers an indirect marker of antioxidative defence. This study aimed to determine thiol/disulfide homeostasis as a new indicator of oxidant and antioxidant defence systems in pediatric CKD patients.
Material and Methods: This prospective case-control study included 50 pediatric CKD patients (34 non-dialyzed and 16 dialyzed) and 50 gender- and age- matched healthy controls.
Results: The native thiol, total thiol, and disulfide levels were significantly lower in the CKD group than in the control group (p=0.003, p<0.001, p=0.002, respec- tively). There was a significant correlation between the glomerular filtration rate, and the native thiol levels and total thiol levels (p=0.003, for each). The native and total thiol levels in the dialyzed patientswere significantly lower than in the non-dialyzedpatients (p<0.001,p=0.002, respectively).
Discussion: We observed that the levels of native thiol, total thiol and disulfide in pediatric CKD were lower than in healthy controls, indicating that low thiol levels might be an important factor in the pathogenesis of CKD.
Keywords: Children; Chronic kidney disease; Dialysis; Dynamic Thiol/Disulphide homeostasis; Oxidative stress
Introduction
Chronic kidney disease (CKD) is an irreversible progression of systemic or primary renal diseases. Oxidative damage caused by increased oxidative stress and decreased antioxidant defence system is suggested to cause the progression of CKD and the development of kidney complications [1-3].
The oxidant and antioxidant defence systems imbalance and an increase in the production of free radicals maybe exacerbated by both hemodialysis and peritoneal dialysis [4-8].
Thiols are important components of antioxidant systems, which can be oxidized by one electron to form disulfide [-SS] bonds, which can again be reduced to thiol groups. This reversible reaction is important for maintaining dynamic thiol/disulfide homeostasis (DTDH) in the body. The total thiol level is indicative of both oxidized and reduced thiol forms, whereas the native thiol level is indicative of only the reduced thiol form. Under oxidative stress conditions, the level of native thiol decreases, while the disulfide concentration increases, but there is no change in the total thiol level [9].
The development of new diagnostic methods for detecting markers of oxidative stress may lead to a better understanding of the negative effects of oxidative stress on oxygenation and transport functions in renal cells [10,11]. Plasma thiol/disulfide homeostasis measurement is achieved with high accuracy and sensitiveness by determining native thiol and reducible dynamic disulfide, individually or together, using a novel method (colorimetric and spectrophotometric) developed by Erel and Neselioglu [9]. Thus, double-sided DTDH (antioxidant/oxidant) components can be easily measured.
The present study aimed to investigate DTDH as a new indicator of oxidative stress in pediatric CKD patients. To the best of our knowledge, this is the first-pilot study investigating dynamic thiol/disulfide homeostasis in pediatric CKD patients using a new method.
Material and Methods
Characteristics of Patients
This prospective case-control study was conducted at the tertiary hospital between January 2015 and July 2015. The study included 50 pediatric CKD patients and 50 age-, gender- and Body Mass Index (BMI)-matched healthy controls. The CKD group was divided into subgroups as dialyzed (hemodialysis [HD]: n=9; peritoneal dialysis [PD]: n=7) and non-dialyzed (n=34) patients. The exclusion criteria were as follows: (1) patients with evidence of acute infections, inflammatory disorders, malignancy; (2) patients with C-reactive protein (CRP) plasma levels > 3 mg/dL; (3) patients who receive HD therapy with a Kt/Vurea<1.4/week; (4) patients who receive PD therapy with a Kt/Vurea<1.7/week: (5) patients with peritonitis 3 months prior to enrolment. None of the healthy controls used an antioxidant agent (N-acetyl cysteine, allopurinol, vitamin supplements, or lipid-lowering medication), received medical or herbal therapy, or used cigarettes and alcohol.
All the HD patients were routinely dialyzed using polysulfone membrane dialyzers containing bicarbonate solutions for four hours a day, three times a week. Continuous ambulatory PD (CAPD) with solutions containing 1.36%-2.27% glucose was administered to all the PD patients.
CKD was defined as a decrease in the glomerular filtration rate (GFR) in this study. The estimated glomerular filtration rate (eGFR) was calculated using the Schwartz method, which is the most popular equation currently used in children [12]. Hypertension was defined as blood pressure >95th percentile for age, gender, and height, according to the Task Force Report on High Blood Pressure in Children and Adolescents criteria for casual BP recordings [13].
Height and weight were measured, and then BMI was calculated using the formula: BMI=kg/m2.
The study protocol was approved by the Ethics Committee of Ankara Yıldırım Beyazıt University (Reference number: 201/02/03) and was performed in accordance with the principles of the Declaration of Helsinki and good clinical practices. Informed consent was obtained from the parents of all patients.
Dynamic Disulfide/Thiol Homeostasis Analysis
Venous blood samples were collected from all participants after fasting for 8 hours (at the start of the mid-day dialysis session in PD patients and at the start of the mid-week dialysis session in the HD patients). Routine laboratory parameters, including hemogram, biochemistry, and CRP levels, were measured in all the participants via standard laboratory techniques.
The samples for DTDH parameters (native thiol, total thiol, and disulfide levels, and the disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios) were centrifuged at 1500 g for 10 min, and stored at −80 °C until analysis. An automated chemistry analyzer (Shimadzu UV-1800 spectrophotometer) with a temperature-controlled cuvette holder and a Cobas c501 automated analyzer (Roche Diagnostics, Mannheim, Germany) were used to measure DTDH parameters as μmol/L [9]. DTDH was determined according to the native thiol and reducible dynamic disulfide levels. Subtracting the native thiol level from the total thiol level, and then dividing the difference by two provides the disulfide bond quantity. In addition, other related parameters (disulfide/total thiol, disulfide/native thiol, and native thiol/total thiol ratios were calculated [9].
Before the advent of Erel and Neselioglu’s novel measurement technique described herein and used in the present study, it was feasible to measure only low-molecular-weight compounds, which include a small portion of the body’s thiol pool; therefore, the levels of thiol and disulfide measured using older methods may not precisely indicate the thiol/disulfide homeostasis status. Thiol/disulfide homeostasis can be creditably, separately, or collectively evaluated using this new method [9].
The CKD and control groups and the patient dialyzed subgroups were compared according to age, gender, CRP, native thiols, total thiols, disulfide, disulfide/native thiols, native thiols/total thiols, and disulfide/total thiols, all of which are parameters of thiol/disulfide homeostasis.
Statistical analysis
Statistical analysis was performed using SPSS for Windows v.15.0. (SPSS, Inc., Chicago, IL). Data are shown as mean ± SD, or median and range. The chi-square test was used to identify differences in categorical variables between groups. Student’s t-test and the Mann-Whitney U test were used to compare numeric demographic variables, laboratory findings, and serum DTDH parameters between the CKD and control groups.
Correlations between thiol/disulfide homeostasis parameters and other clinical and laboratory findings that were normally distributed were determined using Pearson’s correlation analysis. The level of statistical significance was set at p < 0.05.
Results
The mean age in the CKD group was 11.8 ± 5.2 years (median: 12; range: 0-18 years), versus 11.1 ± 4.4 years (median: 12; range: 1-18 years) in the control group. There were 47 girls (47%) and 53 boys (53%) in the study. There were no significant differences in age, gender, or BMI between the CKD and control groups (p>0.05 for each). C-reactive protein (CRP) levels were normal in all the participants. The demographic data, clinical and laboratory findings, and thiol/disulfide homeostasis parameters in both groups are summarized in Table 1.
In the CKD group, albumin and hemoglobin levels, and the GFRwere significantly lower, and blood urea nitrogen, creatinine, and uric acid levels were significantly higher than in the control group (p<0.001 for each) (Table 1).
As shown in Table 2, there were no significant differences in age, gender, BMI, or total protein, albumin, and uric acid levels between the dialyzed and non-dialyzed CKD patients (p>0.05 for each).
Native thiol, total thiol, and disulfide levels were significantly lower in the CKD group than in the control group (p=0.003, p<0.001, and p=0.002, respectively) (Figure 1). The native thiol and total thiol levels were lower in the dialyzed CKD patients than in the non-dialyzed CKD patients (p<0.001 and p=0.002, respectively) (Figure 2). The DTDH parameters of the groups are shown in Figures 1 and 2.
The native thiol and total thiol, disulfide levels were lower in patients with stage IV CKD than in patients with stage II and III CKD (p=0.002, p=0.004 respectively). A significant correlation was observed between uric acid and total thiol (r=0.307, p=0.030), and between uric acid and native thiol (r=0.378, p=0.007)in CKD. The native thiol levels were significantly lower in the PD patients than in the HD patients (p=0.036).
In the dialyzed and non-dialyzed CKD patients, there was a significant correlation between native thiol, disulfide and total thiol, and the GFR, creatinine, and uric acid levels (Table 3).
Discussion
The present study evaluated thiol/disulfide homeostasis in pediatric CKD patients using a novel automated method and found that the native thiol, total thiol, and disulfide levels were significantly lower in the CKD patients than in healthy controls. Our results indicated that not only the oxidative system, but also the antioxidant system is impaired in pediatric CKD patients, and that antioxidant levels decrease to a greater extent than oxidant levels (higher disulfide/native thiol and disulfide/total thiol ratios). The study’s most unique finding is that the most severe oxidative stress imbalance was in peritoneal dialysis patients (p=0.036).
Earlier studies on adults have reported that plasma protein thiols decrease in patients with CKD, and that even in pre- dialysis CKD patients there is an increase in oxidative stress and a decrease in the antioxidant defence system (superoxide dismutase, glutathione peroxidase, catalase, vitamins E and C, and selenium) [3, 14-17].
The oxidative state is further exacerbated by dialysis [4-7]. In our study, the native thiol and total thiol levels and native thiol/ total thiol ratios were lower in the dialyzed patients than in the non-dialyzed patients. This indicates that total thiols, in particular, are affected to a greater degree than native thiols in dialyzed patients.
The higher level of oxidative stress observed in the PD patients than in the HD patients in our study, is thought to possibly be due to an increase in the severity of uremia and inflammatory responses, or a decrease in the albumin level. It has been reported that the free fraction of thiols increased and the protein-related fraction decreased in PD patients [15]. A study on adults reported that the total thiol and native thiol levels were significantly lower in end-stage renal failure (ESRD) patients than in controls, and that the levels were lower in PD patients than in those undergoing other renal replacement therapies [14].
We found that the oxidant disulfide bond formation was significantly lower in the CKD group than in the control group, but there was no significant difference between non-dialyzed and dialyzed CKD patients. HD has been reported to have a positive effect on antioxidant homeostasis [7, 17-19]. The dialyzer membrane and HD treatment can play an important role not only in increasing Reactive oxygen species (ROS) formation, but also in ROS elimination, i.e. they can improve the oxidative state and reverse the increase in oxygen radical production in the blood of ESRD patients [7]. This might be the reason that disulfide level was not significantly different, despite the observed decreases in the native thiol and total thiol levels in our HD and PD patients.
In our study, a positive correlation was foundbetween the GFR, and native thiol and total thiol levels in the CKD patients. In addition, the native thiol and total thiol levels decreased in the pediatric CKD patients as the GFR decreased. These results indicate that uremic patients may not respond adequately to oxidative stress. It has been reported that the severity of uremia, rather than dialysis treatment, contributes significantly to oxidative stress in both dialyzed and non-dialyzed CKD patients [18, 20-23]. Our findings are in agreement with the literature.
Ateş et al. [24] observed that the total thiol level was significantly lower in patients with primary hypertension than in healthy controls.
Our study has some limitations. One of these was the lack of analysis of other markers of oxidative stress that might affect thiol redox status. Other limitations are that the CKD group was heterogeneous. Lastly, the study population included a relatively small number of patients, in particular dialyzed patients. Despite these limitations, the fact that this was a pilot study will contribute to the literature.
To the best of our knowledge, the present study is the first to investigate the effects of oxidative status in non-dialyzed and dialyzed pediatric CKD patients based on analysis of DTDH. Our findings suggest that the decrease in native and total thiol levels in dialyzed CKD patients was greater than in the non-dialyzed patients, but the disulfide levels did not differ significantly between CKD patient subgroups. Given the effects of oxidative stress on the progression of CKD, early detection and correction of oxidative processes may help prevent the progression of CKD and reverse its pathophysiology. This new method might be suitable for large-scale clinical trials and can be used as a useful indicator method of oxidative stress in routine screening. Since this is a pilot study on this subject, our study is very important.
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.20400
Fatma Yazılıtaş, Fatma Zehra Oztek Celebi, Sare Gülfem Özlü, Mehmet Bülbül, Evrim Kargın Çakıcı, Fehime Kara Eroğlu, Gökçe Can, Tülin Güngör, Özcan Erel, Murat Alışık, Özlem Aydoğ. Thiol/Disulfide homeostasis in childhood chronic kidney disease. Ann Clin Anal Med 2021;12(Suppl 2): S149-154
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Determination of maternal lipid peroxidation and antioxidant activities in term and preterm birth in different weeks
Ayse Arslan 1, Kazım Uckan 2, Kasım Turan 3, Halit Demir 4, Canan Demir 5
1 Department of Nutrition, Faculty of Health Sciences, Yuzuncu Yil University, 2 Department of Gynecology, Van Region Education and Research Hospital, 3 Private Gynecology and Obstetrics Clinic, 4 Department of Biochemistry, Faculty of Science, Yuzuncu Yil University, 5 Health Services Vocational High School, Yuzuncu Yil University, Van, Turkey
DOI: 10.4328/ACAM.20402 Received: 2020-11-14 Accepted: 2020-12-21 Published Online: 2021-01-05 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S155-158
Corresponding Author: Ayse Arslan, Department of Nutrition, Faculty of Health Sciences, Yuzuncu Yil University, Tusba/VAN. E-mail: ayse.ars12@gmail.com P: +90 533-551-88-38 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3876-8376
Aim: It has been suggested that oxidative stress may be associated with various pregnancy complications, including preterm birth (PTB). However, the role of oxidative stress in preterm births and its effects on the pregnancy process are not conclusive.
Material and Method: In this study, oxidative stress parameters were investigated in maternal blood samples who delivered at preterm and term. One hundred twelve mothers (<37 gestational weeks) diagnosed with preterm delivery were included in the study as a patient group. Also, sixty-four women who delivered at term as a control group were included in the study. Serum antioxidant enzymes (CAT (Catalase), SOD (Superoxide dismutase), GSHPx (Glutathione peroxidase), GSH (Glutathione) and MDA (Malondialdehyde) levels were determined spectrophotometrically.
Results: Serum antioxidant activity was lower in the preterm groups than in the control group. Also, serum lipid peroxidation levels were higher in the preterm groups than the control group (p< 0.05).
Discussion: Our findings show that women with preterm birth have higher levels of oxidative stress. These results suggest that oxidative stress is associated with preterm labor. However, it is still unclear whether oxidative stress is a cause or a result of preterm birth.
Keywords: Preterm birth; Antioxidants; Lipid peroxidation; Oxidative stress
Introduction
Preterm birth (PTB) is defined as birth that occurs before 37 weeks of gestational age. Worldwide, 15 million babies are born prematurely each year. Preterm birth is a major cause of neonatal morbidity and mortality, especially in developing countries. [1]
Preterm births can be classified into three groups as follows: spontaneous preterm delivery (40-50%), preterm premature membrane rupture (25-40%) and obstetric preterm births (20- 25%). There are also four degrees of prematurity: extreme small preterm (before 28 weeks), very small preterm (28-31 weeks), mild preterm (32-33 weeks) and moderate preterm (34- 36 weeks) [2]. Factors contributing to the establishment of PTB include inflammation or infection, young or advanced maternal age, multiple pregnancies, low maternal body mass index and lifestyle (excessive exercise, alcohol, smoking) [3-4].
Oxidative stress is characterized by excessive production of reactive oxygen species (ROS) with inadequate antioxidant defense mechanisms. Increased oxidative stress results in damages of DNA, proteins and lipids. Antioxidants protect DNA, enzymes, proteins and membrane phospholipids by neutralizing free radicals. [5]. The antioxidant defense system mainly contains enzymes such as superoxide dismutase, glutathione peroxidase, catalase and antioxidant molecules such as GSH. Superoxide dismutase (EC1.15.1.1) is an antioxidant enzyme that catalyzes the decomposition of high reactive superoxide anion into O2 and H2O2. [6]. CAT and GPX play an important role in the detoxification of H2O2. CAT (EC1.11.1.6) reacts with H2O2 and hydrogen donors with peroxidase activity to form water and molecular oxygen. Thus, protection is provided against H2O2 formed inside the cells. GPX (EC1.11.1.19) glutathione peroxidase is an intracellular selenoprotein enzyme that reduces H2O2 using GSH. Glutathione is an intracellular cysteine tripeptide and is primarily present in cells in reduced form (GSH) or in oxidized form (GSSG) [7]. Lipid peroxidation occurs as a result of damage caused by free radicals and produces secondary products containing aldehydes such as malondialdehyde (MDA) [8]. Elevated MDA levels have been reported to be an important indicator of oxidative stress [9]. Different results have been reported in previous studies regarding the relationship between oxidative stress and premature birth. In some of these studies, no difference was found between preterm and term groups in terms of MDA levels [10], while in others, MDA levels were found to be higher in preterm births [11]. Also, some studies have reported that antioxidant levels are higher or lower in women with preterm birth [11,12].
The present study was designed to determine serum lipid peroxidation (MDA) and antioxidant (SOD, CAT, GSHPx and GSH) activitiy in preterm and full-term deliveries.
Material and Methods
Subjects
In this study, 112 cases (<37 gestational weeks) diagnosed as preterm delivery in Obstetrics and Gynecology Department Risky Pregnancy Unit of the Van Regional Training and Research Hospital were included. In addition, 64 healthy pregnant women were included in the study, as a control group, who were followed up in the antenatal unit without any complications of pregnancy.
The pregnant women included in the study were divided into 3 groups according to the gestational week. The first group consisted of healthy pregnant women with a mean gestational age of 39.4 ± 1.89 weeks. The second and third groups consisted of women who had preterm labor. The first preterm group consisted of 56 women and the mean gestational age was 29.3 ± 3.45. The second preterm group consisted of 56 women with a gestational age of 35.3 ± 1.67 weeks. The gestational weeks of the subjects included in the study were calculated based on their last menstrual period and/or based on ultrasound examination performed in the first trimester. Pregnant women with systemic diseases such as gestational diabetes, preeclampsia, thyroid dysfunction, chronic hypertension or membrane rupture, placental pathology, intrauterine growth retardation, fetal abnormalities or fetal distress were excluded from the study. Also, smokers were excluded from both groups. All patients were informed about the details of the study and written consent was obtained. All procedures were performed in accordance with the ethical standards of the Declaration of Helsinki. Permission was obtained from the Van Regional Training and Research Hospital Ethics Committee for Non- interventional Clinical Researches.
The diagnosis of preterm delivery was made in the presence of uterine contractions before the 37th week of pregnancy with intact amniotic membranes. Uterine contractions occur at least twice every 10 minutes and cause cervical changes (cervical dilatation> 2 cm and effacement> 50%) and did not stop, although hydration and bed rest were considered criteria for the diagnosis of preterm delivery. All patients included in the study underwent a routine medical and obstetric examination. Blood and urine samples were obtained for hemogram, ALT, AST, fibrinogen, complete urinalysis, blood group and urine culture. All participants had singleton pregnancies and delivered vaginally without anesthesia.
Biochemical analysis
Biochemical analyzes were performed in the Chemistry Department Biochemistry Laboratory of Yuzuncu Yil University. Blood samples (10 ml) were obtained from all participants during delivery and put into plain tubes. Blood samples were centrifuged at 5000 rpm for 10 minutes to obtain serum. Serum samples were placed in polypropylene tubes and kept in the freezer at -20 ̊C until the working day.
MDA was estimated by measuring TBARS (thiobarbituric acid- reactive substances) in serum samples according to a modified method of Jentzsch et al. [13]. First, 0.2 ml of serum was added to the reaction mixture containing 1 ml of 1% ortho-phosphoric acid, 0.25 ml alkaline solution of thiobarbituric acid-TBA (final volume 2.0 ml), followed by heating for 45 min at 95 ̊C. The results were expressed as mmol MDA per liter of serum. Superoxide dismutase, catalase, glutathione peroxidase and glutathione activities were also measured in serum samples as markers of the antioxidant system. CAT activity: Serum CAT activity was measured using H2O2 as the substrate. The change of H2O2 levels was monitored at 240 nm for 5 min using a spectrophotometer, and enzyme activity was expressed in units per liter (U/L) [14]. Serum SOD activity was measured
in accordance with the method of Sun et al. [15]. The activity of GSPHx enzyme was measured according to Paglia and Valentine [16]. The GSHPx enzyme catalyzes the oxidation of glutathione. When the oxidized glutathione is reduced, NADPH (nicotinamide adenine dinucleotide phosphate) is oxidized and turned into NADP. This change was observed at 340-nm wave and the activation of GSHPx was measured. The results were expressed as units per liter (EU/L) for serum. The GSH level was measured spectrophotometrically at 412 nm by a glutathione disulfide reductase recycling method at room temperature [17]. Statistical Analysis
Descriptive statistical data for the continuous variables were expressed as mean ± SD (Standard deviation). ANOVA (One Way Analysis of Variance), was used for normal distribution conditions and Kruskal-Wallis test statistic was used for cases where a normal distribution condition was not provided. The results were considered to be statistically significant when p<0.05. The data were analyzed using the SPSS 19 software (SPSS Inc., Chicago, IL, USA).
Results
There was no statistical difference between the study and control groups in terms of maternal age, gravida (number of pregnancy) and number of births (parity) (Table 1). However, there was a difference between the groups in terms of the gestational week. While the mean gestational week was 29.3 ± 3.45 in the preterm group I, the mean gestational week was 35.3 ± 1.67 in the preterm group II. The mean gestational week in the control group was 39.4 ± 1.89. Systolic and diastolic blood pressure values of all participants were within normal limits. In addition, blood ALT (Alanine transaminase), AST (Aspartate transaminase), glucose, hemoglobin, fibrinogen, platelet and protein content in spot urine were within normal limits(Table 1).
CAT activity was lower in the preterm II group than the preterm I group, whereas CAT activity in both preterm groups was lower than the control group. GSH and GSHPx activity were lower in both preterm groups compared to the term group. MDA levels were higher in preterm groups compared to the term group. In addition, according to the correlation analysis, there was no relationship between antioxidant activities and MDA level.
Discussion
In this study, serum antioxidant enzymes CAT, SOD, GSH, GSHPx and MDA levels, which are the end product of lipid peroxidation, were investigated in preterm and term delivery. MDA levels were higher in preterm groups than in the term group. On the other hand, antioxidant enzyme activity was lower in preterm groups compared to the term group.
Premature births are the leading cause of neonatal deaths occurring every year around the world. It is estimated that 11% of all births result in premature delivery [1]. Previous studies have reported that oxidative stress during pregnancy may be associated with preterm delivery. [18]. Oxidative stress, defined as an imbalance between antioxidants and reactive oxygen species. In fact, when reactive oxygen species, produced in biological systems are at low levels, it is necessary for some cellular functions such as cell division, inflammation, and immunity [19]. However, excessive free radical production can cause cellular damage by exceeding a biological system’s ability to detoxify them [20]. High levels of oxidative stress in pregnant women may lead to placental dysfunction or other damages leading to preterm delivery [21].
The role of oxidative stress and antioxidants in preterm and term delivery is not fully understood, but some mechanisms have been proposed. First, it has been suggested that increased reactive oxygen species may serve as a precursor for inflammatory responses that can initiate premature labor and damage cervical stroma or collagen in fetal membranes [22]. Secondly, it may cause dysfunctional placenta localization by reducing the spiral arteriole invasion of the myometrial wall in the early period of pregnancy [23].
Balancing oxidative stress can be accomplished with an antioxidant defense system consisting of enzymes such as catalase, superoxide dismutase, glutathione peroxidase, and non-enzymatic antioxidant such as glutathione. Antioxidants protect cells by inhibiting oxidation reactions, and thus play an important role in maintaining cellular function in normal pregnancy [5].
Different results have been obtained in previous studies on the relationship between preterm delivery and oxidative stress. Cinkaya et al. [12] found that total antioxidant levels were lower in women with preterm delivery compared to uncomplicated pregnant women at similar gestational week. Also, Joshi et al. [11] found that MDA levels were higher in preterm delivery compared to term delivery, and found that this correlates with samples from neonatal cord blood. In the same study, maternal blood vitamin C levels were found to be higher in the preterm group than in the term group. However, in some studies, there was no difference between preterm and term deliveries in terms of antioxidant and lipid peroxidation levels. In a study, women of similar age were divided into 3 groups: preterm, term, and non-pregnant healthy controls. As a result of this study, it was determined that GSH and GSHPx activities did not differ between term and preterm groups [24]. In another study, maternal and neonatal cord blood samples were examined for oxidative stress markers and micronutrients, and it was found that there was no difference in MDA levels and micronutrient levels (ß-Carotene, alpha-Tocopherol, lutein) in preterm and term delivery [10]. Another study investigated the association between pregnancy complications and maternal oxidative stress. They compared pregnant women with normal pregnancy and those with complications during pregnancy (preeclampsia, preterm birth, low birth weight). When they compared, It was found that plasma total antioxidant capacity (TAC) and erythrocyte GSHPX and SOD activities did not differ between the two groups. However, in the same study, plasma 8-isoprostane (oxidative stress marker) levels were found to be significantly higher in pregnant women who subsequently developed preeclampsia or SGA (small for gestational age infant) compared with normal pregnancies [25].
Our study has some limitations. Blood samples were taken only from the mother at birth, cord blood samples from newborns were not taken. Therefore, we could not evaluate whether the oxidative stress in the mother affects the baby. In addition, we could not control the effects of maternal characteristics such as body mass index (BMI), exercise and nutritional status.
In conclusion, our findings show that women with preterm birth have higher levels of oxidative stress. These results suggest that oxidative stress is associated with preterm labor. Although the effects and mechanisms of antioxidants on the pregnancy process are not yet fully understood, it should be taken into account when diagnosing treating preterm delivery. On the other hand, the use and effectiveness of antioxidant treatments in risky pregnancy still remain a controversial issue. Also it is still unclear whether oxidative stress is a cause or a result of PTB.
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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Markers predicting critical illness and mortality in COVID-19 patients: A multi-centre retrospective study
Tahsin Karaaslan 1, Cumali Karatoprak 2, Esra Karaaslan 3, Gulsah Sasak Kuzgun 1, Mehmet Gunduz 4, Abdusselam Sekerci 5, Banu Buyukaydin 5, Sabahat Alisir Ecder 1
1 Department of Nephrology, Medeniyet University, Goztepe Training and Research Hospital, 2 Department of Internal Medicine, Bezmialem Vakif University, Medical Faculty, 3 Department of Chest Diseases, Medipol University Sefakoy Hospital, 4 Department of Pediatrics, Medipol University Sefakoy Hospital, 5 Department of Internal Medicine, Bezmialem Vakif University, Medical Faculty, İstanbul, Turkey
DOI: 10.4328/ACAM.20404 Received: 2020-11-15 Accepted: 2020-12-13 Published Online: 2021-01-03 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S159-165
Corresponding Author: Tahsin Karaaslan, Medeniyet University, Goztepe Training and Research Hospital, Department of Nephrology, 34722, Kadikoy, Istanbul, Turkey. E-mail: drtkaraaslan@hotmail.com P: +90 (505) 935 11 22 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1529-1790
Aim: In this study, we aimed to investigate early predictors of critical illness and mortality in patients with coronavirus disease 2019 (COVID-19) based on clinical, biochemical, radiological, and epidemiological findings.
Materials and Methods: This multi-center, retrospective study was conducted in three centers and included a total of 206 confirmed COVID-19 cases using reverse transcription-polymerase chain reaction (RT-PCR). Data of survivors and non-survivors were compared, and predictors of mortality were examined.
Results: Among the patients, 103 (50%) were males with a mean age of 52.8±16.7 years; 88.3% of the patients were discharged in a healthy condition, while 11.7% died. The mean age was significantly higher in non-survivors. Dyspnea occurred in 32.5% of patients, and a significant correlation was found between dyspnea and mortality (p<0.001). Thoracic computed tomography (CT) findings were positive in 88.8% of patients. The most frequent imaging findings were ground-glass opacities in 86.4% and consolidation in 33% of patients. The mortality rate was significantly higher in patients with comorbidities (p<0.001). There was also a significant correlation between lymphocytopenia and mortality (p<0.001). A positive correlation was found between mortality risk and platelet-to-lymphocyte, neutrophil-to-lymphocyte, and red cell distribution width indices. The mortality risk was significantly higher in patients with acute kidney injury (10.7%) (p<0.001).
Discussion: These results suggest that advanced age, coexisting diabetes, hypertension, heart failure, chronic kidney disease, or acute kidney injury are associ- ated with an increased mortality risk. The presence of dyspnoea or consolidation on thoracic CT can predict an increased mortality risk in COVID-19 patients.
Keywords: COVID-19; Kidney injury; Mortality; Lymphocytopenia; Predictor
Introduction
In late December, the first case of novel coronavirus-2019 based on pneumonia of unknown etiology was identified in Wuhan, Hubei Province of China [1]. In February 2020, the World Health Organization (WHO) named the disease as novel coronavirus-2019 (COVID-19). Meanwhile, the International Committee on Taxonomy of Viruses (ICTV) has named the novel virus as severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). In March 2020, the WHO announced the COVID-19 pandemic with the concern of alarming levels of spread and severity of the virus. Currently, COVID-19 has become a global health threat due to its rapid spread around the world and the lack of an effective treatment or vaccine. Since December 2019, more than 3 million cases of coronavirus disease 2019 (COVID-19) and about 200,000 deaths have been reported worldwide [2]. Although transmission may occur from asymptomatic patients or during the incubation period, current evidence suggests that severe symptomatic patients mostly transmit the disease. The diagnosis can be made based on clinical signs and symptoms, and laboratory and imaging findings; however, the non-specific nature of the disease may hamper making a definitive diagnosis. The reverse transcription-polymerase chain reaction (RT-PCR) positivity in respiratory samples is the gold standard for the detection of SARS-CoV-2 ribonucleic acid (RNA) [2].
Rapid and accurate diagnosis of COVID-19 enables prioritization of effective treatment modalities, early transfer to intensive care units (ICUs), and early isolation of diseased patients from healthy individuals. In the present study, we aimed to investigate the predictors of critical illness and early mortality in confirmed cases of COVID-19 based on clinical, biochemical, radiological, and epidemiological findings and to identify possible biomarkers of early screening and diagnosis, as well as in identifying patients progressing to critical illness.
Material and Methods
Description
The fever of each patient was measured with a tympanic thermometer and values above
37.8 0C were considered a high fever. Watery defecation, increased stool volume, or increased stool frequency were considered as diarrhea. The diarrhea was bloodless and mucus free. There was no tenesmus. Patients with respiratory failure requiring mechanical ventilation, shock, or other organ failure requiring intensive care follow-up and treatment were defined as critically ill patients.
Study design and study population
This multi-center retrospective study was conducted in three centers located in Istanbul, Turkey from March 1, 2020 to July 30, 2020. The study included patients aged ≥18 years who were under follow-up with a confirmed diagnosis of COVID-19. The cases were confirmed by RT-PCR nucleic acid test (NAT) positivity using nasopharyngeal swabs. Patients with any hematological or solid organ malignancy, RT-PCR-NAT negativity, and missing data including clinical, biochemical, and imaging test results were excluded from the study. All CT images were acquired at the end of inhalation using a 16-slice CT scanner (Somatom scope power, Siemens Healthineers, Forchheim, Germany).
Written informed consent was obtained from each patient. The study protocol was approved by the Ethics Committee of Istanbul Medeniyet University, Goztepe Training and Research Hospital (Date: 24/06/2020-No: 2020/0407). The study was conducted in accordance with the principles of the Declaration of Helsinki.
Data collection
Data including demographic and clinical characteristics of the patients were recorded. At the time of hospital admission, the complete blood count analysis results including hemoglobin (Hb), white blood cells (WBC), platelets, absolute neutrophil and eosinophil counts, mean corpuscular volume (MCV), mean platelet volume (MPV), and red cell distribution width (RDW) were noted. C-reactive protein and troponin levels were measured. The neutrophil-to-lymphocyte ratio (NLR), platelet- to-lymphocyte ratio (PLR), and MPV/PC ratio were calculated. The patients were divided into groups according to the WBC (<4.5 x109/L, 4.5 to 10.5 x109/L, and >10.5 x109/L), lymphocyte (<1.0 x109/L and >1.0 x109/L), and platelet count (<100 x109/L, 100 to 400 x109/L, and >400 x109/L). They were further divided into subgroups according to creatinine clearance (estimated glomerular filtration rate [eGFR]) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.
All patients were classified into two groups as survivors (n=182) and non-survivors (n=24). They were further divided into five subgroups according to age as follows: 18 to 29 years, 30 to 49 years, 50 to 64 years, 65 to 74 years, and >75 years. Thoracic computed tomography (CT) findings including the presence of ground-glass opacities, consolidation, pleural effusion, and lymphadenopathy were evaluated. Intra- and inter-group analyses were performed, and all test results were compared between the survivors and non-survivors.
Statistical analysis
Statistical analysis was performed using the SPSS version 26.0 software (IBM Corp., Armonk, NY, USA). Descriptive data were presented as mean ± standard deviation (SD), median (min-max), or number and percentage, where applicable. The Student’s t-test was used to compare normally distributed continuous variables, while the Mann-Whitney U test was used to compare abnormally distributed continuous variables. The Chi-square test was performed to examine categorical variables. The Pearson correlation analysis was carried out to analyze possible correlations between variables. A p-value of <0.05 was considered statistically significant.
Results
A total of 938 confirmed SARS-CoV-2-positive cases were screened. Among these patients, 420 were recruited from Centre 1, 350 from Centre 2, and 168 from Centre 3. According to the inclusion and exclusion criteria, 206 cases were included in the study. Baseline demographic and clinical characteristics of the patients are shown in Table 1. Among the patients, 88.3% (n=182) were discharged in a healthy condition, while 11.7% (n=24) died. The mortality rate was identical in both sexes (11.7%). There was no statistically significant correlation between mortality and gender (p=0.59), while there was a significant correlation between advanced age and mortality (r=+0.369; p<0.001) (Table 1).
A total of eight (3.9%) patients were asymptomatic, while 198 (96.1%) had a variety of symptoms. The most common symptoms included fever (n=148, 71.8%), dry cough (n=131, 63.6%), fatigue (n=110, 53.4%), dyspnoea (n=67, 32.5%), myalgia (n=59, 28.6%), diarrhea (n=30, 14.6%), and anosmia/ dysgeusia (n=18, 8.7%). No mortality was seen in asymptomatic patients, and an inverse relationship was observed between asymptomatic status and mortality (p=0.004). In this study, we found no significant correlation between fever, dry cough, fatigue, myalgia, diarrhoea, and anosmia/dysgeusia and mortality (p>0.05), while we observed a significant correlation between dyspnoea and mortality (r=+0.320; p<0.001).
Thoracic CT findings were positive in 183 (88.8%) patients and were normal in 23 (11.2%) patients. No mortality was observed in patients with normal CT findings, whereas 24 (13.1%) of 183 patients with positive CT findings died, indicating a statistically significant difference (p<0.001). The most frequent imaging findings were ground-glass opacities in 178 (86.4%) patients and consolidation in 68 (33%) patients. None of the patients developed pneumothorax, while 14 (6.8%) had pleural effusion and 12 (5.8%) had mediastinal lymphadenopathy. There was no statistically significant correlation between ground-glass opacities, pleural effusion, or mediastinal lymphadenopathy and mortality (p>0.05), while we found a statistically significant correlation between consolidation and mortality (p<0.001). Twenty-two (10.7%) patients developed acute kidney injury (AKI) and one of them (0.5%) required hemodialysis. Among all patients, 20 (9.7%) had chronic kidney disease (CKD). Four (1.9%) patients were renal transplant recipients. The most common comorbidities were hypertension (n= 67, 32.5%), diabetes (n=46, 22.3%), CKD (n=20, 9.7%), and heart failure (n=15, 7.3%). The mortality rate was significantly higher in patients with AKI than those without (p<0.001). Additionally, the mortality rate was significantly higher in patients with CKD than non-CKD patients, in hypertensive patients than non- hypertensive patients, in patients with diabetes than those without diabetes, and in patients with heart failure than those without heart failure (p<0.001 for all).
According to the correlation analysis, there was a strong, negative, and linear correlation between creatinine and eGFR (r=-0.71; p<0.001). Also, there was a positive and significant correlation between the troponin I elevation and an increased mortality risk (r=+0.334; p<0.001) and D-dimer and an increased mortality risk (r=+0.382; p<0.001) (Table 2). On the other hand, there was no significant difference in the MCV, MPV, MPV/PC ratio, WBC, platelet, and eosinophil count between survivors and non-survivors (p>0.05). However, there was a positive and significant correlation between neutrophil count and mortality (r=+0.140; p=0.045), RDW and mortality (r=+0.332; p<0.001), and PLR and mortality (r=+0,320 p<0.001). When we used a median cut-off value of 148.5 for PLR, the significance of the correlation became more prominent (p<0.001). However, we found a negative and significant correlation between lymphocyte count and mortality (r=-0.308; p<0.001) and between Hb and mortality (r=-0.410; p<0.001) (Table 3).
Discussion
SARS-CoV-2 is a single-stranded, non-segmented, enveloped RNA, which belongs to the Beta-Coronaviridae family. A definitive diagnosis of SARS-CoV-2 infection is made using RT- PCR-NAT. The PCR positivity rate has been estimated as 63% for nasopharyngeal swabs [3]. In case of repetitive negative RT-PCR testing, immunoglobulin (Ig) M and IgG antibody titers must be checked to confirm the diagnosis [3].
In a retrospective study including 113 deceased patients, Chen et al. [4] reported that advanced age (>65 years) and male gender (73%) were the main risk factors for mortality. In a meta-analysis including 3,027 patients, Zheng et al. [5] showed that advanced age (>60 years) and male gender were the main risk factors for mortality. In our study, the gender distribution was comparable among the participating centers. Unlike previous studies showing male predominance in mortality, in our study, death events were seen equally in both genders (p>0.05). Although 71.9% of our patients were below 65 years of age, 75% of death events occurred in patients over 65 years of age. This finding indicates that advanced age (>65 years) is the main risk factor for mortality, which is consistent with the literature (p<0.001).
There is growing evidence suggesting that clinical presentation may widely vary from asymptomatic infection to severe pneumonia, acute respiratory failure, and even death. In a study including 72,314 patients conducted by the Epidemiology Working Group for NCIP Epidemic Response, Chinese Center for Disease Control and Prevention, the rate of asymptomatic patients was 1.2% [1]. In our study, this rate was 3.9%. Thoracic CT revealed ground-glass opacities in half of the asymptomatic cases. The mean NLR was 1.38 in asymptomatic patients and 4.52 in symptomatic patients, indicating a statistically significant difference (p<0.001). Similarly, the mean lymphocyte count was 1.337×109/L in symptomatic patients and 1.865×109/L in asymptomatic patients, indicating a statistically significant difference (p<0.05). In a study including 1,099 confirmed COVID-19 cases, Guan et al. [6] found fever in 87.9%, dry cough in 67.7%, and diarrhea in 3.7% of patients. In our study, the most frequent symptoms included fever (71.8%), dry cough (63.6%), fatigue (53.4%), dyspnoea (32.5%), myalgia (28.6%), diarrhea (14.6%), and anosmia/dysgeusia (8.7%). Correlation analysis revealed no significant correlation between fever, dry cough, fatigue, diarrhea, and anosmia/dysgeusia and mortality (p>0.05). The mortality rate was significantly lower in patients with myalgia (p=0.005). However, an increased severity of dyspnoea was found to be a significant predictor of mortality, consistent with previous studies (p<0.001) [4, 5]. In addition, no mortality was observed in the asymptomatic patient group. Previous studies have also shown that mortality rates ranged from 2.3% to 19.2% [7, 8].
Although thoracic CT mostly reveals non-specific lesions in COVID-19 patients, the most common imaging findings are pure ground-glass opacities, ground-glass opacities, consolidation, interlobular septal thickening, and air bronchograms. In a study examining the diagnostic value and consistency of thoracic CT versus RT-PCR assay in 1,014 COVID-19 patients, Ai et al. [9] reported a positivity rate of 59% for RT-PCR and 88% for thoracic CT. The sensitivity of thoracic CT for COVID-19 was found to be 97% based on positive RT-PCR results. The authors concluded that thoracic CT could be used as the main tool for the COVID-19 detection in epidemic areas. In our study, 183 (88.8%) of 206 patients had positive thoracic CT scans, while 23 (11.2%) patients had normal CT scans. No mortality was observed in patients with normal CT findings, whereas 24 (13.1%) patients with positive CT findings died, indicating a statistically significantly higher mortality rate in patients with positive CT findings (p<0.001). Although we found no significant correlation between the presence of ground-glass opacities, pleural effusion, mediastinal lymphadenopathy and mortality (p>0.05), the presence of consolidation was significantly associated with an increased mortality rate (p<0.001).
Several studies have demonstrated that chronic comorbidities in COVID-19 patients such as hypertension, diabetes, heart failure, coronary artery disease, asthma, and chronic obstructive pulmonary disease may worsen the prognosis and increase the mortality rate [8]. The SARS-CoV-2 binds to the angiotensin- converting enzyme 2 (ACE2) receptors and enters into the cells. ACE2 is abundantly present in humans in the epithelia of the lung, heart, kidney, and testicles and, less frequently, in the brain, liver, and small intestines. The relatively high amount of type 2 alveolar epithelial cell line, a major source of ACE2, in males than females has been blamed for the increased mortality rate in males with COVID-19. ACE2 plays a key role in the renin-angiotensin-aldosterone system (RAAS). It functions as the main modulator of RAAS by converting Ang I and II into Ang (1-9) and Ang (1-7), respectively. Previous studies have shown that ACE2 plays a protective role in acute lung injury [10]. Experimental studies have demonstrated that intravenous infusion of ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) increases the number of ACE2 receptors in the cardiopulmonary circulation [11]. In addition, ACE2 exerts a protective effect on atherosclerosis, hypertension, myocardial hypertrophy, and vasoconstriction. It has been well documented that ACE2 levels decrease with advanced age and in patients with diabetes or hypertension. SARS-CoV-2 infection has been shown to decrease ACE activity. The relatively high mortality rates among the elderly and patients with comorbidities can be attributed to the decreased ACE2 activity in these patients. In a study by Liu et al. [12], they showed that angiotensin II levels increased in COVID-19 patients, which was significantly associated with lung injury. In our study, consistent with previous findings, the most common comorbidities were hypertension (32.5%) and diabetes (22.3%). The rate of AKI at the time of hospital admission was ranged from 1% to 29% in previous studies [13]. Similarly, in our study, the rate of AKI was 10.7%. In another study, Zhang et al. [14] reported that mortality was 3.2-fold higher in COVID-19 patients with AKI. Likewise, the mortality rate was significantly higher among COVID-19 patients with AKI in our study (p<0.001). In a meta- analysis including 1,389 COVID-19 patients, Henry et al. [15] observed that the presence of CKD increased infection severity and mortality. In our study, 9.7% of the patients had CKD with a significantly higher mortality rate (55%) (r=+0.443; p<0.001). The downregulation of ACE2 related to SARS-CoV-2 infection adversely affects the cardiovascular system, as the cardioprotective effects of ACE2 are inhibited. Many studies have also shown that the incidence of myocardial injury varies from 10% to 35%, as evidenced by troponin elevation [16]. In addition, existing heart failure and cardiac events are associated with worse COVID-19 progression and increased mortality [16]. Consistent with these data, we found a positive and significant correlation between the troponin I levels and heart failure (r=+0.27; p<0.001). In our study, the rate of heart failure was 7.3% and the mortality rate was significantly higher in the patients with heart failure (p<0.001).
The underlying mechanisms of leukopenia, thrombocytopenia, and lymphocytopenia in viral infections include the bone marrow and stem cells being directly infected with the virus, increased cell destruction through the immune-mediated mechanisms, increased consumption of platelets, particularly in the lung tissue, and increased apoptosis in T lymphocytes [17]. WBC count is usually normal in SARS-CoV-2 infection, while lymphocytopenia can be seen in 50% to 89.2% of patients. In particular, more prominent lymphocytopenia with an increased WBC and neutrophil counts has been associated with an increased mortality rate [18]. Lymphocytopenia is more severe in ICU patients [7, 8]. The incidence of thrombocytopenia has been reported to range from 5% to 41.7%, and a low platelet count has been associated with more critical illness and an increased mortality rate in COVID-19 patients [19]. Several studies have demonstrated that low absolute eosinophil count is correlated with an increased risk of mortality and, when combined with CRP, it can be used as a valuable biomarker in predicting SARS- CoV-2 infection, as well as for the disease progression follow- up [20]. In general, lymphocytopenia is defined as an absolute lymphocyte count of <1.0×109/L. In our study, the rate of lymphocytopenia was 37.9%. The mortality rate was 24.4% in patients with a lymphocyte count of <1.0×109/L, while this rate increased up to 36.4% in patients with a lymphocyte count of <0.750×109/L. According to the correlation analysis, we found a negative and significant correlation between lymphocyte count and mortality (r=-0.31; p<0.001). In the present study, 95.1% of the patients had normal or low WBC count. Also, we could not find a significant relationship between the survivors and non- survivors patient group in terms of MCV, MPV, MPV / PC ratio, WBC, thrombocyte and eosinophil counts (p>0.05). However, we found a significant association between the neutrophil count and mortality (r=+0.14; p=0.045). We found a moderate, negative and significant correlation between Hb levels and mortality (r=-0.41; p<0.001). Consistent with previous studies [21], in our study, RDW increased in deceased patients than survivors. There was also a moderate, positive and significant correlation between RDW and mortality (r=+0.338; p<0.001). In a study by Qu et al. [22], they showed that PLR was associated with the degree of cytokine storm and might be used as a useful inflammatory indicator when monitoring critically ill patients with COVID-19. Similarly, in the present study, we found a moderate, positive and significant correlation between PLR and mortality (r=+0.320; p<0.001), indicating a statistically significantly higher mortality rate among the non-survivors (p<0.001).
The NLR, which is calculated as the absolute neutrophil count divided by the absolute lymphocyte count, is a potential indicator of systemic inflammatory response [23]. Many studies have demonstrated that NLR can be utilized as the most useful marker for predicting mortality [21, 19]. In a study, a cut-off NLR value of >3.13 has been shown to be useful in identifying and classifying COVID-19 critical who are likely to develop critical illness [24]. In our study, there was a moderate, positive and significant correlation between NLR and mortality (r=+0.329; p<0.001), and the use of a cut-off value of NLR as >3.13 significantly increased the mortality rate (22%) (r=+0.313; p<0.001). Furthermore, the increase in the CRP, an acute phase reactant used to detect inflammation, procalcitonin, ferritin, RDW, and neutrophil, platelet, and WBC counts is associated with the increased risk for critical illness and mortality. Similarly, we found a significant correlation between CRP and mortality, between ferritin and mortality, and between procalcitonin and mortality in our study (p<0.001 for all).
Although the underlying mechanisms of thrombotic complications have not been fully elucidated yet, a direct viral cytopathic effect, increased Ang II, which has a higher vasoconstrictor effect, decreased Ang (1-7) and Ang (1-9), which have vasodilator effects, and endothelial dysfunction may lead to microvascular thrombosis due to the increased proinflammatory cytokines [25]. All these mechanisms and the existing ACE2 in endothelial and myocardial cells may induce pulmonary and cardiac injuries. Previous studies have shown a significant association between troponins, markers of myocardial injury, and an increased risk for mortality. Similarly, in the current study, we found a significant correlation between the troponin I and D-dimer and an increased mortality risk (p<0.001).
Nonetheless, this study has some limitations. First, the relatively small number of patients in the non-survivor group may have led to bias in the interpretation of the results. Second, this study included only hospitalized patients, which precludes the generalization of the results to all COVID-19-positive patients. In addition, all patient data were recorded at the time of hospital admission and we were unable to perform the measurements later. Therefore, further large-scale, prospective studies using repetitive measurements are warranted to confirm these results.
Conclusion
Our study results suggest that coexisting diabetes, hypertension, heart failure, or CKD are associated with an increased risk for critical illness and mortality. The development of AKI also increases the mortality risk. The disease presenting with symptoms or positive findings on thoracic CT is of clinical relevance alone for the development of critical illness. Patients with dyspnea should be closely followed to prevent mortality or critical illness. The presence of dyspnea or consolidation on thoracic CT can predict the increased mortality risk in COVID-19 patients. In particular, patients with lymphocytopenia (lymphocyte count <0.750×109/L), an NLR of >5, and a PLR of >149 can be considered for early admission to the ICU.
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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Capecitabine suppresses seizure activity in rats with pentylenetetrazol-induced epilepsy
Ejder Saylav Bora 1, Halil Taşkaynatan 2, Mümin Alper Erdoğan 3, Özüm Atasoy 4, Oytun Erbaş 5
1 Department of Emergency Medicine, İzmir Katip Çelebi University Atatürk Research and Training Hospital, İzmir, 2 Department of Medical Oncology, Private Ege Şehir Hospital, İzmir, 3 Department of Physiology, İzmir Katip Çelebi University, Faculty Of Medicine, Izmir, 4 Department of Radiation Oncology, Dr. Lütfi Kırdar Kartal Research and Training Hospital, Istanbul Medeniyet University, İstanbul, 5 Depatment of Physiology, İstanbul Demiroğlu Bilim University, İstanbul, Turkey
DOI: 10.4328/ACAM.20407 Received: 2020-11-16 Accepted: 2020-12-20 Published Online: 2021-01-11 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S166-170
Corresponding Author: Ejder Saylav Bora, Izmir Katip Çelebi University Ataturk Research and Training Hospital, Emergency Medicine Izmir, Turkey. E-mail: saylavbora@hotmail.com P: +90 532 450 78 55 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2448-2337
Aim: Capecitabine was developed as a pro-drug of 5-FU. Epilepsy is a common and often debilitating neurological disease that is characterized by recurrent spontaneous seizures arising from abnormal electrical activity in the brain. The mechanism of the excitatory properties of folates is uncertain, but there is some evidence that they may act by blocking or reversing GABA-mediated inhibition.
Material and Methods: In this study, we investigated the potential anti-folate effects of capecitabine by administering doses of 250 mg/kg IP and 500 mg/kg IP.
Results: We show that capecitabine statistically suppresses seizure activity in EEG telemetry in the brain, prolongs the time to the first myoclonic jolt, and reduces Racine’s convulsion score, suppresses folate level and therefore significantly reduces PTZ-induced seizures.
Discussion: It can be assumed that the anti-tumoral mechanism and anti-epileptic mechanism are largely due to the anti-Folate effect in the brain.
Keywords: Capecitabine; Cancer therapy; Epilepsy; Folat level; Brain
Introduction
Capecitabine is an oral form of 5-FU. For all the side effects of capecitabine, it is similar to 5-FU but has a more appropriate profile [1]. Neurotoxicities seen in 5-FU are rare but serious. Although fluorouracil (FU) is a neoplastic drug, it is an antimetabolite that is frequently used in the treatment of many malignancies such as breast, esophagus, larynx, gastrointestinal and genitourinary system malignancies.
As this drug is cytotoxic, it has systemic side effects such as neutropenia, gastritis and diarrhea. Capecitabine, on the other hand, is a pro-drug of FU, which has been developed in order to have good tolerance through tumor-specific transformation in malignancies and to increase the concentration of intra-tumor drug transit, and is used orally in multiple malignancies [2].
In the study conducted by Zhang et al., it was shown that the CNS penetration of Capecitabine and 5-FU was not sufficient [3]. However, in a study by Michael L. et al., the efficacy of Capecitabin was demonstrated in patients who had previously received systemic therapy (including 5FU) for brain metastasis and developed progression [4] Albeit, it is not known why Capecitabin is more effective in brain metastases than 5-FU. Epilepsy is a neuronal pathology that results in abnormal episodic increases in electrical activity in certain neurons that can spread throughout the brain. Although our knowledge of epilepsy has expanded significantly over the past 50 years, we are still insufficient to explain its pathophysiology [5].
Antiepileptic drugs are used by 30% of epilepsy patients, but they continue to have seizures and great difficulties in epilepsy treatment. Consequently, it is thought that patients who experience seizures despite antiepileptic use have a refractory or refractory disease [6].
As it is known in the literature, antiepileptic drugs have a narrow therapeutic range, therefore the frequency of side effects is higher. These side effects may occur even in patients whose seizures are prevented by treatment [7].
It was reported that patients using antiepileptic drugs had folate vitamin deficiency and increased epileptic attacks during the administration of folate vitamin therapy to these patients [8]. In experimental studies, it was found that folate is a strong neuro-stimulant and causes more epileptic seizures, especially when applied directly to the nervous system [9].
The mechanism of the neurostimulating properties of folates has not been fully elucidated. However, there is evidence that this occurs as a result of blocking or reversal of GABA-mediated inhibition [10]. The epileptic phenomena caused by folates are similar to those induced by dissulating compounds (Bisuculin, strychnine, penicillin and picrotoxin). However, it differs in many respects from the induction of seizures by neurostimulant drugs (such as Kainic acid, carbachol and neostigmine) [10].
In animal experiments, intravenous (IV) sodium folate administered to animals induces seizure activity only at high doses. However, if the animal is already vulnerable to neurostimulation, or if the blood-brain barrier is damaged due to a local effect (for example, due to heat lesion), the epileptogenic effect of sodium folate administered IV is also reduced. If the blood-brain barrier is bypassed by intraventricular and intra- cortical administration, the convulsive effect is very high in all folate derivatives [9].
Folate-induced epilepsy models can be used to examine the basic mechanisms of epilepsy and the effects and side effects of antiepileptic treatments [9]. However, folic acid increases the kindling pattern of epilepsy and may even be used to directly induce epileptic attacks [10,11].
Low folate levels increase capecitabine-induced toxicity during treatment for colorectal cancer, but the relationship between serum folate level and capecitabine is unknown [12]. Neurotoxicities seen in 5-FU are rare but serious. In this study, we aimed to evaluate capecitabine in terms of folate synthesis and its consequences as an anti-convulsive effects due to folate levels and an anti-tumor mechanism that may be through folate.
Material and Methods
Ethical approval
The experimental methods and analyzes used in this study were approved by the “Experimental Animals and Research Ethics Committee” of the institution where the experiment was conducted. All experiments in our study were carried out in accordance with the ARRIVE experiment guidelines, the Animals Act of 1986, the European Union (EU) Directive 2010/63 / EU for Laboratory Animals and their experiments as per US National Institutes of Health, and the Animal Care and Use Manual. Experimental animal care
In our study, we used 48 male Sprague-Dawley rats weighing 200-250 g. Forty-eight rats were divided into two groups. The separated 24 rats were randomized to the electroencephalogram (EEG)-based experimental group, and the remaining 24 rats were randomized to the behavior-based experimental group. All rats were placed on a 12-hour light and a 12-hour dark cycle. Light for illumination was provided between 07:00 and 19:00. In quiet rooms, the room temperature was set at 22-24 ° C. The rats were fed standard laboratory food and tap water. Experimental procedures
In our study, seizures were induced in rats using PTZ, a convulsant chemical. A total of 24 rats were randomized to Group A for the EEG-based experiment and 24 rats to Group B for the behavioral experiment. All EEG recordings and behavioral evaluations were performed according to the previously described protocol [13]. EEG experiment (Group A)
Electrode implantation was performed in rats in Group A to facilitate EEG recording before the experiment. The rats were deeply anesthetized by intraperitoneal administration of 80 mg /kg ketamine and 4 mg /kg xylazine. Then, using precise stereotactic methods, small burr holes were drilled to accommodate the implants in the skull. Polyamide coated stainless steel wires with a diameter of 0.1 mm and a length of 10 mm with an electrical resistance of less than 1Ω were placed as the EEG electrode. The electrodes were placed in the dura on the frontal cortex, 2 mm lateral to the midline and 1.5 mm in front of the bregma. According to previously published protocols, a reference electrode was placed on the cerebellum at a distance of 1.5 mm posterior to the lambda in the middle [14]. Following successful placement, the electrodes were fixed with dental acrylic, a mixture of alloys and hydrocarbons typically used in dental restoration.
After the 12-day recovery period, the rats in Group A were
also randomized equally into 4 groups as follows: Group A1: Control group. No neurostimulant medication was given or intervention was made in this group; Group A2: Placebo group was given intraperitoneal saline; Group A3: Low-gray Capecitabin was given intraperitoneally at a dose of 250 mg/ kg; Group A4: Capecitabine was given intraperitoneally at a dose of 500 mg/kg. Pentylenetetrazole (PCT) at a dose of 35 mg /kg (intraperitoneal dose) was administered 30 minutes after Capecitabine or placebo administration to induce seizures in groups A2, A3 and A4. At 35 mg /kg PTZ (intraperitoneal), it results in epileptiform activity on the EEG without observable behavioral changes; EEG changes consistent with the seizure were observed with 70 mg/kg (high dose) PTZ (intraperitoneal). At these doses, EEG signals may be distorted.
The EEG recordings were started 5 minutes after the PCT administration and continued for 60 minutes. The rats were not sedated and were kept awake. EEG recordings were placed in special containers throughout all EEG recordings made with BIOPAC MP150 data collection.
The system is available from Biopac System Incorporated in Santa Barbara, California, USA. We recorded each rat’s EEG trace for 60 minutes at a sampling rate of 240 Hz (Hz). The signal was amplified 10,000 times and filtered in the 1-60 Hz range. After recording the EEG, we euthanized the test subject. The presence and severity of seizure activities in our animal model were quantified using the spike-wave percentage method, which is thought to be an ideal way to evaluate epileptiform activity in such studies and has recently been used in experiments. The validity of a sudden increase in the rates of seizures has been investigated and discussed in previous studiesin the literature [15]. EEG interpretation was performed by two blind neurophysiologists to provide quantitative evaluation. To generate a spike-wave percentage score, we split the EEG trace into one-second chunks, and our neurophysiologists evaluated each fragment for the presence of spike waves. The spike wave is defined by the amplitude of the EEG trace at least twice the height of the baseline activity. If there is at least one spike- wave in the next compartment, this segment is considered positive for the presence of spike waves. At intervals of 2 minutes (120 tracks), the number of positive tracks is divided by the total number of pieces (120) to obtain the surge percentage. The overall surge percentage is obtained by averaging the percentages found for every 2 minutes of operation.
Behavioral experiment (Group B)
Twenty-four rats in Group B were evaluated for visually observable seizure activity (Behavioral experiment). Brain electrodes were not placed in this group. As in the EEG experiment, the rats in Group B were randomized into 4 subgroups with 6 rats in each subgroup. Group B1 was an intervention-free control group. Groups B2, B3, and B4 received intraperitoneal PTZ for seizure induction at a dose higher than 70 mg / kg to induce clinically observable seizures.
As in the EEG experiment, 30 minutes after PTZ application, Group B2 was given saline placebo IP, Group B3 received capecitabine at a dose of 250 mg/kg intraperitoneally, and Group B4 received capecitabine at a dose of 500 mg/kg intraperitoneally.
We used two scales to assess the presence and severity of epileptic seizures. The first is Racine’s Convulsion Scale (RCS) [15], and the second is the time to first myoclonic contraction (TFMJ). RCS is a simple and reproducible 6-point scoring system for evaluating the epilepsy in rats, as described previously. It is a simple and reproducible 6-point scoring system for eval- uating murine epilepsy. A score of 0 indicates no visible convulsion. A score of 1 indicates twitching of vibrissae and pinnae. A score of 2 indicates motor arrest with more pronounced twitching. A score of 3 indicates motor arrest with generalized myoclonic jerks. In this experiment, the elapsed time (in seconds) upon which a score of at least 3 is obtained represents the rat’s TFMJ [13]. A score of 4 indicates tonic-clonic seizure activity while the animal still able to stay on its feet. A score of 5 indicates tonic-clonic seizure with loss of the righting reflex, and finally, a score of 6 indicates a lethal seizure.
The TFMJ is recorded in seconds following the administration of PTZ. In our experiment, almost all animals that demonstrated tonic generalized extension died from seizure activity. The observation period for PTZ- induced seizures were limited to 30 min, similar to previous experiments of this nature in the literature [13]. After this 30- minute evaluation, surviving animals were euthanized.
Results
Results of the EEG experiment
We found that administration of 250 mg/kg Capecitabine significantly decreased seizure activity, as measured via spike-wave percentage compared to a saline placebo (89,8% versus 67,2%, p < 0.005). The higher dose of Capecitabine also suppressed seizure activity, with a trend towards greater effectiveness (59,3% versus 89,8%, p < 0.001). However, the difference in seizure suppression between the lower and higher dose of LVDP was not statistically significant (Table 1). Representative tracings of the EEG experiment for each subgroup are provided in Figure 1 with higher resolution for better characterization of epileptiform activity.
Behavioral experiment results
The results of our behavioral experiment also suggest that Capecitabine has an antiepileptic effect in our murine model for epilepsy (Table 2). When compared to the placebo-treated group, Capecitabine significantly reduced RCS scores (via the Kruskal-Wallis test) and delayed TFMJ (via one-way ANOVA and post hoc Bonferroni tests). The mean RCS score decreased from 5.1 (which is quite severe, since a score of 6 indicates fatal seizure activity) to 3.8 (p < 0.05) with the higher dose of Capecitabine. There was a trend towards lower RCS scores with a higher dose of capecitabine as opposed to a lower dose of LVDP, however, this trend was not statistically significant (Mann-Whitney U test).
Likewise, Capecitabine significantly increased the TFMJ at both lower and higher doses (p < 0.05). Compared to the untreated B2 Group with a mean TFMJ of 56.6 s, in the B3 Group with the lower dose of Capecitabine, the TFMJ had increased to a mean of 103.8 s (p < 0.05). In group B4 with the higher dose of Capecitabin, the TFMJ had increased to a mean of 168.2 s (p < 0.01). The difference in mean TFMJ between lower and higher dose of LVDP was not statistically significant.
Discussion
In our study, we planned to investigate the antiepileptic potential of capecitabine, a drug traditionally used in breast cancer, in a rat model. We were motivated to conduct this study as there is new evidence that the pathophysiology of epileptic seizures and cough has overlapping cellular and neurochemical pathways [16,17].
Pre-synaptic and post-synaptic glutamate activity via N-methyl-D-aspartate (NMDA) and other receptors also plays an important role in the pathogenesis of epilepsy [18]. For these reasons, pathways related to GABA and glutamate, the main inhibitory neurotransmitter in the brain, have become common targets of antiepileptics. For example, drugs that increase GABA-mediated inhibition may function as clinically used antiepileptics to treat various syndromes of focal and generalized epilepsy. Glutamate receptor antagonists, both NMDA and non-NMDA, are also potent antiepileptics used in many animal models of epilepsy [19].
Some patients using AEDs are at risk for low serum folic acid levels. RBC and serum folate are reduced in 90% of patients taking phenytoin (PHT), carbamazepine (CBZ) or barbiturate. AEDs that do not induce cytochrome P450 enzymes are not associated with low levels of folic acid [20]. Lamotrigine (LTG), an AED with poor folate properties in vitro, has been reported to have no alterations in serum or RBC folate [21]. Serum folate levels in patients using zonisamide (ZNS) were not different from controls [20]. Therefore, low serum and RBC folic acid increase the risk of fetal birth defects in women of childbearing potential. In both men and women, low levels of folic acid are associated with an increased homocysteine and an increased risk of cardiovascular disease. Studies report that routine folic acid supplementation is important for women and men taking AEDs [19,20].
Data on the effects of valproate (VPA) on folic acid are conflicting. Most authors report that valproate does not reduce folate levels, but can interfere with folate metabolism by inhibiting glutamate formyltransferase, an enzyme that mediates folic acid production [22]. Since valproate does not reduce folic acid level, patients using valproate can be included in future studies to see the effects of Capecitabine.
Various AEDs may decrease folate serum levels affecting secondary cerebrovascular events in various epileptic patients [23]. In our study, it was observed that folic acid levels in the brain in the Capecitabine groups decreased significantly compared to the levels of the PTZ + Saline groups. Normally, folate causes seizures [10], and we think that Capecitabine acts like AEDs by lowering folate levels and possibly halting seizures. According to our data, Capecitabine reduces folic acid in the brain as an AED, and in epilepsy patients taking capecitabine the folate level will likely to decrease significantly for this reason, and patients should probably take folate supplements. In the EEG data, we observed strong evidence of seizure suppression with aapecitabine. In rats not receiving Capecitabin, fluoride EEG abnormalities were observed, including delta, theta, and spike waves. Treatment with aapecitabine at doses of 250 mg/kg and 500 mg/kg IP resulted in decreased epileptiform activity, and thus we concluded that Capecitabine was effective in alleviating PTZ-induced epilepsy.
Studies conducted with levetiracetam and dextromethorphan showed a decrease in RCS and FMJ and spike percentage in parallel with our study. This suggests the assumption that capecitabine, like these drugs, stops epileptic seizures through GABA inhibition [24].
Folate deficiency in normal tissues is associated with DNA strand breaks, impaired DNA repair, increased mutations, and abnormal DNA methylation, thus making them susceptible to neoplastic transformation. In contrast, if DNA replication and cell division are accelerated, folate deficiency causes ineffective DNA synthesis and ultimately results in inhibition of tumor growth and progression. This mechanism forms the basis of antifolate- based cancer chemotherapy [25]. Notwithstanding that Capecitabine does not penetrate the blood-brain barrier sufficiently, people who develop brain metastases benefit from Capecitabin [4]. Although it is not the primary endpoint of this study, it is also possible that brain low folic acid level due to Capecitabine may be the cause of the antitumor effect Capecitabine on brain metastases. Conclusion
In conclusion, Capecitabine behaves like an anti-epileptic drug by using its anti-folate effect. Although Capecitabine does not pass the blood-brain barrier well, we think that it is more effective in brain metastases due to its effect on the amount of folate in the brain. Further studies will clarify different effects of Capecitabine.
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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Ejder Saylav Bora, Halil Taşkaynatan, Mümin Alper Erdoğan, Özüm Atasoy, Oytun Erbaş. Capecitabine suppresses seizure activity in rats with pentylenetetrazol- induced epilepsy. Ann Clin Anal Med 2021;12(Suppl 2): S166-170
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The significance of radiological and laboratory findings in the diagnosis of new COVID-19 disease
Keziban Ucar 1, Yildiz Ucar 2, Hale Turan Ozden 3, Aynur Yonar 4
1 Department of Emergency Medicine, Konya Application and Research Hospital, Baskent University, Ankara, 2 Department of Pulmonary Disease, Konya Private Meram Akademi Hospital, Konya, 3 Department of İnfection Disease, Baskent University Faculty of Medicine, Ankara, 4 Department of Statistics, Faculty of Science, Selcuk University, Konya, Turkey
DOI: 10.4328/ACAM.20408 Received: 2020-11-17 Accepted: 2021-01-12 Published Online: 2021-02-09 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S171-176
Corresponding Author: Keziban Ucar, The Emergency Department of Konya Application and Research Hospital, Baskent University, Selçuklu, Konya, Turkey. E-mail: dr_kezi@hotmail.com P: +90 505 7400983 Corresponding Author ORCID ID: https://orcid.org/0000-0001-9188-0266
Aim: The new coronavirus disease (COVID-19), which first appeared in Wuhan, China in December 2019 and spread rapidly throughout the country, has rapidly becoe a pandemic and a global threat within the first months of 2020. In this study, we aimed to compare the laboratory findings of the patients with negative and positive polymerase chain reaction (PCR) tests results due to COVID-19-like findings in chest computed tomography (CT).
Material and Methods: The study included 49 patients admitted to the emergency department with the suspicion of COVID-19 due to the positive findings on chest CT. Nasopharyngeal swabs were taken from each patient. Whole blood count and biochemical parameters were examined, and as a result of swab investigations, the laboratory values of positive and negative results were compared in order to diagnose COVID-19 cases.
Results: A total of 49 patients were included in the study. The swab specimensobtained from the nasopharynx were evaluated using the reverse transcription PCR (RT-PCR) test. While the RT-PCR positivity was observed in 13 patients (Group 1), the RT-PCR negativity was found in 36 (Group 2). The mean age of all participants was 55.7±17.3 years; in Group 1, however in Group 1, the values of leukocyte, lactate dehydrogenase and ferritin were observed to be higher and lymphocyte count was significantly lower, compared with thosein Group 2.
Dicussion: Previous studies have shown that the diagnosis of new COVIDV-19 disease and its clinical features should be based on a comprehensive understand- ing of radiographic features and laboratory investigations. Patients with clinical suspicion and those with exposure, fever and a history of positive findings on chest CT should be rapidly diagnosed with molecular technology. The RT-PCR test was developed as a widely used method to detect viral RNA. Although the RT-PCR test is considered the gold standard diagnostic method, this method has some limitations. Clinical findings, history, physical examination and radiologi- cal findings were compatible with COVID 19 in our study, the RT-PCR test results were negative in some patients.
The new COVID-19 disease is a very contagious condition leading to devastating consequences. Therefore, the clinical, radiological and laboratory findings should be taken into account as a holistic approach in the diagnosing process of new COVID-19 disease.
Keywords: New Coronavirus; Pandemics; Radiology
Introduction
Corona viruses are undivided positive RNA viruses of the coronaviridae family. Coronaviruses can infect mainly humans, as well as all other mammals [1]. For the first time, the cases of viral pneumonia were reported following contact with the products in a seafood market in Wuhan, Chinain December 2019. Later, the agent was determined to originate from severe acute respiratory syndrome-CoV-2 (SARS-CoV-2), and the disease caused by the coronavirus was named as the new coronavirus disease 2019 (COVID-19) [2]. It has been observed that the clinical findings of SARS-CoV-2 infection in hospitalized patients in Wuhan started as an asymptomatic disease and mild upper respiratory tract infection, and then developed into a broad spectrum accompanied by respiratory failure that could result in severe viral pneumonias [3]. In addition, COVID-19 has been reported to cause the fatality rate of around 2% due to progressive respiratory failure and massive alveolar damage [4]. According to the latest guideline of 2019-nCoV (6th version trial) published by the Chinese Government, it has been reported that the diagnosis of COVID-19 should be confirmed with the reverse transcription-polymerase chain reaction (RT-PCR) test. In addition, the correlation of respiratory functions or blood samples was proposed as a key indicator for hospitalization. However, due to the limitations in collecting and handling specimens and kit performance, the total positive rate of RT- PCR for throat swab samples was reported to be approximately 30 to 60% in the first presentation [5]. In the current emergency, the low sensitivity of RT-PCR means that many COVID-19 patients may not be diagnosed and will not receive appropriate timely therapeutic interventions, and given the highly infectious nature of COVID-19, such patients pose risks to infect larger populations. In terms of pulmonary challenges, chest computed tomography (CT) is a relatively easy approach to perform, and thus the diagnosis can be implemented more rapidly. In this context, chest CT may be beneficial for the diagnosis of COVID-19. As reported in a previous study, chest CT demonstrates typical radiographic features in almost all COVID-19 patients, including in ground-glass opacities, multifocal irregular consolidation and/or interstitial changes with peripheral distribution [6]. Such CT findings have also been observed in patients with clinical symptoms, but having RT- PCR (-) results. In a study, it has been noted that the current RT-PCR test has limited sensitivity, and chest CT can elucidate pulmonary abnormalities compatible with COVID-19 in patients with negative RT-PCR test results at an early stage [7]. In our study, we aimed to compare other laboratory and clinical findings of the patients with negative and positive RT-PCR results compatible with COVID-19 obtained on chest CT.
Material and Methods
The study enrolled, a total of 49 suspected COVID-19 patients who were admitted to the emergency department and followed-up in Konya Application and Research Hospital of Baskent University between March 2020 and April 2020 were included in the study. Approvals from Baskent University and Ministry of Health Ethics Committee were obtained. Based on the history and clinical features, patients with suspected COVID-19 disease underwent chest CT without contrast. In light of CT findings, those with symptoms such as bilateral ground- glass appearance, peripheral and dorsal consolidation, paving- stone patterns mainly in the middle and zones, multilobar air bronchograms and vascular enlargement were hospitalized. Data such as age, gender and patients’complaints were also recorded. Meanwhile, the laboratory investigations detected on admission were evaluated. The values of leukocyte- white blood count (WBC), neutrophil, lymphocyte, platelet, neutrophil/lymphocyte ratio (NLR), monocyte, C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) were assessed and recorded. Afterward, nasopharyngeal and throat swabs were taken from each patient for the RT-PCR test. The patients with RT-PCR (+) and (-) results were classified into two groups: Group1 and Group2, and other laboratory findings like age, gender and patients’ complaints were also compared. Laboratory Investigation:
Complete blood count (CBC) measurements were performed using a routine electronic blood count device (Cell-Dyne 3700, Abbott, Abbott Park, IL, USA). For the measurements of CRP, LDH, ferritin, AST and ALT, routine biochemistry kits were used. Nasopharyngeal and throat swab tested positive for SARS- CoV-2 PCR.
Statistical Analysis
Statistical analysis was performed with the IBM SPSS Statistic 22 and Python 3.7 software. To visualize the data and interpret them better, box-plot graphs for each variable according to groups are also given below. These graphs show the minimum, first quartile, median (second quartile), third quartile, maximum and outliers values of variables by group.
The results of the descriptive statistics for considered variables were given as mean±standart deviation (SD) (min and max). To check the normality and variance homogeneity, the Shapiro- Wilk normality and the Levene tests were used, respectively. The independent t and Mann- Whitney-U tests were subsequently conducted to examine the differences between the groups. P-value of < 0.05 was considered statistically significant.
Results
The study was conductedin Konya Application and Research Hospital of Baskent University between March 2020 and April 2020. A total of 49 patients whose chest CT findings were compatible with COVID-19disease and aged 18 years and over were included in the study. Thirty-three cases whose chest CT findings werenot evaluated in favor of COVID-19; and those having incompatible clinical features with COVID-19 intheir history were excluded from the study. Among the patients, 29 were men (59.1%), and 20 were women (40.9%); the RT-PCR (-) and RT-PCR (+) were detected in 36 (73.4%) and 13 (26.6%) patients, respectively. Patients with RT-PCR (+) and RT-PCR (-) were named as Group 1 and Group 2. Among all patients in Group 1, cough was seen as the most common complaint followed by shortness of breath, fever, nausea, vomiting and fatigue. However, the most common complaint in Group 2 was fever, and such challenges as shortness of breath, cough, muscle pain, nausea, vomiting and diarrhea were detected as accompanying complaints. The mean age of all patients was 55.7±17.3 years, while the age rates were determined
as 57.69±18.186 and 54.94±17.27 in Group 1 and Group 2 respectively. No difference was detected between the average age rates of both groups (p=0.63).
While the average WBC value of the patients in Group 1 was 9.30±4.06, the value was found to be 6.59±3.35 of Group 2. When comparing the WBC values in both groups, the value was found higher in Group-1, and the difference was considered statistically significant (p=0.012). In terms of the average neutrophil values of both groups, no statistically significant difference was observed between the values of both groups (p=0.094). When the lymphocyte values in both groups were compared, the mean lymphocyte value in Group 1 was seen to be lower, and the difference was accepted as statistically significant (p=0.010). As to the NLR values, there was no significant difference between the results of the two groups (p=0.404). In addition, no significant difference was seen between the platelet values of both groups (p=0.99). When the average monocyte counts were compared, it was seen that there was no difference between both groups (p=0.190). In terms of the CRP values of both groups, there was no significant difference betweenthe CRP values of both groups (p=0.549).The difference between the LDH values of both groups wasinsignificant (p=0.777). When the ferritin values of both groups were compared, the mean ferritin value was higher in Group 1 (p=0.003).There was also a significant difference between the mean ALT and AST values between both groups. Both ALT (p=0.013) and AST values (p=0.009) were detected to be higher in Group 1 (Tables 1, 2) (Figures 1, 2, 3).
Discussion
The new COVID-19 disease has become a rapidly raging health issue across the world. SARS-CoV-2 is the seventh member of the coronaviridae family, infecting humans. SARS-CoV2 causes a serious infection in the lower respiratory tract in a similar manner to SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) [10]. The clinical picture of COVID-19 can include such disorders as fever, cough, fatigue, muscle pain, acute respiratory failure progressing with diarrhea and pneumonia, metabolic acidosis, septic shock, coagulopathy and organ failure such as liver, kidney and heart can be seen with fever, cough, fever and fatigue [4].
Considering different age segments prone to the condition, all segments are generally susceptible to COVID-19, regardless of age or gender, and those between 30 and 79 years of age make up 86.6% of all cases [8]. In our study, however, the mean age was 55.7 years, and there was no difference between the mean age of the patients with RT-PCR (+) and (-) test results.
In various studies conducted so far, common symptoms of the hospitalized COVID-19 patients were emphasized as fever (98.6%), fatigue (69.6%), dry cough and diarrhea. In other studies, less common symptoms of COVID-19 were reported to be muscle pain, confusion, headache, sore throat, runny nose, chest pain, sputum production, nausea and vomiting [4,9]. In our study, the most common complaints among the patients with both RT-PCR (+) and RT-PCR (-) test results were also dry cough, fever and shortness of breath.
In diagnosing COVID19, healthcare professionals face many difficulties because laboratory findings and radiographic images may not be always compatible with clinical features and contact history declared by patients [10]. Laboratory tests for COVID-19 include genomic sequencing, RT-PCR and serological methods (enzyme-linked immunosorbent assay (ELISA). In addition, because the appearance of the new coronavirus- induced pneumonia has been varied rapidly, decision-making for early diagnosis and evaluation of the severity of COVID-19, as well as follow-up of patients is highly dependent on the professional experience of specialists. Therefore, there is no definite method for diagnosing this condition yet [11]. Previous studies have shown that the diagnosis of new COVIDV-19 disease and its clinical features should be based on a comprehensive understanding of radiographic features and laboratory tests [12]. In accordance with recommendations in the literature, our study developed an approach, based on the patient’s medical history, clinical picture, physical examination, and chest CT and laboratory findings. We constituted a treatment protocol by taking into account that positive or negative RT-PCR test alone was insufficient to detect COVID-19. As a result, clinically suspected patients and those with exposure, fever and a history of positive chest CT findings should be rapidly diagnosed with molecular technology [13].
The RT-PCR test was developed as a widely used method detect viral RNA. Although the RT-PCR test is considered the gold standard diagnostic method, this method has some limitations. These limitations include short-term positivity of nasopharyngeal swabs, false- negative results, cross- contamination of the specimens and inconsistencies in collecting samplesand preparats, which have also reduced the use and reliability ofthe RT-PCR test. Although clinical findings, history, physical examination and radiological findings were compatible with COVID-19 in our study, the RT-PCR test results were detected negative in some patients. There is no clear complete blood or biochemical markers for the diagnosis of COVID-19 yet. In a study, it is reported that the CBC and CRP values increase in severe cases (the guidelines for diagnosis and treatment of novel coronavirus (2019-nCoV) infected pneumonia (6th ed.) issued by the National Health Commission of China). Several studies have also found that CBC is significantly higher [14]. Thus, CBC is considered to be the most available, efficient and economic examination. In our study, WBC values in all patients were also higher than normal laboratory values, and the increase was determined to be more pronounced in patients with RT-PCR (+). Lymphocytes play a key role in balancing the immune system and maintaining the inflammatory response in the body. There are studies emphasizing that COVID-19 reduces blood lymphocyte levels during the infection period, and this is important for planning a treatment strategy [15,16].
In another study, the lymphocyte count was found to be significantly lower in patients diagnosed with COVID-19. In this context, it was emphasized that lymphopenia is a valuable marker in the diagnosis process [17]. In our study, however, the mean lymphocyte level was below normal laboratory limitsin all patients, and the level was significantly lower in the patients with RT-PCR (+).
NLR is produced from neutrophils and lymphocytes in circulation and is vital due to its association with inflammation. There are studies emphasizing the course of NLR in COVID-19 cases. However based on the literature, NLR has been shown to be more effective in showing the prognosis of COVID-19. Among the patients with poor prognosis, an increase has been reportedin NLR values [18]. In our study, no difference was detected between the NLR values of the patients with RT- PCR (+) and RT-PCR (-). In some studies, thrombocytopenia was detected in COVID-19 patients. However, in these studies, thrombocytopenia was observed in serious cases, or among those where the disease was severe [17]. In our study, it was seen that the patients’ platelet values were within the normal limits, and there was no difference between the patients with RT-PCR (+) and RT-PCR (-). There are also studies demonstrating excessive monocyte and macrophage activation and the related cytokine storm in the development of the complications originated from COVID-19 [19]. Despite this, number of studies investigating the monocyte abnormalities in COVID-19 is patients still limited. A study comparing COVID-19 patients with normal healthy individuals found, no difference between the two groups in terms of monocyte counts, and it was thought that monocytes counts may be proportional to disease severity [20]. In our study, monocyte counts were determined within the normal limits, and no significant change was observed between the monocyte counts in the patients with RT-PCR (+) and RT- PCR (-). Increased CRP is a parameter that can be used for early diagnosis of pneumonia and an important i indicator for the diagnosis and evaluation of severe and infectious pulmonary diseases. CRP levels are associated with the level of inflammation, and the concentration level of CRP is not affected by factors, such as age, gender and physical condition [21].
In a study conducted with patients with COVID-19, increased CRP was stated to be a significant and valuable marker both for diagnosis of pneumonia and for determining its prognosis [22]. The level and course of CRP are recommended for follow-up and treatment of COVID-19 patients. In our study, the CRP values were observed to exceed normal laboratory limits in patients with both RT-PCR (+) and RT-PCR (-) test results.
Previous studies have suggested that LDH plays an important role in detecting lung damage caused by COVID-19 and in determining the severity of the disease [23]. In addition, in another study, the LDH level was considered useful in the diagnosis of COVID 19 [24]. In our study, the LDH level was found to be high in both groups with positive or negative RT-PCR. Moreover, the increase was found to be higher and significant in RT-PCR (+) group, compared to RT-PCR (-) group. In a study conducted with the patients followed due to COVID-19, serum ferritin levels were found to be high in case of severe disease [25]. In our study, the ferritin level was found significantly higher in patients with RT-PCR (+). A study found that patients with RT-PCR (+) had higher AST and ALT values, compared to those with RT-PCR (-) [26]. In our study, AST and ALT values were higher in the RT-PCR (+) group.
Limitation:
In our study, the number of participants was relatively small. In addition, the cases could not be followed-up for a long time, and our study was designed based on laboratory parameters. Conclusion:
The present study, concluded that radiological and laboratory
findings should be evaluated together, rather than the definitive positivity of the RT-PCR tests in the diagnosis of new COVID-19 disease. We consider that the negativity ofthe RT-PCR test alone is insufficient to rule out the diagnosis of COVID-19, and that a combination of clinical parameters, history, and radiological and laboratory findings will be more meaningful and provide a more accurate diagnosis. In addition, we found that lymphopenia was more prominent during the period when the RT-PCR test results were (+), while neutrophil, AST, ALT, ferritin and LDH levels were higher during the period when the RT-PCR test results were (-). We also consider that further studies including larger series should be beneficial to elucidate the entity.
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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Keziban Ucar, Yildiz Ucar, Hale Turan Ozden, Aynur Yonat. The significance of radiological and laboratory findings in the diagnosis of new COVID-19 disease. Ann Clin Anal Med 2021;12(Suppl 2): S171-176
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Antiepileptic activity of Essential Oil isolated from Commiphora Myrrha resin and its effect on brain GABA level
Bader Alsuwayt, Vijay Chidrawar
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Northern Border University, Rafha, Kingdom of Saudi Arabia
DOI: 10.4328/ACAM.20409 Received: 2020-11-21 Accepted: 2020-12-23 Published Online: 2021-01-08 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S177-182
Corresponding Author: Bader Alsuwayt, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Northern Border University, Rafha, 91911, Northern Province, KSA. E-mail: alsuwayt.b@gmail.com P: +966-549944377 Corresponding Author ORCID ID: https://orcid.org/0000-0002-3435-7994
Aim: The present study was undertaken to investigate the antiepileptic activity of the essential oil of the Oleo-gum-resin obtained from Commiphora Myrrha (CM) resins.
Material and Methods: The essential oil from Commiphora Myrrha (EOCM) was isolated using the Clevenger apparatus. The anticonvulsant effect was exam- ined against pentylenetetrazole (PTZ), strychnine, and maximal-electroshock (MES)-induced acute convulsions in mice. Flumazenil and diazepam were added to establish the anticonvulsant mechanism of EOCM. To understand the effect of EOCM on brain GABA level, intact mice brains were harvested and GABA level was determined.
Results: EOCM has shown the maximum decline in spontaneous motor activity at 2 hours. EOCM has not shown any protection against the strychnine-induced model. In the PTZ model, mice treated with EOCM at medium (p<0.01) and high dose (p<0.001) have shown a significant and dose-dependent increase in the latency of tonic convulsions and a decline in % mortality compared to the control group. Against the MES model, EOCM at medium (p<0.05) and high doses (p<0.01) have shown a significant decline in the length of hind-limb tonic extension (HLTE) and % mortality compared to the control group. A high dose of EOCM + diazepam (0.5 mg/kg/bw) has shown a synergistic effect. Flumazenil drastically reverses the protection offered by EOCM and diazepam. Moreover, EOCM plain has increased GABA levels in the brain.
Discussion: EOCM is very useful in the control of clonic seizures, and the effect is related to the GABA-A receptor Cl ̄ channel modulating property and partly by increasing GABA levels in the brain.
Keywords: Acute seizure; Commiphora Myrrha; Essential Oils; Maximal-Electroshock; Pentylenetetrazole; Strychnine
Introduction
Worldwide, nearly 20-30% of patients suffer from seizures due to epilepsy, and around 20% of patients remain refractory to currently available antiepileptic drugs (AEDs) [1, 2]. Recently, extensive research on the medical plants and their isolated compounds has been carried out that may provide new potent and alternative treatment options for the management of various types of CNS disorders [3]. Certain types of aromatic plants are used in medicine because of their essential oils (EOs) and/or phytochemical elements as main elements. In many cultures, including the Middle-East, India, China, and Brazil, EOs have been used as anticonvulsants in traditional medicine [4]. Moreover, recent findings on EOs and their main elements have caught our attention to screen aromatic plants to elucidate their scientific and biological aspects, which could provide us a lead molecule with advantages over synthetic AED [5].
One such herb, Commiphora Myrrha, CM (family: Burseraceae) grows in the Middle-east and Africa and has a long history of medicinal application [6, 7]. Phytochemical screening of myrrh showed the presence of 3–8% essential oils, 30–60% water- soluble gum, and 25–40% alcohol-soluble resins beside a series of metabolites including terpenoids, steroids, flavonoids, lignans, carbohydrates, and long-chain aliphatic alcohol derivatives were reported in Commiphora species [8].
Based upon the traditional claim, the presence of essential oils in the CM, makes the plant venerable for the scientific evaluation. The anti-epileptic activity of EOs isolated from an oleo-gum resin derived from CM was screened epilepsy models with chemoconvulsant (PTZ and strychnine) and electrical stimulation (maximum electric shock).
Material and Methods
Materials
Instruments: Clevenger apparatus, heating mantle, condenser, electro convulsometer (model no: MI.PH-1017), actophotometer (model no:MA-123).
Chemicals: Diazepam, pentylenetetrazole (PTZ), strychnine and flumazenil were purchased from Sigma Aldrich, USA.
Plant authentication
Arial parts of the CM were collected during the middle age of the plant from the Northern region of Saudi Arabia and verified by the Department of Natural products, Northern Border University and a duplicate herbarium was also retained (NBU/ NP/2019-07) in the department.
Collection
The oleo-gum resin of CM was collected from the cracks formed in the bark of the tree between January and February 2020, shade dried for a week and washed with distilled water to remove the unwanted debris.
Extraction of Essential Oil from CM resin
The dried oleo-gum of CM was powered with a pulverizer. The powered resin was then passed through sieve #40 to get a fine powder and processed for EOs separation.
Powdered resin (100 g) was loaded in the 1000 ml round bottom flask (RBF) along with 500 ml of distilled water. Clevenger’s apparatus was attached to the RBF and the temperature of the heating mantle was set to around 160±1oC. The heating mantle was started until the content of the RBF begins to boil; vapors were condensed to cool back into liquid form. At the outlet cocks of Clevenger apparatus, EOs floats on the water. The total amount of separated EO, measured on Clevenger’s apparatus scale, was 0.9 ml as per the method reported by Costa et al. in 2014 [9]. The volatile oil was carefully collected in a sealed bottle and stored at -4O C for further use. Pharmacological Evaluation of EOCM
Acute Toxicity tests:
In vivo testing for the acute oral toxicity was carried out as per the OECD (Organization for Economic and Cooperation Development) section 15-423 guidelines [Available at websitehttps://doi.org/10.1787/9789264071001-en].
A random sampling technique was employed to select animals for toxicity testing. Female albino mice (n=6) weighing 20- 22g were fasted for 4 hours with free access to water only. The animals were divided into 2 groups (n=3), and all the mice were treated only once. Group 1 (control group) was administered with 10ml/kg/bw of maze-oil, while Group 2 (test) was treated with 10ml/kg/bw of extracted essential oil of CM (EOCM), diluted with 1ml of maze-oil p.o. Doses were selected based upon the maximum oral dose-volume, which must not exceed 1 ml/100 gm/bw of the mice. Later, mortality was observed in both the groups for the next 8 hours and once daily for the next 14 days, during this period no drugs were administered. During this period, the animals were observed for any signs of behavioral changes including locomotor activity (lethargy), lacrimation, salivation, defecation, the color of the fur, abdominal respiration, grooming, body weight changes, mortality, etc. (Table 1). Based on the results of acute toxicity testing, a dose of 2.5ml/kg/bw was selected as the median dose, and the other 2 doses were 1ml/kg/bw and 5ml/kg/bw as sub-max and super-max, respectively [10].
Experimental Animals
Official permission was obtained from the Institutional Animal Ethics Committee (IAEC) of the Faculty of Pharmacy, Northern Border University (permission number HAP-09-A-043). Swiss albino mice were strictly handled as per the guidelines mentioned by the National Committee of Bioethics (NCBE). Spontaneous locomotor activity (SMA)
The mice were divided into two groups (n=6). Group 1 received 5ml/kg/bw of EOCM mixed with maze-oil and Group 2 received 5ml/kg/bw of maze-oil only. Treatment in both the groups was by p.o. route. Immediately after the oral administration, the mice were individually placed in an activity cage (actophotometer), and SMA was recorded for 5min. The procedure was repeated for all the animals (Groups 1 and 2), by resetting the counter to zero. The recording was done six times with an interval of 30 minutes (0, 30, 90, 120, 150 and 180min) [11]. Pentylenetetrazole-induced convulsions
A fresh lot of Swiss albino mice weighing 22-24 g were procured from the Central animal house facility at Northern Border University and acclimatized for the next 10 days. The animals were divided into 7 groups (n=8). Group-1, as control (maze-oil, 5ml/kg/bw, p.o) Groups 2 and 3 were treated with diazepam 0.5 and 1 mg/kg/bw, i.p. respectively, whereas Groups 4, 5, and 6 were treated with 1, 2.5, and 5 ml/kg/bw EOCM, respectively. Group 7 received diazepam 0.5mg/kg/bw + EOCM 5ml/kg/bw. All the test and standard groups were treated with PTZ (80mg/ kg//bw, i.p.) after 2 hours and 30 minutes, respectively. Immediately after PTZ administration, the mice were observed for the latency of clonic convulsions and mortality protection for the next 60 minutes. The ability of the EOCM to prevent or delay the onset of the hind-limb extension and to reduce mortality was taken as an indication of anticonvulsant activity [12].
Effect of flumazenil + EOCM on PTZ-induced convulsions
To understand the protective effect of EOCM against PTZ- induced convulsion, we have used flumazenil as a GABA-A receptor antagonist. Thirty-two, male Swiss albino mice were divided into 4 groups (n=8). Group 2 was treated with flumazenil (2mg/kg/bw, i.p.), 5 minutes before the administration of diazepam (0.5mg/kg, i.p.) and PTZ was administered after 30 minutes. For Group 3, the same protocol was followed with the high-dose of diazepam (1mg/kg/bw, i.p.). In Group 4, flumazenil was administered 30 minutes before PTZ administration. In Group 5, flumazenil (2mg/kg/bw, i.p.) was administered 5 minutes before EOCM and 2 hours before PTZ administration [13].
Strychnine-induced convulsions
Another fresh lot of the Swiss Albino mice weighing 22-24g were used to test the EOCM against strychnine-induced epilepsy. The mice were divided into 5 groups (n=8). Group 1 was the control (maze-oil, 1ml/kg/bw, p.o.), Group 2 was used as a standard (diazepam, 0.5mg/kg/bw, i.p.), Groups 3, 4 and 5 were labeled as a test, treated with 1, 2.5 and 5ml/kg/bw of EOCM. Strychnine (2mg/kg/bw, i.p.) was injected i.p to the mice 30 minutes after vehicle/extracts/standard drug administration. The latency to the first convulsion and the percentage of mortality were recorded for 30 minutes. Animals surviving more than 30 minutes were considered to be protected [14]. Maximum Electroshock (MES)-induced seizures
The tonic convulsion of the hind-limb extremities of the mice was induced by passing an alternating electrical current of 50 Hz and 150 mA for 0.2 sec using electrodes in the ear pinna [16]. Another fresh lot of forty Swiss Albino mice were divided into 5 groups (n=8). Group 1 was used as normal control (maze- oil, 1ml/kg/bw, p.o.), Group 2 as a standard (diazepam, 0.5 mg/ kg/bw, i.p.), and Groups 3, 4 and 5 were considered as a test, treated by 1, 2.5 and 5 ml/kg/bw of EOCM. Two hours later, after test drug administration and 45 minutes later after vehicle and standard drug administration, MES was applied. The number of animals protected from hind-limb-tonic-extension seizure (HLTE) and the time spent in this position were determined [15]. Effect of flumazenil + EOCM on MES-induced seizures Thirty-two male Swiss albino mice were divided into 4 groups (n=8). In the second group, animals were treated with flumazenil (2mg/kg/bw, i.p.), 5 minutes before the administration of (*TRE-Tremor, CON-Convulsions, SALI- Salivation, Diah – Diarrhea, LET-Lethargy) diazepam (0.5mg/kg/bw, i.p.) and 30 minutes later, MES was applied as before. In Group 3, the same protocol was followed where the dose of diazepam was 1 mg/kg/bw, i.p. In Group 4, flumazenil was administered 30 minutes before the MES. In the fifth group, animals were treated with flumazenil (2mg/kg/bw, i.p.), 5min before EOCM, and 2 hours before MES. The same parameters were recorded as before.
Determination of brain-GABA level
A separate experiment was carried out in mice to determine the effect of EOCM on the brain GABA level. The mice were divided into 4 groups, (n=6). Group 1 was treated with 5ml/kg/bw maze- oil, p.o. whereas groups 2, 3, and 4 were treated with increasing doses of EOCM i.e., 1 2.5 and 5ml/kg/bw, respectively. All the groups were treated only once, 2 hours later, all the mice were sacrificed by the cervical dislocation and the intact brain was harvested. The brain homogenate was prepared using a tissue homogenizer [16]. GABA level in the brain was estimated as per the method described by Walia et al. in 2019 [17].
Statistical Analysis
Results are expressed as means ± SEM. Comparisons between the averages of series of values were performed by ANOVA followed by Dunnett’s multiple comparisons test using a Graphpad prism 9.
Results
Spontaneous Motor Activity (SMA)
Treatment with EOCM 5ml/kg/bw, p.o. represented a sharp decline in the mean SMA at 90 and 120 minutes of drug administration. The maximum CNS depressant activity was observed at 120 minutes compared to the plain maze-oil- treated group (Table 2).
Effect of EOCM on PTZ-induced convulsions
Animal groups treated with EOCM at medium (p<0.01) and high dose (p<0.001) have shown a significant and dose-dependent increase in the latency of tonic convulsions compared to the control group (Figure 1A).
Mortality protection of EOCM at doses (1, 2.5, 5ml/ kg/bw) were 12.5%, 50%, 62.5%, respectively. Animal group treated with diazepam 0.5mg/kg + EOCM 5ml/ kg/bw has shown 100% protection, the same as the group receiving diazepam 1ml/kg/bw (Figure 1B). Effects of flumazenil + EOCM on PTZ-induced convulsions
Flumazenil (2mg/kg/bw) + diazepam 0.5 and 1mg/ kg/bw significantly (p<0.001) reverses the effect of diazepam in prolonging the latency of clonic seizure. Mice treated with flumazenil + EOCM 5ml/kg/bw significantly (p<0.001) reverses the protective effect of plain EOCM 5 ml/kg/bw. (Figure 1 C)
The animal mortality protection (%) in the maze-oil and flumazenil groups was 0% against PTZ-induced seizure. Amusingly, treatment with flumazenil + EOCM 5ml/kg/bw reduced the protection from 62.5 % to 37.5% compared to the group receiving plain EOCM 5 ml/kg/bw (Figure 1D).
Effect of EOCM on strychnine-induced convulsions
Strychnine produced tonic seizures in all groups.
EOCM (1 and 2.5 ml/kg/bw) did not significantly affect the incidence of seizures and did not increase the latency of the seizure (Figure 2 A).
There was 25% protection offered by the combination of diazepam 0.5 + EOCM 5ml/kg/bw, whereas plain EOCM 5ml/kg/bw offered only 12.5 % protection (Figure 2 B).
Effect of EOCM on MES-induced seizures
Animal groups treated with EOCM at low (ns), medium (p<0.05) and high dose (p<0.01) have shown a significant decline in the length of HLTE compared to the control group. The animal group treated with a high-dose of EOCM + 0.5mg/kg/bw diazepam has shown the most significant (p<0.001) decrease in the duration of HLTE compared to the control group (Figure 3 A).
Mice treated with 0.5mg diazepam + 5ml/kg/bw EOCM have shown 100% protection against MES- induced seizures (Figure 3 B).
Effect of flumazenil + EOCM on MES-induced seizures Flumazenil increases the duration of HLTE when added in EOCM 5ml (p<0.001) compared to plain EOCM (Figure 3C). Flumazenil reverses animal mortality (%) when administered with EOCM 5ml/kg/bw from 50% to 25% compared to the group treated with plain
EOCM 5ml kg/bw (Figure 3D).
Effect of EOCM on brain-GABA level
EOCM has shown a slight but significant up-regulation in the level of GABA in the brain at medium (p<0.05) and high dose (p<0.01) compared to the control group (Table 3).
Discussion
The findings of the present study show that EOCM has potent anti-epileptic property against MES and PTZ-induced epilepsy, while it fails against strychnine-induced seizures. The results of the motor activity indicate the peak decline in SMA after 2 hours of EOCM administration, which gave us an idea to administer EOCM after 2 hours (where it has maximum CNS depressant activity) to induce convulsions in the mice. The normal state of the brain is maintained by a fine balance between excitatory (glutamate) and inhibitory (GABA/glycine) neurotransmitters. GABA-A- is a pentameric transmembrane Cl ̄ channel complex, composed of five α, β, γ subunits gated by a primary ligand (GABA) and modulated by secondary ligands, which include diazepam and few others. The binding site of the GABA is located on the β-subunit, which causes hyperpolarization (due to the influx of Cl ̄ ions) and decreases the firing rate of neurons [18].
It is clear that PTZ competes with GABA in the β-subunit of the GABA-A receptor Cl ̄ channel, whereas diazepam binds to the α/γ subunit interface of GABA-A receptor Cl ̄ channel and enhances the frequency of Cl ̄ channel opening by facilitating the effect of GABA and, hence, blunts the effect of PTZ [19]. EOCM-treated groups of animals have shown a dose-dependent increase in latency and a decrease in the mortality of the animals. There was a synergistic increase in the protection of both parameters by combining a high-dose of EOCM + 0.5 mg/ kg/bw diazepam. These findings suggest that the components of EOCM may be responsible for the above action.
According to a study published by Hanus LO et al. in 2005, the results of gas chromatography of EOCM show the presence of cuminic aldehyde, eugenol, metacresol, pinene, limonene, diterpenes, and sesquiterpenes [20].
Monoterpenes like α-pinene, eugenol, and limonene have proven antiepileptic activity [21]. Past literature suggests that the α-pinene potentiates GABA by binding to the GABA-A receptor at the diazepam binding site [22]. Following our findings and to confirm the above mechanism, flumazenil (2mg/kg/bw) was added along with the high-dose of EOCM and diazepam treated groups against PTZ-induced seizures. Flumazenil blunts the anticonvulsant effect of the EOCM and diazepam treated groups. Flumazenil is a competitive antagonist of diazepam at α/γ subunit interface the function of GABA-A Cl ̄ channels, this fact tells us that EOCM and diazepam have the same binding site.
Strychnine is an alkaloid that causes lethal convulsions by antagonizing inhibitory glycine receptors. EOCM has not shown any protection against the strychnine-induced chemoconvulsant model, and it is stated that the protection offered by the EOCM is not via enhancing the effect of glycine.
In the third model, EOCM has shown a decrease in the duration of HLTE like diazepam treated groups in a dose-dependent manner. The protection offered by the EOCM maybe related to the presence of eugenol [23]. It was also stated that eugenol inhibits the activity of GABA-transaminase, causes a positive GABA-shift, to confirm this, we have introduced flumazenil (2mg/ kg/bw) along with a high-dose of EOCM + diazepam treated groups against MES-induced epilepsy [24]. Flumazenil drops the protection offered by the EOCM and diazepam. These findings propose a decreased level of GABA-transaminase, showing a positive GABA shift, but flumazenil competitively inhibits the binding of diazepam/EOCM to the β-subunit of the GABA-A ion-channel. Additionally, to confirm the aforementioned possibility, brain GABA levels were measured in mice treated with EOCM only. A medium and high dose of EOCM has shown a slight but significant dose-dependent rise in the GABA level. Taken together, it is suggested that EOCM might have down- regulated the GABA transaminase activity in the brain and up- regulate GABA levels, and there is also a strong probability of the agonistic activity of the EOCM to the GABA/benzodiazepine receptor complex.
There are some limitations in this study. The level of brain GABA transaminase was not taken into consideration, whereas the GABA level was estimated. Periodic estimation of GABA level at specified intervals might have answered the pick effect of EOCM on the GABA level, but based on the SMA results, GABA level was estimated only once.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: The author gratefully acknowledges the approval and the support of this research study by grant no PHM-2019-1-10-F 8387 from the Deanship of Scientific Research at Northern Border University, Arar, Kingdom of Saudi Arabia.
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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Bader Alsuwayt, Vijay Chidrawar. Antiepileptic activity of Essential Oil isolated from Commiphora Myrrha resin and its effect on brain GABA level. Ann Clin Anal Med 2021;12(Suppl 2): S177-182
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Are preoperative hematologic parameters predictive of intraoperative bleeding in orthognathic surgery?
Dilek Günay Canpolat 1, Halis Ali Çolpak 2, Nukhet Kutuk 3, Alper Alkan 3
1 Department of Oral and Maxillofacial Surgery, Erciyes University, Kayseri, 2 Department of Oral and Maxillofacial Surgery, Alanya Alaaddin Keykubat University, Antalya, 3 Department of Oral and Maxillofacial Surgery, Bezmialem Vakıf University, Istanbul, Turkey
DOI: 10.4328/ACAM.20410 Received: 2020-11-24 Accepted: 2021-01-06 Published Online: 2021-01-15 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S183-188
Corresponding Author: Dilek Günay Canpolat, Assoc. Prof. in Anesthesiology, Erciyes University, Faculty of Dentistry, Department of Oral and Maxillofacial Surgery, Kayseri, Turkey. E-mail: dgcanpolat@gmail.com P: +90 352 2076666 -29183 F: +90 352 438 06 57 Corresponding Author ORCID ID: https://orcid.org/0000-0002-8985-6918
Aim: Orthognathic surgery is performed to correct dentofacial abnormalities and is generally known as a safe procedure with minimal bleeding. The purpose of this study was to evaluate whether the preoperative hematological parameters help predict intraoperative bleeding in orthognathic surgery.
Material and Methods: This retrospective study was performed with patients who underwent orthognathic surgery. Patients records were evaluated in terms of the demographics (gender, age, weight), duration of the surgery, amount of intraoperative bleeding, and the preoperatively routine complete blood count (CBC) parameters, especially PLT, MPV, MPV/PLT ratio, coagulation tests (PT, a PTT, INR) and NLR were recorded from patient files.
Results: The study included 101 patients with a mean age of 21.7 ± 4.8 years. The female to male ratio was 1.1 (52/49). The median duration of the opera- tion was 270 minutes, ranging from 155 to 420 minutes. The amount of blood loss ranged from 90 to 820 ml in all subjects, with a median of 230 ml. The preoperative median hemoglobin value was 14.4 g/dL. PT, INR, aPTT, and weight were not independent predictors for the amount of bleeding. However, the duration of the surgery was an independent predictor for the amount of bleeding (p<0.001). There was no correlation between the MPV/PLT ratio (r=0.003, p=0.972) and the neutrophil-to-lymphocyte ratio (NLR) (r=-0.008, p=0.935) with the amount of bleeding (ml).
Discussion: Improving possible objective markers to predict intraoperative bleeding amounts is important for avoiding and managing the intraoperative bleed- ing complications for the surgery team in maxillofacial surgery. The results of this study demonstrated no correlation between preoperative hematologic normal ranged parameters such as PLT, MPV, MPV/PLT, NLR, PT, PTT, INR, and intraoperative bleeding in orthognathic surgery. Thus, caution in the preparation of patients and standardized preoperative procedures are essential to avoid undesirable intraoperative bleeding in orthognathic surgery.
Keywords: Intraoperative bleeding; Orthognathic surgery; MPV; Platelet
Introduction
Orthognathic surgery is commonly preferred to correct dentofacial abnormalities for proving ideal functional, anatomic, and esthetic dental structures. Although a variety of procedures are being used by surgeons, Le Fort I Osteotomy and Sagittal Split Ramus Osteotomy (SSRO) are frequently applied together [1,2]. This group of surgical procedures is performed in anatomic areas that are rich in vessels. Thus intraoperative bleeding may occur during the surgery [3,4].
Orthognathic surgery is generally known as a safe procedure with a minimal amount of bleeding despite damaging major vessels. Although estimated blood loss has a wide range according to the type of surgery or varying reasons, it is generally accepted to be approximately 400 ml [4,5]. However, rarely severe bleeding can occur intraoperatively due to an injury to major vessels in the surgical field. Many reasons affect the bleeding including duration of operation, gender [6], weight [7], type of the anesthesia or surgery, surgeon [3,8]. Knowing the various interplays between these risk factors may provide an expectation of intraoperative blood loss, and this would improve preoperative patient management and ensure ideal planning and performance for surgery [9,10].
Several studies have described correlations between routine coagulation test results such as Activated Platelet Time (aPTT), Prothrombin Time (PT), with bleeding time. The relationship between routine coagulation tests and intraoperative bleeding has not been clearly shown. Routine coagulation screening is not suggested with no history of bleeding [2,9,10]. Recently, studies have focused on thrombo-elastography (TEG), which is a predictor of intraoperatively blood loss. TEG methods are used to analyze the viscoelastic properties of whole blood samples and the interaction among coagulation factors and inhibitors such as fibrin clot properties, blood cells, and fibrinolytic factors. But it is an expensive procedure for hospitals [2,10]. Therefore, improving an inexpensive method or tool for predicting intraoperative bleeding may be useful. Today, several new size-related parameters have been introduced to the routine complete blood count (CBC). Automated blood cell counters are able to provide a platelet (PLT) count and derived indices relating to Mean Platelet Volume (MPV). PLT’s effect on clotting is scientifically known information. Furthermore, the MPV is accepted as an indicator of platelet activation and has recently become more important than PLT [11]. High MPV values represent larger and reactive platelets. In the literature, researchers reported that MPV could provide information about preoperative assessment for potential bleeding [12].
The investigators hypothesized that evaluating preoperative PLT, MPV, MPV/PLT, PT, aPTT, INR, and NLR maybe informative regarding intraoperative bleeding risk, and thus provide a prognosis to the surgery team, helping to facilitate intraoperative patient management. The purpose of the study was to determine whether the preoperative PLT, MPV, MPV/PLT ratio, PT, aPTT, INR and NLR are predictors for intraoperative bleeding.
Material and Methods
Study Design and Samples
The investigators designed and implemented observational and retrospective clinical research. The study protocol followed the Declaration of Helsinki on medical research protocols, and the EthicsCommitteeapprovedthestudy.Thestudywasperformed between January 2014 and August 2016, who had undergone orthognathic surgery. To be included in the study sample, ASA I-II (American Society of Anesthesiology Classification) patients who were performed orthognathic surgery due to maxillary and/or mandibular malformations such as deficiency, excess, or asymmetries, to improve occlusion, facial balance, and airways, were listed as the inclusion criteria. Patients who had a hematological disease associated with excess bleeding, or using any antiaggregants, antiplatelets and bleeding-reducing agents were excluded from the study.
Intervention and study variables
Patient data from a total of 101 patients were collected from the file records. The patient demographics such as gender, age, weight, duration of the surgery, and amount of bleeding were recorded. The routine CBC included White blood cell (WBC), hemoglobin (HGB), red blood cell (RBC) count, N (neutrophil), lymphocyte (L), hematocrit (HCT) levels, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), RBC (red blood cell count), red blood cell distribution width (RDW), MPV, PLT were recorded. Also, aPTT, PT, and INR that showed the coagulation status of the patient were recorded from files. Anesthetic Protocol
A standardized general anesthesia method was preferred for all patients. Preoperative evaluation was made by the same anesthesiologist. Routine blood analysis was studied before the surgery. All patients were premedicated with intravenous midazolam just before the operation. A standard hypotensive anesthetic method was applied for less bleeding. For the anestheticinduction,1mcg/kgfentanyland2-3mg/kgpropofol were applied intravenously. To facilitate the nasotracheal intubation, 0.6 mg/kg of rocuronium was applied and repeated if immobility during the operation was needed. Anesthesia was maintained under intermittent positive-pressure ventilation, using a mixture of air and oxygen (50%:50%), and sevoflurane. Providing hypotensive anesthesia, esmolol infusion was applied to maintain an optimal systolic blood pressure of 80 to 100 mm Hg (approximately 20% below normal) during the surgery. Standard noninvasive monitoring procedures were applied with oxygen saturation, non-invasive blood pressure, electrocardiogram, and end-Tidal CO2 (CO2 level after tidal volume). Intraoperative fluid management consisted of intravenous administration of 0.09% NaCl (saline) during the procedure. Neostigmine (0.08 mg/kg) and atropine (0.01 mg/kg) were used intravenously at the end of the operation to reverse the neuromuscular block, and then the patient was extubated. Aftertheoperation,duringrecovery,thepatientswerefollowed up by the post-anesthesia care unit (PACU) and were admitted to the inpatient service.
Surgical Procedure
Buccal infiltrative anesthesia of the maxillary anterior walls and pterygoid plates in the maxilla and bilateral mandibular blocks along with infiltrative anesthesia of the posterior sulcus in the mandible was applied to all patients using 1/1 diluted eight ampoules with 2% articaine and with 1:100.000 epinephrine solution (80 mg) (Ultracain® 2% Ampoule, Sanofi Aventis,
Istanbul, Turkey) 10 minutes before both Le Fort I and sagittal split ramus osteotomies (SSRO) in all patients.
A horizontal incision was made between the second premolars in the vestibular sulcus of the maxilla. Maxillary anterior and lateral walls and pterygoid plates were exposed to the lower level of infraorbital foramen. The horizontal osteotomy was made using a Piezosurgery (Mectron, Italy) at the level of the nasal floor at a safe distance (~5 mm) from the apices of the teeth. Pterygoid plates were separated using a curved pterygoid osteotome. Lateral nasal walls and nasal septum were also separated with osteotomies. Down-fracture of the maxilla was performed with the help of a bone hook at the anterior, and a bone spreader at the posterior aspect of the maxilla. Tessier mobilizers were then used to pull the maxilla forward. Remaining bony bridges at the posterior aspect of the maxilla were transected under direct vision and soft tissues were protected to minimize bleeding. Maxillo-mandibular fixation was performed to position the maxilla to the desired relationship with the mandible using a surgical splint. Four L-shaped mini plates were placed along with the pyriform aperture and the zygomaticomaxillary buttress.
A full-thickness incision was made just lingual to the external oblique ridge, halfway up the mandibular ramus superiorly to the mesial of the second molar inferiorly. Subperiosteal dissection was carried to allow adequate visualization of the body and mandibular ramus. Medial ramus, sagittal and buccal osteotomies were made using a Lindeman bur. Chisel osteotomies were used to deepen the osteotomy cut through the cortical bone. A lower border separator at the lower end of the buccal osteotomy and a bone spreader at the sagittal osteotomy were used to split the distal and proximal bone segments of the mandible. Care was taken not to injure the inferior alveolar nerve during the split. Maxillo-mandibular fixation was performed to position the mandible to the final relationship with the maxilla using the second surgical splint. Mini plates were placed to fixate the distal and proximal segments.
The amount of bleeding was calculated using the volume of suctioned fluids and total irrigation solution and weighing the gauze during the operation, and noted.
Data Analyses
Descriptive statistics were presented as mean ± standard deviation or median (min-max) depending on the normal distribution of the variables. Categorical variables were expressed as numbers and percentages. The Kolmogorov- Smirnov test and the Shapiro-Wilk test were used to check the normality of the numerical variables. In a comparison of the two independent groups, the Mann-Whitney U test was used when the numerical variables did not distribute normally. We evaluated possible correlations between the amount of bleeding and hematologic parameters using the Spearman correlation coefficient. Univariate and multivariate linear regression models were used to evaluate the factors that affected the amount of surgery related to bleeding. Receiver operating characteristics curve (ROC) analysis was used to evaluate the predictive ability of a certain platelet count cut-off to predict the increased amount of surgery-related bleeding. The Youden index, optimal cut-off point, 95% confidence interval, and area under the curve
(AUC) were calculated by the DeLong method with the Medcalc Statistical Software trial version. “Jamovi project (2020), Jamovi (Version 1.2.22) [Computer Software] (Retrieved from https://www.jamovi.org) and JASP (Version 0.13) (Retrieved from https://jasp-stats.org) were used for statistical analyses. A p-value <0.05 was accepted as statistically significant.
Results
A total of 101 patients with a mean age of 21.7 ± 4.8 years were included in the study. The female to male ratio was 1.1 (52/49) of patients. Demographics, clinical and laboratory characteristics of the study group are given in Table 1. The median duration of the operation was 270 minutes, ranging from 155 to 420 minutes. The amount of bleeding ranged from 90 to 820 ml in all subjects, with a median of 230 ml. However, the need for perioperative blood transfusion was not detected in any patient. There was a positive correlation between the duration of the operation and the amount of bleeding (p<0.001). The preoperative median hemoglobin value was 14.4 g/dL. Although the median white blood cell count was 7.3 x103cell/ μL, it ranged from 3.9 to 24.3 x103cell/μL. The platelet count (PLT) with its minimum and maximum values was within the normal reference values. In the study group, the median NLR and MPV were calculated as 2.2 with a range of 1.1 to 15.5 and 0.03 with a range of 0.02 to 0.07. The median values of PT and INR were within the normal range. The linear regression analysis determined the independent predictors of the amount of intraoperative bleeding (Table 2). None of the included parameters in Table 2 were independent predictors of intraoperative bleeding.
None of the studied hematologic parameters showed a significant correlation with the amount of intraoperative bleeding (Table 3).
In addition, neither NLR, nor MPV/platelet ratios were significantly correlated with coagulation parameters including PT, INR, and aPTT. Furthermore, a schematic representation of density and correlation between the amount of bleeding (ml) and MPV/platelet ratio (r=0.003, p=0.972) and neutrophil-to- lymphocyte ratio (NLR) (r=-0.008, p=0.935) are given in Figure 1 and Figure 2, respectively.
Discussion
Orthognathic surgery aims to correct dentofacial malformations, is a complex procedure with potential blood loss and complications. Although it is generally a safe surgery in terms of bleeding, not only do some authors find major blood loss to be particularly associated with double-jaw surgery with interpositional bone grafting, but others also associate it with the complexity and prolonged duration of procedures [15-17]. Well-known knowledge of the basic anatomy of bimaxillary surgery, the development of instrumentation specifically designed for the operation, and the use of hypotensive anesthesia techniques have significantly decreased blood loss, morbidity, and transfusion requirements [15,18,19]. The consensus found in the literature reviewed was that orthognathic surgery should be performed under general hypotensive anesthesia [15,17-19]. Hypotensive anesthesia was shown to improve the visual quality of the surgical field in orthognathic surgery. Despite hypotensive anesthesia, blood loss increased gradually with prolonged operation time [19]. In this study, it has been determined that the duration of the surgery affected the amount of bleeding with a positive correlation, but preoperative hematological parameters in the normalrangewerenotrelatedtobleedingintheintraoperative period. Prediction of intraoperatively bleeding before the procedure in orthognathic surgery is important for maxillofacial surgeons to provide better patient management. Similar to the literature,esmololinfusionwasadministeredtoallpatientsto reduce or control the surgery-related bleeding as a standard hypotensive anesthesia method. Moderate hypotension was provided during the surgery and the amount of median bleeding ranged was found to be 230 ml, which is reported as 400 ml in the literature [4,5]. No need for intraoperative or postoperative blood transfusion was required in such a young patient population in terms of avoiding the transmission of disease or graft versus host reactions.
The experience of the surgeon is a factor to determine the total bleeding amount during the surgical procedures, which includes compressing the area with gauze and ligating the vessels [5]. A good knowledge of anatomy and surgery experience of the surgeon may prevent major bleeding during surgery [20]. In this retrospective study, the surgery was performed at the same surgery times, thus differences between the personal applications have been eliminated.
The normal clotting mechanism includes vascular mechanisms, platelets, coagulation factors, some prostaglandins, enzymes, and proteins. Primary hemostasis is the formation of a weak platelet plug is achieved in four phases: vasoconstriction, platelet adhesion, platelet activation, and platelet aggregation. Secondary hemostasis is actualized, which involves the coagulation cascade. First, the activation of clotting factors is triggered, and then conversion of prothrombin to thrombin and conversion of fibrinogen to fibrin occurs. At the end of the clotting mechanism, fibrin, the functioning form of fibrinogen, stabilizes this weak platelet plug [21]. PLT count is the main factor for intraoperatively bleeding. MPV symbolizes the volume of the platelets, and is an indicator of platelet activation [11]. The MPV measurement may reflect either the level of platelet stimulation and platelet production rate. Larger platelets are more adhesive and provide better aggregation than smaller ones [11,22]. Furthermore, laboratory-testing involving aPTT or PT/INR reflect the bleeding time, and does not affect primary hemostasis. PTT shows the intrinsic pathway of secondary hemostasis, and the PT/INR shows the extrinsic pathway of secondary hemostasis [22]. The purpose of the study was to research the relationship between the preoperative hematological parameters especially PLT, MPV, MPV/PLT, PT, PTT, and INR with bleeding. The relationship was found to be meaningless in normal ranged preoperative values. The importance of this study was that mentioning preoperative evaluation and providing a certain standardization may ensure a successful orthognathic surgery procedure with less bleeding. In summary, preoperative patient preparation with anamnesis, examination, and laboratory tests is essential to avoid surgery or anesthesia-related complication in surgery clinics.
Praveen et al. [15] compared hypotensive and normotensive anesthesia procedures to determine the differences in terms of bleeding and reported the average bleeding as 200 mL (maximum 400 ml) in the hypotensive group and 350 mL (maximum 1,575 mL) in the normotensive group, whereas in our study, it was 230 ml. Some researchers preferred to use some medications that reduce bleeding, such as tranexamic acid [23]. No patients were administered bleeding-reducing medications in this study.
Point-of-care testing of hemostatic function such as thromboelastography, thromboelastometry, and platelet function assays allow specific targeted therapy of coagulopathy [24]. Not using this methods may be a limitation of this study.
Conclusion
Improving possible objective markers to predict intraoperative bleeding amounts is important in avoiding and managing the intraoperative bleeding complication for the surgery team in maxillofacial surgery. This present study demonstrated no correlation between preoperative hematologic parameters in normal ranges such as PLT, MPV, MPV/PLT, NLR, PT, PTT, INR, and intraoperative bleeding in orthognathic surgery. Therefore, caution to evaluate patients preoperatively and providing good standardization is essential to avoid undesirable bleeding in orthognathic surgery. Further prospective studies on this topic should include larger populations.
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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Dilek Günay Canpolat, Halis Ali Çolpak, Nukhet Kutuk, Alper Alkan. Are preoperative hematologic parameters predictive of intraoperative bleeding in orthognathic surgery? Ann Clin Anal Med 2021;12(Suppl 2): S183-188
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Association of new coronavirus (COVID-19) with hand hygiene score
Haşim Çapar, Fadime Çınar
Department of Health Management, Faculty of Health Sciences, Istanbul Sabahattin Zaim University, Istanbul, Turkey
DOI: 10.4328/ACAM.20412 Received: 2020-11-24 Accepted: 2020-12-26 Published Online: 2021-01-19 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S189-193
Corresponding Author: Haşim Çapar, Istanbul Sabahattin Zaim University, Halkalı cad. No: 2, Halkalı, 34303, Kucukcekmece, Istanbul, Turkey. E-mail: hasim.capar@izu.edu.tr P: +90 212 692 89 94 F: +90 212 693 82 29 Corresponding Author ORCID ID: https://orcid.org/0000-0001-7056-7879
Aim: In this study, we aimed to investigate the interaction between the COVID-19 pandemic and hand hygiene.
Material and Methods: This study was planned as a descriptive cross-sectional involving 856 people living in Turkey between March 22 and April 5, 2020. The difference-in-differences-type design was used to investigate the effect of COVID-19 disease on hand hygiene. _ _
Results: Accordingly, the participants’ average hand hygiene scores before, during, and after COVID-19 were X = 3.350234 ± 1.092372, X = 4.603353 ± .4628307, and X= 3.365169 ± 1.557933. The average age of the participants was X= 28.68 ± 9.34 years. According to education level, the scores obtained from the individuals’ hand hygiene score showed a statistical difference (p<0.05). According to the difference-in-differences-type design prediction results, the coefficient (16.65898±3.685992) of DTr X DPost interaction gave us the effect of the COVID-19 pandemic disease on the hand hygiene scores of individuals. Accordingly, it can be stated that the COVID-19 disease increased 17 points of the hand hygiene score of individuals by approximately 7.1%.
Discussion: It was seen that hand hygiene gained significant importance during periods of infectious disease outbreaks.
Keywords: COVID-19; Hand hygiene; Infectious diseases; Pandemics
Introduction
It is stated that 80% of the world’s population health is threatened due to insufficient hand hygiene practices (available at: http://bit.do/fLFYS, http://bit.do/fLFYX). Various authors consider hand hygiene as a very important preventive tool that eliminates infections and viruses’ infectiousness and prevents infectiousness [1,2]. In the light of the findings obtained from some scientific studies, it has been found that good hand hygiene reduces the risk of diarrheal diseases by 23%- 48% and respiratory infections by 21% to 23% [1,3]. It is stated that water and soap are two vital ingredients for individuals’ hand hygiene (available at: http://bit.do/fLFYS, http://bit.do/ fLFZc). These two sources of life are considered as individual hygiene measures [4]. It is stated that providing hand hygiene is extremely important in protecting and improving general public health during the COVID-19 pandemic (available at: http://bit. do/fLFZj).
In daily life, the hands are the most polluted part of the body. Hand washing, also called hand hygiene, is one of the most influential and inexpensive ways to prevent all kinds of infectious diseases at home, at work, in hospitals, in school, etc. (available at: http://bit.do/fLFZq, http://bit.do/fLFZu, http://bit. do/fLFZP). In some scientific studies, it has been reported that hand hygiene practice is the most effective method of fighting infections and viruses (available at: http://bit.do/fLFYX, http:// bit.do/fLFZE, http://bit.do/fLFZY).
All measures taken to protect and maintain health are called hygiene. All practices that individuals make to keep thier body clean and healthy are defined as personal hygiene. Personal hygiene is crucial to solve health problems and prevent many diseases, especially infectious diseases (available at: http://bit. do/fLFZE).
COVID-19, which was detected in Wuhan city of Hubei province in China at the end of 2019 and spread worldwide in a short time, has caused a significant and urgent public health problem [3]. With the worldwide spread of the new type of coronavirus (COVID-19) pandemic, the importance of personal cleaning habits is emphasized primarily by the World Health Organization, heads of state, health ministers, and experts [5]. There is no vaccine developed against the COVID-19 virus yet. The most important way to prevent disease is not to be exposed to the virus (available at: http://bit.do/fLFZj, http://bit.do/fLFZP, http:// bit.do/fLFZY). According to available evidence, the SARS-CoV-2 virus is transmitted by droplet and contact among humans. Effective methods to prevent transmission of the COVID-19 virus are frequent hand washing with soap and water for at least 20 seconds (available at: http://bit.do/fLFZc, http://bit.do/ fLFZj, http://bit.do/fLFZP, http://bit.do/fLFZY). Hand washing is very useful in killing viruses likely to be found (available at: http://bit.do/fLFZE). Washing hands is very important, primarily in public places or when contacting other people. When water and soap cannot be reached, it is recommended to use hand disinfectants containing at least 60% alcohol (available at: http://bit.do/fLFZj, http://bit.do/fLFZu). In addition to hand hygiene, it should be paid attention to keeping hands away from face, eyes, and mouth during the day (available at: http:// bit.do/fLFYS, http://bit.do/fLFYX, http://bit.do/fLFZc, http://bit. do/fLFZj, http://bit.do/fLFZu, http://bit.do/fLFZY). Hands can efficiently mediate the transmission of the virus. Contact with organs such as the face, eyes, and mouth can cause the virus to enter the body and develop the disease (available at: http:// bit.do/fLFZc).
Hospital-based studies have shown that non-compliance with hand hygiene recommendations is associated with health- related infections and the spread of highly resistant organisms and contributes significantly to outbreaks. Studies have also shown that the prevalence of health-related diseases decreases as hand hygiene measures increase [1,5-8].
This study investigates the interaction between the COVID-19 pandemic, which is called the new coronavirus by WHO, and hand hygiene score, and examines whether disease caused by the COVID-19 virus affects hand hygiene score.
Material and Methods
Study type and sample size
This study was planned as a descriptive cross-sectional, which was conducted with 856 people living in Turkey between March 22, 2020 and April 5, 2020.
Data collection tools
The questionnaire created for this study was provided with two data collection tools. One is the Descriptive Information Form, and the other is the Combine of Hand Hygiene Belief Scale and Hand Hygiene Practices Inventory.
The Descriptive Information Form is a 6-question form that includes the participants’ characteristics such as age, gender, marital status, education, tobacco use, and employment status. Combine of the Hand Hygiene Belief Scale and the Hand Hygiene Practices Inventory questionnaire has been prepared for COVID-19 as a combination of the Hand Hygiene Belief Scale and Hand Hygiene Practices Inventory scales, which were developed by Karadağ et al. [9]. Combine of the Hand Hygiene Belief Scale and the Hand Hygiene Practices Inventory is a 16-items scale prepared in a 5-point Likert type. The higher the score, the higher the hand hygiene score.
Before and after COVID-19 and control group
To measure the effectiveness of any policy, intervention, or treatment, the difference between the scores obtained before and after the policy, intervention, or treatment is examined [10]. The difference-in-differences estimation design was used to minimize the effect of time effect and other unobservable factors [11-13]. In this estimation design, two groups are used to compare those exposed to the policy or practice and those who do not, to eliminate problems arising from the classical pre-post-assessment design [10, 14-16].
Outcome measures
Three different scores were determined for the outcome measures. The first is the hand hygiene score of the participants before COVID-19, this measurement is shown with the variable “Pre”. The second is the hand hygiene score of the participants throughout the COVID-19 period, this measurement is shown by the variable “During”. The third is the hand hygiene score of the participants after COVID-19, this measurement is shown by the variable “Post”. Average scores of each participant from all three different scores were calculated. At the end of these calculations, the variables (Pre, During, and Post) were scored between 1 and 5. If these values are 3.5 and above, it can be said that the participant’s hand hygiene score is good. For all three variables, we re-represented the participants’ hand hygiene scores using a dummy variable. These dummy variables (DPre, DDuring, DPost) take 1 if the participant’s hand hygiene score is 3.5 and above, or 0 if not. Thus, the interaction between these dummy variables will show the impact of the COVID-19 outbreak on hand hygiene.
Statistical analysis
We created dummy variables with hand hygiene scores obtained in this descriptive cross-sectional study. We tried to estimate these dummy variables’ interactions with each other using regression analysis and the pure effect of the COVID-19 outbreak on hand hygiene.
We used the difference-in-differences analysis, a semi- experimental study design, to determine the association between individuals’ hand hygiene scores and the COVID-19 outbreak and to determine the effect attributed to the COVID-19 outbreak on individuals’ hand hygiene scores [11].
The association between COVID-19 and individuals’ hand hygiene beliefs and practices was identified by the difference between pre-COVID-19, during-COVID-19, and post-COVID-19 scores. The interaction term of these three variables was the predictor of the difference between the differences. The coefficient of this interaction estimated the magnitude of the relationship between the COVID-19 outbreak and the dependent variable hand hygiene score.
It was also analyzed whether individuals’ hand hygiene scores differed in three different time periods, according to age, gender, marital status, education, tobacco use, and working status. For the statistical analysis, the Stata / SE 14.0 version was used with a p-value=0.05 ve 95% confidence interval (available at: http://bit.do/fLF2r).
Results
Descriptive analysis
These are the results of the participants’ hand hygiene beliefs and practices in three different periods. Accordingly, the average of hand hygiene beliefs and practices scores of the participants before COVID-19 was X_ = 3.350234 ± 1.092372, the average of hand hygiene beliefs and practices scores during COVID-19 was X_ = 4.603353 ± .4628307, and the average of hand hygiene beliefs and practices scores after COVID-19 was X_ = 3.365169 ± 1.557933. Also, the average age of the participants was X_ = 28.68 ± 9.34 years.
Among the participants, 56.78% (n=486) were women, and 43.22% (n=370) were men; 51.75% (n=443) of the participants had a job at the study time, while 48.25% (n=413) of the participants were not working at the study time; 41.12% of the participants used at least one tobacco product during the study, while 58.88% did not use any tobacco at the study time. The percentages of the participants according to the level of education were as follows:
Primary-secondary school: 7.01% (n=60), high school: 5.96% (n=51), associate degree: 10.86% (n=93), graduate: 51.40% (n=440) and postgraduate: 24.77% (n=212). Among the participants, 49.53% (n=424) were single, 50.47% (n=432) were married.
Analysis of differences in hand hygiene scores according to descriptive variables
According to demographic data, the difference between the participants’ three different hand hygiene scores was examined. Accordingly, in terms of education level, only during the COVID-19 outbreak, hand hygiene scores of the participants differed statistically (p<0.05). However, no statistical difference (p>0.05) was found for all other hand hygiene scores according to demographic data. The Bonferroni test, one of the post hoc tests, was conducted to determine which groups showed differences in the hand hygiene scores during COVID-19 according to the level of education. Accordingly, it was observed that participants with different educational levels differed from each other in hand hygiene scores during COVID-19. Mainly, hand hygiene scores of COVID-19 participants with an associate education level were statistically significantly higher than all other groups.
Regression analysis with difference-in-differences (diff-in-diff) approach
We used the difference-in-differences (diff-in-diff) approach to determine the interaction between the hand hygiene score and the COVID-19 outbreak. The difference- in- differences (diff-in- diff) approach is expressed as a quasi-experimental research method used to determine the effect of any policy, intervention, or treatment [11].
The regression model applied to explain the interaction between COVID-19 and individuals’ hand hygiene scores and definitions of the model’s abbreviations are shown below.
Control= Not exposed to COVID-19; Tr=Was exposed to COVID-19; Pre=Measure before COVID-19; During= Measurement during COVID-19; Post= Measure after COVID-19; DD=Difference in Differences. See Table 1 and Equation 2.
In Equation 2, Y is the total hand hygiene score COVID-19; DPost is hand hygiene score after COVID-19 dummy (1= ≥ 3.5 points); DTr is hand hygiene score before COVID-19 dummy (1= ≥ 3.5 points); DPost DTr is hand hygiene score before COVID-19 X hand hygiene score after COVID-19; β3 is the DD estimate, and X is the vector of control variables. The difference-in-differences-type design analyzed the interaction between hand hygiene scores and COVID-19. According to this analysis, a statistically significant (p<0.01) interaction was detected between COVID-19 and hand hygiene score at a 95% confidence interval (Table 2). According to the difference-in-differences-type design prediction results, the coefficient (16.65898±3.685992) of DTr X DPost interaction gave us the effect of the COVID-19 pandemic disease on the hand hygiene score of individuals. Accordingly, it can be stated that COVID-19 disease increased 17 points of hand hygiene score of individuals by approximately 7.1% (17/240).
Details regarding the model of the analysis carried out with diff-in-diff-type design are shown in Table 3. Accordingly, it can be stated that the proposed model is statistically significant in the 95% confidence interval (F (3, 852) = 267.05, p <0.01). Also, the Adj R-squared value of the model was determined as = 0.4828. Accordingly, the variables included in the model explain 48% of the variance. Although this value seems surprising, it can be accepted considering the economic status of the hand hygiene score, the individuals’ position, their access to water and soap, and their cultural values.
Discussion
This is the first study to investigate the interaction between COVID-19, a coronavirus disease, and the Turkish people’s hand hygiene score. This study is also the first study conducted with the difference-in-differences design, a semi-experimental approach, on the effect of pandemic disease on hand hygiene score. Unlike previous scientific studies conducted with the difference-in-difference design approach, this study was also conducted with scores obtained from the hand hygiene scale prepared for different times for the same people at the same time.
It is known that the vital role of hand hygiene in infectious diseases was the subject of study in the early 19th century [17,18-21]. It has been reported in various scientific studies that hand hygiene is a straightforward but very effective weapon against the transmission of viruses. Accordingly, it is reported that viruses die when hand hygiene is provided [3]. When hand hygiene is supplied with soap and water, since the structure of 100% of the viruses deteriorates, the infectiousness of the virus is stopped and it does no harm [1,21]. In an empirical study, the ebola virus’s effect on hand hygiene was determined [22]. By increasing the number of people with clean hands in the community by only 10%, the transmission rate of infectious disease can be slowed by 37%. Besides, by increasing individuals’ motivation to deal with hand hygiene, a possible pandemic’s infectiousness can be inhibited by 24% – 69% [23]. It is stated that the health of approximately 80% of the world’s population can be protected by providing hand hygiene (available at: http:// bit.do/fLFYS, http://bit.do/fLFYX).
Hands are the most actively used organ. Therefore, the probability of contamination of the hands is much higher than that of other organs. Microorganisms, viruses, etc. on contaminated hands cause infectious diseases to spread when they are infected or unconsciously enter the mouth, ear, eyes, and nose (available at: http://bit.do/fLFYX, http://bit.do/ fLFZE). However, it is stated that frequent hand washing for at least 20 seconds, or in the absence of water and soap, hands disinfection with cologne or alcoholic disinfectant containing at least 60% alcohol prevents viruses from entering the body from the hands (available at: http://bit.do/fLFZq, http://bit.do/fLFZu, http://bit.do/fLFZE).
Maintaining personal hand hygiene is stated to be crucial, especially to stop the spread of viruses and prevent disease or to infect existing diseases (available at: http://bit.do/ fLFZE, http://bit.do/fLFZY). The participants’ hand hygiene scores were reported, respectively, for three different times as follows: average hand hygiene score for Pre- COVID-19=3.350234±1.092372, average hand hygiene score for During-COVID-19=4.603353±.4628307, average hand hygiene score for Post-COVID-19=3.365169±.4628307. Accordingly, it was determined that especially hand hygiene scores of the participants increased with COVID-19. These findings are similar to the results of previous studies [22].
It is stated that the importance given to hand hygiene has increased with the increase of education years [24]. In this study, we found a difference in hand hygiene scores according to education. According to this, mainly, hand hygiene scores of COVID-19 participants with associate’s education level were statistically significantly higher than all other groups. In the light of these data, it can be said that the effect of the education variable on the hand hygiene score varies up to a certain level of education, but the difference, which is not significant between the undergraduate and graduate levels, significantly decreases the effect of the education variable on hand hygiene after a certain level.
In a study by Liu et al. [25] to determine risk factors of COVID-19 disease, smoking was a serious risk factor for the progression of COVID-19 disease (OR = 14.28; 95% CI: 1.58–25.00; p = 0.018). In this study, unlike previous studies, it was found that the use of tobacco products, which are the risk factors for COVID-19 disease, did not affect hand hygiene score. This is an exciting result because smoking was a significant risk factor for disease progression, smokers who wanted to protect themselves from this risk would be expected to pay more attention to hand hygiene. However, this exciting result is thought to be caused by smokers who are unaware that smoking is a severe risk in the progression of COVID-19 disease.
According to the findings obtained from this study, in which we investigated the effect of COVID-19 effect on hand hygiene score, it was observed that COVID-19 disease increased the hand hygiene score by approximately 17 points; that is, approximately 7% of the hand hygiene scores were attributed to the effect of COVID-19 disease. This result is significant because, when the COVID-19 disease has emerged, hand hygiene has become the most emphasized by public health professionals, health ministers of the states, and related authorities. On the other hand, these warnings and recommendations are thought to change people’s handwashing habits and provide more hand hygiene scores.
As a result, it was seen that hand hygiene gained significant importance in the periods of infectious disease outbreaks. Training programs that emphasize the vital importance of hand hygiene should be provided. Although pandemic diseases such as COVID-19 have serious disadvantages, it is in our hands to turn this into an opportunity for public health. Therefore, it should be known that the importance of hand hygiene should be increased through training or campaigns, the most important work that should be taken to the agendas of the authorities and those who practice in this field in the practical life.
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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Haşim Çapar, Fadime Çınar. Association of new coronavirus (COVID-19) with hand hygiene score. Ann Clin Anal Med 2021;12(Suppl 2): S189-193
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Effect of precautionary and normalization steps on course of COVID-19 pandemic in Turkey
Sedat Bostan 1, Gokhan Agac 2, Saime Şahinöz 3
1 Department of Healthcare Management, Faculty of Health Sciences, Ordu University, Ordu, 2 Department of Healthcare Management, Faculty of Health Sciences, Gümüşhane University, Gümüşhane, 3 Department of Internal Medical Sciences, Faculty of Medicine, Ordu University, Ordu, Turkey
DOI: 10.4328/ACAM.20413 Received: 2020-11-26 Accepted: 2020-12-26 Published Online: 2021-01-07 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S194-200
Corresponding Author: Gokhan Agac, Department of Healthcare Management, Faculty of Health Sciences, Gümüşhane University, 29100, Gümüşhane, Turkey. E-mail: gokhanagacc@gmail.com P: +90 5455246370 F: +90 4562331179 Corresponding Author ORCID ID: https://orcid.org/0000-0002-4753-4689
Aim: The COVID-19 pandemic began in China and has now spread across the whole world, and many countries such as Turkey are still fighting against this pandemic. The aim of this study was to investigate the impact of precautionary and normalization steps taken by the Turkish government on the number of confirmed cases, current cases, and deaths due to the COVID-19 in Turkey.
Materials and Methods: The study used exponential regression models to estimate the number of confirmed cases, deaths, and current cases. The study data were collected from the Turkish Ministry of Health, Turkish Ministry of Internal Affairs, and the national public broadcaster of Turkey.
Results: The precautions taken during the COVID-19 pandemic have caused the exponentially increasing number of cases to be brought under control and to decrease exponentially. The normalization steps taken paused the exponential decrease in the number of cases and caused the number of cases to remain flat during the summer months and then rise again. If the normalization steps were not implemented and the precautions taken continued in the same way, it was calculated that the numbers of COVID-19 current cases would be reset on June 26, 2020. The total number of deaths would remain at 4423 and the total number of confirmed cases would be 150586.
Discussion: As a result, the impact of precautionary and normalization steps on the course of the COVID-19 pandemic was examined. It has been observed that the impact of these steps on the pandemic is exponential. The results provide guidelines for health authorities and administrators to take necessary precautions.
Keywords: COVID-19 pandemic; Turkey; Case estimation; Precautions; Normalization steps
Introduction
Contagious diseases threatening a large number of people simultaneously in the world are called a pandemic. According to the World Health Organization’s (WHO) definition, three criteria are sought for a disease to become a pandemic (available at: https://www.who.int/csr/disease/swineflu/frequently_asked_ questions/pandemic/en/). It is a new virus; it can be spread worldwide; most people’s immunity cannot resist it.
Cases of pneumonia of unknown etiology detected in Wuhan City, Hubei Province of China were reported by the WHO China Country Office on December 31, 2019 (available at: https:// www.who.int/csr/don/05-january-2020-pneumonia-of-unkown- cause-china/en/). On January 7, 2020, the causative agent is identified as a new coronavirus (2019-nCoV), which has not previously been detected in humans (available at: https:// covid19bilgi.saglik.gov.tr/depo/rehberler/COVID-19_Rehberi. pdf). Later, the name of the 2019-nCoV disease was accepted as COVID-19, and the virus was named as SARS-CoV-2 because of its close resemblance to SARS CoV (available at: https:// covid19bilgi.saglik.gov.tr/depo/rehberler/COVID-19_Rehberi. pdf). Since the emergence of the COVID-19 pandemic, it has rapidly spread across China and many other countries and has become a major global health concern. The disease has spread rapidly due to its ability to spread from person to person [1]. The WHO has started publishing situation reports on the latest data and information on COVID-19 (available at: https:// covid19.who.int/table). According to these reports, globally, as of October 31, 2020, the total number of confirmed cases of COVID-19 has reached approximately 43 million including 1.15 million deaths. The top 10 countries with the highest number of cases and deaths were the USA, India, Brazil, Russia, France, Argentina, Spain, Colombia, Mexico, and Peru, respectively. Although China was the country where the pandemic was first seen, it has managed to reduce the number of cases with the precautions it has taken and dropped from first place to fiftieth. Since the necessary precautions were not taken in time, the speed of cases and deaths in Italy and Spain increased so quickly that the health system collapsed. Now, a similar situation may be in question for the USA, India, and Russia. In these countries, the situation is gradually getting worse, and the number of confirmed cases and deaths continues to dangerously fluctuate. By the end of October, the number of confirmed cases (deaths) in the first three countries was approximately 8.5 million (83 thousand), 8.0 million (45 thousand), and 5.0 million (27 thousand), respectively.
In Turkey, the first COVID-19 case was detected on the 11th March 2020 with the first death taking place on the 17th March 2020 (available at: https://covid19.saglik.gov.tr/?_Dil=2). The number of confirmed cases and deaths in Turkey was increasing rapidly, and it took twenty-first place in terms of the number of cases and deaths in the world (available at: https:// covid19.who.int/table). As of October 31, 2020, approximately 360 thousand confirmed cases and 10 thousand deaths were identified (available at: https://covid19.saglik.gov.tr/?_Dil=2). The government of the Republic of Turkey and the Ministry of Health (MoH) established the first COVID-19 pandemic center on January 6, 2020 to combat the COVID-19 pandemic when it first appeared in China, and established the Scientific
Committee on January 10. On February 5, all flights from China were stopped. The first case was announced on March 11, and education was interrupted at all schools on March 12. The first death occurred on March 17. Afterwards, prohibitions for the population over 65 and under 20, and in major cities prohibitions on holidays and weekends are declared. In the fight against COVID-19, the government continues to strictly fulfill its obligations.
The Turkish Statistical Institute has announced Turkey’s population as 83 million by the end of 2019 and 9.1% of Turkey’s population constitute elderly population over 65 years of age (available at: http://www.turkstat.gov.tr/Start.do). Turkey is a country with a young population compared to other western countries. Considering that COVID-19 targets the elderly and chronic patients, Turkey has an important advantage in combating pandemic. A health care reform that lasted from 2002 to 2012 in Turkey is concerned. As a result of the reform process, which is also exemplified by the WHO, the Turkish health system has strengthened and significantly increased its healthcare capacity (available at: www.sourceoecd.org/ socialissues/9789264051089).
The Turkish government has taken normalization steps for returning to the normal daily life of its citizens after taking the necessary precautionary steps to ensure control of the spread of the COVID-19 pandemic. The aim of this study was to investigate the impact of the precautionary and normalization steps taken by the Turkish government on the course of the COVID-19 pandemic in Turkey. The study planned to show the impact of these steps on the number of confirmed cases, current cases, and deaths due to the COVID-19. For this purpose, the study seeks answers to the following two main research questions:
Question 1: How have the precautionary and normalization steps affected the number of current cases of COVID-19 in Turkey?
Question 2: What would happen if precautions are continued in the fight against the COVID-19 pandemic in Turkey?
Material and Methods
Data sources
The study used two types of data to carry out research. The first data were related to the precautionary and normalization steps taken by the Turkish government during the COVID-19 pandemic. The related data were obtained from the Turkish Ministry of Internal Affairs (available at: https://www.icisleri. gov.tr/) and TRT HABER website that is the national public broadcaster of Turkey (available at: https://www.trthaber.com/ haber/turkiye/turkiyenin-koronaviruse-karsi-gun-gun-attigi- adimlar-477903.html).
Another data were related to the number of confirmed cases, recovered cases, and deaths due to the COVID-19 in Turkey. The data were collected from the information web page of the Turkish Ministry of Health COVID-19 (available at: https:// covid19.saglik.gov.tr/?_Dil=2). In addition, the number of current cases was obtained by subtracting the total number of recovered cases and deaths from the total number of confirmed cases. While creating the data set, the number of confirmed cases, deaths, recovered cases, and current cases were collected on a daily basis between 01 April 2020 and 10 May 2020.
Statistical model
The study used a regression analysis technique to estimate the number of confirmed cases, deaths, and current cases. The regression analysis is a kind of modeling technique, which is used in the prediction of the dependent variable, based on the relationship between the dependent (predicted) and independent (predictor) variables [2]. The time-dependent change (spreading) rate of the COVID-19 pandemic varies exponentially [3,4]. Therefore, the study preferred exponential regression models to estimate the number of confirmed cases, deaths, and current cases. The analysis of the data to be used in the regression models was performed using Curve Fitting ToolboxTM in MATLAB R2015b (The MathWorks Inc., Natick, Massachusetts, USA) software program.
Results
Public authorities in Turkey, like other countries in the region, have taken many precautions to ensure social isolation to fight the COVID-19 epidemic. When the epidemic was brought under control, and the number of cases decreased to a certain level, normalization steps were taken by spreading over time to control the normalization of social life. Thus, by reducing the level of social isolation, it has been tried to normalize life under new conditions. The precautions taken against the COVID-19 pandemic and the chronology of the subsequent normalization practices in Turkey are presented in Table 1. The matching of the implementation dates of the precautions and normalizations in the table with the current case process is shown in Figure 1. At the same time, Figure 1 enables monitoring of the effect of the precaution and normalization applications on the number of current cases.
In Turkey, public authorities have closely monitored the COVID-19 pandemic in China, and precaution packages have been put into practice as of January 10, 2020, considering that the disease will spread to our country. As the pandemic reached Europe and Turkey, attempts were made to prevent the spread of the disease, and the number of cases and deaths could be controlled with precautions such as school holidays, travel restrictions, curfews. COVID-19 cases since March 11 in Turkey have begun to increase exponentially. With tighter social isolation precautions, in line with the increase in cases, the increase in the number of cases slowed down and the epidemic peaked on April 23. As of April 23, the number of cases has dropped exponentially under the influence of the precautions. The public authorities aimed to reduce the problems that society and the economy face due to social isolation, and at the same time, to keep the disease under control. The public authorities have started to take normalization steps since 11 May. The normalization steps slowed down the exponential decline in the cases, and the graph started to move horizontally. Since the effect of normalization steps on the number of cases was within the minimum incubation period of the disease of 4-5 days, the differentiation started to be reflected in the number of cases and deaths as of May 15.
The answer to the first question that the research is trying to answer can be summarized as follows: as seen in Figure 1, the precautions taken by the government ensured that the number of current cases, which increased exponentially, peaked on April 23, 2020 and decreased exponentially until May 15, 2020. With the normalization steps, the exponential decrease in the number of current cases has stopped. The number of current cases continued to decline horizontally and fluctuate until August 4, and since then the second rising trend has started.
The study used the regression analysis technique to answer the other main question of the study: “What would happen if precautions continued in the fight against the COVID-19 pandemic in Turkey?” The coefficients of the regression models and their fitting scores are shown in Figure 2. According to the figure, the values of R-squared (with a 95% confidence bounds) ranged from 0.90 to 0.99 for all models. Table 2 contains actual data and estimation data obtained using regression models. A comparison of the two data, including the number of confirmed cases, current cases, and deaths due to the COVID-19 is given in Figure 3.
When examining Table 2 according to the predictive model developed in the study, if normalization steps had not been taken and the current social isolation precautions continued, the number of current cases would have been reset on June 26, 2020. The total number of deaths would remain at 4423, and 642 people could be prevented from dying due to COVID-19. Thus, by keeping the total number of confirmed cases at 150586, 43925 people would have been prevented from having COVID-19 (Figure 3). the number of current cases decreased to 10647 at the end of July. After the holiday of Eid al-Adha, which is celebrated between July 31 and August 3, the number of COVID-19 cases has increased again since August 4.
The increase in the number of cases and deaths, which started on August 4, continues as of October 27, 2020, when the study was conducted. As of this date, the total number of confirmed cases was 366208; the number of current cases is 38739; the total number of deaths was 9950. If, according to the prediction model, it is assumed that the number of COVID-19 cases was
After 16 normalization steps taken between May 5 and July 1, zero on June 26, and then there will be no COVID-19 cases again, it can be claimed that 215622 people can be prevented from having COVID-19 and 5526 people can be prevented from dying from COVID-19.
According to the findings of the research, the answer to the second question of the research is as follows: if the normalization steps were not taken as of the beginning of May and the precautions continued, the number of current cases would have dropped on June 26, 2020. Also, the number of deaths could remain at 4423, while the total number of confirmed cases could account for 150586.
Discussion
In this study, the impact of the precautionary and normalization steps taken by the Turkish government on the number of confirmed cases, current cases, and deaths due to the COVID-19 in Turkey was researched. The study collected two types of data to perform the analysis. In addition, exponential regression models were used to estimate the number of cases of the COVID-19 pandemic. The analysis indicated that the impact of precautionary and normalization steps on the course of the COVID-19 pandemic was exponential.
The rate at which COVID-19 will spread will vary according to demographic, epidemiological, and socioeconomic factors because such factors of society such as education, culture, customs and traditions will play a big role in combating the pandemic [5]. In societies with strong family ties, such as Turkey, it is difficult to enforce social isolation or enforce rules. For example, immediately after the holiday of Eid al-Adha, the number of cases increased rapidly.
Another reason for the increase in the number of cases in Turkey could also be hosting a significant number of refugees. In Turkey, in particular, there are approximately 4 million refugees and asylum seekers, most of whom are refugees escaping from the civil war in Syria (available at: https://www.unhcr.org/tr/ unhcr-turkiye-istatistikleri). Such vulnerable groups often live together and in the near abroad. In addition, such low-income groups have limited access to health resources and personal protective equipment. Therefore, these groups cause a high mortality rate and a greater epidemic impact [5].
On the other hand, the findings on the number of COVID-19 cases regarding behavior change are similar to the studies in different countries. Ismail et al. [6] tried to predict the course of COVID-19 in 187 countries using time series. As a result of the study, the number of cases in some countries showed an exponential, and in some countries, showed an exponential + linear behavior. Komarova et al. [7] conducted a study examining the spread behavior of COVID-19 for 174 countries, similar to the previous study. When the findings of the study were examined, it was observed that the number of cases displayed exponential behavior in the early stages of the pandemic, while the number of cases displayed power-law behavior in the advanced stages of the pandemic.
The study examined the course of the COVID-19 epidemic in Turkey according to the precautions taken and in terms of normalization steps. The event was viewed from the perspective of fighting the COVID-19 pandemic. Public authorities first took precautions to increase social isolation to fight the disease. When they believed that the epidemic had been taken under reasonable control, they took normalization steps to meet the social and economic needs of the society in a limited way. The precautions have enabled us to quickly and sharply control the pandemic. The normalization steps have led to horizontal fluctuations in the number of cases and deaths, and prevented the possibility of ending the COVID-19 epidemic in June. Thus, the COVID-19 pandemic was carried over to the fall season, causing an increase in the number of cases and deaths. COVID-19 epidemic process in Turkey continues in a similar way in Europe and many other countries. Some countries, such as China, where the COVID-19 epidemic started, Japan and South Korea, declare that they reset the number of cases or keep them very little. If, Turkey had acted in decisive precautions, could Turkey reset the number of cases as predicted in this study? The answer to this question will always be curious.
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.20413
Sedat Bostan, Gokhan Agac, Saime Şahinöz. Effect of precautionary and normalization steps on course of COVID-19 pandemic in Turkey. Ann Clin Anal Med 2021;12(Suppl 2): S194-200
Citations in Google Scholar: Google Scholar
Comparison of different anesthetic techniques used for geriatric patients who underwent TUR-P operation: A single-center experience
Ozge Gozcu 1, Elzem Sen 1, Haluk Sen 2, Omer Bayrak 2
1 Department of Anesthesiology and Reanimation, University of Gaziantep, School of Medicine, 2 Department of Urology University of Gaziantep, School of Medicine, Gaziantep, Turkey
DOI: 10.4328/ACAM.20414 Received: 2020-11-27 Accepted: 2021-01-12 Published Online: 2021-01-22 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S201-204
Corresponding Author: Haluk Sen, University of Gaziantep, School of Medicine, Department of Urology, 27310, Gaziantep / Turkey. E-mail: drhaluksen@yahoo.com P: +90 532 3321032 F: +90 342 3603998 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2608-0008
Aim: In this study, we aimed to investigate impacts that affect intensive care unit admission, mortality, and cost according to demographic and clinical param- eters of patients, and different anesthetic techniques performed in patients who underwent TUR-P operation.
Material and Methods: The data of 234 patients aged 60 years and older who underwent TUR-P operations were evaluated retrospectively. The patients were examined in two groups as neuraxial and general anesthesia groups. The Charlson Comorbidity Index, preoperative laboratory parameters, the presence of comorbidity, preoperative intensive care requirement, operation duration were obtained from hospital records. The cost calculation was based on the length of the patient’s stay in the hospital and intensive care unit.
Results: According to the ASA score, no significant difference was observed between operation duration, length of hospital stay and intensive care unit stay. According to the CCI score, there was no significant difference in the operation time; however, when the patient’s CCI was 3 and above 3, the duration of intensive care stay and hospital stay were significantly longer. The cost increased significantly when CCI was 3 and above 3, but did not change according to the ASA score.
Discussion: In our study, it was observed that the type of anesthesia did not affect the duration of surgery, the rate of entrance to the intensive care unit, the length of stay in the intensive care, length of hospital stay, mortality and the cost. However, it was observed that the duration of hospitalization and the rate of admission to the intensive care unit increased in patients with CCI 3 and above, therefore the cost was increased.
Keywords: Anesthetic techniques; ASA; Charlson Comorbidity Index; Cost; TUR-P
Introduction
Along with the aging population, the number of older people with urinary system diseases is also increasing. Benign prostatic hypertrophy (BPH) can cause progressive and chronic lower urinary tract symptoms in older men [1.2]. The incidence of BPH is approximately 50% in men aged 50-60 [3]. In patients with BPH, voiding and storage symptoms can be often observed, and these symptoms can have adverse effects on quality of life [4]. Transurethral prostate resection (TUR-P) operations used for the treatment of BPH, contribute to the improvement of moderate to severe symptoms significantly [5,6].
The annual cost of BPH treatment in the United States in 2006 was estimated at $ 4 billion. In Europe, it causes a significant economic burden with a treatment cost of 858 Euros per patient. Due to the demographic shift towards the elderly population, the cost of treating lower urinary tract symptoms associated with BPH is predicted to increase substantially [7,8]. Transurethral prostate resection may be associated with serious morbidity and even mortality [9]. Therefore, the most appropriate anesthetic technique should be selected for each patient individually. Considering the benefits and risks of these methods, various preoperative indices have been developed. The most commonly used indexes are the Charlson Comorbidity Index (CCI), the age-adjusted CCI, and the American Society of Anesthesiologists Physical Status Classification (ASA). These indexes reveal the risk of mortality in the preoperative evaluation of the patient [10].
In our study, we aimed to show the impacts that effect an entrance to intensive care units, mortality, and cost; according to demographical and clinical parameters of patients, and different anesthetic techniques performed on patients who underwent TUR-P operation.
Material and Methods
The study was carried out according to the Helsinki Declaration (October 2013) after obtaining the approval of the Local Clinical Research Ethics Committee (No:2018/41, date: 26.01.2018). The data of patients who underwent TUR-P operations between 04.01.2012- 15.12.2017 in our clinic were evaluated. Records of 311 patients aged 60 years and older, who underwent neuraxial anesthesia (NA) and general anesthesia (GA) were analyzed retrospectively, from the intensive care unit files and the hospital administration management system.
Patients with insufficient records, patients who were under 60 years of age, who underwent combined general and neuraxial anesthesia patients who were followed up in the intensive care unit in the preoperative period, and who were evaluated as ASA IV-V were excluded from the study. Retrospectively, 234 cases that met the study criteria were evaluated within the scope of the study. Spinal and epidural anesthesia were handled together under the head of neuraxial anesthesia. Patients’ demographic data, history of smoking, American Society of Anesthesiologists (ASA) score were examined in two groups: NA and GA groups. The Charlson Comorbidity Index (CCI), preoperative laboratory parameters, the presence of comorbidity, preoperative intensive care requirement, operation times were obtained from hospital records. The length of stay in the intensive care unit, length of hospital stay, mortality rates, and cost estimates were noted. The CCI score was calculated based on the preoperative information in the hospital information management system (Table 1). The cost was calculated at the average dollar (USD) rate at the time of the patient’s hospitalization. The cost calculation was based on the length of the patient’s stay in the hospital and intensive care unit. GA is preferred in cases where NA is contraindicated, such as patients’ refusal, receiving anticoagulant therapy, coagulopathies, and skin infection at the injection site.
Statistical Analysis
Descriptive properties of the data obtained are presented as mean and standard deviation for quantitative variables, and as frequency and percentage distribution for qualitative variables. While chi-square analysis was used for comparisons of mortality status and intensive care follow-up rate according to the type of anesthesia; One-Way Analysis of Variance was used to compare cost, length of hospital stay, and intensive care unit accordingtothetypeofanesthesia.AccordingtotheASAscore and CCI, independent samples t-test was used for comparison of hospital stay, duration of surgery, duration of intensive care unit stay. The analyzes were carried out with the help of SPSS for Windows program.
Results
It was determined that 83 (35.4%) of 234 patients who met the study criteria underwent GA, and 151 (64.5%) patients underwent NA. According to age (P = 0.28), history of smoking (P = 0.731), body mass index (BMI) (P = 0.672), ASA (P = 0.36) and CCI (P = 0.586) parameters, there was no statistically significant difference between the GA and NA groups. Demographic data of the patients are demonstrated in Table 2.
There was no statistically significant difference between the two groups according to the type of anesthesia in the following parameters: the duration of surgery (P = 0.14), the number of patients who were followed up in the intensive care unit (P = 0.879), length of stay in the intensive care unit (P = 0.914), length of hospital stay (P = 0.08), mortality (p = 0.759), and cost (P = 0.685) (Table 2).
According to the ASA score, no significant difference was observed between operation time (p = 0.153), hospital stay (P = 0.217) and intensive care unit stay (P =0.313). According to the CCI score, there was no significant difference in the operation time; however, when the patient’s CCI was 3 and above 3, the duration of intensive care stay (P = 0.001) and hospital stay (P = 0.06) was significantly longer (Table 3).
In 34 (40.9%) of 83 patients who received GA, intensive care unit hospitalization was envisaged, but 2 (5.8%) patients were admitted to intensive care unit; Hospitalization in the intensive care unit was envisaged for 44 (29.1%) of 151 patients who received NA, but a total of 3 patients (6.8%) were hospitalized in the intensive care unit. There was no statistically significant difference between the type of anesthesia, and the rate of hospitalizations in the intensive care unit (p= 0.879). Cost increased significantly when CCI was 3 and above 3 (p= 0.872), but did not change according to the ASA score (p = 0.001). At CCI below 3, the cost was 461.3 ± 173.1 dollars; with a CCI above 3, the cost was calculated as 1033.7 ± 1225.3 dollars (p = 0.001).
Discussion
The aging population results in an increased number of surgical procedures in elderly patients. Several risk factors for morbidity and mortality after surgery increase with aging. However, increasing age itself is an important risk factor for postoperative morbidity and mortality [11]. The most important factor affecting perioperative morbidity and mortality in elderly patients is concomitant diseases originating from organs and systems, especially cardiovascular, pulmonary, endocrine, and neurological systems [12.13].
More than 75% of TUR-P operations are performed under regional anesthesia. Spinal anesthesia is generally accepted as the technique of choice [14]. Regional anesthesia provides early detection of complications such as TUR-P syndrome and bladder perforation. It also potentially reduces blood loss, provides analgesia in the early postoperative period, and reduces the incidence of deep venous thrombosis. Increased blood flow due to sympathetic blockade can help reduce thrombosis and prevent mental or cognitive dysfunction in elderly patients [14]. However GA is performed in cases such as the patient’s refusal to accept spinal anesthesia, coagulopathy, taking anticoagulant therapy, infection at the injection site or aortic stenosis. Kaufman et al. [15] reported that intraoperative NA administration could reduce the need for an intensive care unit after orthopedic surgery, especially in high-risk patients (GA; n=38 and NA; n=45) In addition, it has been shown that NA could reduce the need for postoperative mechanical ventilation even in high-risk patients such as the elderly and myasthenia graves [16]. In our study, the need for preoperative intensive care was seen in a large number of patients, since the elderly patients with comorbidities were examined. However, due to the fact that the duration of surgery was short and the form of anesthesia was mostly NA, the intensive care unit need was low. Although different anesthesia methods were performed, there was no statistically significant relationship between the cases for the intensive care requirement.
ASA and CCI are commonly used as preoperative evaluation scales. In these evaluations, each methodology was found to be related to the rate of operative complications [17]. In a prospective study by Valerio et al. [18] ASA grade was noted as an important and independent predictor of early morbidity after transurethral procedures. The use of ASA can assist clinicians in the decision-making process to determine the benefit and harm of the procedure for the patient. In a recent analysis by Mandal et al. [17] 722 patients who underwent TUR-P showed that men with higher CCI scores had a higher morbidity rate than men with low scores; and that CCI was a fast, simple and reproducible score. It was emphasized that it was a system that could accurately predict operative complications after TUR-P. Guo et al.[19] found that surgical complications in male patients with CCI 0, 1, and ≥2 were 10.6%, 10.0%, and 13.1%, respectively. The authors reported that although there was no significant difference in patients with ASA≥3 or CCI≥2, the rate of operative complications tended to be higher than in those with low scores (p= 0.183 and p= 0.593, respectively). Therefore, they reported that they could not predict higher complications in patients with higher ASA grades or CCI scores. In our study, length of hospital stay and intensive care unit stay were statistically analyzed according to ASA, and no significant difference was observed. However, when the patient’s CCI score was 3 and above 3, it was seen that the length of stay in the intensive care unit (ICU) and hospital were statistically significantly longer (P = 0.001).
Treatment of BPH in the geriatric population creates an economic burden. Since BPH is a disease seen in older ages, it increases factors affecting the treatment costs of these patients. We did not find any study calculating the cost of TUR-P operations according to the type of anesthesia in geriatric patients. In our study, the reasons that increase the cost of TUR-P surgeries were investigated. Retrospectively, the relationship between costs and preoperative values of patients, comorbidity indices, duration of surgery, forms of anesthesia, and duration of intensive care unit stay were examined. Accordingly, the number of additional diseases in the patient was three and over three, and the CCI index 3 and above 3 significantly increased the cost. In our study, since there were only 5 patients who went to the intensive care unit, a significant relationship could not be established between the duration of intensive care unit and the cost. However, the cost of patients staying in intensive care unit was found to be higher. Although costs of anesthesia change hospital costs, the propotion of anesthesia cost is small because intraoperative anesthesia costs are less than 6% of total hospital costs [20]. The study provided evidence that the probability of reducing total hospital costs is low, depending on different anesthetic techniques [21]. In our study, no significant difference was found between the technique of anesthesia and its cost (p = 0.685).
This study has certain limitations. Our study was retrospective in nature, and because of this, we could not perform randomization. Our results should be supported by prospective, and randomized trials.
Conclusion
In our study, in which we aimed to evaluate the choice of anesthesia method to reduce the need for intensive care, mortality and cost in patients undergoing TUR-P due to the increase in the geriatric population. It was observed that the type of anesthesia did not affect the duration of surgery, the rate of entrance to intensive care unit, the length of stay in the intensive care unit, length of hospital stay, mortality and cost. However, it was observed that the duration of hospitalization and intensive care unit entrance increased in patients with CCI 3 and above, therefore the cost increased. It was concluded that ASA scoring was not as significant as CCI for predicting the rate of ICU entrance and length of hospitalization.
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. Sarma AV, Jacobson DJ, McGree ME, Roberts RO, Lieber MM, Jacobsen SJ. A population based study of incidence and treatment of benign prostatic hyperplasia among residents of Olmsted County, Minnesota: 1987 to 1997. J Urol. 2005;173:2048- 53.
3. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol 1984;132:474-9.
4. McVary KT, Roehrborn CG, Avins AL, Barry MJ, Bruskewitz RC, Donnell RF, et al. Update on AUA guideline on the management of benign prostatic hyperplasia. J Urol. 2011;185(5):1793-803.
5. Oelke M, Bachmann A, Descazeaud A, Emberton M, Gravas S, Michel MC, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2013; 64(1):118-40.
6. Madersbacher S, Alivizatos G, Nordling J, Sanz CR, Emberton M, de la Rosette JJ. EAU 2004 guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (BPH guidelines). Eur Urol. 2004;46(5):547-54.
7. Taub DA, Wei JT. The economics of benign prostatic hyperplasia and lower urinary tract symptoms in the United States. Curr Urol Rep. 2006;7(4):272-81.
8. van Exel NJ, Koopmanschap MA, McDonnell J, Chapple CR, Berges R, Rutten FF. Medical consumption and costs during a one-year follow-up of patients with LUTS suggestive of BPH in six european countries: report of the TRIUMPH study. Eur Urol. 2005;49(1):92-102.
9. Rassweiler J, Teber D, Kuntz R, Hofmann R. Complications of transurethral resection of the prostate (TURP)–incidence, management, and prevention. Eur Urol. 2006;50(5):969-79.
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15. Kaufmann SC, Wu CL, Pronovost PJ, Jermyn RM, Fleisher LA. The association of intraoperative neuraxial anesthesia on anticipated admission to the intensive care unit. J Clin Anesth. 2002;14(6):432-6.
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Ozge Gozcu, Elzem Sen, Haluk Sen, Omer Bayrak. Comparison of different anesthetic techniques used for geriatric patients who underwent TUR-P operation: A single-center experience. Ann Clin Anal Med 2021;12(Suppl 2): S201-204
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The biomechanical comparison of screw fixation and cross pinning methods in salter harris type 2 distal femoral fractures using the finite element method
Kerim Öner 1, Alaettin Özer 2, Ahmet Emre Paksoy 3
1 Department of Orthopedics and Traumatology, Karadeniz Technical University Faculty of Medicine, Trabzon, 2 Department of Mechanical, Yozgat Bozok University Faculty of Engineering, Yozgat, 3 Department of Orthopedics and Traumatology, Atatürk University Faculty of Medicine, Erzurum, Turkey
DOI: 10.4328/ACAM.20415 Received: 2020-11-28 Accepted: 2020-12-27 Published Online: 2021-01-07 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S205-209
Corresponding Author: Kerim Öner, Karadeniz Technical University Faculty of Medicine, Farabi Hospital, Department of Orthopedics and Traumatology, Trabzon, Turkey. E-mail: dr.kerimoner@hotmail.com P: +90 5434267752 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8415-1057
Aim: The most common type of distal femur physis fractures is Salter-Harris type 2 (SH type 2). These fractures have high complication rates and can cause a significant loss of function. Anatomical reduction is important in treatment. In this study, we aimed to compare two methods commonly used in SH type 2 fractures, cross pinning, and two parallel screw fixation methods using the finite element method.
Material and Methods: The SH type 2 fracture model was created in the femur model obtained from the 3-dimension (3D) computed tomography (CT) scans. The fracture in the first model was fixed with crossed Kirschner (K) wires. The fracture in the second model was fixed with two parallel screws placed from the metaphyseal part. The two models created were moved to the Ansys Workbench program. Axial overload, varus, valgus, anterior, posterior bending, and torsional forces were applied and analyzed with the 3D finite element method.
Results: In axial overload, the max stress in growth cartilage K wire was 0.40 MPa, while in the screw- 1.24 MPa. The varus bending was 0.32 MPa and 1.71 MPa, respectively. Also, the valgus bending was 0.15 MPa and 0.56 MPa, respectively. The anterior bending was 0.85 MPa and 1.30 MPa, respectively. Also, the posterior bending was 0.56 MPa and 2.01 MPa, respectively When torsional force was applied, it was found as 0.008 MPa and 0.16 MPa, respectively.
Discussion: In SH type 2 distal femoral fractures, the cross-pinning method is superior to the two parallel screw methods placed from the metaphyseal part in bending, torsion and axial loads.
Keywords: Finite element; Cross pinning; Screw fixation; Physis fracture
Introduction
Distal femoral physeal fractures compose less than 1% of pediatric fractures. It constitutes 6-9% of the physis fractures [1,2]. Distal femur epiphysis provides 70% of the lengthening of the entire femur and 40% of the lower limb lengthening [3]. Various complications due to physeal injury, such as deformity formation and extremity length discrepancy, can cause morbidity. [4].
The Salter-Harris classification is used for the classification of these fractures [5]. This classification is important when choosing treatment and determining prognosis. According to the Salter-Harris fracture classification, four types of fracture are defined. The most common one of these is the Salter- Harris type 2 fracture (SH Type 2) [6,7]. Conservative and surgical treatment methods can be preferred in the treatment of these fractures according to the displacement amount of the fracture [8]. In type 2 distal femoral epiphysis fractures, it is important not to damage the growth cartilage as much as possible and to provide a stable fixation in treatment. Cross- pinning and fixation with two parallel screws placed from the metaphyseal part are commonly the preferred fixation methods [9]. Although there are various studies on the clinical results of these methods, there are not enough studies comparing these two methods biomechanically. In this study, we biomechanically compared the cross-pinning methods with two parallel screws placed from the metaphyseal part for fracture, which has sufficient metaphyseal parts, using the finite element method.
Material and Methods
The Finite Element Method (FEM) is a mathematical based computational technique used in solving complicated and analytically difficult structural problems. In this way, one creates a model similar to real body with solid modeling programs such as SolidWorks. This model was obtained using real CT images from real CT scans. The modified solid model in the solid modeling program according to the problem is then sent to analysis software such as Ansys Workbench. Ansys Workbench is a useful tool for especially engineers to solve various engineering problems by modeling them.
The femur model we used in our study was obtained from a three-dimension (3D) computerized tomography (CT) scan. The SH type 2 fracture model was created in the femur model. The fracture in the first model was fixed with crossed2.5 mm Kirschner (K) wires. The fracture in the second model was fixed with 4.5 mm fully threaded two parallel screws placed in the metaphyseal part (Figure 1).
The two models created were transferred to the Ansys Workbench program and analyzed using the 3D finite element method by applying axial loading, varus bending, valgus bending, anterior bending, posterior bending, and torsional forces. Von Mises stress distributions in growth cartilage were recorded as megapascal (MPa).
Higher-order Solid187 3D elements were used to generate a fine Finite Element mesh volume. The contact interfaces with the bone to screw and K-wires were assumed bonded contact. The fracture interface was considered completely broken, the frictional sliding contact and the friction coefficient was taken as 0.2 [10]. Bone to growth cartilage interface was considered as friction and 0.04 as a friction coefficient. Considering and analyzing six different load configurations for each model, simulating real-life physiological loads: Axial Loading with 350N from femur head by fixing the epiphyseal plate,150 N. moments from the epiphyseal plate by fixing the metaphysis and diaphysis, and 150N transverse force from the epiphyseal plate by fixing the metaphysis and diaphysis in the varus, valgus, anterior and posterior directions [10] (Figure 2). Material properties were used for simulations as cortical bone E= 16GPa, u=0.3, growth cartilage E= 5MPa, u=0.46 and E=110GPa, u=0.33 as screw and K-wires and assumed linear elastic and isotropic [10].
Results
When the von Misses stress distribution in the growth cartilage was examined, the maximum stress was 0.40 MPa in the model fixed with K-wire in axial loading, while the maximum stress was found as 1.24 MPa in the model fixed with a screw (Figure 3 a1, b1). In varus bending loading, K-wire and screw models were found to be 0.32 MPa and 1.71 MPa, respectively (Figure 3 a2, b2). Valgus bending loading was 0.15 MPa and 0.56 MPa, respectively (Figure 3 a3, b3). While the anterior bending loading was 0.85 MPa and 1.30 MPa, respectively, the posterior bending loading was 0.56 MPa and 2.01 MPa (Figure 3 a4, b4, a5, b5). When the torsional loading was applied, the maximum stress in the growth cartilage was 0.008 MPa in the model applied to K-wire and 0.16 MPa in the screw applied model (Figure 3 a6,b6) (Table 1)
Discussion
The result of this study is that fixation with parallel two screws from the metaphyseal part for SH type 2 fractures under physiological loads causes higher stresses in the growth cartilage than fixation with cross-K wire.
Salter and Harris stated that type 1 and type 2 epiphyseal fractures are relatively benign and have a good prognosis according to their classification [5]. However, in many studies, unsuccessful results have been reported with a high incidence of Salter Harris type 2 fractures [11]. Abulfotooh et al. found 53.8% of satisfactory results in their study [3]. They concluded that these fractures should not be regarded as innocent fractures with a good prognosis. They stated that there was a reduction loss of up to 30% after closed reduction and plastering, displacement over 2 mm was critical, and anatomical reduction and internal fixation increased success [3,12]. Arkader et al. found 33% bad results in their studies [13]. Since SH type 2 fractures do not directly concern the joint and are considered as relatively innocent, we think that inadequate treatment may be experienced and therefore more attention should be paid. Fixation with K-wires is the most commonly used method in the treatment of SH type 2 distal femoral physeal fractures [14]. In a study by Inal et al., they analyzed von Mises stress distributions in the growth cartilage in the models pinned in four different configurations in SH type 2 fractures. They said that the increase in stress values in the fracture line was an indication that the stability of the fixation was low. As a result of their analysis, they indicated that the cross-pinning model was the most stable model from a biomechanical point of view [10]. Although the pinning method is a frequently used method in treatment, it has important complications. Although there are studies that found that the K-wires, crossing the growth cartilage, do not form physeal bars, many studies have stated that it increases the formation of the physeal bar, which causes elongation problems and deformities [15-17]. In addition, pin tract infection due to percutaneous K-wires can be seen frequently, while septic arthritis has also been reported [14]. Two parallel screw methods, placed from the metaphyseal part, are a method that protects the growth cartilage. Garet et al. stated that if the metaphysical part is large enough in SH type 2 fractures, the parallel screw technique that protects the physis and is placed from the metaphysis is an ideal treatment and provides stable fixation [14,15,18]. Ilharreborde et al. stated that fixation with screws inserted from the metaphysis in SH type 2 fractures may not provide sufficient stability and fixation should be protected with plaster [11].
In our study, we tried to determine which method is the most stable by comparing the methods of cross pinning and fixation with two parallel screws placed from the metaphyseal part biomechanically. As a result of our analysis, we found that in the cross-pinned model, in axial loading, varus bending, valgus bending, anterior bending, posterior bending, and torsional loads, the stresses of growth cartilage was significantly lower. Based on these data, we can say that the cross pinning method provides more stable fixation with two parallel screws, placed from the metaphyseal part, and reduces the stress more in the growth cartilage.
The first displacement amount and displacement direction of the fracture is an indicator in terms of instability. Arkader et al. found a correlation between the type of fracture and the amount of displacement and complications. They did not find a significant relationship between displacement direction and complications [13]. We think that the direction of displacement of a fracture is guiding in the direction in which it can be displaced in the follow-up. In our study, we found that in valgus bending performed, models fixation with cross K.-wire reduces the overloading on the growth cartilage by 6 times compared with fixation with a screw. Similarly, we found that the stress value in the growth cartilage decreased by approximately 4 times in the model we applied varus bending, which was fixed with cross K-wire. Based on these results, we think that preferring the cross pinning method is biomechanically safer, especially in fractures with high coronal plane displacement. Our study is a computer-supported biomechanical study. Therefore, the inability to analyze data such as immobilization time and weight-bearing status, which may affect the prognosis of pediatric fractures, can be shown as our missing side. New clinical experimental studies are needed on this subject.
In conclusion, in Salter Harris type 2 distal femur fractures, the cross-pinning method was biomechanically superior and provided more stable fixation than the two parallel screw method placed from the metaphyseal part. It is safer to prefer the cross pinning method, especially for fractures displaced in the coronal plane. The parallel screw method may be preferred in fractures with large metaphyseal parts because it protects the growth cartilage, but it should be taken into consideration that it may not provide sufficient stability.
Acknowledgment
We would like to thank Ahmet Çankaya, who made the modelling work for the purposes of this study.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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13. Arkader A, Warner WC, Horn BD, Shaw RN, Wells L. Predicting the outcome of physeal fractures of the distal femur. J Pediatr Orthop. 2007; 27(6):703–8.
14. Murgai RR, Compton E, Illingworth KD, Kay RM. The Incidence of Pin Tract Infections and Septic Arthritis in Percutaneous Distal Femur Pinning. J Pediatr Orthop. 2019;39(6):462–6.
15. Garrett BR, Hoffman EB, Carrara H. The effect of percutaneous pin fixation in the treatment of distal femoral physeal fractures. J Bone Joint Surg Br. 2011;93(5):689–94.
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Kerim Öner, Alaettin Özer, Ahmet Emre Paksoy. The biomechanical comparison of screw fixation and cross pinning methods in salter harris type 2 distal femoral fractures using the finite element method. Ann Clin Anal Med 2021;12(Suppl 2): S205-209
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The accuracy of different generation intraocular lens power formulas in eyes with axial length less than 22 millimeter
Aydin Yıldız, Sedat Arıkan
Department of Ophthalmology, Onsekiz Mart University, Canakkale, Turkey
DOI: 10.4328/ACAM.20418 Received: 2020-11-29 Accepted: 2021-01-06 Published Online: 2021-01-18 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S210-214
Corresponding Author: Aydin Yıldız, Department of Ophthalmology, School of Medicine, Canakkale Onsekiz Mart University, Barbaros Street, 17100, Canakkale, Turkey. E-mail: aselmelek528@gmail.com P: +90 533 559 48 50 F: +90 21 269 548 29 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0396-5900
Aim: In this study, we aimed to investigate the accurate formulas for eyes with axial length (AL) less than 22 millimeters among usually used six intraocular lens (IOL) calculation formulas.
Material and Methods: This retrospective study included 137 eyes with short ALs below 22 mm of 122 patients who underwent phacoemulsification surgery with the same type of IOL implantation. The biometric values of the patients were obtained using optical low coherence reflectometry (OLCR) for six formulas involving Hoffer Q, SRK-T, Haigis, Barett Universal II, Holladay 2 and Hill-RBF. All patients in the postoperative period had the best-corrected visual acuity level equal to or higher than 20/40. While comparing the accuracy of these six IOL calculation formulas, the mean absolute error (MAE), and the median absolute error (MedAE) values were taken into account.
Results: The MAE values for Hoffer Q, SRK-T, Haigis, Holladay 2, Hill-RBF and Barrett Universal II formulas were 0.390, 0.390, 0.324, 0.327, 0.331 and 0.208, respectively. Also the rank of MedAE values for the mentioned formulas was 0.245, 0.310, 0.310, 0.250, 0.255 and 0.190. The lowest MAE and MedAE values were found in the Barrett Universal II formula, whereas the highest one was in the SRK/T formula with a statistical significance (p<0.001). After Bonferroni correction, there was no statistically significant difference between the Barrett Universal II formula and the other formulas except for SRK/T (p>0.01). Three patients (2.5%) were in the ±0.75 D range, 15 patients (12.3%) were in the ±0.50 D, and the remaining 104 (85.2%) patients were during the ±0.25 D at the first-month follow-up.
Discussion: Although Barrett Universal II appears to be the most accurate IOL calculation formula, third, fourth and other newer generation formulas have also good predictive value for accurate estimation of IOL power in short eyes.
Keywords: Cataract; Intraocular lens; Short eye
Introduction
The lens extraction and IOL implantation surgery is performed either to remove the lens opacification or for the purpose of refractive correction in subjects who are not suitable for keratorefractive approach. Combined advances in the surgical technique and IOL design, such as small incision cataract surgery with implantation of aspheric monofocal, toric or multifocal IOL, have increased refractive outcomes for quality of vision. In uncomplicated lenticular surgery, two main factors can affect the postoperative good visual acuity. The first one is the surgical factor that may involve, for example, the site and width of the corneal incision, and the second factor is the detection of the postoperative accurate IOL power. Although the first factor partially depends on the experience of the surgeon, the second one seems to be more predictable if the proper IOL power is selected for the surgery.
The main factors determining an accurate calculation of IOL strength are accurate measurement of axial length (AL), corneal optical power, namely keratometry (K), and assessment of postoperative effective lens position (ELP). Among these determinants, AL measurement error is the most common cause of incorrect calculation of the IOL force. [1,2]. There are no major problems when calculating the IOL power for normal eyes with AL between 22-26 mm. However, for those outside of this range, known as short (AL≤22 mm) and long eyes (AL≥26mm), accurate lens determination may occasionally be problematic while using the first (Binkhorst), the second (SRK- II), the third (Holladay 1, SRK-T and Hoffer Q) generation IOL calculation formulas, incorporating mainly AL and K.
It has been noted that an important reason for incorrectly calculating IOL power for short and long eyes is associated with an incorrect prognosis of postoperative ELP [3]. Therefore, apart from only the use of AL and K, additional parameters, such as measurement of anterior chamber depth (ACD), lens thickness (LT), lens factor (LF), and white-to-white (WTW) distance, were included in the fourth generation (Haigis, Holladay 2 and Olsen) and new generation (Barrett Universal II, Hill-RBF) formulas to assess postoperative ELP [4,5]. Although several studies have shown insignificant difference between Haigis, Holladay 2, Hoffer Q, Holladay 1, SRK/T and SRK II for calculating the accurate IOL power in short eyes [6-8], a study by Macleran et al., showed that Haigis is more accurate than Hoffer Q [9], while Gavin et al. suggested that Hoffer Q yielded better results than SRK-T [10].
Aristodemou et al. in their comprehensive study suggested that Hoffer Q has a good performance in IOL calculation for ALs from 20 to 20.99 mm, and along with Holladay 1, from 21 to 21.49 mm [11]. However, there is little research in the literature on the effectiveness of new generation IOL calculation formulas, especially Barrett Universal II, for the short eyes [3,12].
In the present study, it was aimed to compare the effectiveness of IOL calculation formulas between third and fourth generation formulas such as SRK-T, Hoffer Q, Holladay 2, Haigis, and new generation formulas such as Barret Universal II, and Hill-RBF in short eyes.
Material and Methods
This retrospective clinical study was carried out by examining
the medical records of the patients who experienced a cataract surgery between 2014 and 2018. The institutional review board of Canakkale University approved the study protocol (desicion date: 02.01.2019, desicion number: 2019-11). This study included patients with AL lower than 22 millimeters who underwent uneventful cataract surgery with the same type of monofocal IOL implantation (Acriva UD 613®, VSY Biotechnology, Turkey). Other inclusion criteria for this study were the availability of the measurement of IOL power obtained using OLCR alone (Lenstar LS-900, Haag-Streit AG, Koeniz, Switzerland) and the determination of the postoperative best-corrected visual acuity level ≥20/40 in the first-month visit. Patients with a history of traumatic cataract, previous refractive surgery, and retinal detachment, as well as the ones with keratoconus, corneal scarring, corneal dystrophy, macular edema, complicated cataract surgery, and also the patients who had not come to first-month visit, were excluded from the present study.
All patients were subjected to detailed ophthalmic examination with a slit-lamp biomicroscopy during the pre-and postoperative period. The AL and K values and ACD measurements were obtained by OLCR. The phacoemulsification surgery was performed with a 2.8 mm clear-corneal incision, 5.0-5.5 mm capsulorhexis diameter and IOL implanted into the bag. None of the corneal incisions required suture. The characteristics of the implanted IOL were as follows: mono-focal lens with a plate haptic design, the optical diameter was 6.0 mm, the total diameter was 13.0 mm, the haptic-optic angle was 0 degree, the refractive index was 1.46. In previous studies, since all formulas were not registered in one device, the calculation of new generation formulas was made from the websites. The optimization values of the Acriva UD 613 can be also found in ULIB website [(A constant=118.0), (Haigis a0=0.95, a1=0.40, a2=0.10), (Hoffer Q pACD=5.19), Holladay 1 (sf=1.43), and (A constant for SRK/T= 118.4)]. The Lenstar LS-900 contains the software for the IOL calculation formulas that were included in this study and all formulas were pre-installed on this biometer. Therefore, no additional calculation from the websites was used in the current study.
A total of six formulas (Holladay 2, Hoffer Q, SRK/T, Haigis and the Hill-RBF, an artificial intelligence based radial basis function method) were compared with Barett Universal II. In terms of the number of variables in the IOL calculation, formulas are as follows: Hoffer Q and SRK/T formulas have 2 variables [K and AL values], Haigis formula has 3 variables [ACD in addition to K and AL]. The Barrett Universal II formula has 5 variables [AL, K, ACD, WTW, and LT]. Holladay 2 formula has 7 parameters [K, AL, ACD, LT, WTW, preoperative refraction and patient age].
To reduce the problems owing to IOL constant optimization, similar to the study by Carifi et al. [7], only subjects with the same type of monofocal IOL (Acriva UD 613®, VSY Biotechnology, Turkey) were included in this study.
The refractive prediction error, namely the MAE and also the MedAE values, were calculated by subtracting the postoperative spherical equivalent (SE) value from the estimated error value for each formula. The MAE values were used as the main data for the comparison of the accuracy of formulas. For each formula, the benchmarks as ± 0.25 D, ± 0.50 D, and ± 0.75 D were calculated. The subjective refraction was performed at
the first month visit. The SE value was calculated by adding half of the cylindrical power to the spherical power.
Statistical Analysis
Statistical analysis was performed using the Statistical Package for the Social Sciences and Social (Version 21.0, SPSS, Inc.). Friedman’s test was applied for the comparison among the groups. The Bonferroni correction was implemented for multiple comparisons, and the statistical significance was accepted as a p-value of less than 0.01 after Bonferroni correction.
Results
A total of 137 eyes of 122 patients were included in this study. Fifteen patients were operated on two eyes and a randomly selected eye was included in the study. The mean age of the patients was 66.5 ± 5.7 (min: 55, max: 81) years. Forty-three patients were female (35%) and 79 were male (65%). The mean AL was 21.38 ± 0.53 (min: 20.03, max: 21.98, median: 21.59) mm. The mean IOL power was 26.4 ± 2.2 (min: 23.5, max: 32.5) D. The data related to the refractive values are given in Table 1. The MAE values were 0.390 for Hoffer Q, 0.390 for SRK-T, 0.324 for Haigis, 0.327 for Holladay 2, 0.331 for Hill-RBF, and 0.208 for Barrett Universal II. The ranks of MedAE values for the mentioned formulas were 0.245, 0.310, 0.310, 0.250, 0.255 and 0.190, respectively. The lowest MAE and MedAE values were found in Barrett Universal II, while the highest value was in the SRK/T formula. All MAE and MedAE values are shown as minimum, maximum and standard deviations in Table 2. Although there was a statistically significant difference between the Barret Universal II and SRK/T formula (p<0.001) , no statistically significant difference was determined between the Barrett Universal II and the other formulas after Bonferroni correction in terms of MAE value (p>0.01). Also, a statistically insignificant difference was found between other formulas other than the Barrett Universal II formula (p>0.01).
While the mean and the median preoperative SE values were +4.47 D and +4.38 D, respectively, their postoperative values were -0.16 D and -0.25 D, respectively. Three patients (2.5%) were in +/- 0.75 D range, 15 patients (12.3%) in +/- 0.50 D, and the remaining 104 patients (85.2%) were in +/- 0.25 D in the first month visit. All patients were in the benchmark of 1.00 D suggested by Gale et al. [13].
Discussion
Unlike those with long and normal AL, calculating IOL power can sometimes be difficult in patients with short eyes. This condition is mostly attributed to an incorrect estimation of postoperative effective lens position (ELP) that is defined as the distance between the secondary principal plane of the cornea and the principle of the IOL [14]. The minimal deviation in the ELP is said to cause a considerable error in postoperative refraction, particularly in patients with short eyes, likely due to the implantation of thicker IOLs [9]. A potential risk of myopia may occur if the IOL is even minimally more anteriorly located than the expected, while hyperopic shift can emerge in case of its posterior location. Olsen et al. have put in order the important sources of error for IOL power calculation, such as incorrect measurements of AL (%54), ACD(38%), and corneal power (8%) [4]. However, Olsen reported in another study that most of the faults in IOL power calculations might be related to the underestimation of ACD rather than AL [2]. An error of one millimeter in the ACD measurement results in approximately 1 D, 1.5 D, and 2.5 D postoperative refractive error in myopic, emmetropic, and hyperopic eyes, respectively [15]. In addition, each 0.1 mm error in the AL measurement results in a deviation in the optical plane of almost 0.27 D [2]. Hence, the correct assessment of postoperative ACD becomes as important as measurement of AL, especially in patients with short eyes.
The refractive surprises arising from the incorrect measurement of AL have been largely resolved using non-contact biometry devices such as OLCR. Taking into account the fact that measurement error in short eyes causes 5 times more refractive error than myopia [2], resolving AL measurement problems using non-contact biometry has improved the refractive outcomes, particularly in these subjects. Another important benefit of non-contact biometry is the ability to correctly measure ACD. Factors affecting the ELP are classified, firstly, as anatomic causes such as K value, AL, white-to-white distance, preoperative ACD, and lens thickness (LT), and secondly, as IOL related causes such as shape, length, elasticity, angle, and haptic material of the IOL. As it is known that members of third-generation formulas like SRK/T, Holladay I and Hoffer Q, respectively, use the constant A (its value differs depending on the manufacturer and type of the IOL, as well as its position inside the eye), the surgeon factor (SF), and postoperative ACD for ELP assessment. However, unlike the third generation, fourth-generation formulas involving Haigis formula (a0, a1, a2 constants), Holladay II formula (AL, K, ACD, LT, W-to-w, preoperative refractive error, and age) and Olsen formula (AL, K, white-to-white, LT and ACD) use additional variables besides the measurement of preoperative ACD for strengthening the estimation of ELP.
Several studies can be found in the literature comparing the accuracy of IOL power calculation between the third, fourth and newer generation formulas (Barrrett Universal II, Hill-RBF) either in patients with various AL, or in patients with short eyes. According to these studies, almost all IOL calculation formulas have been suggested to obtain favorable refractive results in average ALs. However, some IOL power calculation formulas have become more preferable in patients with short AL because of their success in reducingrefractive surprises. Narvaez et al. have reported equal refractive results when comparing the efficacy of Hoffer Q, Holladay 1, Holladay 2 and SRK/T formulas for short, medium and long eyes [16]. Karabela et al. have obtained good outcomes for both short and long eyes by using the SRK/T formula [17]. In contrast to these studies, Aristodemou et al. have demonstrated the superiority of SRK/T and Hoffer Q in eyes with AL greater than 26 mm, and less than 21.5 mm, respectively, in their comprehensive study [11]. However, either the study by MacLaren et al. or the study by Wang et al. have found that the Haigis formula can yield more accurate postoperative refractive results than Hoffer Q, SRK/T and Holladay 1 for short eyes [9,18]. Although the Haigis formula also showed more accurate results than the Hoffer Q, SRK/T and SRK II for shorter eyes in a meta-analysis by Wang et al. [14], Roh et al. reported the insignificant difference between Haigis and Hoffer Q formulas [19]. Since Hoffer Q and Haigis formulas include preoperative ACD measurement, their increasedaccuracy for shorter eyes may be associated with the increased true estimation of ELP. Olsen has defined an equation containing preoperative ACD, preoperative LT and “C constant” for the precise prediction of postoperative IOL position [20]. On the other hand, a new generation formula that is a mathematical approach, Hill-RBF does not use vergence formula and ELP separately for IOL power calculation. This formula makes calculations using ACD, AL, K and a special software that is preinstalled in OLCR (Lenstar, Haag-Streit) device.
Although Gokce et al. have suggested similar results between Barrett Universal II, Haigis, Hill-RBF, Hoffer Q, Holladay 1, Holladay 2, and Olsen formulas in 86 patients with AL equal to or less than 22 mm, the highest MAE value was determined with the Haigis formula followed by the Olsen formula in their study [3]. In contrast to this study, besides the superiority of the Barrett Universal II formula over SRK/T, Hoffer Q and Hill- RBF formulas, there was also a slight difference in MAE values between some third, fourth and new generation formulas in short eyes in the current study. Since in the present study all formulas except SRK/T contain the ACD variable for IOL power calculation, the highest MAE value due to the SRK/T formula might have arisen from the decreased prediction of ELP. In the current study, the second highest MAE values, followed by the SRK/T formula, were detected in the Hoffer Q and Hill- RBF formulas. The reason for the higher MAE value in these formulas may be result of reduction in the prediction of ELP, because Hill-RBF uses ELP estimation separetely, and unlike Hoffer Q formula, fourth and newer generation formulas involve more variables to strengthen the precise prediction of ELP apart from using ACD, for example, Haigis formula contains a0, a1 and a2 constants.
Although in contrast to the present study, Kane et al. have revealed lower MAE value using the Hill-RBF formula compared to the Barrett Universal II formula in shorter eyes, which contradicts the result of the current study, none of the new generation formulas was shown to yield more accurate postoperative refractive outcome than the Barrett Universal II formula, or the best third generation formulas in the same study [8].
In the Olsen formula, two different softwares, OlsenStandalone, and OlsenOLCR have been suggested to give distinct outcomes [21]. In the present study, the Olsen formula could not be included in the comparison because of the lack of information about its version installed in the biometric device, namely, it was not known whether the software was OlsenStandalone, or OlsenOLCR, and it is considered as the major limitation of the present study.
Conclusion
It is thought that despite the superiority of the Barrett Universal II formula in the estimation of accurate refractive outcome in shorter eyes, the other generation IOL power calculation formulas may also provide satisfactory results for these patients in case of unavailability of software of new generation formulas in the biometric device.
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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Aydin Yıldız, Sedat Arıkan. The accuracy of different generation intraocular lens power formulas in eyes with axial length less than 22 millimeter. Ann Clin Anal Med 2021;12(Suppl 2): S210-214
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The perceptiveness about the preventable measures and complications of viral hepatitis in Arar City-KSA
Syed Sajid Hussain Shah, Yazeed Lafi N. Alanazi, Sami Nayir H. Alanazi, Abdulhamid Qaed A. Alenezi
Department of Pathology, Faculty of Medicine, Northern Border University, Arar, Kingdom of Saudi Arabia
DOI: 10.4328/ACAM.20421 Received: 2020-12-02 Accepted: 2021-01-23 Published Online: 2021-02-23 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S215-218
Corresponding Author: Syed Sajid Hussain Shah, Professor of Pathology, College of Medicine, Northern Border University, Arar, Kingdom of Saudi Arabia. E-mail: prof.sajid99@gmail.com P: +966537759649 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3425-6293
Aim: This study is aimed to assess the level awareness of the risk factors and complications of viral hepatitis among the residents of Arar city – KSA.
Material and Methods: A pre-designed questionnaire was used, which was filled by willing participants who were residents of Arar city, KSA. The questionnaire included fourteen questions about factors, which increase the risk of HBV & HCV infection, and four questions about the complication of HBV, HCV and HEV infection. The questionnaire also included three questions about risk factors of hepatitis A and E virus infection. The participants have been divided into two categories. Category 1 included people with a school education, while category 2 included persons with a university education.
Results: A total of 482 willing participants completely filled the questionnaire, of which 79.5% were males and 20.5 % females. Among these participants, 78.8% had a university education, while 21.2% belonged to category 1 (school level education). Awareness of the risk factors for HBV and HCV infection is better among the people with a university education than among people with lower education level. Awareness of the risk of spreading HBV and HCV after needle-stick injury (needle of used syringes), close contact with infected person’s blood and body fluids, and from an infected mother to a baby is low in the significant majority of persons from both categories.
Discussion: Awareness of certain factors, which increase the risk of transmission of HBV and HCV is deficient among people, and awareness of these factors needs to be raised in the community.
Keywords: Hepatitis C virus; Hepatitis B virus; Awareness; Risk factors
Introduction
Hepatitis is an inflammatory condition of the liver in which hepatocytes are damaged by injurious agents leading to necrosis and apoptosis. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are common causative agents of hepatitis. HBV and HCV affect more than a billion persons around the whole world and cause more than one million deaths every year [1,2]. The HCV infection has been found to be more common compared to HBV when screening asymptomatic persons before blood donation and cataract surgery [3,4]. A study conducted on the diagnosed cases of tuberculosis revealed that 7.75 % of these patients had HCV infection [5]. Damage to liver cells by these pathogens may lead to fulminant hepatitis, chronic hepatitis, cirrhosis and cancer.
The HBV and HCV are transmitted through the use of contaminated syringe needles, unsafe barber razors, needle stick injuries, intravenous drug abuse, sexual contact, surgery with contaminated equipment, unsafe transfusion of blood and blood products, and vertical transmission from mother to child [6-8]. Healthcare providers and patients attendants may also be at greater risk of acquiring the infection, as these viruses may be present in many body fluids of patients, such as blood, saliva, semen, vaginal fluid and effusions.
Other causative agents of viral hepatitis include hepatitis A virus (HAV) and hepatitis E virus (HEV), which are spread through drinking contaminated water or ingestion of contaminated food. HAV and HEV usually cause self-limited infections, but HEV infection during pregnancy is associated with high mortality. Awareness of the preventable risk factors and complications of viral hepatitis may reduce the spread of infection and decrease mortality and morbidity due to liver diseases in the community. This study is aimed to assess the awareness level about the risk factors and complications of viral hepatitis and to compare the level of knowledge with respect to the educational level of the residents.
Material and Methods
The study was approved by the local committee of bioethics. A pre-designed questionnaire was used, which was filled out by the willing participants from the Arar city – KSA. A convenient sample method was employed to select participants. The questionnaire included items to collect data about age, educational level and 14 questions about the factors, which increase the risk of HBV and HCV infection and four questions about the complication of HBV, HCV and HEV infection. The questionnaire also included three questions about risk factors of hepatitis A and E virus. The participants were divided into two categories. Category 1 included persons with a school (primary and secondary) education, while category 2 included people with a university education. The data were analyzed using a computer.
Results
A total of 482 willing participants among the residents of Arar city, KSA completely filled the questionnaire, of which 79.5% were males and 20.5 % were females. Among these participants, 78.8% had a university education (category 2), while 21.2% belonged to category 1 (primary and secondary school education). Participants with a higher level of education (University education level) had significantly higher percentage of those who knew the majority of risk factors that increases the risk of HBV and HCV virus infection, compared with people with a lower education level (primary and secondary school education). The majority of persons in both categories are unaware of the risk of spreading of HBV and HCV after needle- stick injury (needle of used syringes), close contact with infected person’s blood and body fluids and from an infected mother to a baby. The results are depicted in Table 1.
A significant number of participants in both categories are aware of the risk factors, which increase the chance of transmission of HAV and HEV and subsequent complications of HBV, HCV and HEV infections. The results are shown in Tables 2 and 3.
Discussion
The analysis of the present study revealed that the awareness level regarding the factors that increase the risk of HBV and HCV infections is relatively better in people with higher education level. But there are certain risk factors, about which the majority of the community has a low awareness level, particularly, about a needle stick injury (needle of used syringes), close contact with an infected person’s blood and body fluids, and from an infected mother to a baby.
A study was conducted in KSA in 2017 to assess knowledge, attitude and practice (KAP) on HBV among Internet Users in Taif city. The study found that only 20.5% had satisfactory knowledge, whereas the urban residency, university education and working in the medical field are significantly associated with satisfactory knowledge [9]. Another KAP study was done in the community in 2017, which revealed that most of them are well aware of hepatitis B transmission, the definition, symptoms and complications [10]. A recent study, which was done in 2020 to assess the awareness about the hepatitis C virus among medical students in Dammam city, found that more than 50% of them had fair knowledge about HCV screening, clinical presentation, complications and treatment, while 75% of students had poor knowledge about HCV transmission [11]. A study was done in Yemen among the medical laboratory and nursing students. The results of the study revealed that the students are poorly informed about HBV and HCV [12].
Other studies have also revealed low public awareness of HBV, especially modes of transmission, screening, vaccination and complications [13,14]. Higher educational level was a significant predictor of higher level of knowledge about HBV [15]. Conclusion: There is insufficient awareness about the certain factors, which increase the risk of HBV and HCV transmission. The findings of the present study raise the need for dissemination of knowledge regarding the factors that facilitate the spread of hepatitis viruses from infected cases to healthy persons in the community. In this regard, print, electronic and social media may be used for better public awareness about these pathogens along with the other possible means.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Jefferies M, Rauff B, Rashid H, Lam T, Rafiq S. Update on global epidemiology of viral hepatitis and preventive strategies. World J Clin Cases. 2018; 6(13):589– 99. DOI:10.12998/wjcc.v6.i13.589
2. Tordrup D, Hutin Y, Stenberg K, Lauer JA, Hutton DW, Toy M, et al. Additional resource needs for viral hepatitis elimination through universal health coverage: projections in 67 low-income and middle-income countries, 2016–30. The Lancet Global Health. 2019;7:e1180–8. DOI:10.1016/ S2214-109X(19)30272-4
3. Fatimah M, Tehrim H, Fayyaz H, Sadiq F, Bhatti S. Seropositivity of Hepatitis B and C in Healthy Blood Donors at Ghurki Trust Teaching Hospital, Lahore, Pakistan. PJMHS. 2020;14(2); 371-3.
4. Mansha M, Azhar F , Afzal F, Shahbaz M, Mustafa A. Prevalence of Hepatitis B and C among Cataract Surgery Patients in Avicenna Hospital Lahore. PJMHS. 2019;13(4): 876-77.
5. Rehman UA, Razzaq A, Butt NI, Farooq U, Mushtaq F. Prevalence of Co- infection with Hepatitis C among tuberculosis patients presenting at Gulab Devi Hospital, Lahore. PJMHS. 2020: 14(2): 403-4.
6. Yin W, Huang C, Qiu F, Liu L, Wang F, Zhou J, et al. Risk factors of hepatitis C virus transmission and genotype distribution in former blood donors from Chinese rural area. BMC Public Health. 2015;15:184. DOI:10.1186/s12889-015-1535-6
7. Weis-Torres SMS, Fitts SMF, Cardoso WM, Junior MGH, Lima LA, Bandeira LM, et al. High level of exposure to hepatitis B virus infection in a vulnerable population of a low endemic area: a challenge for vaccination coverage, International Journal of Infectious Diseases. 2020;90: 46-52. DOI:10.1016/j.ijid.2019.09.029
8. Spengane Z, Korsman S, Mkentane K, Davids LM, Zemanay W, Africa M, et al. Blood and virus detection on barber clippers. S Afr Med J. 2018;108(4):278-82. DOI:10.7196/SAMJ.2018.v108i4.12830
9. Elbur AI, Almalki N, Alghamdi A, Alqarni Alqarni HA. Knowledge, Attitude and Practice on Hepatitis B: A Survey among the Internet Users in Taif, Kingdom of Saudi Arabia. J Infect Dis Epidemiol. 2017;3(3). DOI:10.23937/2474-3658/1510036
10. Wedhaya MA, Kurban MA, Abyadh DA, Alshamrani ASR, Alzahrani GS, Alhabi1 HA, et al. Assessment of Knowledge, Attitude and Practice towards Hepatitis B among Healthy Population in Saudi Arabia, 2017. The Egyptian Journal of Hospital Medicine. 2017;69 (2):1973-7. DOI:10.12816/0040632
11. Almansour AH, Darwish MA, Abdel Wahab MM. Hepatitis C infection awareness among fourth year medical students at University of Dammam. J Family Community Med. 2017;24(1):49-54.
12. Almualm YK, Banafa NS, Al-Hanshi AS. Knowledge, Attitude and Practice (KAP) about Hepatitis B and C among Students of Hadhramout University, Al- Mukalla City, Yemen. Acta Scientific Medical Sciences. 2018;2(7):87-95.
13. Hislop TG, Teh C, Low A, Li L, Tu SP, Yasui Y, et al. Hepatitis B knowledge, testing and vaccination levels in Chinese immigrants to British Columbia, Canada. Can J Public Health. 2007; 98(2):125-9. DOI: 10.1007/BF03404323
14. Ma GX, Shive SE, Fang CY, Feng Z, Parameswaran L, Pham A, et al. Knowledge, attitudes, and behaviors of hepatitis B screening and vaccination and liver cancer risks among Vietnamese Americans. J Health Care Poor Underserved. 2007;18(1):62-73. DOI:10.1353/hpu.2007.0013
15. Yau AHL, Ford J, Kwan PWC, Chan J, Choo Q, Lee TK, et al. Hepatitis B Awareness and Knowledge in Asian Communities in British Columbia. Can J Gastroenterol Hepatol. 2016; DOI:10.1155/2016/4278724.
Download attachments: 10.4328_ACAM.20421
Syed Sajid Hussain Shah, Yazeed Lafi N. Alanazi, Sami Nayir H. Alanazi, Abdulhamid Qaed A. Alenezi. The perceptiveness about the preventable measures and complications of viral hepatitis in Arar City-KSA. Ann Clin Anal Med 2021;12(Suppl 2): S215-218
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Determination of kidney stone prevalence in Sivas city center: A retrospective research
Hüseyin Saygın 1, Ziynet Çınar 2, Abuzer Öztürk 1, Emre Kıraç 1, Ismail Emre Ergin 1, Arslan Fatih Velibeyoğlu 1, Esat Korgalı 1
1 Department of Urology, Cumhuriyet University Faculty of Medicine, 2 Department of Biostatistics, Cumhuriyet University Faculty of Medicine, Sivas, Turkey
DOI: 10.4328/ACAM.20422 Received: 2020-12-03 Accepted: 2021-01-06 Published Online: 2021-01-18 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S219-222
Corresponding Author: Hüseyin Saygın, Cumhuriyet University Faculty of Medicine, Department of Urology, Sivas, Turkey. E-mail: dr.saygin@hotmail.com P: +90 346 2580521 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6875-0882
Aim: In this study, it was aimed to determine the prevalence of urinary stone disease (USD) in the center of Sivas based on data from patients who were diagnosed with USD at the urology clinic of the hospitals in Sivas center.
Material and Methods: This is a retrospective study. The records of the patients who applied to the Urology Department of the Faculty of Medicine of Sivas Cumhuriyet University and Sivas Numune Hospital i between 2014 and 2019 were examined in this research. Evaluations of statistics were made on the basis of data to determine the prevalence of USD in Sivas center.
Results: The data of 30218 people (20114 males and 10104 females) who applied to the Urology Policlinic of Sivas Central Hospitals in 2014 and 2019 were evaluated for USD. Also, 4739 patients who were operated in both hospitals were evaluated according to gender and age. Results significantly increased with age for both genders (p<0.05). On the other hand, the number of people treated with Extracorporeal Shock Wave Lithotripsy (ESWL) in both hospitals was 1543. They were evaluated by age and gender, and results were not statistically significant (p>0.05).
The prevalence of USD in the Sivas Center was determined as 8%. Agglomeration was observed in 31-70 age groups in both sexes. The results showed that the risk of USD was twice as high among men in both Numune Hospital and C.U Hospital.
Discussion: Our country is one of the regions where USD is common, but there are not enough prevalence studies on this subject. It is a known fact that pro- cesses of diseases and treatment put a great burden on the economy of the country. Knowing the frequency of the disease makes it easier to take precautions. More epidemiological studies in larger populations are needed to direct health policies.
Keywords: Urinary stone disease; Sivas; Prevalence
Introduction
Changings of economic balances, living conditions, eating habits and the huge amount of refugees, which increased in last years have changed the frequency and distribution of diseases in our country.
Epidemiological researches give an idea about the prevalence of diseases and provide precautions to be taken. However, epidemiological researches are rarely done in our country. It is a known fact that processes of diseases and treatment put a great burden on the economy of the country. Knowing the frequency of the disease makes it easier to take precautions. Prevalence studies are widespread in the world [1-7]. Our country is considered a risky area for urinary stone disease (USD), but epidemiological studies are scarce [8-10]. USD is seen from birth to death at any age and sex and may lead to chronic kidney disease (CKD), which is extremely troublesome for the patient and expensive to treat when untreated [11-13]. In this study, it was aimed to determine the prevalence of USD in the center of Sivas based on the data of patients who were diagnosed with USD at the urology clinic of the hospitals in Sivas center.
Material and Methods
This is a retrospective study. Records of the patients who applied to Sivas Cumhuriyet University Faculty of Medicine, the Urology Department and Sivas Numune Hospital between 2014 and 2019 were examined in this research. The number of patients diagnosed with USD, the number of patients who received ESWL and the number of operated patients was determined. The data obtained from the study was uploaded to SPSS (ver: 22.01 program). Age, gender and years were compared. Statistical evaluations were made based on the data to determine the prevalence of USD in the Sivas center. The Ethics Committee of Sivas Cumhuriyet University approved this study (2020-01/23).
Results
In the study, the data of 30214 people who received a diagnosis of USD and applied to the Urology outpatient clinics of Sivas Central Hospitals from 2014 to 2019 were determined (C.U. Hospital 11732, Numune Hospital 18482 patients).
These patients, who were treated in both hospitals, were evaluated according to gender. There were 10100(♀) females and 19914 (♂) males in both hospitals. There were twice as many male patients as female patients. When age distribution was examined, the frequency was seen in both sexes in the age range of 31-70 years (Table1). Patients with bladder stones were excluded because their primer etiology is lower urinary system obstructions and commonly seen in males older than 65. Age and gender groups were compared. The result was statistically significant (p<0.05).
In the hospital, 6418/10100 (♀) females and 13627/20114 (♂) males were in the 31-70 age range. Age and gender groups were compared. The result was statistically significant (p<0.05) (Table 1). The prevalence significantly increased with age for both genders (p<0.05).
In the hospital, 7818 /12210 males (64%) and 4392/12210 females (36%) had kidney stones. For ureteral stones, 7186/10238 men (70.2%) and 3052/10238 women (29.8%), for kidney + ureteral stones, 5110/7766 (65.8%) males and 2656/7766 (34.2%) females, in total 20114 men (66.6%) and 10100 women (33.4%) were included in the study.
Among 30214 patients, 4739 were operated; 4739 patients (15.6%) who underwent surgery in both hospitals were evaluated according to gender. There were 3332 men (70.3%) and 1407 women (29.7%) for percutaneous nephrolithotomy (PCNL) and ureterorenoscopy (URS) (Table2).
Among 30218 patients, 1543 (5.1%) underwent ESWL. Patients were examined by age, gender and years. The difference was not statistically significant (p>0.05) ( Table 2).
For ESWL, 1101 male (71.3%) and 442 female (28.7%) patients were found. Evaluation of operation cases (PCNL/URS) and ESWL results were also reported by years (Figure 1). The frequency was observed in the 31-70 age group. The incidence of stone was twice as high in males. This study was based on the 2019 Sivas/Center population registration systems, a database of the Turkish Statistical Institute. The prevalence of USD in the Sivas Center was determined as 8%. All statistical evaluations, (except ESWL) were found significant (p<0.05
Discussion
The incidence of kidney stone disease in adults increases within time, and its prevalence ranges from 2 to 20% worldwide [14- 16]. The urinary stone disease affects 1-5% of the industrial population. Regardless of gender and race, there has been an increase in prevalence since the last quarter of the twentieth century [6,17-19]. It is reported that the disease is most commonly seen (1.5 times more) in 30-40 years old males, and there is no difference in the prevalence among urban and rural inhabitants [8,15,16]. The recurrence rate of urinary stone disease is 35-50% in 10 years [16,17,20]. Obesity, diabetes, malnutrition and rural-urban migration have become more common problems, increasing the risk of stone disease [18,20]. As the prevalence increases, the cost of treating kidney stone disease increases, and the productivity loss generates the socio-economic side of the problem [12]. The prevalence of stone disease is reported to be 2-8% in the USA [5,6]. In studies conducted in other countries, prevalence was found as follows: in Argentina 4%, in China 8% (♂), 5% (♀), in Korea 3.5%, in Taiwan 9.6%, in Iran 5.7% [4,19,21-23]. The prevalence of stone disease was 4.7% in Germany, 4.3% in Iceland and 10% in Italy [24,25]. Studying the relationship between uric acid stone and gout in Italy, Borghi et al. found a positive correlation between family history and stone disease and gout. The frequency of uric acid stones was high 26.5% [7] .
Our country is one of the regions where stone disease is common, but there is not enough prevalence study on this subject. Akıncı et al. have reported that the prevalence of the disease in general was 14.8% [8]. Their study involved 1500 people from 14 regions throughout the country, with the incidence of 2.2% in 1989. It is reported that the disease is most commonly seen between the ages of 30 and 40, 1.5 times higher in males, and more common in people with low socio-economic status and lower education, whereas there is no difference in prevalence between urban and rural residents.
According to the study by Uluocak et al. in Tokat province, the lifetime prevalence of urinary stone disease was 11.42% [9]. In another regional study, individuals with stone disease were separated according to their regions, and 28.6% of the cases were from the Southeastern Anatolia region, 28.6% from the Eastern Anatolian region, 22.8% from the Marmara region, 14.3% from the Black Sea region. and 5.7% from the Central Anatolia region [10].
Türkan et al. performed a retrospective review of patient files in the Western Black Sea Region. In their study, the distribution of stone diseases according to localized kidney stones was found as 9040 (34.7%), ureter stones: 15264 (58.6%) and bladder stones: 1740 (6.7%) [14]. In our research, the prevalence of USD in the Sivas Center was determined as 8%, kidney stones: 12214 (40.4%), ureteral stones: 18004 (59,6%).
USD leads to varying degrees of kidney dysfunction and some secondary diseases [11]. It is noteworthy that recurrent febrile urinary tract infections and renal stone may cause permanent kidney damage, especially in children [11]. CKD progresses to renal failure, resulting in the need for renal replacement such as hemodialysis, peritoneal dialysis and transplantation. This puts a serious economic burden on society and impairs the quality of life of patients [13].
As a result, stone disease is an important public health problem in our country. If we think that the main purpose of modern medicine is to protect against diseases, improve nutritional habits, lifestyle and fluid intake, which are corrected risk factors for stone disease, and it is necessary to revise health education policies to balance socio-economic level. It is important for Turkey to determine a more accurate incidence. Making incidence studies in all cities lets us gather more accurate data. Training activities can be conducted in risk groups and high- risk areas. The population can be warned about “lifestyle, fluid intake and proper nutrition”. More epidemiological studies in larger populations are needed to direct health policies.
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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3. Iguchi M, Umekawa T, Katoh Y, Kohri K, Kurita T. Prevalence of urolithiasis in Kaizuka City, Japan—an epidemiologic study of urinary stones. Int J Urol. 1996;3(3):175-9.
4. Kim Hh, Jo MK, Kwak C, Park SK, Yoo KY, Kang D, et al. Prevalence and epidemiologic characteristics of urolithiasis in Seoul, Korea. Urology. 2002;59(4): 517-21.
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6. Stamatelou KK, Francis ME, Jones CA, Nyberg Jr LM, Curhan GC. Time trends in reported prevalence of kidney stones in the United States: 1976–1994. Kidney Int. 2003;63(5): 1817-23.
7. Borghi L, Ferretti PP, Elia GF, Amato F, Melloni E, Trapassi MR, et al. Epidemiological study of urinary tract stones in a northern Italian city. Br J Urol. 1990; 65(3): 231-5.
8. Akinci M, Esen T, Tellaloğlu S. Urinary stone disease in Turkey: an updated epidemiological study. Eur Urol. 1991; 20(3): 200-3.
9. Uluocak N, Erdemir F, Atilgan D, Erkorkmaz Ü, Çetin I, Parlaktas BS. Tokat ilinde üriner sistem tas hastaligi prevalansi/The prevalence of urinary system stone disease in Tokat province. Turkish Journal of Urology. 2010; 36(1):81.
10. Tefekli A, Tok A, Altunrende F, Barut M, Berberoglu Y, Muslumanoglu AY. Life style and nutritional habits in cases with urinary stone disease. Turk Uroloji Dergisi/ Turkish Journal of Urology. 2005;31(1):113-18.
11. Gambaro G, Favaro S, D’Angelo A. Risk for renal failure in nephrolithiasis. Am J Kidney Dis. 2001;37(2): 233-43.
12. Lotan Y. Economics and cost of care of stone disease. Adv Chronic Kidney Dis. 2009; 16(1): 5-10.
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15. Fetter TR, Zimskind PD, Graham RH, Brodie DE. Statistical analysis of patients with ureteral calculi. JAMA. 1963; 186(1): 21-3.
16. Leusmann DB, Niggemann H, Roth S, Von Ahlen H. Recurrence rates and severity of urinary calculi. Scand J Urol Nephrol. 1995;29(3): 279-83.
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18. Köseler E.Current Approaches in Medical Nutrition Therapy of Kidney Stone. Turkiye Klinikleri J Health Sci. 2018;3(2):146-53.
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Hüseyin Saygın, Ziynet Çınar, Abuzer Öztürk, Emre Kıraç, Ismail Emre Ergin, Arslan Fatih Velibeyoğlu, Esat Korgalı. Determination of kidney stone prevalence in Sivas city center: A retrospective research. Ann Clin Anal Med 2021;12(Suppl 2): S219-222
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Effect of anesthesia type (local or general) on neurocognitive functions in carotid endarterectomy
Ferhat Borulu 1, İzzet Emir 2, Muhammed Enes Aydın 3, Ümit Arslan 1, Eyüpserhat Çalık 1, Bilgehan Erkut 1
1 Department of Cardiovascular Surgery, Ataturk University Faculty of Medicine, Erzurum, 2 Department of Cardiovascular Surgery, Erzincan Binali Yıldırım University Faculty of Medicine, Erzincan, 3 Department of Anesthesia and Reanimation, Ataturk University Faculty of Medicine, Erzurum, Turkey
DOI: 10.4328/ACAM.20600 Received: 2021-03-17 Accepted: 2021-05-26 Published Online: 2021-06-12 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S228-232
Corresponding Author: Ferhat Borulu, Ataturk University. Faculty of Medicine, Department of Cardiovascular Surgery, 25100 Erzurum / Turkey. E-mail: fborulu@gmail.com P: +90 505 351 1762 Corresponding Author ORCID ID: https://orcid.org/0000-0001-9731-9998
Aim: Neurocognitive disorders and major neurological complications can develop after carotid endarterectomy. The aim our was to investigate the effect of local or general anesthesia during carotid endarterectomy on these neurocognitive functions via objective tests.
Material and Methods: The study included 30 patients who underwent carotid endarterectomy under different types of anesthesia (general anesthesia in 16 patients or local anesthesia in 14 patients) between June 2017 and August 2019. Postoperative neurocognitive functions of the patients were compared using tests to quantitatively evaluate their cognitive performance (Standardized Mini-Mental Test and Clock Drawing Test).
Results: Twenty-one patients were male and nine were female. There was no serious coronary lesion, except for carotid artery stenosis. None of the patients developed major complications such as stroke or transient ischemic attack. Length of stay in the intensive care unit and hospital was shorter in the local anesthesia group (p=0.005 and p=0.001). Although the preoperative Standardized Mini-Mental Test and Clock Drawing Test results of the groups were similar (p=0.765 and p=0.999), there was a significant difference in favor of the local anesthesia group in both tests in the pre-discharge period (p=0.001).
Discussion: Although there is no significant difference in terms of major neurological complications, local anesthesia applications show positive results in terms of neurocognitive functions. We believe that the use of local anesthesia in carotid endarterectomy operations, to the extent allowed by other clinical features of the patient, is important for neurocognitive functions, despite surgical difficulties.
Keywords: Carotid Endarterectomy; Local Anesthesia; General Anesthesia; Neurocognitive Functions
Introduction
Atherosclerotic cardiovascular diseases (CVDs) are one of the major causes of mortality throughout the world. Among these diseases, carotid artery occlusion (CAO) has a prominent place. Increased intima-media thickness in the carotid arteries and luminal stenosis due to atherosclerosis cause approximately 20% of ischemic stroke events [1,2]. The first attempt at carotid endarterectomy (CEA) was performed in 1954 to eliminate this vascular problem, and it became more popular in the following years. It is considered as a treatment method that significantly reduces the risk of cerebrovascular events in patients with stenosis of 60% or greater [4-6]. Despite the development of techniques and intraoperative monitoring methods, major complications such as stroke, myocardial infarction, and mortality are commonly observed [7]. Although CEA is accepted as the gold standard for treatment of patients with severe carotid artery stenosis, there are still controversies about the anesthesia method to be applied during the operation. Both methods have their advantages and disadvantages. General anesthesia is accepted as the most comfortable method for the surgeon. During this method, the patient can be ventilated more safely and medical interventions made by the anesthetist for cerebral protection are easier. However, the assessment of cerebral functions is highly restricted. In local anesthesia, it is easier to follow the neurological functions, but the need for patient compliance comes to the fore. The disadvantages of this method include the patient’s agitation in the failure of local anesthesia and the need to urgently return to general anesthesia in the presence of respiratory problems [8].
The incidence of complications including stroke, myocardial infarction, and mortality in CEA is less than 7% [9,10]. Although they are rarer than others, hemorrhages due to the opening during the early period of arteriotomy, and pseudoaneurysms from the arteriotomy site in the late period may occur [11]. Although CEA aims to reduce possible neurological complications, minor neurological complications such as a decline in neurocognitive functions and transient ischemic attack, major complications such as stroke, may develop depending on the surgery performed [12]. Intraoperative hemodynamic instability, disruptions in cerebral blood flow, cerebral embolization, and undesirable side effects of anesthetic agents used are involved in the development of these complications [13,14]. Although major neurological complications can be identified using imaging methods and classical physical examinations, several neurological problems that may arise due to impaired cerebral blood flow or microembolism cannot be identified with radiological methods. Among these complications, a decline in neurocognitive functions is the prominent one. Its incidence reaches 25% regardless of the type of anesthesia. Although the type of anesthesia used has been comprehensively compared in the General Anesthesia Versus Local Anesthesia (GALA) trial, discussions regarding the type of anesthesia are still ongoing. This study aimed to compare the effect of anesthesia types used in CEA operations on neurocognitive functions in the early postoperative period using objective tests that were not used before in this regard.
Material and Methods
Patient selection, grouping and study design
The study included patients who were hospitalized for operation (60% and above) due to severe isolated carotid artery stenosis. The patients were divided into two groups in turn. The order of patients who had special requests for the type of anesthesia and who had contraindications for the type of anesthesia was changed. Patients with a special demand regarding the type of anesthesia were included in the group of their choice. The patients were divided into two groups namely Group 1 consisting of 16 patients (11 males, 5 females) and Group 2 consisting of 14 patients (10 males, 4 females). Group 1 was operated under general anesthesia and Group 2 was operated under local anesthesia. The standardized Mini-Mental Test (SMMT) and Clock Drawing Tests (CDT) were applied the day before the operation, the first postoperative day, and the day before discharge to measure neurocognitive functions of the patients. The same test was performed three times in total for each patient. Demographic data, intraoperative monitoring, and postoperative follow-up parameters of the patients were recorded. All patients were informed about the study and their written consent was obtained. This study was approved by the local ethics committee (Atatürk University Faculty of Medicine Clinical Researches of Ethical Committee. Ethical Approval Number: B.30.2.ATA.0.01.00/283)
Anesthesia applications and surgical procedures
General anesthesia
On the morning of the surgery day, the patient was admitted to the operating room and standard American Society of Anesthesiologists monitoring was performed. All patients underwent standardized preoperative assessment, sedation, and anesthetic management. Anesthesia was induced with 0.5 mg/kg midazolam, 5 mg/kg thiopental sodium, 0.6 mg/kg rocuronium was administered. Remifentanil was administered as a 0.3 mcg/kg bolus just before induction, followed by an infusion of 0.1-0.25 mcg/kg/min throughout the surgery. Anesthesia was maintained with %2 sevoflurane and intermittent doses of rocuronium. Remifentanil infusion dose adjustment was left under the supervision of the anesthesiologist.
Local anesthesia
Patients were taken to the regional anesthesia room 30 minutes before the surgery. Vascular access was established with routine monitoring. In the supine position, the patient’s head was turned towards the side opposite to the side planned for surgery. The 18-Hz Linear ultrasound transducer (Esaote MyLab 30 Genova-Italia) was placed transversely in the middle of the sternocleidomastoid muscle (SCM). Advancing towards the posterior, the endpoint of the muscle was displayed on the screen. From this region, a 22-gauge 5-mm sonovisible peripheral nerve block needle (B. Braun Melsungen AG, Melsungen, Germany) was inserted towards the bottom of SCM through an in-plane technique. The area was confirmed by 1-2 mL saline injection. A total of 15 mL of local anesthetic mixture containing 0.25% bupivacaine and 1% lidocaine was used; 10 mL was injected between SCM and the prevertebral fascia and 5 mL was injected along the carotid sheath. All procedures were
performed in accordance with the rules of aseptic and antiseptic surgery. Before the start of the surgery, it was confirmed that all patients were completely anesthetized with a superficial cervical plexus block and then, the surgery was initiated. Regardless of the type of anesthesia, heparinization was performed after surgical exploration in all patients. After the clamp was placed, arteriotomy was performed and atherosclerotic plaques were cleaned. Vascular forceps were used to perform the endarterectomy and the arteriotomy area was closed with a pericardial patch. No shunt was used in any of the patients, since there was no severe stenosis in the other carotid arteries. General anesthesia had to be performed due to the severe agitation affecting the operation in one of the patients undergoing local anesthesia. This patient was excluded from the study. Patients with carotid artery stenosis accompanied by coronary artery stenosis, and those who underwent simultaneous coronary artery bypass operation were also excluded from the study.
The Clock Drawing Test
Patients are drawn to one hour, asked to put the numbers in the appropriate positions and mark the time reported to the patient. Structural praxis and comprehension and planning ability are tested with this test. The total score is 6. Scores below 4 indicate cognitive dysfunction. Scoring is done as follows:
• The position of the number twelve is correct: 3 points,
• All twelve numbers were written down: 1 point,
• The hour and minute hands were drawn: 1 point,
• The time announced to the patient was marked correctly: 1 point.
Advantages of the clock drawing test:
– A short test,
– It requires a shorter time to apply
– Includes the fact that it has a high negative predictive value. However, test scoring is subjective, and there is a high level of false negativity as the disadvantages of the results. Standardized Mini Mental Test (SMMT)
The standardized mini mental test is used for the quantification of cognitive performance. Although it has limited specificity for differentiating clinical syndromes, it can be used for a global assessment of cognition as a brief, convenient, and standardized method. It comprises eleven items categorized under five major themes, which are orientation, registration memory, attention and calculation, recall, and language. The highest total test score is 30.
Statistical Analysis
Statistical analyses were performed using the Number Cruncher Statistical System (NCSS) 2007 (Kaysville, Utah, USA). Descriptive statistics (mean, standard deviation, median, frequency, percentage, minimum, and maximum) were used to evaluate the study data. The distribution of the data was evaluated using the Shapiro-Wilk Test. The Mann-Whitney-U test was used to compare quantitative data between two groups that did not show a normal distribution. The Chi-Square test was used in qualitative data. A p- level of <0.01 and 0.05 was considered statistically significant.
Results
There was no difference between the two groups in terms of demographic characteristics (e.g. age, sex, etc.) (Table 1). Operation time was significantly longer in patients undergoing general anesthesia compared to those receiving local anesthesia (p=0.835). The clamping time was similar between both groups (Table 2). None of the patients had serious neurological complications. Although facial paralysis occurred in two patients in Group 1 and one patient in Group 2 in the early postoperative period, it disappeared in the first-month control. Moderate hoarseness occurred in one of the patients in Group 2. An improvement was achieved in these complications within 15 days with steroid treatment. Furthermore, none of our patients developed myocardial complications in the preoperative and postoperative periods. One patient in the general anesthesia group was re-operated for hematoma developed at the postoperative fourth hour, and bleeding revision was performed under local anesthesia. All patients in the group operated under general anesthesia were extubated in the intensive care unit (ICU).
Although there were no differences between the two groups in the preoperative period (p=0.999) in terms of the clock drawing test, which was one of the tests performed to evaluate neurocognitive functions, a significant decrease was detected on the first postoperative day in Group 1 (p=0.001). The tests performed on the day before discharge similarly showed a significant decrease in Group 1 (p=0.001). In the evaluation made within the groups, a significant decline was observed in both the postoperative first day and pre-discharge values in Group 1. This decline was higher on the postoperative first day than on the day before discharge (p=0.001). Although there was also a decrease in these values in Group 2, these changes were not statistically significant (p=0.882).
As in the other test, there was no difference in terms of the preoperative SMMT values (p=0765). Unlike the other test, both measurements made on the postoperative first day and the day before discharge were significantly higher in the local anesthesia group in this test (p=0.001) (Table 3). The intragroup evaluation showed that the results of the postoperative first day and pre-discharge period in Group 1 were significantly lower than the preoperative period (p=0.001). Although there was a decrease in Group 2, it was not statistically significant (p=0.094).
There was no statistically significant difference in the length of stay in ICU and the discharge times, although the length of stay in the ICU was longer in Group 1 (p=0.215). The length of hospital stay was found to be similar between the groups. The length of hospital stay was significantly lower in the local anesthesia group than in the other group (p=0.001).
Discussion
The CEA is a highly effective method to reduce the frequency of major cerebrovascular events in patients with severe carotid stenosis. Numerous studies have revealed sufficient evidence in this regard [15,16]. It has an important place in vascular surgery operations all over the world.
This surgical method has been successfully performed under both general anesthesia and local anesthesia for many years. Although discussions about the choice of anesthesia type have decreased slightly with studies, particularly the comprehensive GALA trial [17] conducted in 2009 and meta-analysis studies by Vaniyapong et al. [18], the issues not addressed in these studies and some recent studies have shown that the discussions on this issue are ongoing. There is a limited number of studies on the evaluation of neurocognitive functions for the selection of anesthesia type. Most of these studies were based on laboratory tests that can be used to evaluate these functions. In this prospective controlled randomized trial, it has been tried to contribute to the previous studies on this subject by using some tests accepted as objective measurement methods. Similar demographic characteristics and preoperative neurocognitive function test results, obtained despite the hospitalization of the patients included in the study with a diagnosis of isolated carotid stenosis and performing operation under different anesthesia methods repeatedly have contributed to the interpretation of the study results in terms of the type of anesthesia.
The effects of the anesthesia type on neurocognitive functions after surgery are not fully clarified. Decreases in cerebral blood flow and micro-level embolism are the underlying reasons for these changes after CEA operation [19]. The relationship of these reasons with the type of anesthesia has not been fully established yet. This study investigates the results, not the formation mechanism of the event. In operations performed under general anesthesia other than CEA, no deterioration in neurocognitive functions is observed in postoperative tests. This loss of function in CEA operations has been attributed to hypoperfusion caused by clamping [20]. There are studies reporting that perfusion disorder, which may occur due to clamping, can be reduced by using shunts [21]. Since no shunt was used in any patient in our study, no difference was observed between the groups in this respect. There are also studies suggesting that the decline in neurocognitive dysfunction after CEA is due to the hypoperfusion occurring during the operation, regardless of the type of anesthesia. In this study, Heyer et al. suggested that imaging methods cannot reveal any differences [22]. However, the underlying basis of this study was slightly weakened since the impairments in neurocognitive functions cannot be detected radiologically in general. In the present study, neurocognitive functions of patients operated under two types of anesthesia were assessed using tests, tests that were recognized as useful, rather than imaging methods.
The standard clock drawing test, which was one of the tests used in this study, did not differ between the groups in the preoperative period. The absence of a significant difference between the groups made it easier to perform the analyses at the beginning. Although these test results were better in the local anesthesia group on the postoperative first day, these values decreased on the day before discharge. This indicates that the loss of function that occurred in the early operational period decreased in the following days. In this respect, our study is similar to the study conducted by Weber et al. [14] in 2009. However, the results obtained from SMMT, which was one of the other tests performed to evaluate neurocognitive functions, were similar between the groups in the preoperative period, whereas the local anesthesia group was found to have better results on the postoperative first day and day before the discharge.
Antiplatelet therapy started before operation is also effective in determining the type of anesthesia to be used in CEA operations. In general, it is recommended that patients using these drugs should be operated without stopping the ongoing therapy and general anesthesia should be preferred. Although this leaves anesthesiologists in doubt about bleeding complications during local anesthesia, local anesthesia is successfully performed under ultrasound guidance for these patients in our hospital. Some studies on this subject are also suggestive in this regard [23].
The surgeon’s preference, as well as all of these factors, are very important in determining the type of anesthesia. With the exception of surgical requirements, most of the surgeons prefer general anesthesia as it is more comfortable [24]. Although there are justified reasons such as difficulties in blood pressure control and agitation, local anesthesia is also highly preferred because of its advantages such as postoperative discharge times, costs, and differences in neurocognitive functions. In the present study, the neurocognitive functions of the patients were not evaluated as a priority for being discharged from the ICU. Therefore, no significant difference was observed between the groups, although the length of stay in the ICU was shorter in the local anesthesia group. However, there was a difference in favor of the local anesthesia group in terms of the length of hospital stay. We believe that changes in neurocognitive functions and readiness for discharge within a shorter period of time in this patient group have been effective in the formation of this difference. Although there has been no significant difference between the groups in terms of major neurological complications in the present study, local anesthesia seems to be more advantageous due to its positive effects on neurocognitive functions. Local anesthesia can be successfully applied in patient groups in whom general anesthesia may be associated with a high risk (e.g. chronic obstructive pulmonary disease). Since the number of patients was not high in the present study, the number of patients whose anesthesia type was selected according to this factor was very low.
Study limitations
Since the incidence of isolated carotid artery stenosis in the community is not very high, the number of patients included during the study remained low.
In our study, radiological imaging was not performed to the patients in the post-operative period. The comparison was made only with objective tests.
Conclusion
There is no significant difference between the types of anesthesia used for CEA operations in terms of major complications and mortality rates. However, each anesthesia type has advantages and disadvantages that come to the forefront. The results obtained from this study, in which objective tests that have not been used before in this regard, except for biochemical parameters or imaging methods, have been used, suggests that neurocognitive functions are better preserved in patients undergoing local anesthesia. We believe that it would be beneficial to prefer local anesthesia in patients without definitive contraindications.
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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Ferhat Borulu, İzzet Emir, Muhammed Enes Aydın, Ümit Arslan, Eyüpserhat Çalık, Bilgehan Erkut. Effect of anesthesia type (local or general) on neurocognitive functions in carotid endarterectomy. Ann Clin Anal Med 2021;12(Suppl 2): S228- 232
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The role of plasma cytokine levels in the differential diagnosis of epileptic and psychogenic non-epileptic seizures
Özgül Ocak 1, Yaşar Zorlu 2, Güldal Kırkalı 3, Gamze Tuna 4
1 Department of Neurology, Çanakkale Onsekiz Mart University Faculty of Medicine, Çanakkale, 2 Neurology Clinic, Izmir Tepecik Educational and Research Hospital, İzmir, 3 Department of Medical Biochemistry, Dokuz Eylul University Faculty of Medicine, İzmir, 4 Department of Medical Biochemistry, Dokuz Eylul University Faculty of Medicine, İzmir, Turkey
DOI: 10.4328/ACAM.20702 Received: 2021-05-17 Accepted: 2021-06-11 Published Online: 2021-06-16 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S223-227
Corresponding Author: Özgül Ocak, Çanakkale Onsekiz Mart University Faculty of Medicine, Department of Neurology, Terzioğlu Campus, 17020, Çanakkale, Turkey. E-mail: dr_ozgul@hotmail.com P: +905058320631 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8276-0174
Aim: In this study, we aimed to evaluate the use of plasma cytokine levels in the differential diagnosis of epileptic and psychogenic nonepileptic seizures.
Material and Methods: Thirty-three epilepsy patients with generalized seizures, 23 patients with psychogenic nonepileptic seizures and 31 control patients were included in the study. Blood was drawn from all patients at 1 and 24 hours after seizures, and IL-1β, IL-1Ra, IL-6 and TNF-α levels were measured. The results were evaluated in terms of differences by groups and hours.
Results: A significant increase was observed in IL-1β, IL-6 and IL-1Ra levels in the epileptic seizure group compared to controls in the first hour. This increase is significantly different only for IL-1β with the psychogenic non-epileptic seizure group. IL-1β appears to be the marker that best distinguishes the epileptic seizure group from both control and psychogenic non-epileptic seizure groups. IL-1β values were not significantly different between the 1st and 24th- hour measurements in the epileptic seizure group. TNF-α levels decrease significantly in psychogenic non-epileptic seizure patients compared to both epileptic seizure and control groups, but show significant increase over time between 1 and 24 hours.
Discussion: Checking blood cytokine levels can be used as an adjunct method in the differential diagnosis when distinguishing between epileptic and psycho- genic non-epileptic seizures. In our study, the importance of blood cytokine levels in the differential diagnosis and the time at which they are checked were shown.
Keywords: Cytokines; Epileptic Seizure; PNES
Introduction
According to the definition of the World Health Organization, epilepsy is a dysfunction of the whole or a part of the brain, which is seen as a result of repetitive, abnormal discharges of neurons that have become over-excitable in the brain, which manifests itself with clinical features of sudden and transient, motor, sensory, autonomic and psychic nature [1]. Psychogenic non-epileptic seizure (PNES) is mainly used to describe non- epileptic clinical conditions that are not associated with epileptic electro encephalogram (EEG) disorders, but have an epileptic seizure-like appearance and often seen secondary to psychiatric disorder [2].
Many clinical and experimental studies have shown an increase in inflammatory cytokine levels in epileptic seizures [3]. Pro- inflammatory cytokines are concentrated in low amounts within the brain, increasing after seizures. After the seizure, mRNA expression of interleukin-1 beta (IL-1β), IL-6 and TNF-α has been shown to be upregulated in the hippocampus [4-6].
In experimental studies, it has been shown that IL-1β is proconvulsant and neurotoxic, and interleukin-1 receptor antagonist (IL-1Ra) is anticonvulsant and neuroprotective [7]. IL-1β, a member of the interleukin receptor family, activates the GluN2B subunit of the N-methyl-D-aspartate (NMDA) receptor and induces seizures by causing upregulation of NMDA receptors on postsynaptic cells [8].
It was found that IL-1β in the cerebrospinal fluid (CSF) increased significantly in epileptic pediatric patients compared to the control group, indicating that IL-1β plays an important role in the onset and progression of epilepsy [9].
It has also been shown that IL-1β is proconvulsive in rabbit epilepsy models induced with kainic acid, with worsening of seizures and prolongation of seizure activity after intrahippocampal injection of IL-1β [10]. Indirect evidence of the proconvulsive effects of IL-1β is the reduction in induced convulsions after intracerebral injection of IL-1Ra in mice [11]. IL-1β not only induces nitric oxide production and increases seizure sensitivity, but also increases neuronal excitability by inhibiting direct Gamma-Aminobutyric acid (GABA) receptors, increasing NMDA receptor function, and reducing potassium efflux [7,12]. It is known that IL-1Ra cells bind to IL-1β receptors and prevent IL-1β from binding. In some studies, it has been found that intracerebral administration of IL-1Ra (this is a natural antagonist of endogenously produced IL-1β) has a very strong anticonvulsant effect. Similarly, mice that produce excess IL-1Ra have resistance against seizures [11].
In humans, it has been shown that IL-6 and IL-1Ra levels increase in the CSF and blood, and there is no significant change in the level of IL-1β after focal seizures and secondary generalized tonic clonic seizures [13-15].In animal studies, it has been shown that IL-6 mRNA increases rapidly in the hippocampus, amygdala, dentate gyrus, cortex, and meninges [16].
Neither CSF nor blood TNF-α levels were observed to change within 24 hours of tonic clonic seizure and partial secondary generalized seizure. Again, no changes were found in TNF-α concentrations in the blood and CSF of patients with febrile seizures [17].
Studies show that the effect of TNF-α is concentration dependent. TNF-α shows its proconvulsive effect at low
concentration and anticonvulsive effect at high concentration in seizures mediated by Shigella. In addition, the p55 pathway is activated at low concentrations of TNF-α, while the p75 pathway is activated at higher concentrations. In conclusion, while TNF-α creates a proconvulsive effect through the p55 receptor at low concentrations, it has an anticonvulsive effect through the p75 receptor at high concentrations [18].
In our study, we looked at postictal blood cytokine levels at 1 and 24 hours in a group of patients with epileptic seizures and PNES and compared the groups with both themselves and with the control group, we searched the availability of the difference, if detected, as an auxiliary method in the differentiation of epileptic seizures and PNES.
Material and Methods
In this study, 33 epilepsy patients (17 females, 16 males) with primary generalized seizures and 23 patients with PNES (18 females, 5 males) and 31 healthy volunteers (18 females, 13 males) who applied to the neurology service, neurology outpatient clinic and emergency service of İzmir Tepecik Training and Research Hospital were included. Local ethics committee approval was obtained for the study.
In epileptic seizure and PNES groups, blood cytokine levels were measured by taking 2 tubes of blood at 1 and 24 hours after the seizure and 1 tube of 5 cc blood from the control patients. Patients with acute cerebrovascular disease, alcohol or substance abuse, pregnancy and lactation, oral contraceptive, hormone or anti-inflammatory drug use, chronic renal failure or dialysis patients, and those with signs of infection were excluded from the study.
EEG, 1.5 Tesla Cranial MRI, liver function tests, kidney function tests, and hemogram examinations were performed in all patients and the control group.
TNF-α, IL-1β, IL-1Ra, IL-6 levels in serum samples were measured by the “sandwich” ELISA (Enzyme Linked Immunosorbent Assay) (Human TNF-α Ultrasensitive ELISA, Invitrogen, Camarillo, CA 93012) method. Serum samples were diluted with dilution buffer at a ratio of 1/2 and studied. According to the ELISA method, patient samples were sandwiched between immobilized polyclonal antibodies and biotin-labeled polyclonal specific antibodies conjugated with streptavidin-peroxidase. After the unbound material was removed by washing, the process was stopped after a while after the addition of peroxidase enzyme substrate (tetramethylbenzidine) and the resulting color was measured at 450 nm wavelength. Values were calculated as pg/mL using the standard graph drawn. The determined values were multiplied by the dilution coefficient and the real values were obtained.
The SPSS (version 26.0) program was used for the analyses. After all data were transferred to the digital environment and controlled, the frequency and percentage values for categorical variables, mean and standard deviation values for continuous variables were given. The normality of the distribution of continuous variables was evaluated using the Kolmogorov- Smirnov test. Since there was no normal distribution in variables in all groups, non-parametric tests were preferred. The Chi- square test for categorical variables, the Kruskal-Wallis test for continuous variables and Dunn’s test for post hoc analysis were used for intergroup comparisons. The Wilcoxon Signed Ranks test was used to compare TNF-α, IL-1β, IL-1Ra and IL-6 values at 1 and 24 hours. Test constants and absolute p-values were given for all analyzes. The general significance limit in the study was accepted as p<0.05.
Results
The age and gender characteristics of the epileptic seizure, PNES and control groups included in the study are given in Table 1. There is no statistically significant difference between the gender distribution and mean age of the cases according to the groups (p>0.05).
IL-1β, IL-6, IL-1Ra and TNF-α values of the seizure patients’ 1st hour samples and control group are shown in Table 2. There was a significant difference between the groups for all four variables measured.
Postictal first-hour interleukin levels in the study groups are shown in Figure 1. In the post-hoc comparison of IL-1β levels between the groups, there was a significant difference between the epileptic seizure and the PNES group (Z=17.308; p=0.035) and between the epileptic seizure group and the control group (Z=28.533; p<0.001), while there was no significant difference between the PNES group and the control group (Z=11.225; p=0.317).
In the post-hoc comparison of IL-6 levels between the groups, there was no significant difference between the epileptic seizure group and the PNES group (Z=14.408; p=0.170). There was a significant difference between the control group and epileptic seizure group (Z=31.577; p<0.001) and control group and PNES group (Z=17.168; p=0.040).
In the post-hoc comparison of IL-1Ra levels between the groups, there was a significant difference between the epileptic seizure group and the control group (Z=21.660; p=0.002), while there was no significant difference between the epileptic seizure and PNES group (Z=8.689; p=0.616) and control group and the PNES group (Z=12.971; p=0.186).
In the post-hoc comparison of TNF-α levels between the groups, there was a significant difference between the epileptic seizure group and the PNES group (Z=17.397; p=0.034) and between the PNES group and the control group (Z=21.503; p=0.006), while there was no significant difference between the epileptic seizure group and the control group (Z=4.106; p=1,000). Comparison of IL-1β, IL-6, IL-1Ra and TNF-α values at 1 and 24 hours, obtained according to the study groups of the participants is shown in Table 3. There was significant difference only in IL-6 values in the epileptic seizure group, and in IL-1β, IL-6, and TNF-α values in the PNES group.
Discussion
For years, clinicians have been trying to define the nature of episodic neurological symptoms. Events associated with marked motor activity or altered consciousness are often predicted to be epileptic seizures. However, the event actually represents one of a broad spectrum such as syncope, parasomnias and movement disorders or conversive paroxysmal events. It is known that an important type of episodic behavior is the psychogenic conversion seizure.
In our study, we examined the possibility of using postictal blood cytokine levels to identify and differentiate seizures. When the first-hour measurements were compared with the control group, a significant increase was observed in the levels of IL- 1β, IL-6 and IL-1Ra for the epileptic seizure group. This increase is significantly different for only IL-1β with the PNES group. IL-6 was also significantly higher than in the control group in the PNES group, while PNES group values for IL-1Ra levels did not differ from the epileptic seizure and control groups. On the other hand, TNF-α levels were significantly decreased in the PNES group compared to the control and epileptic seizure groups. IL-1β appears to be the marker that best distinguishes the epileptic seizure group from both the control and PNES groups. IL-1β values were not significantly different between the 1st and 24th hour measurements in the epileptic seizure group. This can be interpreted as the differential value of this marker continues for the following hours in the differentiation of epileptic seizures. However, it should be noted that there is a small but significant increase in IL-1β values between the 1st and 24th hours in the PNES group. Significant reduction of TNF-α levels in both epilepsy and control groups in PNES patients may support diagnostic power. However, it should be noted that TNF-α levels significantly increase over time between the 1st and 24th hours in PNES patients and lose this power. Significant increases in IL-1β, IL-6 and IL-1Ra in the epileptic seizure group can be evaluated as the diagnostic power will increase when all of these markers are used together, but mixed and contradictory situations may also be encountered in all patients due to the lack of a change in the same direction. Increased IL-1 production was detected in temporal lobe epilepsy in the literature. The detection of IL-1β, IL-1Ra, and IL-1α gene polymorphism in drug-resistant epilepsy patients suggests a relationship between haploid types of cytokine genes and the development of focal seizures [19].
In a study conducted on rats, it was found that there was an increase in IL-1β and IL-1Ra immunoreactivity, mainly in microglial cells after kainic acid-induced seizures [20]. It was found that the changes in plasma IL-6 level seen in patients with complex partial epilepsy were very low compared to patients with secondary generalized tonic clonic epilepsy, which showed that seizure severity and IL-6 level were correlated [21]. There was no significant change in IL-1β levels in the postictal period when compared with preictal levels in the studies. A striking increase in IL-1Ra levels was detected at the second and twelfth hours after the seizure. These increases seen in IL-1Ra were higher, especially after generalized seizures, but this difference was not statistically significant [15]. In another study, an increase in IL-6 levels was found in postictal blood samples taken immediately after the seizure. The average increase was 51% after 1 hour and 87% after 24 hours. No difference was found in the postictal IL-1β and TNF-α levels. IL-6 levels were slightly higher in patients with secondary generalized tonic clonic epilepsy compared to those with focal seizures, but this difference was not statistically significant. Gender was not found to have an effect on serum cytokine levels. Basal IL-6, TNF-α, IL-1β levels did not differ in patients with hippocampal sclerosis (HS) or without HS, but patients with HS had significantly less elevated levels of postictal IL-6 compared to others and were taken to preictal measurements. Those with right-sided temporal seizure onset had higher serum IL-6 levels in all measurements than those with left-onset [23]. Our study showed that blood cytokine levels can be used to differentiate between epileptic seizures and PNES.
Conclusion
Results associated with epilepsy and blood cytokine levels are few and contradictory. Existing changes in the patient profiles taken in the studies and the seizure types of the patients affect the results of different studies. Epilepsy patients and healthy controls were compared in the studies conducted. Our study performed a separate comparison between patients with epileptic seizures and PNES patients and their comparison with healthy control groups. In our study, the increase in IL-1β, IL-6 and IL-1Ra levels after epileptic seizures was significant, the most distinctive difference was associated with IL-1β levels. TNF-α levels were significantly lower in the PNES group than in the control group and epileptic seizure patients. When evaluated together with the results of other studies, cytokine levels can be considered to be used diagnostically, but it should be kept in mind that there are many differences in interpersonal genetics, seizure type, drugs used, and the etiological factors of seizures. More studies should be conducted on the relationship between blood cytokine levels, which, in our opinion, may have an important place in the differential diagnosis of epilepsy patients. The place of blood cytokine levels in differential diagnosis with long-term and large-group studies will become clearer in the upcoming years.
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. Saccomani L, Cirrincione M, Savoini M. Pseudo-epileptic seizures in children and adolescents. Dev Med Child Neurol. 1993;35(4):359-61
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4. Scorza C, Marques M, Gomes da Silva S, Naffah-Mazzacoratti M, Scorza F, Cavalheiro E. Status epilepticus does not induce acute brain inflammatory response in the Amazon rodent Proechimys, an animal model resistant to epileptogenesis. Neurosci Lett. 2018; 668:169-73.
5. Han T, Qin Y, Mou C, Wang M, Jiang M, Liu B. Seizure induced synaptic plasticity alteration in hippocampus is mediatedby IL-1β receptor through PI3K/Akt pathway. Am J Transl Res. 2016;8(10):4499–509.
6. Plata-Salaman CR, Ilyin SE, Turrin NP, Gayle D, Flynn MC, Romanovitch AE, et al. Kindling modulates the IL-1β system, TNF-α, Tgf-β1, and neuropeptide mRNAs in specific brain regions. Brain Res Mol Brain Res. 2000; 75(2):248–58.
7. Vezzani A, Moneta D, Conti M, Richichi C, Ravizza T, De Luigi A, et al. Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc Natl Acad Sci U S A. 2000; 97(21):11534– 9.
8. Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, et al. Interleukin-1 beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci. 2003; 23(25):8692–700.
9. Shi L, Chen R, Zhang H, Jiang C, Gong J. Cerebrospinal fluid neuron specific enolase, interleukin-1β and erythropoietin concentrations in children after seizures. Childs Nerv Syst. 2017;33(5):805–11.
10. Somjen GG. Lonregulation in the brain: implications for pathophysiology. Neuroscientist. 2002;8(3):254-67.
11. Donnelly S, Loscher CE, Lynch MA, Mills KH. Whole-cell but not acellular pertussis vaccines induce convulsive activity in mice: evidence of a role for toxin- induced interleukin-1beta in a new murine model for analysis of neuronal side effects of vaccination. Infect Immun. 2001; 69(7):4217–23.
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13. Peltola J, Palmio J, Korhonen L, J Suhonen, A Miettinen, M Hurme, et al. Interleukin-6 and Interleukin-1 receptor antagonist in cerebrospinal fluid. Epilepsy Res. 2000; 41(3):205–11.
14. Lehtimäki KA, Keränen T, Huhtala H, Hurme M, Ollikainen J, Honkaniemi J, et al. Regulation of IL-6 system in cerebrospinal fluid and serum compartments by seizures: the effect of seizure type and duration. J Neuroimmunol. 2004; 152(1- 2):121–5.
15. Lehtimäki K, Keränen T, Palmio J, Mäkinen R, Hurme M, Honkaniemi J, et al. Increased plasma levels of cytokines after seizures in localization-related epilepsy. Acta Neurol Scand. 2007; 116(4):226–30.
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21. Bartfai T, Schultzberg M. Cytokines in neuronal cell types. Neurochem Int. 1993; 22(5):435–44.
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Özgül Ocak, Yaşar Zorlu, Güldal Kırkalı, Gamze Tuna. The role of plasma cytokine levels in the differential diagnosis of epileptic and psychogenic non-epileptic seizures. Ann Clin Anal Med 2021;12(Suppl 2): S223-227
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Giant prostatic urethral stones in a young patient
Aydemir Asdemir 1, Huseyin Saygin 2, Esat Korgali 2, Tugba Yildiz Asdemir 3
1 Urology Clinic, Suluova Public Hospital, Amasya, 2 Department of Urology, Faculty of Medicine, Cumhuriyet University, Sivas, 3 Department of Old Care, Sabuncuoglu Serefeddin Vocational School Of Health Services , Amasya University, Amasya, Turkey
DOI: 10.4328/ACAM.20394 Received: 2020-11-06 Accepted: 2020-12-14 Published Online: 2020-12-27 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S233-235
Corresponding Author: Aydemir Asdemir, Urology Clinic, Suluova Public Hospital , 05500, Amasya, Turkey. E-mail: aydemirasdemir@hotmail.com P: +90 5068943216 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9141-6727
Giant prostatic urethral stones have been reported as a very rare entity, and the etiology of these stones is not clear. Here we report a case of a 44-year-old man with giant multiple prostatic urethral stones presented with voiding difficulty and recurrent urinary tract infections. A big stone in the right cavity was observed endoscopically, some of them protruding into the urethra, and two other big stones in the left cavity were observed after resection of the surface tissue on the stones on the prostate. Following cystoscopy, giant prostatic stones were removed endoscopically after holmium-YAG laser lithotripsy.
Keywords: Giant; Prostate; Urethra; Stone
Introduction
Even though giant prostatic urethral stones are reported to be common in elderly men, they are quite exceptional to be encountered in younger adults. Prostatic parenchymal calculi are very common and consist of calcified corpora amylacea usually incidental, findings on computed tomographic (CT) scan or transrectal ultrasound. As reported their incidence increase with age, they are often rare in children but common in middle- aged and old males[1]. Prostatic calculi are almost associated with benign prostatic hyperplasia (BPH) or chronic prostatitis, and some papers have reported that they do not influence the level of prostate specific antigen (PSA) in men without clinically detectable prostatitis. Seldomly, although there is no certain association between them, moreover they may be present in association with prostate cancer [2]. They are associated with chronic inflammation, epithelial damage, and obstruction of the glandular tissue on histological examination. However, the clinical significance of prostatic calculi is unknown. Prostatic calculi are asymptomatic in most cases, but large calculi may lead to urinary retention, prostatitis, or chronic pelvic pain syndrome. It has been reported that a prostatic calculus is actually a cluster of bacteria and that these calculi may be the cause of prolonged bacteriosis in patients with recurrent urinary tract infections [3]. In the literature, giant prostatic urethral stones were rare in males particularly before the sixth decade [4].
Case Report
A 44-year-old man presented with urgency, frequency and strangury. These symptoms have persisted for about three years. His digital rectal examination revealed a moderately enlarged peripheral soft prostate gland and with stony hard consistency in some inner areas, but not fixed as a tumor nodule. Prostate- specific antigen (PSA) was 0,47 ng/dL. Creatinin was within normal limits. His urinary sediment demonstrated microscopic hematuria and pyuria, and his urine was infected with ESBL (+) E.Coli. The infection was treated with a 1gr meropenem IV every eight hours for a week and after treatment, the control culture was sterile. An examination of the kidneys, ureter, and bladder (KUB), X-ray study, and CT scan (Figure 1 ) revealed two giant prostatic urethral stones, each greater than 2.5 cm in size. The upper urinary tract and bladder appeared to be normal in CT. We decided not to plan a biopsy because there was no nodule determined by digital rectal examination. Also, a CT scan secondary to erythrocytosis in urinary sediment showed us prostatic urethral calculi and our young patient had low PSA level. The patient underwent cystourethroscopy. Cystourethroscopy revealed almost complete closure of the prostatic urethra by the giant stones. Two giant prostatic urethral stones were removed endoscopically (Figure 2). We made only minimal resection of the left lobe of the prostate to extract the stone, but we did not make complete resection of the prostate because the patient did not accept it before the operation. He only wanted us to extract the stones because of his age and probable complications, especially retrograde ejaculation. In addition, we decide to follow up his uroflowmetry because, after stone extraction, cystourethroscopy revealed that the prostate was moderately small, and the prostatic urethra was open. After surgery, a urethral catheter was placed. After the urethral catheter was taken on the postoperative second day, the patient voided with a good stream. During the first month of operation, the patient had no complaints regarding his voiding pattern. His urine culture remained sterile. Ultrasonography and X-ray examinations revealed no remaining calculi in the lower urinary tract. His post-operative period was uneventful and he was started on alpha-1A blocker in the postoperative period because of his uroflowmetric patterns and international prostate symptom score. His average flow was 10.7ml/sec and maximal flow was 14.3 ml/sec. His international prostate symptom score was 14. We did not take uroflowmetry measurement before the operation because of urethral stones and the patient urinating drop by drop. At follow-up during the first month after the surgery, the patient emptied with a good stream.
Discussion
Prostatic calculi are usually subclinical, but if inflammation is present along with the calculi, various symptoms of the lower urinary tract can be present. Shoskes et al. [5] found that prostatic calculi were generally identified in patients with chronic prostatitis and postulated that because of the presence of prostatic calculi, there was more inflammation in the prostates of these men and that these men had to strain more to urinate than men without prostatic calculi.
Prostate calculi were commonly reported to be asymptomatic in most cases, and some papers have reported that these calculi are actually a cluster of bacteria and may cause urinary tract infections. Most articles have reported that the degree of LUTS may be relative to the presence of large prostatic calculi and inflammation [6]. Although prostatic calculi are relatively common, and complications are rare [4]. Less than 20 cases of giant prostatic calculi have been reported in the literature. They occur more frequently in younger men, unlike microscopic prostatic calculi, which are usually seen in men above the age of 50. Patients can present with lower urinary tract symptoms, urinary retention, pain, and urethral strictures. The etiology of prostatic calculi is not clear. It is generally accepted that prostatic calculi are part of the normal process of aging and only rarely may have clinical importance [7]. True prostate calculi are formed by deposition of calcareous material on corpora amylacea [4]. The pathogenesis of the formation of prostate calculi is thought to be the deposition of hydroxyapatite crystals in corpora amylacea, which is assembled by desquamation of aciner cells and stasis of prostatic fluid following obstruction of prostate ducts. Prostatitis is implicated as one of the predisposing causes that initiate the cascade of prostatic calculi formation. Chronic prostatitis and recurrent urinary tract infections have been implicated in their development. Such infection and stasis likely result in increased pressure and often results in “autoprostatectomy” of the prostate tissue. Enucleation of the gland is therefore seldom necessary as part of stone management. In the current patient, the stone composition was calcium phosphate and calcium carbonate; similar chemical compositions have been reported for other giant prostatic calculi [8]. Prostatic calculi have also been reported in association with ochronosis, hemospermia, hyperparathyroidism, prostatic hyperplasia and carcinoma in the literature. Kamai et al. [4] reported sudden urinary retention in a 70-year-old man with giant prostatic calculi. Since the patient had no prior history of any known predisposing diseases, such as urethral stricture, prostatic hyperplasia and chronic prostatitis, they suggested a congenital diverticulum in the prostatic urethra or a persistent utricle as the cause of giant prostatic stones. Since the present case provides no history of common predisposing factors such as congenital diverticulum or persistent utricle, it could be stated that this is a possible cause, as well. However, endoscopy remained unrevealing for any anatomic abnormality in the lower urinary tract. Management techniques for giant prostatic calculi have included radical prostatectomy, cystotomy with bladder neck incision, and endoscopic lithotripsy [8]. Since the endoscopic approach is the first choice in our case, the patient underwent endoscopic lithotripsy without removing prostate tissue, multiple giant prostatic urethral stones were removed using the endoscopic urethral route.
Conclusion
Giant prostatic calculi are uncommon and usually associated with obstruction voiding, and are easy to diagnose. The infrared analysis revealed that the majority of the prostatic calculi are mainly composed of calcium phosphates. Several management techniques for giant calculi were described. Enucleation of the gland is therefore seldom necessary as part of stone management. We performed a successful treatment using a single-step endo-urological intervention with holmium-YAG laser lithotripsy.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Kim SH, Jung KI, Koh JS, Min KO, Cho SY, Kim HW. Lower urinary tract symptoms in benign prostatic hyperplasia patients: orchestrated by chronic prostatic inflammation and prostatic calculi? Urol Int. 2013;90(2):144–9.
2. Klimas R, Bennett B, Gardner WA. Prostatic calculi: a review. Prostate. 1985; 7(1):91–6.
3. Eykyn S, Bultitude MI, Mayo ME, Lloyd-Davies RW. Prostatic calculi as a source of recurrent bacteriuria in the male. Br J Urol. 1974;46:527–32.
4. Kamai T, Toma T, Kano H, Ishiwata D. Urethral obstruction due to protruding prostatic calculi. J Urol. 1999; 162:163–4.
5. Shoskes DA, Lee CT, Murphy D, Kefer J, Wood HM. Incidence and significance of prostatic stones in men with chronic prostatitis/chronic pelvic pain syndrome. Urology. 2007;70(2):235–8.
6. Gandaglia G, Briganti A, Gontero P, Mondaini N, Novara G, Salonia A, et al. The role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH). BJU Int. 2013;112(4):432–41.
7. Sondergaard G, Venter M, Christensen PO. Prostatic calculi. Acta Pathol Microbiol Immunol Scand. 1987; 95(3):141-5.
8. Bedir S, Kilciler M, Akay O, Erdemir F, Avci A, Ozgök Y. Endoscopic treatment of multiple prostatic calculi causing urinary retention. Int J Urol. 2005;12:693–5.
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Aydemir Asdemir, Esat Korgali, Huseyin Saygin, Tugba Yildiz Asdemir. Giant prostatic urethral stones in a young patient. Ann Clin Anal Med 2021;12(Suppl 2): S233-235
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ANCA- positive IgA nephropathy presented as alveolar hemorrhage in a COVID-19 patient
Hakan Apaydın 1, Serdar Can Güven 1, İsmail Doğan 1, Aysel Çolak 2, Şükran Erten 1
1 Department of Rheumatology, Ankara City Hospital, 2 Department of Pathology, Ankara City Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.20424 Received: 2020-12-03 Accepted: 2021-01-03 Published Online: 2021-01-10 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S236-240
Corresponding Author: Hakan Apaydın, Ministry Of Health Ankara City Hospital, Department of Rheumatology, Ankara, Turkey. E-mail: drhakanapaydin@gmail.com P: +90 5423498009 Corresponding Author ORCID ID: https://orcid.org/0000-0001-7219-1457
Coronavirus disease 2019 (COVID-19) is a global pandemic caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The SARS-CoV-2 virus primarily targets the respiratory system, but extrapulmonary involvements can be frequently seen. We presented a COVID-19 case with anti-neutrophil cyto- plasmic antibody-positive IgA nephropathy, alveolar hemorrhage, and rapidly progressive kidney disease. The patient received pulse corticosteroids, plasma exchange, and intravenous immunoglobulin as treatment. Azathioprine was added as an immunosuppressive therapy. To the best of our knowledge, this is the first reported case of IgA nephropathy coexisting with COVID-19 infection.
Keywords: Alveolar hemorrhage; ANCA; COVID-19; IgA nephropathy; Intravenous immunoglobulin; Plasmapheresis
Introduction
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people and caused thousands of deaths. SARS-CoV-2 is known to cause significant pulmonary diseases, including pneumonia and acute respiratory distress syndrome (ARDS), and may also present with diffuse alveolar hemorrhage (DAH) [1]. DAH can complicate many clinical situations and can be life- threatening, requiring immediate treatment.
Various extrapulmonary manifestations of COVID-19 have been reported. Acute kidney injury (AKI) is commonly reported in the COVID-19 course [2]. IgA nephropathy (IgAN) is the most prevalent form of primary glomerulonephritis and a significant cause of chronic kidney disease and end-stage renal failure. Infectious diseases are a known cause of IgAN, however, the relation with COVID-19 has not yet been clarified.
Herein, we report a COVID-19 case presented with rapidly progressive kidney failure and alveolar hemorrhage during disease course with positive antineutrophil cytoplasmic antibodies (ANCA) and a kidney biopsy specimen highly suggestive of IgAN.
Case Report
An 18-year-old male patient without any remarkable medical history was admitted to the emergency department on September 7 with fever, cough, and malaise. On admission, the patient was conscious and cooperative, with a blood pressure of 124/54 mm Hg, a heart rate of 98 beats per minute, a body temperature of 37°C, and a respiratory rate of 20 per minute. Oxygen saturation on room air was 94%. Laboratory results were as follows: hemoglobin 14.1 g/dL (12.2-18.1), platelet and white blood cell (WBC) count was normal, lymphocytes count 660 (1100- 4500), creatinine 0.96 mg/dL (0.67-1.17), C-reactive protein (CRP) 86 mg / dL (0-5), liver function tests, cardiac enzymes, ferritin, procalcitonin, coagulation parameters were normal. Serum immunoglobulin levels were within normal ranges.
The patient was diagnosed with COVID-19 with a positive nasopharyngeal SARS-CoV-2 polymerase chain reaction (PCR) test. The patient was then hospitalized, and was prescribed favipiravir, hydroxychloroquine, and low-molecular-weight heparin (LMWH).
The next day, the patient developed hemoptysis of 30-40 cc at a time with a total bleeding of 2-3 cups. O2 saturation was 95% with 2 L/min nasal oxygen. Repeated laboratory evaluation revealed decreased hemoglobin (8.1 gr/dL) and elevated serum creatinine (1.20 mg/dL). In the urinalysis, 140 erythrocytes, 5 leukocytes were detected, the spot urine protein/creatinine ratio revealed a protein excretion of 987 mg/day. In the urine sediment, abundant isomorphic erythrocyte, granular and leukocyte casts were observed. Computed tomography (CT) of the chest revealed fused consolidation and infiltrations in the form of ground-glass opacity, which were common in both lungs, especially in the left lung. This was interpreted primarily in favor of diffuse hemorrhage (Figure 1). The patient was then admitted to the intensive care unit and LMWH treatment stopped. Serum creatinine level further increased to 1.86 mg/dL and O2 saturation dropped to 82%, requiring high- flow oxygen therapy. Further laboratory tests were negative for anti-nucleated antibodies, anti-dsDNA, anti-extractable nuclear antigens panel, and anti-glomerular basal membrane antibody, but positive for proteinase 3 (PR3) – ANCA in indirect immunofluorescence assay (IFA) (1/320) and positive for PR3- ANCA in enzyme-linked immunosorbent assay (ELISA) (> 200 RU/mL). Serum complement 3 level was low and complement 4 level was normal. The patient was then consulted by the rheumatology department.
At presentation, the patient had rapidly progressive kidney disease and active urinary sediment, chest CT findings primarily suggested alveolar hemorrhage and a positive PR3-ANCA ELISA test. The patient was considered as ANCA associated pulmonary- renal syndrome possibly triggered by COVID-19 infection. Pulse methylprednisolone 1000 mg/day for three days was started, followed by 60 mg/d, and fresh frozen plasma exchange every day for seven courses by initiating on September 9. Intravenous immunoglobulin (IVIG) therapy at a dose of 0.4 g/kg/day was given to the patient for five days after the plasma exchange regimen completed. The favipiravir and hydroxychloroquine regiments were simultaneously completed for up to five days. Pulmonary findings rapidly regressed, hemoptysis did not recur, the patient was no more O2-dependent, and CRP levels lowered to the normal range. A significant regression was observed on chest radiography (Figure 2). However, the serum creatinine level continued to progress, reaching over 3 mg/dL.
On the 14th, 15th and 16th of September, the patient’s COVID-19 PCR tests were negative. The patient was transferred from the intensive care unit to the rheumatology clinic. A kidney biopsy was scheduled due to the persistent elevation in the serum creatinine level. On September 29, a tru-cut biopsy was performed from the lower pole of the right kidney, revealing fibrocellular crescent in one glomerule, an early stage of cellular crescent morphology in one glomerule, and segmental sclerosis in one glomerule. Fibrinoid necrosis accompanied crescentic glomeruli. In some other glomeruli, mild mesangial cellular proliferation and an increase in the thickness of the basement membranes in one glomerule were noted. In the immunofluorescence examination, focal, mesangial coarse granular staining with IgA, IgM and C3 complement was observed. The renal biopsy was compatible with IgA nephropathy (Figure 3).
During the follow-up of the patient, the serum creatinine level increased to 1.15 mg/dl. Methylprednisolone 60 mg/d was planned to be continued for one month, and to be tapered gradually thereafter. On October 15, azathioprine 150 mg / day was added to the treatment as an immunosuppressive and steroid-sparing agent. The patient was discharged on October 19.
Discussion
Herein, we described an 18-year-old male COVID-19 patient presented with diffuse alveolar hemorrhage and acute renal failure diagnosed as ANCA positive IgAN.
There is growing evidence of extrapulmonary manifestations of COVID-19. In the United States, the incidence of AKI in patients hospitalized with COVID-19 has been reported to be around 37% [2]. IgAN was the most common primary glomerulonephritis worldwide. The clinical manifestations of IgA nephropathy can vary widely. However, asymptomatic hematuria and progressive loss of kidney function are common.
ANCAs are serologic markers of ANCA-associated vasculitis (AAV) and play an important role in the pathogenesis of various autoimmune diseases. There are a number of reports about patients with IgAN and seropositive ANCA. Bantis et al. defined a case series of 8 patients with a total of 393 patients with IgA nephropathy diagnosed by kidney biopsy (2.04% prevalence) [3]. Among them, five had anti-MPO, and three had anti- proteinase 3 (PR3) antibodies. All patients presented with the clinical syndrome of rapidly progressive glomerulonephritis and reached a peak serum creatinine level of 4.2±2.2 mg/ dL in the first 3 months versus 2.5±1.9 mg/dL in ANCA- negative patients. Furthermore, ANCA- positive patients had a higher percentage of crescent glomeruli (54.3% vs 34.5%) than ANCA-negative patients. ANCA-positive patients treated with intensive immunosuppressive medications (consisting of cyclophosphamide and corticosteroids) demonstrated substantial improvement in renal function. Contrarily, only a minority of the ANCA-negative group received aggressive therapy (5/26); the other patients received steroids alone, mycophenolate mofetil or angiotensin-converting enzyme inhibition. All of these patients demonstrated further progression of kidney failure during the 6-month follow-up period. Yang et al. demonstrated that ANCA-positive IgAN patients had more severe clinical and histological characteristics than ANCA- negative IgAN patients, and their renal prognosis was relatively better with aggressive immunosuppressive therapy in the short term [4]. These studies have shown that ANCA-positive IgAN patients may respond very well to immunosuppressive therapy, and it is similar to the regimens used in patients with classical ANCA-positive vasculitis with renal involvement.
IVIG is a biological product including polyclonal immunoglobulin G. IVIG has been shown to inhibit ANCA-induced neutrophil activation and cytokine release in vitro, and anti-idiotypic antibodies against ANCAs have been explored in IVIG preparations [5]. In addition, IVIG has been used successfully in AAV with relapsing disease and refractory disease [6]. In Wuhan, in a small case series of 3 patients who had deteriorated due to COVID-19, they showed clinical and radiographic improvement with the onset of IVIG [7]. Therefore, we used IVIG due to its successful results in COVID-19 disease and AAV.
Plasma exchange has been successfully used in anti-GBM disease, AAV, SLE, and other autoimmune disorders [8]. In the study conducted by Klemmer et al., in 20 patients who received a combination of intravenous immunosuppressive therapy and plasma exchange in patients with small-vessel vasculitis, DAH showed 100% recovery and some improvement in renal function [8].
In the present case, our patient improved after pulse methylprednisolone, seven plasma exchange sessions and intravenous immunoglobulin. The patient’s renal function improved and the DAH recovered completely. Due to the simultaneous COVID-19 infection, the use and timing of immunosuppressive therapy should have been chosen carefully in this life-threatening condition.
Infections are known to trigger AAV and IgAN. This case highlights that SARS-CoV-2 could be the trigger for IgAN and AAV, and this should be kept in mind in such cases. Although ANCA-positive patients have a more severe course, their response to aggressive immunosuppressive therapy is excellent. Therefore, ANCA antibodies should be determined in all patients with IgA nephropathy, and in cases with COVID-19, treatments such as IVIG, pulse steroids and plasma exchange can be applied, depending on the disease severity.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
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2. Hirsch JS, Ng JH, Ross DW, Sharma, P, Shah HH, Barnett RL, et al. Acute kidney injury in patients hospitalized with COVID-19. Kidney Int. 2020;98(1):209-18. DOI:10.1016/j.kint.2020.05.006
3. Bantis C, Stangou M, Schlaugat C, Alexopoulos E, Pantzaki A, Memmos D, et al. Is presence of ANCA in crescentic IgA nephropathy a coincidence or novel clinical entity? A case series. Am J Kidney Dis. 2010;55(2):259-68. DOI:10.1053/j.ajkd.2009.09.031
4. Yang YZ, Shi SF, Chen YQ, Chen M, Yang YH, Xie X-F, et al. Clinical features of IgA nephropathy with serum ANCA positivity: a retrospective case–control study. Clin Kidney J. 2015;8(5):482-8. DOI:10.1093/ckj/sfv078
5. Rossi F, Jayne DRW, Lockwood CM, Kazatchkine MD. Anti-idiotypes against anti- neutrophil cytoplasmic antigen autoantibodies in normal human polyspecific IgG for therapeutic use and in the remission sera of patients with systemic vasculitis. Clin Exp Immunol. 1991;83(2):298-303. DOI:10.1111/j.1365-2249.1991. tb05631.x
6. Jayne DRW, Chapel H, Adu D, Misbah S, O’donoghue D, Scott D, et al. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM. 2000;93(7):433-9. DOI:10.1093/qjmed/93.7.433
7. Cao W, Liu X, Bai T, Fan H, Hong K, Song H, et al. High-dose intravenous immunoglobulin as a therapeutic option for deteriorating patients with coronavirus disease 2019. Open Forum Infect Dis. 2020;7(3):102. DOI:10.1093/ ofid/ofaa102
8. Klemmer PJ, Chalermskulrat W, Reif MS, Hogan SL, Henke DC, Falk RJ. Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis. Am J Kidney Dis. 2003;42(6):1149-53. DOI:10.1053/j. ajkd.2003.08.015
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Hakan Apaydın, Serdar Can Güven, İsmail Doğan, Aysel Çolak, Şükran Erten. ANCA- positive IgA nephropathy presented as alveolar hemorrhage in a COVID-19 patient. Ann Clin Anal Med 2021;12(Suppl 2): S236-240
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Caries vaccine: A narrative review
Siraj DAA Khan 1, Anwar Alhazmi 2, Yousef Almordef 2, Abdullah Almerdef 2, Mesfer Alshehri 2, Amjad AJ Maghfory 3
1 Pediatric Dentistry, Faculty of Dentistry, Najran University, 2 BDS, Najran, 3 Faculty of Dentistry, Najran University, Najran, Saudi Arabia
DOI: 10.4328/ACAM.20419 Received: 2020-11-30 Accepted: 2021-01-12 Published Online: 2021-01-23 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S241-244
Corresponding Author: Siraj DAA Khan, Pediatric Dentistry, Faculty of Dentistry, Najran University, Najran, Saudi Arabia. E-mail: sdkhan@nu.edu.sa P: +966 175427960 Corresponding Author ORCID ID: https://orcid.org/0000-0002-7015-2232
Streptococcus mutans is the microorganism that is responsible for dental caries. A vaccine targeted at this microorganism could be beneficial to prevent dental caries. Even after various researches, successful immunization against dental caries remains an object yet to be achieved. The aim of the present narrative review to discuss various aspects of the dental caries vaccine.
Keywords: Dental caries; Vaccine; Immunization; Streptococcus Mutans
Introduction
Dental caries is an irreversible disease of the calcified tissue of the teeth, which causes demineralization of the inorganic portion and destruction of the organic part of the teeth [1]. Dental caries is a multifunctional disease caused by environmental, host and agent factors. This disease not only impacts the individual but the whole family. People who cannot afford the treatment at the right time can face many complications at a later stage. This ultimately results in tooth loss, malfunctioning of the tooth, a problem in having a normal diet, which leads to many health-related issues.
Scientists research and figure out that prevention of dental caries can be done by creating a dental vaccine, which can simply be done by developing antibodies against dental caries. The dental vaccine is currently under development using the mechanism of inoculating against bacteria, particularly S. mutans, as its pathophysiology has various phases and each phase can be targeted for immunological intervention [2,3]. History suggested the success of vaccines is associated with disease eradication like chickenpox, which one way to achieve similar results for dental caries, which can effectively be applied in public health.
Many techniques, such as removing plaque mechanically by scaling, using pit and fissure sealants and using fluoride, were adopted and used for the prevention of dental caries. Most of these strategies are effective but these methods neither reduce the susceptibility of the host to get affected by dental caries, nor can reach a wide range of population. Therefore, in that scenario, the community needs an alternative approach that can help reduce the likelihood of dental caries [4]. An alternative to this approach to prevent the dental caries is the caries vaccine. The vaccine is well-suited and easy to implement in the public health system and can be available to more people, especially those who cannot afford or not able to visit the dentist on regular basis or cannot visit the dentist. This technique will surely help in taking prevention steps against dental caries in the community, especially in the younger age group.
Vaccine
Vaccines are immune biological substances designed to produce specific protection against a specific disease. It stimulates the production of protective antibodies and other immune mechanisms. Vaccines are prepared from living modified organisms, inactivated or killed organisms, extracted cellular fractions, toxoids, or a combination thereof.
Testing of Caries Vaccine
Smith (1993) tested on rats and concluded that a mucosal vaccine induces antibodies in saliva against S. mutans’ surface structures, which provide adhesion to the tooth surface and reduce the bacterial acid production [5,6].
Immune response
Primary Response
Once an antigen is administrated in the human or animal body, an induction period of 3 to 10 days must pass, during which antibodies are produced in the blood cell. Initially, IgM antibodies appear, which rise within 2-3 days and, reaching a peak, decline at the same speed. Secondly, IgG antibodies appear, the peak of which appears within 7-10 days, and it takes from a week tomonthtodecrease.Duetotheslowreduction,both B and T
lymphocytes produce memory cells, which are responsible for the immunological memory generated after immunization [7,8]. Secondary Response
Secondary or booster response is very different from the primary response. In this process, both IgM and IgG antibodies are produced. There is a short production of IgM antibodies and prolonged production of IgG antibodies in booster response. Vaccination and revaccination are the actual basis of the immune response and immunological memory [7,8].
Route of Immunization
To induce a protective immune response towards the antigens of the dental caries vaccine, various mucosal routes have been used, such as lymphoid tissues in the gut, nasal, brachial, or rectal sites. Various studies show that these mucosal routes used generated immune responses locally as well as remotely [9].
Oral
The oral route of administration has been used earlier, but studies show that it was not effective due to the determinant effects of the stomach acidity on the antigen. Masaaki et al., (1990) immunized mice orally with a recombinant Streptococcus lactic strain, which carries the structural gene for a surface protein antigen from S. mutans serotype C, resulted in significant salivary immunoglobulin A and serum immunoglobulin G responses [10]. In another study on monkeys by Michael et al., (2004), it was observed that secretory IgA induction was not significant [11]. Thomas (1992) suggested that the oral route is not ideal because stomach acidity affects antigens and the inductive site is also relatively far [12]. Intranasal
The intranasal route targeted the nasal associated lymphoid tissues. Many attempts are made to induceprotective immunity at this site, which is anatomically closer to the oral cavity. Smith (2002) used the intranasal route on rats and observed a reduction in both S.mutans colonization and dental caries.[13] Tonsillar
Many studies done on tonsillar-induced caries vaccine suggested that the ability to trigger immune responses in the oral cavity through tonsillar antigen application is a significant concern. A study on rabbit showed that repetitive tonsillar injection of a particular antigen can trigger the IgA producing cells in both minor and major salivary glands [12].
Minor Salivary gland
Minor salivary glands, because of their short and broad secretory ducts, are considered as a potential route for immunization, which is supported by the studies that show that labial application of GTF significantly reduces the S. mutans in saliva over a 6-week period [12].
Subcutaneous
Studies suggested that subcutaneous administration of S. mutans to monkey induce IgG, IgM and IgA antibodies, which can be found in the gingival crevicular fluid [14].
Rectal
This route can be used as an alternative in children with respiratory problems, which blocks the intranasal application of the vaccine.
Active Gingivo-Salivary route
Gingival crevicular fluid has been used as a route of administration to localize the immune response, and both IgG and IgA levels have been found to increase in saliva [15]. Advances in dental vaccine
DNA Vaccine
A new anti-caries DNA vaccine significantly prevents dental caries. Studies have shown a successful reduction in dental caries and the cell surface protein PAc and the GTF domain (N- terminal catalytic sucrose-binding domain and C-terminal glucan-binding domain), which are known as virulence factors in S. mutans [2,13,14].
Delivery Systems and Adjuvants
Very few clinical studies demonstrated the efficacy of antigen- based active immunization against dental caries. Long-term IgA responses have rarely been achieved by topical application of a soluble peptide antigen to the oral mucosa. This has resulted in the redirection of research efforts to improve immunomodulators or adjuvants and delivery mechanisms that increase mucosal response to the vaccine against caries [2,13,16].
Synthetic peptides
The use of chemically synthesized peptides can strengthen the immune response and can prevent hypersensitivity reaction due to animal or human-derived antigens. Researches by using synthetic peptide have shown the immunogenicity of the alanine-rich Ag I/II region from S. mutans, while higher level of IgG antibodies were found in the protective immunity provided by mucosal immunization [2,13,16].
Coupling with Cholera and E. coli toxin subunits
The nontoxic unit of the Cholera Toxin (CT) has been shown to be a powerful mucosal immunoadjuvant, which can be used in combination with proteins to interrupt the proliferation of S. mutans. Mucosal immunity was improved when a small amount of CT or E. coli heat-labile enterotoxins (LT) was applied with peptides or soluble proteins [2,3,14].
Recombinant vaccines
The recombinant technology, used in the production of synthetic peptides, enables the expression of larger functional sequences. Avirulent Salmonella strains are one of the most effective vectors for the recombinant fusion technique. Effective oral immunization with recombinant Salmonella against S. sobrinus has been documented in rat studies [2,15,16].
Liposomes
Specifically, it has been used in anti-cancer research to target anomalous cells and facilitate successful drug delivery. Once it is used for the prevention of dental caries, a significantly improved mucosal immune response was observed by increasing the absorptions of M cells and the transmission of antigens to inductive tissue lymphoid elements [2,3,14].
Microcapsules and microparticles
Oral immunization with microspheres allows the vaccines to be released safely and in a controlled manner in the gut-associated lymphoid tissues (GALT) [2,14,16]. The local delivery system of Poly lactide-co-glycolide (PLGA) combines the advantage of a regulated and sustained release rate without triggering any inflammatory reaction.
Conjugate vaccines
A substantially enhanced immunogenic response to a T-cell- independent polysaccharide component can be achieved by
chemical conjugation of functionally related protein/peptide components with bacterial polysaccharides [2,14,16].
ISCOM
These are solid particles combined with antigens along with biocompatible detergent and adjuvant carriers that can be helpful in dental caries prevention [2,13].
Plantigens and Plantibodies
Cariogenic microbes from plants perform better action against dental caries without causing side effects. CaroRX (2008), an improved plant-derived antibody and secretory IgA in nature, was developed in tobacco plants and seen to prevent dental caries [17].
Transgenic plants
The development of antibodies in transgenic plants like Nicotiana tabacum is one of the latest steps in the use of passive immunization. Rather than injection, these antibodies can be painted on the teeth [17,18].
Apples and Strawberries
David (2000) noted that injecting S. mutans blocking peptides into fruits like apples and strawberries minimizes dental caries [14,16].
Bovine milk and whey
Cattle immunization with S. mutans vaccine increases the polyclonal IgG antibodies in cattle milk and helps in the reduction of dental caries [2,14].
Egg-yolk
Hamada (1990) introduced hens’ egg-yolk IgY antibodies, which can prevent the dental caries [2,13,14].
Recent Advances
The protein p1025 is the most recent significant development in the caries vaccine field. It replicates the surface structure of S. mutans. This has a major impact on S. mutans by causing false stimuli [19,20].
Future Prospects and Potential Impact
Since dental caries typically grows slowly and may occur during life, the immune defense can be expected to be equally long- lasting. Vaccine therapy is done to prevent infection. Since the association of S. mutans is seen as early as the 34th day in the mouth of the child, immunization against dental caries for people with more chances of infection must be started as early as the second year of life [4]. It is necessary to initiate subsequent immunization if the bacterial colonization is completed after the eruption of all primary teeth. The advantage of early immunization will continue until secondary teeth start to erupt. Two paths can be proposed for future studies. Primarily, to look for new target virulence genes or antigenic proteins to develop a vaccine, as well as using the best adjuvant and administration techniques that have been proven, and to further expand the use of nanotechnology. For example, a completely new protein (PstS), was examined by Ferreira et al., (2016), which showed significant results. Secondarily, improving the best-proven animal studies vaccines up to the required standard [21]. Instead of working isolated, joint efforts should be made towards the most promising vaccine. In animal studies, outcome measures such as serum and salivary antibody measurements and their effectiveness in preventing both in-vivo and in-vitro S mutans adherence should also be standardized. Furthermore, for different vaccines, the scores of caries should be calculated and compared for effectiveness.
The objective of a vaccine against diseases is generally to provide a person with almost complete protection against infection and to achieve a sufficiently high prevalence of immunity in a population that breaks the transmission chain and cannot sustain the pathogen in the community. The biology of caries, however, is distinct from that of acute infections, and it is possible that immunization will not achieve maximum efficacy as with other modalities of action. However, the effectiveness of almost 50% may have significant effects on the burden of the disease and the related social and economic cost. It has been found that the majority of dental caries occurs in a high-risk population group, and targeting such an individual would increase its impact.
Conclusion
It is an understatement to note that more research is needed in the coming days to achieve an agent that can not only be used as a potent caries vaccine, but also be available at a lower cost to the general population. The issue of sufficient financial and infrastructural support is a major shortcoming of this research work, as the project is aimed at the elimination and eradication of dental caries, which are the bread and butter for the major portion of the dental health profession. However, dentists are looking forward to further research and development of caries vaccine that will be a blessing in the care of a patient with medical or physical difficulties, as well as in geriatric and pediatric dentistry.
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. Smith DJ. Dental caries vaccines: prospects and concerns. Expert Rev. Vaccines. 2010;9(1):1-3.
3. Russell MW, Childers NK, Michalek SM, Smith DJ, Taubman MA. A caries vaccine? Caries Res. 2004;38(3):230-5.
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6. Mandel ID. Caries prevention: current strategies, new directions. JADA. 1996;127(10):1477–88.
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9. Hajishengallis G, Michalek SM. Current status of a mucosal vaccine against dental caries. Oral Microbiol Immunol. 1999;14(1):1–20.
10. Iwaki M, Okahashi N, Takahashi I, Kanamota T, Konishi YS, Aibara K et al. Oral immunization with recombinant Streptococcus lactis carrying the Streptococcus mutans surface protein antigen gene. Infect Immun.1990;58(9):2929-34.
11. Russell MW, Childers NK, Michalek SM, Smith DJ, Taubman MA. A Caries Vaccine? The state of the science of immunization against dental caries. Caries Res. 2004;38(3):230-5.
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13. Smith DJ. Dental caries vaccines: Prospects and concerns. Crit Rev Oral Biol Med. 2002:13:335-49.
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20. Pathak TR. Dental caries vaccine: Need of the hour. Int J Oral Health Med Res. 2016;2(5):138-9.
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Siraj DAA Khan, Anwar Alhazmi, Yousef Almordef, Abdullah Almerdef, Mesfer Alshehri, Amjad AJ Maghfory. Caries vaccine: A narrative review. Ann Clin Anal Med 2021;12(Suppl 2): S241-244
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Mental statuses of nursing students in the Covid-19 pandemic period: A systematic review
Sevgi Keskin 1, Birgül Özkan 2
1 Graduate Program of Mental health and Nursing, Ankara Yıldırım Beyazıt University, Institute of Health Sciences, 2 Department of Nursing, Mental health and Nursing, Ankara Yıldırım Beyazıt University, Faculty of Health Sciences Ankara, Turkey
DOI: 10.4328/ACAM.20654 Received: 2021-04-11 Accepted: 2021-06-07 Published Online: 2021-06-16 Printed: 2021-06-15 Ann Clin Anal Med 2021;12(Suppl 2): S245-249
Corresponding Author: Sevgi Keskin, Ankara Yıldırım Beyazıt University, Esenboğa Külliyesi, Esenboğa/Ankara/Turkey. E-mail: kskn.sevgi@hotmail.com P: +90 (312) 324 15 55 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9827-7125
This research is a systematic review conducted to evaluate nursing students’ mental status in theCOVID-19 pandemic period. The study was conducted by scanning Cochrane, Science Direct, PubMed, and Google Academic databases. The index of COVID-19 and Nursing Students, Nursing Students in the Pandemic, Anxiety in Nursing Students were the English keywords. Thirteen articles meeting the evaluation criteria were reviewed. According to the results obtained from the studies evaluated, nursing students experienced mental problems such as anxiety, stress, depression, decreased self-esteem, and emotional exhaustion in the COVID-19 pandemic period.
Keywords: COVID-19; Nursing Students; Anxiety; Stress
Introduction
SARS-CoV-2spread first across China, then to Asian countries, America, Africa, and European countries. As a result of the rapid spread of this virus, the WHO declared a global epidemic (pandemic) on March 11, 2020 [1,2]. Similar to many countries, Turkey has also resorted to isolation methods aimed at the prevention of the virus. These methods were in the form of home isolation, social distance, closing of businesses, including schools/universities, and travel restrictions [3]. There have been many changes regarding the pandemic and educational processes at universities have been affected by it. How nursing students are affected mentally by the changing educational processes has been evaluated as an important issue.
Under normal conditions, nursing education includes challenging and intense processes. Students who receive this training naturally continue to go through a difficult education process while experiencing various mental problems simultaneously. It is observed that students generally experience anxiety during nursing education. Complex interpersonal relationships, difficulties of the clinical environment [4], and caring for chronic and terminally ill patients [5] may cause more anxiety among nursing students than any student from other health disciplines[6]. It is stated that nursing students mostly experience anxiety about academic performance, pressure to be successful, and post-graduation plans [7]. In addition to the problems that students usually experience during their education process, it is thought that their mental status is also affected due to the increasing problems they experience in the pandemic process. Therefore, it is crucial to investigate this issue and determine how their mental statuses are affected. Although the interruption of education in the COVID-19 pandemic period is an unexpected situation among nursing students, clinical applications could not be performed or were partially performed. It is observed that this situation caused anxiety in nursing students. Nursing education mostly consists of clinical practices, and it is not clear when, where, and how compensatory clinical education will be performed. Therefore, nursing students may develop the idea that their own clinical skills will be inadequate and experience more anxiety.
Anxiety is a disturbing emotion and experience that affects people’s lives [8]. Although anxiety arises from the threat of self-integrity, it can also arise as a result of the reflection of various events on the individual [9]. In a study in which 140 first, second, and third-year nursing students participated, it was reported that 82% of the participants experienced tension due to uncertainty related to the hospital environment and fear of making a mistake and academic failure, and that 63% tried to cope with these problems [10].
In the course of COVID-19, the uncertainty brought about by the pandemic process and the limitations in their social life cause nursing students to worry and experience more stress as a result. A study conducted revealed that nursing students perceived stress at a moderate level in the COVID-19 pandemic period. In addition, it was found that watching the news, feeling anxious about the risk of infection, and curfews affected their stress levels [3].
Depression is a syndrome in which the individual feels worthless, weak, reluctant, and pessimistic, along with a slowdown in thought, speech, and movements in a deeply sad emotional state [11,12]. A study to determine the depression levels of nursing studentsrevealed that the students with a risk of depression were 33.3% (Temel E, Bahar A, Çuhadar D. Determination of coping attitude with stress and depressionlevel of nursing students. This work, XIV. Presented as a poster at the National Biotechnology Congress (31 August-2 September 2005 in Eskişehir). Another study found that 25% of the 334 nursing students who participated in the study were at risk for depression [13].
This study aims to compile the results of studies dealing with nursing students’ mental status during the COVID-19 pandemic period and contribute to the literature.
Material and Methods
This study was conducted to examine the results of studies that determined nursing students’ mental status in the COVID-19 pandemic period. The study covers studies conducted on nursing students. The most recent scanning process, which was in January 2021, was carried out by checking Cochrane, Science Direct, PubMed, and Google Academic databases. In this study, searches were carried out by combining the search terms “COVID-19”, “nursing students”, and “pandemic.” Thus, the keywords in English were the index of COVID-19 and Nursing Students, Nursing Students in the Pandemic, Anxiety in Nursing Students.
Within the scope of the inclusion criteria, full text-articles of the studies examining the mental problems experienced by nursing students in the pandemic period were accessed. Inclusion criteria were determined in accordance with PICO [P (Patient/ Population/Problem), I (Intervention/Indicator), C (Comparison of Intervention), O (Outcome of Interest)]. Accordingly, studies considered were those that evaluated the concern, anxiety, stress, and depression levels of nursing students, operating in the COVID-19 pandemic period and applying social isolation, receiving distance education in initiatives, complying with social isolation rules, using personal protective equipment (Table 1). The investigations with the determined keywords on this subject were conducted in four databases. Relevant titles and abstracts were examined (n = 1934). Those suitable for the study were determined (n = 75) among them, and duplicates were deleted (n = 2). After obtaining the full texts of the remaining studies, articles meeting the inclusion criteria were selected (n = 13) (Figure 1).
Results
Thirteen research articles were examined in this study. One of the articles was written in Turkish (Okuyan et al., 2020), and the others in English. The findings obtained from the studies were presented under the titles of “country characteristics,” “sample characteristics,” “methods and techniques used,” “measurement tools.”
Country characteristics of the studies
The distribution of studies by countries and the results are discussed in this section. Six of the studies were conducted in Turkey (Okuyan et al., 2020; Akman et al., 2020; Aslan et al., 2020; Ersin et al., 2020; Uğurlu et al., 2020; Cici et al., 2020), two in Spain (Gomez et al., 2020; Villarroya et al., 2021), two in
Israel (Savitsky et al., 2020; Savitsky et al., 2020), and others, respectively, in the United States (USA) (Keener et al., 2020), in Egypt (Eweida et al., 2020) and China (Sun et al., 2020). Sample Characteristics of the Studies
This section contains results regarding the sample characteristics of the studies examined.
In their studies, Okuyan et al. (2020) [14] included 305 students enrolled in the nursing faculty of a university, Akman et al. (2020) [15] included 105, Aslan and Pekince (2020) [3] 662, and Ersin and Kartal (2020) [16] 372 nursing students. In addition, Uğurlu et al. (2020) [17] carried out their study with 411 students, and Cici and Yılmazel (2021) [18] with 322 first- year students. Gomez et al. (2020) [19] included 138 second- year students studying nursing, while Villarroya et al. (2021) [20] included 305 first-year nursing students and carried out an application on the same students in 2020 (in their fourth year). Savitsky et al. (2020) [6] included 244 nursing students in their study. In another study conducted, Savitsky et al. (2020) [21] included 244 first and fourth-year students studying in the nursing department. Keener et al. (2020) [22] included 150, Eweida et al. (2020) [23] 152, and Sun et al. (2020) [25] 474 nursing students in their studies.
Methods and Techniques Used in the Studies
In this systematic evaluation, 13 studies that directly investigated the mental statuses of nursing students were examined. Descriptive design was used in five of these studies, cross-sectional design in five, cross-sectional and descriptive design in two, and observational design in one. Questions used in the studies were delivered to the participants electronically in twelve studies. In one study, the questions were delivered both face-to-face and electronically, since the questionnaire used consisted of two stages, and the first stage was carried out in 2017. The aim of the first article reviewed was the health anxiety of nursing students of COVID-19 to determine the effect on the levels (n=305) [14]. The aim of the second article is to examine the anxiety levels among nursing students in relation to the COVID-19 pandemic that is affecting them (n= 198,working group: 105) [15]. In the third article, the aim was to evaluate the views of nursing students about the COVID-19 outbreak and their perceived stress levels (n= 662) [3]. The aim of another article was to determine the perceived stress levels and health protective behaviors of nursing students during the COVID-19 pandemic (n=372) [16]. The examination of the relationship between nursingstudents’ depression, anxiety and stress levels and restrictive, emotional, and external eating behaviors in COVID-19 socialisolation process was made in the article by Uğurlu et al. (2020) (n= 438), working group: 411) [17]. The aim of another article was to determine the anxiety levels of nurse candidates in the COVID-19 pandemic and to examine their perspectives in the nursing profession( n= 461, working group: 322) [18]. The purpose of the article by Gomez et al. (2020) was to evaluate the stress levels of nursing students in the COVID-19 epidemic (n=148, working group: 138) [19]. In the article by Villarroya et al. (2021) the aim was to examine whether the pandemic affects the mental health of senior nursing students (n=305) [20]. In the article by Savitsky et al. (2020) the aim was to evaluate anxiety levels and ways of coping among nursing students(n=244) [21]. In the tenth article, the aim was to compare the changes in anxiety levels and coping strategies when the restrictions were lifted with the period of application of the most severe restrictions (n=244) [6]. The aim of the eleventh article was to examine the relationship between quality of life, resilience, and related factors among nursing students during the COVID-19 outbreak and the subsequent social distancing needs (n=152) [22]. In the twelfth article, the aim was to examine the mental tension among nursing trainee students and changes in the psychological health center during the COVID-19 pandemic (n=150) [23]. In the thirteenth article, the aim was to evaluate nursing students’ understanding of preventing COVID-19, as well as their concerns about the disease and their perception of their professional identity after the pandemic (n= 474) [24].
Characteristics of the Measurement Tools
The studies examined in this section evaluated the effect of the COVID-19 pandemic period on the mental health of nursing students using various methods and measurement tools.
In their study, Okuyan et al. (2020) collected data on students’ sociodemographic characteristics and their knowledge about the pandemic, what kind of support they needed in the process, their thoughts about it, and how they were affected by being obliged to stay at home due to the pandemic. The researchers used the “Health Anxiety Level Inventory.” In the study carried out by Akman et al. (2020), the data were collected through the “Sociodemographic and COVID-19 Pandemic Form” to measure the knowledge and attitudes of nursing students towards COVID-19 and the “State and Trait Anxiety Inventory” in order to determine the level of anxiety. In the study by Aslan et al. (2020), the “Perceived Stress Scale (PSS)” was employed in the data collection stage to measure how stressful the students perceived their situation. In Ersin and Kartal’s (2020) study, the data were obtained by using the “Personal Information Form,” which included the students’ school year, age, gender,marital status, income level, perceived health, chronic disease status, smoking status, regular exercise status, regular sleep, and regular nutritional status as well as their level of knowledge about COVID-19, and the “Perceived Stress Scale” (PSS) to measure how stressful the students perceived their situations. The study of Uğurlu et al. (2020) obtained data with the “Personal Information Form,” “Depression, Anxiety and Stress Scale (DASS-42),” and “Dutch Eating Behavior Questionnaire (DEBQ).” In the study conducted by Cici and Yılmazel (2020), the data were collected using “Personal Information Form,” “State Anxiety Scale,” and “Beck Anxiety Inventory.”
In the study by Gomez et al. (2020), the data were collected using the “Student Stress Inventory” to determine the stress levels of the students. In the study carried out by Villarroya et al. (2021), the data were obtained using the “General Health Questionnaire,” “Emotional Exhaustion Scale (EES)’, “Rosenberg Self-Esteem Scale,” and “Sense of Coherence Scale” to measure students’ stress, burnout, and self-esteem.
The study by Savitsky et al. (2020) obtained data using the ‘Generalized Anxiety Disorder 7-Item Scale’ to measure the students’ anxiety levels. Again, in another study by Savitsky et al. (2020), the data were collected with the “Questionnaire Form.”
The study of Keener et al. (2020) obtained data using the “World
Health Organization Quality of Life-BREF,” “Connor Davidson Resilience Scale,” and “Questionnaire Form.”
In the study by Eweida et al. (2020), the data were collected using the “MERS-CoV Personnel Questionnaire” and the “General Health Questionnaire (GHQ-12)” in order to determine the feelings of the participants and the factors that caused stress in the participants.
In the study by Sun et al. (2020), the data were obtained with the “Questionnaire Form” used to determine the factors affecting anxiety in the students.
Conclusion and Recommendations
As a result of the literature review, it was determined that in the COVID-19 pandemic, nursing students experienced mental problems such as anxiety, stress, depression, decreased self- esteem, and emotional exhaustion.
The study by Okuyan et al. (2020) determined that 67.9% of nursing students indicated that distancing from recreational and social life affected them the most, and 66.6% of them stated that they most needed psychological support in the pandemic process. It was determined that nursing students had high levels of health anxiety in the pandemic process.
The students were adversely affected by staying at home due to the pandemic, felt overwhelmed and nervous, and experienced the fear of infection and fear of death. In the study by Akman et al. (2020), when the state anxiety levels of nursing students were examined, it was determined that 41.90% had mild anxiety, 45.71% had moderate anxiety, and 12.38% had severe anxiety. When trait anxiety levels were examined, it was determined that 14.28% had mild anxiety, 80.95% had moderate anxiety, 4.76% had severe anxiety, and it was found that there were no students who did not experience anxiety. It was determined that as the level of knowledge of nursing students about coronavirus increased, so did the trait anxiety level. Their level of trait anxiety decreased as they found effective hand washing sufficient to prevent coronavirus infection. As anxiety levels about the coronavirus infection increased, both state and trait anxiety scores increased. As their concerns about infecting family members increased, their levels of state anxiety increased. In the study by Aslan et al. (2020), it was found that the stress levels of the female students between the ages of 18-20 were high, and that watching the news, anxiety about infection risk, and curfew increased the stress levels of the students. Ersin and Kartal’s (2020) study determined that the perceived stress subdimension mean scores of the female students, students who indicated their income levels as poor, perceived their health as bad, had chronic diseases, did not sleep, and eat regularly, and did not wear masks and used disposable wipes during coughing/sneezing were statistically significantly higher. In the study conducted by Uğurlu et al. (2020), mild anxiety symptoms were determined in 17.8% of the students and mild stress symptoms in 29.7%. It was determined that the stress levels of the female students were high, the level of depression increased with age, the stress level of students staying with their families during the social isolation process was high, the level of depression decreased as the number of people living together at home increased, and that eating behaviors increased as the level of depression increased in the students. The study by Cici and Yılmazel (2020) determined that the students’ positive views about the nursing profession before the pandemic decreased from 63.4% to 50.6%,and there was a significant increase in the anxiety scores of students with a negative perspective towards the profession and a reluctance to practice their profession in the future.
The study by Gomez et al. (2020) determined that the students’ stress levels increased significantly when the periods before and after the restrictions were compared. In the study by Villarroya et al. (2021), it was determined that the pandemic period caused a decrease in self-esteem and led to emotional exhaustion in nursing students.
The study of Savitsky et al. (2020) revealed that fear of infection increased the level of anxiety in the students and that the students who gained flexibility had low anxiety levels. Another study by Savitsky et al. (2020) concluded that restrictions increased the anxiety level of the students.
The study by Keener et al. (2020) concluded that nursing students were not flexible enough and had poor quality of life. In the study conducted by Eweida et al. (2020), it was determined that the possibility of contracting the COVID-19 infection and infecting their families with the disease was a serious stress factor in the students, and that 77.3% of them felt tense, worthless, and depressed (64.7%, 62.7%).
The study by Sun et al. (2020) determined that the students experienced anxiety in the pandemic period and that this anxiety harmed the professional identity of nursing.
In line with these results obtained, it is recommended to create
psychological counseling units to serve students, considering that the mental statuses of nursing students are negatively affected in the pandemic period. In addition, it is recommended that training, conferences, courses, etc., which include effective coping methods in cases such as epidemics, should be organized for nursing students.
Discussion
According to the studies reviewed in this review; It has been determined that nursing students experience mental problems such as anxiety, stress, depression and emotional exhaustion during the pandemic process. However, it is seen that the psychological state of nursing students who continue their undergraduate education can be affected by their gender, age, and the characteristics of the individuals they live with. According to the results obtained, the establishment of psychological counseling units for nursing students during the pandemic process, training including effective coping methods, conferences, etc. It is recommended that the programs be organized both face-to-face and online.
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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Sevgi Keskin, Birgül Özkan. Mental statuses of nursing students in the Covid-19 pandemic period: A systematic review. Ann Clin Anal Med 2021;12(Suppl 2): S245-249
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COVID 19: A global health problem from the perspective of obstetricians
Harun Egemen Tolunay, Erol Nadi Varlı, Özgür Arat
Department of Perinatology, Etlik Zübeyde Hanım Kadın Hastalıkları EAH, Ankara, Turkey
DOI: 10.4328/ACAM.20406 Received: 2020-11-16 Accepted: 2020-12-14 Published Online: 2020-12-23 Printed: 2021-06-15
Corresponding Author: Harun Egemen Tolunay, Department of Perinatology, Etlik Zübeyde Hanım Kadın Hastalıkları EAH, Ankara, Turkey. E-mail: harunegementolunay@gmail.com P: +90 5557736303 F: +90 3125674019 Corresponding Author ORCID ID: https://orcid.org/0000-0002-8922-4400
To the editor: Coronavirus disease 2019 (COVID-19) has become a global health problem threatening billions of people worldwide. Severe acute respiratory syndrome is caused by a new coronavirus called coronavirus 2 (SARS-CoV-2). Although antiviral treatment has been performed, there is currently no effective cure or vaccination [1].
To the editor:
Coronavirus disease 2019 (COVID-19) has become a global health problem threatening billions of people worldwide. Severe acute respiratory syndrome is caused by a new coronavirus called coronavirus 2 (SARS-CoV-2). Although antiviral treatment has been performed, there is currently no effective cure or vaccination [1]. People with concomitant medical diseases such as diabetes or hypertension, congenital or acquired cardiac disease history, cancer patients, severe respiratory illness such as cystic fibrosis or advanced asthma, chronic liver or kidney disease, those with a history of congenital metabolic diseases such as sickle cell anemia and the presence of the use of immunosuppressive drugs are more vulnerable to this disease [2]. The current literature on the course of the disease during pregnancy and on mortality and morbidity during pregnancy is limited. There is no evidence of an increased rate of miscarriage or early pregnancy loss in pregnant women with COVID-19. Besides, the fact that SARS and MERS infections, which have been shown in previous studies, are not associated with complications such as miscarriage and early pregnancy loss strengthens this hypothesis [3].
In pregnant women, as in adult patients, 85% of cases may have pulmonary findings in the acute period. The ground glass image with multilobar involvement is typical. In prolonged cases, the image becomes clear in the lower lobes. Lesions may be distributed in the periphery, reticular opacities, and vascular thickening can be observed. In cases that are not severe, there may be no findings on the tomography. Tomography may be more sensitive in suspected patients with a negative RT-PCR test. Also, the lungs can be evaluated using a 3.5 MHz convex ultrasound probe. Thoracic ultrasonography is easy to apply, does not contain radiation, and is easy to sterilize. Due to its bedside applicability, it can be used in the first triage by experienced people in light and stable cases. With the COVID-19 pandemic, it is of great importance to reduce the frequency of antenatal follow-up as much as possible, especially in crowded environments such as hospitals. Examinations such as the 1st-trimester screening test and 2nd level ultrasound scanning should not be neglected. While the frequency of follow-up is reduced, patients should be informed about the necessity of following the fetal movements and obstetric emergencies. Besides, it should be explained that the symphysis pubis-fundus distance should be monitored, and in cases where it does not increase sufficiently, adverse pregnancy outcomes may accompany, and the doctor should be informed that it should be consulted earlier. The latest data indicate that there is no vertical transmission to the fetus, and no virus has been found in the cord blood of newborns born to COVID-19 positive pregnant women, nasal sampling, and amniotic fluid and placenta of pregnant women [4].
Suspected or possible cases should be followed in isolated rooms and confirmed cases in negative pressure rooms, and this treatment should be done in tertiary hospitals. If there is no negative pressure room, suspicious/possible patients should be followed in isolated places, and cases with COVID-19 should be followed in shared rooms. In countries where clinically mild, asymptomatic pregnancy is common, and health institutions do not have sufficient capacity, it is appropriate to protect family members and keep them under quarantine at home. In mild cases, it is necessary to ensure the fluid-electrolyte balance and carry out symptomatic treatment. Based on current data, antiviral therapy is not recommended in mild cases. For bacterial in- fections (blood, urine culture), monitoring should be done. If a secondary infection develops, antibiotherapy should be started at an appropriate time. Both maternal and fetal mortality rates are high in cases with severe pneumonia. In addition to aggressive treatment, oxygen therapy and hydration should be given. Pregnant women should be followed up and treated by multidisci- plinary teams in negative pressure rooms, if possible, in intensive care units. Blood pressure monitoring, appropriate O2 satu- ration and fluid balance should be provided. Low molecular weight heparin should be used for severe cases, as microthrombi develop in addition to macroscopic hemorrhages in the liver and lungs. Severe cases should be evaluated by a multidisciplinary team below the 32nd gestational week, and if the decision to give birth is to be made, it should be made by that team. If the labor cannot be delayed in a pregnant woman with suspected COVID-19, delivery should be performed by providing protective measures. The minimum possible number of people should be involved in the surgery. Regarding its effects during labor, it has been stated that fetal distress is seen at a higher rate during labor. Therefore, if vaginal delivery is planned in these patients, continuous electronic fetal monitoring is considered more reliable [5].
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2. Sahin D, Tanacan A, Erol SA, Anuk AT, Eyi EGY, Ozgu-Erdinc AS, et al. A pandemic center’s experience of managing pregnant women with COVID-19 infection in Turkey: A prospective cohort study. Int J Gynaecol Obstet. 2020; 151(1): 74-82. DOI:10.1002/ijgo.13318.
3. Rasmussen SA, Smulian JC, Lednicky JA, Wen TS, Jamieson DJ. Coronavirus Disease 2019 (COVID-19) and pregnancy: what obstetricians need to know. Am J Obstet Gynecol. 2020; 222(5): 415-26. DOI: 10.1016/j.ajog.2020.02.017
4. Rasmussen SA, Jamieson DJ. Coronavirus disease 2019 (COVID-19) and pregnancy: responding to a rapidly evolving situation. Obstet Gynecol. 2020; 135(5):999-1002. DOI: 10.1097/AOG.0000000000003873.
5. Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infec- tion in nine pregnant women: a retrospective review of medical records. Lancet. 2020; 395(10226): 809-15.
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Harun Egemen Tolunay, Erol Nadi Varlı, Özgür Arat. COVID 19: A global health problem from the perspective of obstetricians. Ann Clin Anal Med 2021;12(Suppl 2):DOI: 10.4328/ACAM.20406
Citations in Google Scholar: Google Scholar