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January 2022


Original Article

Our results of high tibial osteotomy in medial knee osteoarthritis

Mesut Uluöz

Department of Orthopedics and Traumatology, Health Sciences University, Adana City Training and Research Hospital, Adana, Turkey

DOI: 10.4328/ACAM.20800 Received: 2021-07-28 Accepted: 2021-10-20 Published Online: 2021-10-25 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):1-5

Corresponding Author: Mesut Uluöz, Adana Şehir Eğitim ve Araştırma Hastanesi, Yüreğir, Adana, Turkey. E-mail: mesutuluoz@hotmail.com P: +90 530 827 53 01 Fax: +90 0322 344 03 05 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0319-3832

Abstract
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Abstract

Aim: Knee osteoarthritis is very common and causes serious dysfunction of the joint. HTO is the most commonly used method in cases of active and young patients suffering from medial knee osteoarthritis. Although many techniques have been described for HTO, opening-wedge osteotomy is the most commonly used method. Given the rare availability and osteointegration of the allograft, autograft use is more common. In our clinic, we prefer using ipsilateral autografts. Grafts of different sizes were taken for each patient. In this study, we aimed to introduce this procedure and investigate the effect of surgical treatment on outcome.

Material and Methods: WOMAC, Lyslom score, knee ROM, and mechanical axis were evaluated in 32 patients with a mean age of 53 years. We fixed the mechanical axis using the lamina spacer and cable method during HTO surgery. After autograft placement, we provided fixation with a locked T-plate.

Results: While there was a statistically significant improvement in WOMAC, Lyslom score, and mechanical axis values, there was no significant difference in ROM value. Good and excellent results were achieved in all patients except one.

Discussion: The rate of excellent results increases in younger patients, which is consistent with the literature. HTO, which is applied with appropriate patient selection and the right technique, can be used safely and successfully in knee medial osteoarthritis. In HTO surgeries performed in our clinic, we take autografts of different sizes according to the degree of correction in each patient. We think that this autograft retrieval technique facilitates surgery and contributes to stability.

Keywords: Knee Medial Osteoarthritis, High Tibial Osteotomy, Autograft

Full Text

Introduction

Osteoarthritis is a progressive disease that occurs upon the destruction of articular cartilage [1]. Knee osteoarthritis is very common and causes serious dysfunction of the joint [2]. Methods such as arthroscopy, high tibial osteotomy (HTO) and partial and total arthroplasty have been described for this condition [3,4]. HTO is the most commonly used method in cases of active and young patients suffering from medial knee osteoarthritis [5]. Although many techniques have been described for HTO, the most commonly used methods are opening-wedge and closing-wedge osteotomies are [6]. Among these, opening-wedge osteotomy is more advantageous since it requires only a single incision and not fibula osteotomy [7]. The stability problem in opening-wedge osteotomy has been largely resolved with the use of locking plates. However, there are studies reporting that stabilization is improved with the use of a wedge-shaped allograft [8]. Given the rare availability and osteointegration of the allograft, autograft use is more common. In our clinic, we prefer using ipsilateral autografts. We follow a non-standard procedure during the collection of the autograft from the iliac bone and its application. In this study, we aimed to introduce this procedure and investigate the effect of surgical treatment on outcome.

Material and Methods

Our study was commenced upon obtaining the approval of our hospital’s ethics committee (date: 06/05/2021, no: 1389). Patients who were admitted to our hospital with knee medial osteoarthritis between 01/06/2019 and 01/12/2021 and operated using medial opening-wedge osteotomy (MOWO) were evaluated retrospectively. All surgeries were performed by a single physician. Those with a follow-up period of <6 months were excluded from the study. Patients with medial osteoarthritis of the knee were classified according to the preoperative Kellgren–Lawrence Radiological Criteria. Those classified as stage 4 were excluded from the study.

In the study, preoperative preparation and postoperative control were performed using an orthorontronogram that included the hip and ankle.
Surgical technique

After spinal anesthesia was applied to the patient, the surgery was started using a tourniquet in the supine position. An oblique incision was made medial to the knee to access the anterior edge of the medial collateral ligament (MCL). The MCL was retracted posteriorly, and an oblique K-wire was inserted under the guidance of fluoroscopy, starting from the medial and targeting the fibular head laterally. After positioning the knee in 15° flexion, another K-wire was sent 1 cm anterior to the fibular head, ensuring that both wires were visible one over the other on the coronal plane. After control with scopy, osteotomy was performed with sharp-ended osteotomes until 0.5 cm to the lateral cortex of the tibia. The amount of correction of the mechanical axis was decided using the cable technique [9]. The lamina separator was placed posterior to the osteotomy line. The cable was distracted with a lamina separator until it reached the Fujisawa point [10]. The MCL was partially loosened in patients who had difficulty in distraction. SLOP control was performed by taking a side view of the knee with fluoroscopy.

The opened osteotomy line was measured anteriorly and posteriorly with a ruler. Two wedge-shaped tricortical grafts were removed from the ipsilateral iliac bone and nailed to the osteotomy line. Grafts of different sizes were taken for each patient, with the measurements made at the osteotomy line being the base of the triangular grafts. After the grafts were nailed, the lamina separator was removed. The fix performed was not impaired. (Figure 1). The T- plate was then fixed with locking screws. Finally, scopy control was performed, and the operation was terminated (Figure 2).

Patients were called for follow-up visits at 3, 6 , and 3 months. The patients were followed up for at least 6 months.
For radiological evaluation of the patients, preoperative and postoperative femorotibial angles were measured. For functional evaluation, the Lysholm score was measured in the preoperative period and at the postoperative sixth month. WOMAC (Western Ontario and McMaster Universities Arthritis Index) scoring was used for pain control. These values were assessed statistically. Patients whose union was later than 12 weeks were considered to have delayed union.

Statistical analysis

The SPSS (Statistical Package for the Social Sciences) 23.0 package program was used for statistical analysis of the data. Continuous measurements were summarized as mean and standard deviation (median and minimum-maximum, wherever appropriate). The Shapiro–Wilk test was used to establish whether the parameters in the study showed normal distribution. The Wilcoxon test was used to assess the patients for variance in preoperative and postoperative measurements of the mechanical axis, Lysholm score, and joint-range values. Spearman’s correlation test was used to identify whether variations in these measurements were related to the age, weight, and body mass index (BMI) of the patients,. Statistical significance level was set as 0.05 in all tests.

Results

A total of 32 patients were enrolled in the study, including 26 women and 6 men. Their mean age was 53 (43–64) years. The patients had a mean weight of 79 (73–88) kg and a mean BMI of 25 (23–28). Demographic characteristics of the patients are listed in Table 1.

According to the Kellgren–Lawrence Radiological Criteria, 50% of the patients were in stage 2 and 50% were in stage 3.

Good results were also obtained in the patient who was excluded from the study because she was stage 4 according to the Kellgren-Lawrence Criteria, but was operated on because she was 42 years old (Figure 3).

Preoperative mechanical axis varus was 9.53(±1.93) degrees, and the postoperative valgus was 4.91(±1.22). While the preoperative Lysholm score was 67.25 (±4.79), it was 90.28 (±5.53) postoperatively. According to the Lysholm score, 15 of the 32 patients had excellent results, 16 had good results, and 1 patient had a moderate result. While the WOMAC SCORE was 39.6 preoperatively, it was lowered to 12.5 at the postoperative 6th month. The timely union was observed in all patients except one. No embolism or wound problem was observed in any of the patients. Weight-bearing was started at the 6th week, and unassisted walking was begun at the 12th week. The knee joint range of motion (ROM) was measured as 124.5(±2.42) preoperatively and 122.91(±2.33) postoperatively (Table 2). Postoperative measurements of the mechanical axis (p < 0.001) and postoperative Lysholm scores were found to be significantly higher (p < 0.001) than preoperative scores. WOMAC SCORE was found to be significantly lower in the postoperative period (p < 0.001) than that in the preoperative period. There was no significant difference in the postoperative measurements of joint ROM (p < 0.001) when compared with the preoperative period (Table 3).

Discussion

The technique is known to alleviate pain by reducing the load on the medial compartment by correcting the mechanical axis. In addition, there are publications showing that HTO contributes to pain reduction by alleviating medial meniscus extrusion [11]. The risk of peroneal nerve injury in closing-wedge osteotomy is eliminated with the technique of opening-wedge osteotomy [12]. In a study by Gupta et al. in 2019, it was concluded that in a patient who is scheduled for ACL reconstruction, HTO should be considered in addition to ACL reconstruction if the SLOP value is >12 degrees. In this study, the authors emphasized the importance of the increase in SLOP in the sagittal plane as well as the varus deformity in the coronal plane [13]. There is a possibility to correct SLOP in open wedge osteotomy.

Locking plates and peek plates are currently used in osteotomy fixation [14-16].
While collapse of the wedge part opened in the long term was previously a significant problem, the use of locking plates resolved this problem to a great extent. In a study comparing opening-wedge osteotomies using a titanium locking plate with and without grafting, no difference was found between the two groups [17]. On the other hand, in a biomechanical study conducted by Belsey et al. in 2019, researchers compared groups of synthetic wedge grafting, allograft wedge grafting, and the use of plate without grafting on the osteotomy line. The grafted groups were consistent with each other and were more robust than the non-grafted groups [18]. Donor site problems may occur with the use of autografts. However, many clinics prefer autografts since their use is associated with an increased potential for union and the fact that allografts are difficult to access for economic reasons.

As can be understood from the preceding sections, the factors affecting surgical success in opening-wedge osteotomy can be summarized as osteotomy technique, graft use, and fixation material.
The autografts used in our study were recovered from the iliac bone in a size unique for each case by measuring the gap in the osteotomy line. We are of the opinion that the graft recovered in this manner contributed to stability.

In a study published in 2020, Chuaychoosakoon et al. emphasized the importance of SLOP preservation during the surgical technique and reported that they solved this problem with a distraction tool developed using 4 K wires, two wires at the proximal and two at the distal part of the osteotomy [19]. A classical distractor was used in our study. SLOP control was achieved using scopy once a suitable position was obtained according to the Fujisawa point with the cable method. Subsequently, the anterior and posterior spaces of the osteotomy were measured. Based on these measurements, two wedge grafts were recovered from the iliac bone and nailed to the osteotomy line. Even after the distractor was removed, it was observed that the correction remained intact. Thus, the distractor was prevented from causing difficulties in plate placement. We think that this grafting method will be beneficial for those who are unable to access the distraction tool developed by Chuaychoosakoon et al. We obtained similar results with this study.

In the osteotomy technique, the most important points are to make the osteotomy as close as possible to the varus deformity in the proximal tibia and to stop the osteotomy half a centimeter to the lateral cortex. In one of our cases, although we thought that the required correction was intraoperatively achieved, the mechanical axis remained at zero degrees in the postoperative x-ray. While the intraoperative correction was good, we attribute this loss of correction after surgery to a fracture of the lateral cortex. Being the only one who had moderate success according to Lysholm scoring and delayed union in our study, this patient is the one referred to have a fractured lateral cortex.

In the study by Sarman et al. in 2019, titanium wedge plates produced for opening-wedge osteotomy were studied and their success was mentioned [17]. The wedge thickness of these plates was adjusted according to the osteotomy opening, but the anterior and posterior thicknesses of the wedge were equal. When the sagittal plane correction is made in patients with a large SLOP angle, the osteotomy line is opened differently in the anterior and posterior regions; hence, the wedge plate becomes incompatible [17]. It would be more appropriate to use a locked T plate in SLOP corrected HTO surgeries. In this study, a locking T plate was used, which yielded satisfactory results. The limitations of our study are that there was no control or comparison group, and that the follow-up period was short. When we excluded the only patient with delayed union, all others had good and excellent results according to the Lysholm scoring. The mean age of the patients with excellent results was 51.4, while the mean age of those with good results was 54.5. The contribution of the mean age to surgical success is consistent with the literature. When BMI values were compared, it was 25.33 in patients with excellent results and 25.25 in patients with good results. We attribute the lack of significant difference to the fact that this surgical method was not applied in obese patients.
Only an angled adjustable knee brace was used postoperatively. In this way, early initiation of movement prevented loss of joint range of motion.

In a study conducted in 2021 in which total knee prostheses PCL sparing and PCL sacrificing were compared, range of motion was significantly higher in the group with PCL preservation. This result revealed the importance of intra-articular structures. For this reason, it suggests that one should be more courageous when deciding on HTO, which is joint-sparing surgery [20]. Conclusions

In conclusion, MOWO using a titanium locking plate can be performed safely and with very good results in patients under 55 years of age and with stage 2–3 medial knee osteoarthritis according to the Kellgren–Lawrence Criteria. If autograft is to be used, the use of the graft as described in our study is likely to contribute to the success of the surgery.

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. Maheu E, Bannuru RR, Herrero-Beaumont G, Allali F, Bard H, Migliore A. Why we should definitely include intra-articular hyaluronic acid as a therapeutic option in the management of knee osteoarthritis: Results of an extensive critical literature review. Semin Arthritis Rheum. 2019;48(4):563-72.

3. Doma K, Grant A, Morris J. The Effects of Balance Training on Balance Performance and Functional Outcome Measures Following Total Knee Arthroplasty: A Systematic Review and Meta-Analysis. Sports Med. 2018;48(10):2367-85.

4. Lee YS, Kim HJ, Mok SJ, Lee O-S. Similar Outcome, but Different Surgical Requirement in Conversion Total Knee Arthroplasty following High Tibial Osteotomy and Unicompartmental Knee Arthroplasty: A Meta-Analysis. J Knee Surg. 2019;32(7):686-700.

5. Lu J, Tang S, Wang Y, Li Y, Liu C, Niu Y, et al. Clinical Outcomes of Closing and Opening-Wedge High Tibial Osteotomy for Treatment of Anteromedial Unicompartmental Knee Osteoarthritis. J Knee Surg. 2019;32(8):758-63.

6. Kim JH, Kim HJ, Lee DH. Leg length change after opening wedge and closing wedge high tibial osteotomy: A meta-analysis. PloS One. 2017;12(7):e0181328.

7. Hoell S, Suttmoeller J, Stoll V, Fuchs S, Gosheger G. The high tibial osteotomy, open versus closed wedge, a comparison of methods in 108 patients. Arch Orthop Trauma Surg. 2005;125(9):638-43.

8. Belsey J, Diffo Kaze A, Jobson S, Faulkner J, Maas S, Khakha R, et al. The biomechanical effects of allograft wedges used for large corrections during medial opening wedge high tibial osteotomy. PloS One. 2019;14(5):e0216660.

9. Krettek C, Miclau T, Grün O, Schandelmaier P, Tscherne H. Intraoperative control of axes, rotation and length in femoral and tibial fractures. Technical note. Injury. 1998;29 (Suppl 3.):S29-39.

10. Fujisawa Y, Masuhara K, Shiomi S. The effect of high tibial osteotomy on osteoarthritis of the knee. An arthroscopic study of 54 knee joints. Orthop Clin North Am. 1979;10(3):585-608.

11. Astur DC, Novaretti JV, Gomes ML, Rodrigues AG, Kaleka CC, Cavalcante ELB, et al. Medial Opening Wedge High Tibial Osteotomy Decreases Medial Meniscal Extrusion and Improves Clinical Outcomes and Return to Activity. Orthop J Sports Med. 2020;8(4):2325967120913531.

12. Brinkman JM, Lobenhoffer P, Agneskirchner JD, Staubli AE, Wymenga AB, van Heerwaarden RJ. Osteotomies around the knee: patient selection, stability of fixation and bone healing in high tibial osteotomies. J Bone Joint Surg Br. 2008;90(12):1548-57.

13. Gupta A, Tejpal T, Shanmugaraj A, Horner NS, Simunovic N, Duong A, et al. Surgical Techniques, Outcomes, Indications, and Complications of Simultaneous High Tibial Osteotomy and Anterior Cruciate Ligament Revision Surgery: A Systematic Review. HSS J. 2019;15(2):176-84.

14. Polacek M, Nyegaard CP, Høien F. Day-Case Opening Wedge High Tibial Osteotomy with Intraosseous PEEK Implant. Arthrosc Sports Med Rehabil. 2020;2(2):145-51.

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Mesut Uluöz. Our results of high tibial osteotomy in medial knee osteoarthritis. Ann Clin Anal Med 2022;13(1):1-5

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Clinical characteristics of children with multisystemic inflammatory syndrome associated with COVID-19

Ayşegül Alpcan 1, Serkan Tursun 1, Yaşar Kandur 2

1 Department of Pediatrics, 2 Department of Pediatric Nephrology, Kırıkkale University, School of Medicine, Kırıkkale, Turkey

DOI: 10.4328/ACAM.20804 Received: 2021-08-02 Accepted: 2021-09-26 Published Online: 2021-10-07 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):6-10

Corresponding Author: Ayşegül Alpcan, Kırıkkale University Hospital, General Outpatient Clinic, 71450, Yahsihan, Kırıkkale, Turkey. E-mail: ozcalk@yahoo.com P: +90 318 357 42 42 F: +90 318 225 28 19 Corresponding Author ORCID ID: https://orcid.org/0000-0001-9447-4263

Abstract
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Aim: Coronavirus disease 2019 (COVID-19) has become a public health threat to people all over the world in 2020 and 2021. The Centers for Disease Control and Prevention (CDC) and WHO (World Health Organization) have named a novel disease multisystem inflammatory syndrome in children (MIS-C). Herein we aimed to present a group of pediatric patients with MIS-C, who were followed up in our clinic.

Material and Methods: We retrospectively reviewed the medical records of patients who were followed up at our University Hospital with the diagnosis of MIS-C between January 2021 and May 2021.

Results: The mean age of 9 patients was 87.4 ±17.8 years (range 6-161 months); six of the patients were male. All patients had fever at admission. The duration of the fever was between 3 and 7 days. Four patients (44.4%) had terminal ileitis on ultrasonic examination. The laboratory tests of the patients revealed leukocytosis in 4 (44.4%) patients, anemia in 5 (55.5%) patients, thrombocytopenia in 1 (11.1%) patient, and a high CRP level in 8 (88.8%) patients. All patients had high sedimentation rates and procalcitonin levels. One (11.1%) patient was operated on for terminal ileitis. All patients were treated with steroids (1-2 mg/kg prednisolone) and IVIG (2gr/kg). Patients who needed ICU admission were also treated with vasoactive drug infusion (intravenous dopamine).

Discussion: There is a need for increased awareness among pediatricians that MIS-C should come to mind, especially in patients with long-lasting fever and signs and symptoms that resemble Kawasaki disease.

Keywords: Multisystem Inflammatory Syndrome, Children, Hyperinflammation, Steroid, Intensive Care, COVID-19

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Introduction

Coronavirus disease 2019 (COVID-19) has become a public health threat to people all over the world in 2020 and 2021. The lower airway tract is the primary target of the infection [1]. Acute respiratory distress syndrome (ARDS), septic shock, and coagulation disorders are severe complications of this infection, which are rare in children [2]. Children constitute about 1% of all COVID-19 cases in Turkey. COVID-19 has a milder clinical course in children than in adults [3]. Previous reports have shown that the incidence of hyper-inflammation in children is relatively low in comparison to adults [4]. However, Riphagen S. et al. [5] reported several pediatric cases with previous COVID-19 who suffered systemic symptoms that resemble Kawasaki disease (KD) (World Health Organization. Multisystem Inflammatory Syndrome in Children and Adolescents with COVID-19: Scientific Brief, 15 May 2020) . Afterward, a lot of similar cases have been reported from around the world. The Centers for Disease Control and Prevention (CDC) and WHO (World Health Organization) named this novel disease multisystem inflammatory syndrome in children (MIS-C), which differs in clinical presentation from KD, Toxic shock syndrome (TSS), and Macrophage activation syndrome (MAS)/Hemophagocytic lymphohistiocytosis (HLH) [6] (Centers for Disease Control and Prevention. Manage Anxiety & Stress. Atlanta, GA; 2020). Herein we present a group of pediatric patients with MIS-C, who were followed up in our clinic. We evaluated and compared the clinical characteristics of these patients.

Material and Methods

We retrospectively reviewed the medical records of patients who were followed up at our university hospital with the diagnosis of MIS-C between January 2021 and May 2021. Children who were diagnosed with severe COVID-19 disease and met the criteria for MIS-C provided by WHO and CDC were included in the study (World Health Organization. Multisystem Inflammatory Syndrome in Children and Adolescents with COVID-19: Scientific Brief, 15 May 2020). Patient data, including demographic characteristics, medical history, symptoms, signs, laboratory findings, and outcomes, were collected from the patients’ medical records. Written informed consent was obtained from their parents. The inclusion criteria required proof of COVID-19 exposure confirmed by PCR (polymerase chain reaction) analysis, antigen test, and/or serology. Suspected cases with a positive PCR result or serum-specific antibodies against SARS- CoV-2 were considered confirmed cases [7].

Statistical Analysis

We reported the categorical variables as frequency rate and percentage and continuous variables as mean and standard deviation (SD). All statistical analyses were performed using SPSS (Statistical Package for the Social Sciences) version 20.0 software (SPSS Inc.)

Ethics committee approval for the study was obtained from the Clinical Research Ethics Committee of XXX University (Date: 30.06.2021 / Decision no:2021.06.21)

Results

The mean age of the 9 patients was 87.4 ±17.8 months (range 6-161 months); six of the patients were male. Seven patients had a history of contact with a COVID-19 positive person. The diagnosis of COVID-19 was made by PCR in 2 patients, by serology in 4 patients, and by antigen test in 3 patients. All patients had fever at admission. The duration of the fever was between 3 and 7 days. Six (66.6%) patients had nausea, 5 (55.5%) had abdominal pain, 5 (55.5%) had a rash, 3 (33.3%) had a headache, 7 (77.7%) had somnolence, 3 (33.3%) had conjunctivitis, 1 (11.1%%) had arthritis/arthralgia, and 6 (66.6%) had hypotension. Four patients (44.4%) had terminal ileitis on ultrasonic examination.

The laboratory tests of the patients revealed leukocytosis in 4 (44.4%) patients, lymphopenia in 3 (33.3%) patients, anemia in 5 (55.5%) patients, thrombocytopenia in 1 (11.1%) patient, a high CRP level in 8 (88.8%) patients, and a moderate CRP elevation in 1 (11.1%) patient. All patients had high sedimentation rates and procalcitonin levels. Seven (77.7%) patients had high fibrinogen levels. The Pro-BNP levels of 7 patients were above normal (n>350 pg/ml), with two of them had considerably high levels (7488 and 3590 pg/ml) (Table). One (11.1%) patient was operated on for terminal ileitis. Three patients needed intensive care unit admission. Two of them were siblings (M/M), both had metabolic disease, namely neuronal ceroid lipofuscinosis type 1, and both had respiratory distress. One of these patients died of multiorgan failure and the other was intubated. Both of them had the highest procalcitonin (5.4 and 4.4 ng/ml) and the lowest albumin levels (2.5 and 2.6 gr/dl) in the whole study group. The deceased patient had the highest D-Dimer level. The third patient, a 116-month-old female, needed ICU admission due to convulsion and thrombocytopenia. None of these three patients had conjunctivitis. All of patients had hypotension. None of the patients, except for the deceased patient, developed acute kidney failure or liver failure.

All patients were treated with steroids (1-2 mg/kg prednisolone) and IVIG (2gr/kg). Patients who needed ICU admission were also treated with vasoactive drug infusion (intravenous dopamine).

Discussion

The experience with COVID-19 during this pandemic has shown that symptoms are less severe in children than in adults [8]. In the present study, we reported clinical manifestations of 9 Turkish children with MIS-C, whose PCR/Serology/Antigen test was positive for COVID-19. The incidence of MIS-C was reported as 2 per 100,000 persons below 21 years of age [9]. We should emphasize that children may still develop MIS-C despite an asymptomatic COVID-19 course [10].

All patients had a persistent fever that was one of the main characteristics of MIS-C . A previous report [11] found that conjunctivitis and rash were also the significantly distinctive features of MIS-C. This report suggested that if conjunctivitis is supported by higher acute phase reactants, the diagnosis of MIS-C seems likely.

In our patients, elevated levels of acute-phase reactants, namely CRP, sedimentation rate, fibrinogen, or procalcitonin were noteworthy. Although fever, conjunctivitis, rash, and elevated acute phase reactants remind us of Kawasaki disease [12,13], abdominal pain and signs of terminal ileitis were the distinguishing findings in our MIS-C patients. Moreover, proof of previous COVID-19 disease confirms the diagnosis of MIS-C. Cardiac injury associated with COVID-19 infection has been described in the adult population [14]. Some case series have shown left ventricular dysfunction in MIS-C [15,16]. Myocardial dysfunction diagnosed by ECHO and/or increased troponin-I or pro-BNP levels has been reported in 51-90% of patients with MIS-C [16-18]. Only the deceased patient had congestive heart failure, whereas the rest of the patients had normal echocardiographic findings. However, the Pro-BNP levels of seven patients were above normal, with two of them having had considerably high levels. These two patients recovered. Therefore, we suggest that the Pro-BNP level may not be a prognostic factor. We also suggest that the mechanism of cardiac failure is not associated with myocardial damage associated with acute SARS-CoV-2infection. Cardiac features overlapped with toxic shock syndrome together with cardiac inflammation (MIS-C).

In a previous study [19], 83.3% of patients had GI involvement. Among them, five patients had severe GI manifestations presenting with appendicitis in three of them, and pancreatitis in two patients. Studies have shown that ACE2 receptors are abundant in the GI tract [17]. These findings supported the high prevalence of GI involvement in patients with MIS-C. Six (66.6%) of our patients had nausea/vomiting. Five (55.5%) of them had abdominal pain and 4 of these patients also had terminal ileitis on USG. Three of these patients were female, which was a noteworthy point.

The neurotropic and neuro-invasive potentials of coronaviruses have been reported previously. However, the absence of the virus in the cerebrospinal fluid in COVD-19 patients supports the existence of other factors. Researchers suggest that cellular edema of neurons due to inflammatory response and immune-mediated neuronal damage may be the reason for the neurological manifestations in children with MIS-C [20]. In our study, none of the children manifested severe neurological signs and symptoms, but 7 patients had somnolence.

The American College of Rheumatology (ACR) issued a clinical guideline for the management of MIS-C [21], since hyper- inflammation is a common process in MIS-C according to this guideline, IVIG and/or glucocorticoids are recommended as first-line treatments. Thus, we started steroids and IVIG in all patients. During the follow-up period, 6 patients recovered completely with this treatment.

Conclusion

Although MIS-C is a rare clinical entity, it appears to be highly fatal. Therefore, it is urgent to diagnose the condition and start appropriate treatment. Hence, there is a need for increased awareness among pediatricians that MIS-C should come to mind, especially in patients with long-lasting fever and signs and symptoms that resemble KD.

Scientific Responsibility Statement

The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

Animal and human rights statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

Funding: None

Conflict of interest

None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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6. Bhat CS, Gupta L, Balasubramanian S, Singh S, Ramanan AV. Hyperinflammatory Syndrome in Children Associated With COVID-19: Need for Awareness. Indian Pediatr. 2020;57(10):929-5.

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9. Dufort EM, Koumans EH, Chow EJ, Rosenthal EM, Muse A, Rowlands J, et al.; New York State and Centers for Disease Control and Prevention Multisystem Inflammatory Syndrome in Children Investigation Team. Multisystem Inflammatory Syndrome in Children in New York State. N Engl J Med. 2020;383(4):347-58.

10. Chiotos K, Bassiri H, Behrens EM, Blatz AM, Chang J, Diorio C, et al. Multisystem Inflammatory Syndrome in Children During the Coronavirus 2019 Pandemic: A Case Series. J Pediatric Infect Dis Soc. 2020;9(3):393-8.

11. Ozsurekci Y, Gürlevik S, Kesici S, Akca UK, Oygar PD, Aykac K, et al.. Multisystem inflammatory syndrome in children during the COVID-19 pandemic in Turkey: first report from the Eastern Mediterranean. Clin Rheumatol. 2021;40(8):3227-37.

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14. Inciardi RM, Lupi L, Zaccone G, Italia L, Raffo M, Tomasoni D, et al Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020;5(7):819-24.

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16. Dolhnikoff M, Ferreira Ferranti J, de Almeida Monteiro RA, Duarte-Neto AN, Soares Gomes-Gouvêa M, Viu Degaspare N, et al. SARS-CoV-2 in cardiac tissue of a child with COVID-19-related multisystem inflammatory syndrome. Lancet Child Adolesc Health. 2020;4(10):790-94.

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Ayşegül Alpcan, Serkan Tursun, Yaşar Kandur. Clinical characteristics of children with multisystemic inflammatory syndrome associated with COVID-19. Ann Clin Anal Med 2022;13(1):6-10

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Assessment of palliative approach in the pain management in endodontic emergencies during Covid-19 outbreak: Retrospective cohort study

İsmail Uzun 1, Banu Arıcıoğlu 2, Kevser Şenel 1, Ali Afzal 3, Hakan Arslan 4

1 Department of Endodontics, Faculty of Dentistry, Ondokuz Mayıs University, Samsun, Turkey, 2 Department of Endodontics, Faculty of Dentistry, Recep Tayyip Erdoğan University, Rize, Turkey, 3 Department of Conservative Dentistry and Endodontics, Pacific Dental College and Hospital, Rajsthan, India, 4 Department of Endodontics, Faculty of Dentistry, Istanbul Medeniyet University, Istanbul, Turkey

DOI: 10.4328/ACAM.20816 Received: 2021-08-14 Accepted: 2021-10-01 Published Online: 2021-10-13 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):11-15

Corresponding Author: Banu Arıcıoğlu, Department of Endodontics, Faculty of Dentistry, Recep Tayyip Erdoğan University, Rize, Turkey. E-mail: banu.arc@gmail.com P: +90 464 222 00 00 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1124-1905

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Aim: During the coronavirus disease, a palliative approach was recommended for the management of endodontic emergencies. This retrospective cohort study was conducted to investigate the effectiveness of dexamethasone or ibuprofen-acetaminophen combination for pain management in endodontic emergencies.

Material and Methods: One hundred and eight records of patients who presented to the emergency department with dental pain were evaluated retrospectively. Since interventional procedures were not performed during the pandemic period, Specific analgesics/antibiotics for the management of pain were preferred. A follow-up protocol with a questionnaire was developed to observe the effectiveness of palliative treatment and make changes if necessary. All participants received a questionnaire to rate the pain levels 6, 12, 18, 24, 48, and 72 hours after taking the drug. All data were collected from the patient file and assessed. After inclusion and exclusion criteria, 32 patients were included (n = 19, ibuprofen + acetaminophen; n = 13, dexamethasone). Data were analyzed using the chi-square test (P = 0.05).

Results: In both groups, a significant decrease in pain was experienced immediately after medication and at 6, 12, and 18 hours, with no significant difference (P > .05). However, dexamethasone (Group II) resulted in lower pain levels than ibuprofenacetaminophen (Group I) at 24 and 48 hours (P < .05)

Discussion: Both dexamethasone and ibuprofen-acetaminophen can be good palliative choices in endodontic emergencies in pandemic conditions. However, at 24 and 48 hours, dexamethasone resulted in lower pain levels.

Keywords: Acetaminophen, Dexamethasone, Endodontic Emergency, Ibuprofen, Pain

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Introduction

The coronavirus disease 2019 (COVID-19) spreading from Wuhan is originated from coronavirus 2 (SARS-CoV-2), which causes serious acute respiratory syndrome, and has been identified as an international public health emergency by the World Health Organization (WHO) [1]. The most frequent routes of contamination of SARS-CoV-2 include direct contact and direct transmission through oral, nasal and eye mucous membranes [2]. Hence, the pathogens can be generated and transferred during oral examinations and become a real challenge for dental practitioners, and patients [3]. Recently, the American Dental Association (ADA) published a statement that includes the management of emergency dental care against the risk of contamination (available at: https://www.ada.org). They reported that cases regardless of potentially life-threatening, ongoing tissue bleeding, widespread soft-tissue infection with edema and cellulite, and intraoral or extraoral swelling can be treated with elective or palliative procedures [4]. Moreover, the British Endodontic Society suggested using specific analgesics/ antibiotics for the management of typical symptoms of endodontic infection according to pain levels (available at: https://britishendodonticsociety.org.uk). Therefore, clinicians have tended to palliative therapy during the pandemic period. Dexamethasone is a corticosteroid drug that has been used to manage pain in endodontic routine proven by experimental and clinical studies [5]. It decreases symptoms of inflammation and the release of inflammatory mediators [6]. Ibuprofen is a safe and successful non-steroidal anti-inflammatory drug (NSAID) that overcomes mild to moderate odontogenic pain and inflammation [7]. The combination of ibuprofen and acetaminophen, defined as crossfire or multimodal analgesia, has been reported to provide greater pain relief without increasing adverse drug reactions [8]. However, there is no study that compares the effect of dexamethasone or ibuprofen- acetaminophen combination on pain levels for endodontic emergency management. Therefore, the aim of this study was to evaluate the success of dexamethasone or ibuprofen- acetaminophen combination in an endodontic emergency in a pandemic period. The initial hypothesis was established that there is no significant difference in pain management between the two groups of medicaments.

Material and Methods

This retrospective cohort study was carried out by evaluating a total of 108 patients aged 18-65 years who applied to the emergency department of the Faculty of Dentistry due to toothache between June and September 2020 during the COVID quarantine period. The study was approved by the Ondokuz Mayıs University Clinical Research Ethics Committee (No: OMÜ KAEK 2020601).

The patients in non-COVID status by taking the detailed history and body temperature between 970F-990F were seen in the clinic. Detailed medical and dental histories of previously registered patients were evaluated. Records included age, gender, chronic diseases and medications, date of diagnosis, apical periodontitis symptoms, pulp and periapical diagnoses, radiographic images, and a VAS scale (0-17 cm).

Clinical and Radiographic Diagnosis, Treatment Protocol, Pain Evaluation
Clinical and radiographic examinations of the patients admitted to the emergency department were performed by the assigned clinician. All periapical radiographs, digital x-ray (Schick Technologies Inc., Long Island City, NY, USA) and electronic x-ray machine (Dabi Atlante Indústrias, Médica Odontológica, Ribeirão Preto, São Paulo, Brazil) 60 kV and 10 for 0.2 seconds at mA were used.

All the clinical and radiographical evaluations were performed by a single calibrated individual (K.Ş.). Percussion test was performed using the posterior end of the mouth mirror in the clinical examination. Firstly, it was first applied to a healthy contralateral tooth and the patient was told that the sensitivity felt should be scored between 0 and 170 on the 17 cm visual analogue scale (VAS). Then percussion was applied to the problematic tooth, and the patient was asked to mark the degree of percussion pain on the VAS. Signs ≥85 were recorded as symptomatic apical periodontitis. Palliative drug therapy was started according to the systemic condition of the patient. Since interventional procedures were not performed during the pandemic period, except for life-threatening emergencies, a follow-up protocol with a questionnaire was applied to monitor the effectiveness of palliative treatment and make changes when necessary.

Patient Questionnaire and Data Evaluation

All participants were given a questionnaire to rate their pain levels at 6, 12, 18, 24, 48, and 72 hours after taking the drug and were asked to record it. A clinician recalled the individuals and recorded the data. All these data were collected from the patient chart and analyzed retrospectively.

Inclusion criteria were as follows: systemically healthy patients aged 18–65 years; the maxillarymandibular teeth with the diagnosis of symptomatic apical periodontitis (painful reaction to percussion or biting); moderate to intense percussion pain score (85-114) (Heft–Parker VAS, 0–170 mm); radiographically, periapical index score 1 -3 proposed by Ørstavik et [9]. Exclusion criteria were as follows: patients with COVID-19 symptoms (cough, dyspnoea, fever); pregnancy and systemic disease (diabetic, bronchial asthma) or allergic reactions; sensitiveness or adverse drug reactions; patients who have taken any analgesics or anti-inflammatory medicament within the last 3 days; patients taking steroids, for instance, because of autoimmune diseases; necrotic pulp, periapical index score 4- 5 proposed by Ørstavik et al. [11]; serious periodontal infection or periodontal pocket deeper than 4 mm; the presence of large intraradicular posts; swelling or acute/chronic abscess; active orthodontic appliances; cracked teeth.

After inclusion and exclusion criteria, 32 patient records were evaluated for the study. Consort Flow diagram was shown in Figure 1.
Pain levels on the Heft–Parker VAS diagram (0–170 mm)

No pain, 0
Mild pain, 1–54 mm
Moderate pain, 55–114 mm
Severe pain, >114 mm
Statistical Analysis:
The statistician was blinded to the procedures. The Kolmogorov–Smirnov test was performed to determine if the data were normally distributed. Independent samples t-test and the Mann–Whitney U test were used for the data of pain level and age. The data on the presence of pain on palpation and based on gender and tooth numbers were analyzed using the chi-square test.

Results

The distribution of demographic data was shown in Table 1. Among the evaluated 32 patients, 19 were females (59%), and 13 were males (40%). The average age of the patients was 29.00 ± 10.02 years in the ibuprofen + acetaminophen group (Group I) and 35.15 ± 12.70 years in the dexamethasone group (Group II). Among the total 32 teeth that were defined as symptomatic apical periodontitis, 12 (37.5%) were molar and 10 were premolar (31.2%). In the records, it was determined that 19 patients were prescribed Ibuprofen 600 mg + acetaminophen 500 mg twice for 3 days, and 13 patients were prescribed 4 mg dexamethasone 1 day and 2 times. Statistically no significant difference was observed between the groups in terms of demographic details (P > .05).

The recorded pain levels in each group are shown in Table 2. No significant difference was observed between the groups in terms of premedication pain levels (P > .05). Additionally, no significant difference was observed between the groups

Discussion

In the pandemic stage of the COVID-19, pain management has become challenging for dentists due to the inability to use most of the diagnostic tools and the lack of active clinical interventions to relieve pain [2]. According to a new study conducted in Turkey, it was reported that the number of patients and interventional procedures in dental clinics decreased by approximately 90% [10]. Another study from Italy reported that, on average, only three patients per month were treated daily in clinics due to the pandemic period [11]. The British Endodontic Society published a document recommending pharmacological treatment method with analgesic and antibiotic prescription for alleviating non- life-threatening endodontic pain and inflammation (available at:https://britishendodonticsociety.org.uk).

NSAIDs inhibit cyclooxygenase (COX) enzymes (COX-1) and (COX-2), which play a key role in the development of inflammation and pain [12]. Acetaminophen is a powerful analgesic, although it has poor anti-inflammatory action. Unlike NSAIDs, it is not a potent prostaglandin (PG) inhibitor, but its clinical efficacy is similar to that of selective COX-2 inhibitors [8]. Dexamethasone is a corticosteroid drug that exhibits perfect anti-inflammatory activity by interrupting synthesis and/or release of inflammatory mediators [13 14].

Systematic reviews showed that the ibuprofen-acetaminophen combination has a perfect analgesic effect on pain of endodontic origin and they can be given alternately or together to prolong the effect without overdose [15]. However, data on the success of palliative treatment in endodontic emergencies during the pandemic are limited. Thus, this study aimed to research the success of dexamethasone or ibuprofen-acetaminophen combination in endodontic emergencies during the pandemic stage.

In the present study, 13 of 32 patients were prescribed dexamethasone 4 mg (2 × 1) for 1 day, while 19 patients were prescribed ibuprofen 600 mg + acetaminophen 500 mg (2 × 1) for 3 days. It has been reported in the literature that a single dose of dexamethasone (4 mg) is effective in relieving pain in the short term without side effects [16]. Therefore, analgesic intake was limited to the minimum number of days during which the analgesic effect was achieved in order to minimize the risk of liver damage.
In both groups, a significant reduction in pain was observed immediately after the medication. At 6, 12, and 18 hours, the pain gradually decreased with no significance in both groups. However, at 24 and 48 hours, dexamethasone resulted in lower pain levels than the ibuprofen-acetaminophen combination. Consistent with this result, it was reported that dexamethasone showed greater pain reduction compared to a single dose of NSAIDs at 6, 12, 24, 48 and 72 hours [17]. In another study, Pochapski et al [16], reported that although dexamethasone resulted in greater pain reduction than acetaminophen at 4 and 12 hours, no significant difference was detected at 24 and 48 hours. On the contrary, in a meta-analysis, NSAIDs were found to be more effective at 6 hours, whereas corticosteroids were found to be more effective at 12 and 24 hours [18]. Differences between the results may be due to different kinematics of the medicaments, patient’s genotype and polymorphism, age, emotional status, anxiety, periapical anatomy, pulpal status or pulp vitality [19].

During the chronic pulp and periapical inflammation process, nociceptor terminals may sprout, and thus the peripheral anatomy of the pain system may change [20]. Therefore, the patient’s individual response to pain and the systemic effect of oral drugs may not be the same.

With oral administration, absorption through the gastrointestinal mucosa is delayed and well-defined peaks (Cmax) values are reduced by 41% and 50% for ibuprofen and paracetamol respectively [21]. Ibuprofen starts to react rapidly between 0.5- 1 hours after oral consumption, reaches a plasma half-life between 2- 4 hours, and is absorbed approximately between 4 and 6 hours [22]. Similarly, the plasma half-life of dexamethasone is almost 1.5–4 hours, but the period of action is 36–54 hours [16]. From a clinical point, this may explain the lack of significant difference between the two groups at the time immediately post medication.

Another factor affecting drug activity is the genetic polymorphism of the cytochrome P450 enzyme. When patients with CYP-2C8 and CYP-2C9 polymorphisms have a reduced ability to clear ibuprofen, cumulative strain produces an increased magnitude of analgesia, but this can also increase side effects [19]. On the other hand, the analgesic and anti-inflammatory efficacy of NSAIDs is much more selective, in contrast to the multiple anti-inflammatory effects of glucocorticoids [14]. This might be one of the reasons for the higher efficacy of dexamethasone than ibuprofen.

A limitation of the current study was the difficulty of reflecting the subjective experience of pain on a quantitative scale. Although the VAS is practical, it requires training to administer, and especially elderly patients with physical impairment may have difficulty understanding and therefore completing the scale [23]. In the present study, age-related problems in scoring are thought to be minimal, by including the relatively young and middle-aged group and excluding the over-65 age group. Another limitation was that dose scaling based on body mass index was not considered at the prescribing stage. In the present study, standard drug doses were administered to each patient.

However, for an accurate assessment of the effectiveness of oral drugs, it is more appropriate to consider the optimum or minimum effective dose and work on a mg/kg basis [24]. However, in oral administration of systemic drugs, patient compliance is required to maintain optimum blood levels. Third, the sample size was not sufficient to allow multivariate analysis. The decrease in the number of patients admitted to the hospital with the risk of COVID-19 transmission during the pandemic period has resulted in a small sample size. Conclusion

Within the limitations of this retrospective cohort study, the use of dexamethasone or ibuprofen-acetaminophen combination can be a good palliative choice for pain management in patients with endodontic emergencies in pandemic conditions. In both groups, a gradual reduction in pain was detected immediately after medication. However, at 24 and 48 hours after medication, dexamethasone resulted in lower pain levels than the ibuprofen-acetaminophen combination.

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

The authors declare that they have no conflicts of interest

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İsmail Uzun, Banu Arıcıoğlu, Kevser Şenel, Ali Afzal, Hakan Arslan. Assessment of palliative approach in the pain management in endodontic emergencies during Covid-19 outbreak: Retrospective cohort study. Ann Clin Anal Med 2022;13(1):11- 15

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Evaluation of state and trait anxiety levels in adolescents undergoing endoscopy under anesthesia: A prospective study

Ümran Karaca, Derya Karasu, Şermin Eminoğlu, Şeyda Efsun Özgünay, Tuğba Onur, Nermin Kılıçarslan

Department of Anesthesiology and Reanimation, Health Sciences University, Bursa Yüksek Ihtisas Training and Research Hospital, Bursa, Turkey

DOI: 10.4328/ACAM.20819 Received: 2021-08-15 Accepted: 2021-09-21 Published Online: 2021-09-23 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):16-20

Corresponding Author: Ümran Karaca, Department of Anesthesiology and Reanimation, Health Sciences University, Bursa Yüksek Ihtisas Training and Research Hospital, Emniyet Street, No:35, 16290, Yıldırım, Bursa, Turkey. E-mail: umransuna@hotmail.com P: +90 505 494 16 87 Corresponding Author ORCID ID: https://orcid.org/0000-0001-5922-2300

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Aim: Our study aimed to evaluate the pre-procedure state and trait anxiety levels of adolescent patients hospitalized for gastrointestinal endoscopy performed under sedation.

Material and Methods: In this study, 180 children between 11 and 18 years of age (77.5% girls) who were scheduled for anesthesia to undergo endoscopy at our hospital were included. The patients were asked to complete the state (STAI-I) and trait anxiety scale (STAI-II) forms.

Results: According to the STAI-I anxiety scale, the total average anxiety scale score was significantly higher for middle school students than high school students (p=0.004). With the increase of the mother’s education, the STAI-I score also increased (p=0.04). In children living in rural areas compared to those living in cities, STAI-I and STAI-II scores were statistically significant (p<0.001). In line with the parents’ income levels, STAI-I and STAI-II scores of the children also changed (p<0.001). The STAI-I score was higher in children who did not have a previous endoscopy history than those who had undergone endoscopy before (p=0.01). A weak negative correlation was observed between the age of the children and the STAI-I score (r=-0.195, p=0.033). A positive correlation was found between the number of siblings and STAI-II score (r=0.187, p=0.041).

Discussion: Increased anxiety before endoscopic anesthesia was observed in this population, including adolescents in low-income families, those from families with many children, and those from families living in rural areas.

Keywords: Adolescent, Anxiety, State and Trait Anxiety, Endoscopy, Anesthesia

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Introduction

Anxiety is a disorder that is more relevant for adults. It is detected at a frequency of approximately 6.5% in childhood and adolescence [1]. Anxiety is usually considered in the two different forms of state anxiety and trait anxiety [2]. State anxiety can be defined as follows: (i) the emotional reaction that occurs due to the interpretation of certain situations as threatening; (ii) the subjective fear felt by an individual concerning a stressful situation experienced by the person. Its severity and duration are related to the perceived threat and the persistence of one’s interpretation of the dangerous situation. The state anxiety level increases when the stress is intense and decreases when the stress disappears. Trait anxiety, on the other hand, may be explained as an individual’s overall tendency toward a state of anxiety. Individuals with more prominent trait anxiety have a tendency to perceive their situations as constantly stressful, and they experience a feeling of unhappiness and discontent as a result of the perception of a threatening element. Individuals with high levels of trait anxiety can be easily demoralized, become pessimistic, and are demonstrated to experience increased levels of state anxiety more frequently [3]. Adolescence, a period in which physiological and hormonal developments are extremely swift, is also a time in which individuals’ self-expression needs and emotional ups and downs are most intense. The periods of growth and development have an unstable status while emotional evolution continues. Illness is one of the common sources of stress in any individual and may be particularly influential among developing children. It has been found that surgical or interventional procedures performed for children affect the children’s and their mothers’ anxiety levels and quality of life [4]. Additionally, a child’s response to ordeals may be associated with family structure and the parents’ socioeconomic and educational status. With these points in mind, we aimed to evaluate the anxiety and trait anxiety levels of adolescents scheduled for gastrointestinal (GI) endoscopy under sedation after being admitted for a single day in patients before the procedure.

Material and Methods

A total of 180 pediatric patients who underwent GI endoscopy in our hospital between June 1, 2019, and March 1, 2020, were included in our study. Approval was obtained from the local ethics committee (2011-KAEK-25 2019/05-13) and informed consent was received from the patients’ relatives. In addition, demographic data (age, gender, height, weight, educational status, school, and grade), additional diseases, and additional diagnoses were recorded. Children aged 11-18 years, ASA I-II, cooperative, literate, and undergoing elective endoscopic procedures were included in the study. Children younger than 11 years old, uncooperative, illiterate, with known psychiatric disorders or usage of psychiatric drugs, or undergoing endoscopy due to an emergency such as ingestion of a caustic substance were excluded from the study. Before the procedure, a form evaluating state and trait anxiety levels (Spielberger’s State and Trait Anxiety Scale) and another form consisting of demographic data were distributed to the patients in the waiting room. We requested that the children fill out the forms themselves. After monitoring in the endoscopy unit, sedation was administered with routine IV anesthetic drugs by an experienced anesthesiologist (midazolam, 0.05-0.1 mg/kg; propofol, 1.0 mg/kg). Oxygenation was provided with nasal O2 in all patients. Heart rate (HR), mean arterial pressure (MAP), and oxygen saturation (SpO2) were monitored. Complications (bradycardia, tachycardia, arrhythmia, hypotension, hypertension, bronchospasm, decrease in SpO2, apnea) were recorded.

Spielberger State and Anxiety Scale

Spielberger developed the State Anxiety Scale (STAI) in 1970, and the validity and reliability study for the Turkish form was conducted by Oner et al. in 1983 [11, 12]. Both subsections (I and II) are responded to in the style of a Likert-type scale. While the STAI-I anxiety level is scored as “(1) never, (2) somewhat, (3) frequently, and (4) almost always,” the scoring options for the STAI-II are “(1) almost never, (2) sometimes, (3) most of the time, and (4) almost always.” There are two types of expressions on these scales. Direct expressions reflect negative emotions while the other type reflects reversed expressions that represent positive feelings. Two different total score weights are calculated for each of the direct and reverse expressions. The total score for reverse expressions is subtracted from the total score obtained for direct expressions and then a predetermined and unchanging value is added to this score (50 was added to the score obtained for the STAI-I as the constant value, while for the STAI-II, this value was 35). The final value obtained is the individual’s anxiety score. Theoretically, the scores obtained from both scales vary between 20 and 80. A higher score indicates a high anxiety level and a lower score indicates a low anxiety level. The average score level has been reported to range from 36 to 41 in various applications. The classification of anxiety levels (none, mild, moderate, severe, and panic-level anxiety) was performed (Figure 1).

Statistical Analysis

Statistical evaluations were conducted using SPSS 23.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics for numerical variables were expressed as mean ± standard deviation, while numbers (n) and percentages (%) were used for categorical data. The compliance of variables to normal distribution was evaluated with the Kolmogorov-Smirnov test. The Student t-test was used to compare variables with normal distribution. The Kruskal-Wallis test was used for multiple comparisons that did not conform to normal distribution. Pearson correlation was calculated for the correlation analyses between continuous variables. Results were evaluated at a 95% confidence interval and any p-value of <0.05 was considered significant.

Results

Sociodemographic characteristics of the 180 patients included in the study are shown in Table 1. Upper GI endoscopy was performed for 92.2% (n=166) of the patients, while colonoscopy and endoscopy were performed in 7.8% (n=14). The patients’ STAI-I total mean anxiety level was measured as 41.60±11.07 and the STAI-II total mean anxiety level was 42.40±8.37. Thus, moderate anxiety was observed in the majority of children according to scale classification (Figure 1). The majority of the parents’ education level was primary school (70.6% and 50.6%, respectively). The vast majority of the fathers were laborers and the mothers were mostly housewives. According to the STAI-I anxiety scale, the total average anxiety score among students in middle school was significantly higher than the average anxiety score among high schoolers (p=0.004) (Table 2). Higher mother’s education was also significantly associated with higher STAI-I anxiety scale scores (p=0.04) (Table 2). For children living in rural areas compared to children living in cities, STAI-I and STAI-II anxiety scale scores were found to be statistically significant (p<0.001 ) (Table 2). According to parents’ income levels, children’s STAI-I and STAI-II anxiety scale scores also changed, which was significant (p<0.001) (Table 2). The STAI-I anxiety scale score was significantly higher in children who did not have an endoscopy history than those who had previously undergone endoscopy (p=0.01) (Table 2). A weak negative correlation was observed between the children’s age and STAI-I scores (r=-0.195, p=0.033) (Table 3), while a positive correlation was found between the number of siblings and STAI- II scores (r=0.187, p=0.041) (Table 3). Midazolam and propofol were administered for anesthesia. The average HR measured during the intervention was 92.85±8.51 and the average SpO2 level was 98.81±0.77. In terms of complications, nausea was identified in 17 patients, vomiting in 6 patients, and a decrease in oxygen saturation in 14 patients.

Discussion

Gastrointestinal endoscopy is an effective method used for the diagnosis and treatment of various pediatric GI disorders. In outpatient endoscopy applications, anxiety is observed in many patients. In addition, pediatric patients and their parents have anxiety due to pain associated with the intervention and possible complications. The necessity of anesthesia for preventing pain is crucial for them [5]. Therefore, sedation is frequently used in pediatric patients to increase procedure safety, success, and patient comfort [6]. This study examined pre-procedural anxiety levels in pediatric patients who underwent elective upper GI endoscopy or colonoscopy with sedation concerning age, gender, education, and socioeconomic conditions affecting this anxiety.

Adolescence shows great differences between genders and even individuals [7]. Studies revealed that GI endoscopy in children is mostly performed for girls [8, 9]. Similar to the literature, in our study, GI endoscopy application was observed more frequently in girls than in boys (77.5%). It can be considered that girls have a higher frequency of GI diseases than boys. They may also be applying to the hospital at more frequent intervals due to their different biological and personality structures, mental characteristics, coping styles, and social and cultural positions. In parallel with this, when the literature is reviewed to assess differences between the genders for anxiety, it is seen that female patients are reported to have higher anxiety levels than males [10, 11]. However, in another study, when adolescents’ state and trait anxiety scores were examined in terms of gender, there was no statistically significant difference between male and female adolescents [12]. Similarly, in our study, there was no difference between the mean anxiety scores of the girls and boys.

Anxiety can be inspected at any age and in all age groups for different reasons. Çubukçu and Ercan examined the effect of sociodemographic characteristics of children on dental care-related anxiety. Dental care-related anxiety was seen to decrease with increasing age [13]. Similarly, a study examining the relationship between pre-procedural anxiety levels and conscious sedation practices in patients undergoing GI endoscopy found that anxiety decreased with increasing age [14]. In our study, a negative correlation was found between age and state anxiety scale scores, in accordance with the literature. Analyzing these data, it can be asserted that, as the age of the child increases, fear and anxiety related to medical procedures decreases. Likewise, patients in middle school had significantly higher state anxiety levels than those in high school. This situation suggests that increased age and education levels result in improved abilities to handle anxiety.
The state-trait anxiety level is affected by the individual’s current state and conditions such as the parents’ ages, education, lifestyle, and personality features. For example, Battal et al. reported that psychiatric scale scores increased in children with younger mothers with greater anxiety [15]. In another study, however, it was observed that there was no difference or correlation between maternal age and state and trait anxiety scale scores [16]. In studies investigating the effects of parents’ education levels, it was reported that the mother’s education level did not affect anxiety, whereas, in another study, higher maternal education was associated with increased anxiety [17, 18]. In our study, no statistically significant correlation was observed between the total score of the scales and the age of the mother and father. Despite this, we observed that state anxiety also increased as the mother’s education level increased, but the father’s education level was not effective on state anxiety. This may be explained by the fact that the person closest to the child is the mother, and improvement in the level of consciousness of the mother with knowledge acquired from education affects the level of anxiety.

Another subject emphasized in studies is that economic stress can affect adolescent development by influencing parents’ negative emotions and making them more susceptible to future stressors [19, 20]. Studies have found that children who face financial difficulties at home during adolescence have lower self-confidence, higher levels of distress, and more social and emotional problems. In these circumstances, adolescents are more sensitive and negative in their relationships with others [21, 22]. Similarly, in our study, an increased level of anxiety was observed in adolescents with low socioeconomic levels. As the cause of this situation, low socioeconomic level and multi-sibling adolescents living in rural areas were evaluated as having inadequate doctor-family communication. The lack or failure of family-child information and the reflection of the family’s stress onto the child should be other criteria to consider in approaching adolescents. Insufficient preparation for processing, especially in children from large families with low socioeconomic levels, was associated with increased anxiety.

A previous study investigated the anxiety levels of mothers whose children had histories of hospitalization versus mothers whose children had not been hospitalized before. There were significantly higher state anxiety scale scores among the mothers whose children were previously hospitalized. However, there was no difference or correlation between the mother’s age and state and trait anxiety scale scores [16]. No difference was observed in anxiety scale scores in children with a family history of hospitalization in our study. However, the state anxiety scale scores were lower in children who had previously experienced endoscopy. Positive and unproblematic previous endoscopy experience can support the child’s sense of security. It is thought that information about procedures assists the child in understanding what awaits him or her and thus reduces anxiety. It is also noteworthy that as the number of siblings increases, state-trait anxiety scores also increase. Charan et al. found a correlation of being an only child with a high level of anxiety [23]. On the contrary, our study observed that the number of siblings increased trait anxiety in children. High trait anxiety suggests that children are under stress in their home life.

Limitations

The main limitations of our study are its single-center nature, lack of information on anxiety status before admittance or after the intervention, lack of parental anxiety level assessments, and the fact that we did not determine the causes of anxiety in children. Furthermore, pre-anesthesia patient visits, informative dialogues with the patients and their relatives (pre-anesthesia interviews), and premedication before the procedure were not performed. In addition, we did not assess the depth of anesthesia during the procedure, which may be another limitation of the study.

Conclusion

In this study, we observed that individual and sociocultural characteristics affect pre-intervention anxiety in adolescents. Anxiety levels were higher in children living in rural areas and children from families with low income levels. We think that communication between physicians and patients is important before the intervention.

Acknowledgment

We would like to acknowledge the surgical team, who were not involved in this article’s idea, application, or writing process.

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. Polanczyk GV, Salum GA, Sugaya LS, et al. Annual research review: A meta-analysis of the worldwide prevalence of mental disorders in children and adolescents. J Child Psychol Psychiatry. 2015; 56:345-65.

2. Spielberger CD, Gorsuch RL, Lushene RE. Test manual for the State-Trait Anxiety Inventory. 1st ed. California: Consulting Psychologists Press 1970.

3. Oner N, Le Compte A. A State-Trait Anxiety. Inventory Handbook. Istanbul, Boğaziçi University, Publishing, 1985.

4. Hagiwara S, Nakayama Y, Tagawa M, et al. Pediatric Patient and Parental Anxiety and Impressions Related to Initial Gastrointestinal Endoscopy: A Japanese Multicenter Questionnaire Study. Scientifica (Cairo). 2015; doi:10.1155/2015/797564.

5. Jones MP, Ebert CC, Sloan T, et al. Patient anxiety and elective gastrointestinal endoscopy. J Clin Gastroenterol. 2004; 38:35-40.

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7. LacombaTrejo L, Valero Moreno S, Montoya Castilla I, et al. Psychosocial Factors and Chronic Illness as Predictors for Anxiety and Depression in Adolescence. Front Psychol. 2020; 11: 568941. DOI: 10.3389/fpsyg.2020.568941.

8. Arıcan Ş ,Yücel A, Yılmaz R, et al. Anxiety level and risk factors among pediatric patients in endoscopic procedures outside the operating room: A cross-sectional study J Surg Med. 2020;4:693-697

9. Mohapatra S, Agarwal V, Sitholey P. Pediatric anxiety disorders. Asian Journal of Psychiatry. 2013; 6: 356–63.

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13. Çubukçu EÇ, Ercan I. The effect of socio-demographic factors on dental anxiety of children admitted to a hospital-setting pediatric dental care. The Journal of Current Pediatrics. 2008; 6: 53- 7.

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17. Cagiran E, Sergin D, Deniz MN, et al. Effects of sociodemographic factors and maternal anxiety on preoperative anxiety in children. J Int Med Res. 2014; 42: 572- 80.

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Ümran Karaca, Derya Karasu, Şermin Eminoğlu, Şeyda Efsun Özgünay, Tuğba Onur, Nermin Kılıçarslan. Evaluation of state and trait anxiety levels in adolescents undergoing endoscopy under anesthesia : A prospective study. Ann Clin Anal Med 2022;13(1):16-20

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Failed endometrial metabolite synthesis contributes to subfertility in women with unexplained infertility

Cemil Karakus 1, Nurettin Turktekin 2

1 Vocational School of Health Services, Beykent University, 2 Operating Room Services Department, Nisantası University, Vocational School, Istanbul, Turkey

DOI: 10.4328/ACAM.20821 Received: 2021-08-18 Accepted: 2021-09-21 Published Online: 2021-09-25 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):21-24

Corresponding Author: Cemil Karakus, Vocational School of Health Services, Beykent University, Istanbul, Turkey. E-mail: drckarakus@gmail.com P: +90 532 348 30 33 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3389-7662

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Abstract

Aim: This study compares endometrial metabolite signal intensities of patients diagnosed with unexplained infertility (UEI) with those of fertile women.

Material and Methods: A total of 20 patients diagnosed with UEI and 20 fertile women with at least two children were included in the study. UEI patients were matched with the fertile group in terms of age and BMI. UEI was defined as the absence of conception despite 12 months of unprotected intercourse, not explained by anovulation. Endometrial spectroscopy was applied to the women in both groups in the mid-luteal phase of the cycle. The endometrial signals of choline (Cho), creatine (Cr), lactate, and lipids were measured in units and denominated in parts per million.

Results: All patients in both groups underwent successful spectroscopy and the main metabolites of Cho, Cr, lactate, and lipids were recorded. Cho (2.93±1.03 vs. 3.22±2.04, p<0.05) and Cr (2.33±1.30 vs. 2.76±1.43, p<0.01) metabolite signal intensities were found to be significantly lower in UEI patients compared to fertile controls. Lactate (0.56±0.11 vs. 0.62±0.30, p>0.66) and lipid (0.70±0.02 vs. 0.78±0.61, p>0.54) signal intensities were found to be similar between the groups.

Discussion: Decreased Cho and Cr signals, which are physiological indicators of endometrial function, may be the possible cause of subfertility in UEI patients.

Keywords: Unexplained Infertility, Choline, Creatine, Endometrium, Spectroscopy

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Introduction

About 10-30% of couples with normal fallopian tubes, ovulatory functions, and semen analysis results are diagnosed with unexplained infertility (UEI) [1, 2]. The mechanisms that cause infertility in this patient group are not clearly known. Some physicians use standby therapy, while others offer intrauterine insemination or IVF. The application of different treatments is due to the lack of useful data on the underlying cause of UEI. The only pleasing aspect of the diagnosis of UEI is that these patients have a 13-27% chance of spontaneous pregnancy [3]. Endocrinological disorders, immunological defects, and genetic causes have been considered among the potential causes of UEI [4]. The least studied area in the etiology of UEI is the endometrium. The reason for this is mostly due to the fact that the endometrium is evaluated only as thin or thick in ultrasonographic evaluations, and further evaluations are done late due to the invasiveness of procedures such as hysteroscopy and endometrial biopsy. Although a thin endometrium is weak in terms of receptivity, the presence of a thick endometrium does not always predict successful implantation. It is obvious that there is a need for a test to evaluate endometrial functions noninvasively in cases of UEI. In this context, the only method by which we can evaluate the endometrium noninvasively is spectroscopy [5].

About a decade ago, it was reported that MR spectroscopy is an effective method for evaluating the physiological cycle of the endometrium [5-7]. The feasibility of spectroscopy in the evaluation of the endometrium was confirmed by subsequent studies [8]. Choline (Cho), creatine (Cr), lactate, and lipid signals to be obtained by spectroscopy will provide us with clues about the physiopathological changes that occur at the cellular level in the endometrium [5-7]. However, it remains to be determined whether spectroscopy of the endometrium can help the physician in having knowledge about the status of endometrial function in cases of UEI. If the data to be obtained with this noninvasive method are meaningful, it may provide a new perspective in the diagnosis and treatment of UEI. This case-controlled study was planned to compare the endometrial metabolite signal types of UEI patients with the signal characteristics of fertile women.

Material and Methods

A total of 20 women diagnosed with UEI and 20 fertile women with at least two children were included in the study. UEI patients were matched with the fertile group in terms of age and BMI. UEI was defined as the absence of conception despite 12 months of unprotected intercourse, not explained by anovulation. In addition to ovulatory values of serum luteinizing hormone (LH) surge or mid-luteal progesterone presence and normal semen parameters according to World Health Organization criteria, the presence of patent fallopian tubes during hysterosalpingogram or laparoscopy was considered in the diagnosis of UEI. Patients with endometrial polyps, leiomyoma, adhesion, and congenital uterine anomaly were excluded from the study. Patients diagnosed with hydrosalpinx, endometrioma, or endometriosis were also excluded, as were anovulatory PCOS patients. Patients in both groups underwent endometrial MR spectroscopy in the mid-luteal phase of the cycle. Spectroscopy was performed 7-9 days after the LH surge.

LH surge was considered as a twofold or more increase in serum LH levels compared to the average of the previous three days. Spectroscopy analysis of the endometrium was performed using MR imaging. T1-weighted and T2-WI images with 4-mm-thick sections were analyzed in the axial and coronal planes. Multi- voxel point-resolved spectroscopy techniques with short and long TEs were applied. The metabolite peaks of endometrial cells were analyzed with Magnetic Resonance User Interface software. The endometrial signals of Cho, Cr, lactate, and lipids were measured in units and denominated in parts per million. First, the endometrium was visualized in both the UEI and fertile control groups by magnetic resonance imaging before the voxel was inserted. The volume of interest of the voxel was placed at the center of the endometrium. Care was taken to prevent abdominal or myometrial tissue from entering the voxel area. Endometrial metabolites were quantitatively analyzed from spectroscopic images and recorded as ppm. Metabolite peaks included Cho located at 3.2 ppm, Cr located at 3-3.1 ppm, lactate located at 1.4 ppm, and a compound peak containing lipids and lactate located at 0.8-1.4 ppm. The signal intensities of Cho, Cr, lactate, and lipids in UEI were analyzed and compared with the results of fertile women. 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 Declaration of Helsinki and approval for the study was obtained from the institutional review board.

Statistical analysis

All statistical analyses were performed using SPSS 21.0 (IBM Corp., Armonk, NY, USA). Normally distributed variables were analyzed with the independent samples t-test. Non-normally distributed variables were analyzed with the Mann-Whitney U test. Categorical variables were analyzed with chi-square tests. The correlations between demographic variables, hormonal parameters, and metabolite values were evaluated using Pearson correlation coefficients. Data are given as mean ± standard deviation for continuous variables according to normality of distribution and as frequency for categorical variables. Values of p<0.05 were accepted as statistically significant.

Results

Participants in both groups were similar in terms of age (27.4±1.04 vs. 28.1±0.2 years, p>0.61) and BMI (27.1±1.03 vs. 26.5±1.91, p>0.40). There was no significant difference between the two groups in terms of other demographic and hormonal parameters. While 13 of the women in the fertile group had delivered by cesarean section, 7 had a history of normal vaginal delivery. All of the women in both groups underwent successful spectroscopy and the levels of the main metabolites of Cho, Cr, lactate, and lipids were obtained. Cho (2.93±1.03 vs. 3.22±2.04, p<0.05) and Cr (2.33±1.30 vs. 2.76±1.43, p<0.01) metabolite signal intensities were found to be significantly lower in UEI patients compared to fertile controls. Lactate (0.56±0.11 vs. 0.62±0.30, p>0.66) and lipid (0.70±0.02 vs. 0.78±0.61, p>0.54) signal intensities were found to be similar between the groups. The most prominent metabolite peaks in the fertile group were Cho and Cr, respectively. In UEI patients, these two metabolite peaks were either weak in intensity or the signals in spectroscopy did not show clear peaks. Lactate and lipid peaks, which are indicators of endometrial hypoxia and necrosis, were found to be very weak in both fertile women and UEI patients. There was no difference between the groups in terms of lactate and lipid metabolites, which are endometrial pathology peaks. There was no significant correlation between demographic and laboratory parameters and metabolite signals of the women in either group.

Discussion

Approximately 30-40% of patients followed with a diagnosis of infertility are examined under the title of “unexplained infertility,” since no underlying pathology was detected as a result of the initial infertility tests [4, 9]. Most clinicians believe that women in this patient group can conceive spontaneously or with different treatments. Indeed, about one-third of these patients may become pregnant within a certain period of time. However, the remaining two-thirds have to pursue assisted reproductive techniques because they have difficulty in conceiving. What could be the mechanism that prevents pregnancy in these women with normal semen analysis, normal tubal and uterine cavity passages, and healthy ovulation? The first answer that comes to mind is the endometrium, because the endometrium is the only region that is not taken into consideration when diagnosing UEI. The absence of space- occupying lesions such as polyps and myomas in the cavity and the detection of a triple-line endometrium of sufficient thickness on ultrasonography does not mean that everything is suitable for implantation. In many diseases such as PCOS and endometrioma, which cause infertility, although the endometrium appears morphologically healthy, it is found to have some defects at molecular and/or genetic levels in histopathological and RT-PCR examinations [10]. Since the ovulatory function and tubal passage are normal in UEI cases, we should expect the embryo to attach to the endometrium. In order for the endometrium to accept the embryo, it must have undergone adequate decidualization, developed pinopodes, and have upregulated sex steroid receptors. For all these changes to occur, sufficient energy production must be ensured at the cellular level in the endometrium, membrane integrity must be preserved, and necrotic events with hypoxia and tissue death must not occur [5-7].

Cho is the main indicator of cell membrane integrity and regeneration capacity. Cr is another metabolite that shows that the energy pathways necessary for the realization of vital functions in the cell are active [5,7,11]. In cells with a healthy life cycle, both Cho and Cr signals should be of sufficient intensity. In contrast to the patients in the fertile control group, we found that both Cho and Cr signals were significantly reduced in UEI patients. Decreased Cho and Cr metabolite levels in tissue with a dense mitotic capacity, such as the endometrium, indicate a problem at the cellular level. Although the endometrium appears to be morphologically normal in cases of UEI, decreased Cho and Cr signals suggest that there is a problem in both endometrial mitosis and the decidualization process [12, 13]. Since the endometrium is associated with the brain via follicle- stimulating hormone (FSH), LH, and the ovaries via estrogen and progesterone, the decrease in Cho and Cr signal intensities may be of central or ovarian origin. Subtle changes in FSH and LH secretion or defects in sex steroid synthesis and release that are not reflected in the laboratory may be the cause of decreased Cho and Cr signals. On the other hand, endometrial estrogen or progesterone receptor defects may also decrease the signal intensities of these two metabolites.

Since the lactate and lipid signal peaks of the fertile group and UEI patients were similar, there was no irreversible damage to the endometrium in these cases of UEI. Lactate is an indicator of anaerobic glycolysis. In the UEI group, lactate levels similar to those of the fertile group indicate the presence of sufficient oxygen in the endometrium for energy production [5, 11]. Lipid signals are indicative of the disruption of cell membrane integrity. The presence of the lipid signal at a level similar to the fertile group in UEI patients suggests that the membranes of the endometrial cells are healthy. All these findings suggest that UEI patients have a temporary impairment in energy production in the endometrium. The fact that many patients become pregnant spontaneously also supports the assumption that the problem in the endometrial cells is transient. If the diagnostic value of endometrial spectroscopy is clearly proven as a result of more comprehensive studies to be carried out by increasing the number of cases considered, infertility physicians will have a cheap, easily applicable, and non-invasive endometrial screening test for women with UEI.

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. Dokuzeylül Güngör N, Güngör K. Ovarian stimulation drugs alter the metabolite content of the growing follicle: in vivo spectroscopic evaluation of follicle fluid. J Turk Ger Gynecol Assoc. 2021;22:132-138.

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Cemil Karakus, Nurettin Turktekin. Failed endometrial metabolite synthesis contributes to subfertility in women with unexplained infertility. Ann Clin Anal Med 2022;13(1):21-24

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Comparison of PCR-negative patients with CT findings and PCR-positive COVID-19 patients

Adem Durmaz 1, Duru Mıstanoğlu Özatağ 2

1 Kütahya Yıldırım Beyazıt Family Health Center, 2 Department of İnfectious Diseases, Kütahya Health Sciences University, Kütahya, Turkey

DOI: 10.4328/ACAM.20826 Received: 2021-08-20 Accepted: 2021-10-05 Published Online: 2021-10-12 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):25-29

Corresponding Author: Duru Mıstanoğlu Özatağ, Kütahya Health Sciences University, Department of İnfectious Diseases, Kütahya, Turkey. E-mail: durumistan@gmail.com P: +90 505 854 27 90 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0005-192X

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Abstract

Aim: The gold standard diagnostic method for the diagnosis of COVID-19 is based on the demonstration of viral RNA in samples taken from the upper respiratory tract in reverse transcriptase-polymerase chain reaction (RT-PCR). However, in emergencies, the World Health Organization (WHO) also recommends to use computed tomography (CT) in order to reduce the loss of time and to provide rapid diagnosis, treatment and isolation of suspicious cases. In our study, we aimed to compare the laboratory values of patients with PCR negative CT findings and PCR positive patients.

Material and Methods: The medical records of 1280 COVID-19 patients registered at our Family Medicine Center were reviewed retrospectively.

Results: In our study, it was found that 66,70 % of PCR- negative patients with CT findings were aged 60 years and older, and 50.70% of PCR-positive COVID-19 patients were between the ages of 40-59 years; 61.30% of the patients with CT findings and 48% of the PCR-positive patients were male; 73% of PCR-positive patients had lung involvement. When CRP, fibrinogen and D-dimer values were examined, it was found that in PCR-negative COVID-19 patients with CT findings these values were statistically significantly higher.

Discussion: Although the definitive diagnosis of the disease is made using a PCR test, it should not be overlooked that the patients may remain PCR negative, and it should not be forgotten that thoracic tomography findings are a good diagnostic method for this group.

Keywords: Computed Tomography, PCR, COVID-19

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Introduction

We are experiencing one of the biggest epidemics in the history of the world. The epidemic that started in China in 2019 and spread all over the world has caused the death of more than 3,9 million people (available at: https://covid19.who.int/

World Health Organization. WHO Coronavirus (COVID-19) Dashboard ). The COVID-19 outbreak threatens all humanity, health systems and economies [1]. COVID-19 disease is caused by SARS-COV 2, an RNA virus [2-4]. It can present with a wide clinical spectrum from asymptomatic infection to multiorgan insufficiency. The most common symptoms in patients are fever, weakness, nasal congestion, muscle and joint pain, dry cough, nausea, vomiting, diarrhea, headache, dizziness, smell and taste disturbances [5]. It is also predicted that the epidemic will continue its effect in waves for a while. Due to the emerging new mutations, the effect of vaccines and treatments may decrease [6].

The gold standard diagnostic method for the diagnosis of COVID-19 is based on the demonstration of viral RNA in samples taken from the upper respiratory tract in reverse transcriptase- polymerase chain reaction (RT-PCR) (PCR) [7]. However, in emergencies, the World Health Organization (WHO) also recommends to use computed tomography in order to reduce the loss of time and to provide rapid diagnosis, treatment and isolation of suspicious cases (available at: https://apps.who.int/ iris/handle/10665/332326 World Health Organization. Use of chest imaging in COVID-19: a rapid advice guide: web annex A: imaging for COVID-19: a rapid review ). In addition, lung imaging methods, in general, help us in cases where the PCR test is initially negative in cases where laboratory tests are not available, especially when RT-PCR is not available, the results are delayed or in the presence of symptoms that make the diagnosis of COVID-19 [8]. Currently, in most countries, diagnosis and treatment planning is made with the findings of thoracic tomography in the presence of emergency kit insufficiency and similar conditions. In COVID-19, the most common image (so-called typical) is ground glass image (74.20%) and consolidation (60.20%) observed in the lower lobes and symmetrically, in addition, reticular appearance, Crazy paving pattern (thickened interlobular septa and intralobular lines observed with ground glass overlapping), air bronchogram, vascular dilatation, interlobular septal thickening, bronchodilation, pleural thickening and pleural effusion, fibrous bands may be observed [9,10]. In our study, we aimed to compare laboratory values of patients with PCR-negative CT findings and PCR-positive patients, and to emphasize the importance of thorax tomography in the diagnosis of the disease with the results obtained.

Material and Methods

The necessary permission for this study was obtained from the Ministry of Health. In addition, on 16.12.2020, the approval was obtained from the Non-Interventional Ethics Committee of Kütahya Health Sciences University with the number 2020/17- 23. The medical records of 1280 patients under family medicine follow-up were reviewed retrospectively. Seventy-five patients were included in the study, with at least two negative RT-PCR tests and findings that suspect COVID-19 in their thorax CT (viral pneumonic infiltration, especially ground glass appearance, etc.). In addition, 75 patients with positive RT- PCR test were selected as a control group. Patients whose PCR test was performed only once were excluded from the study. In addition, those who had diseases (such as leukemia, deep vein thrombosis) or those using drugs (anticoagulants, drugs that will affect thrombocytes) were excluded from the study.

The following parameters were evaluated in 150 patients at the time of diagnosis: D-dimer, fibrinogen, C-reactive protein (CRP), hemogram, White blood cell (WBC) count, lymphocytes (lymph), neutrophils (neutral), eosinophils (eos), platelets (PLT) Mean platelet volume (MPV), Platelet distribution width (PDW). RT-PCR (PCR) (Real-Time Polymerase Chain Reaction- Polymerase Chain Reaction) was evaluated using a Bio Rad CFX96 Real-Time PCR machine. The data were recorded in the SSPS (Statistical Package for the Social Science, Inc.; Chicago, IL, USA) 23 package program and statistical analysis was performed. Numerical variables were shown as mean ± standard deviation and median (minimum, maximum), categorical variables as number (n) and percentage (%). Student’s t-test and one way ANOVA test were used to compare the categorical variables of the patient and control groups. A p<0.05 was considered statistically significant.

Results

In our study, it was found that 66.70% of thePCR-negative patients were 60 years old and above, and 50.70% of the PCR- positive COVID-19 patients were between the ages of 40-59 years; 61.30% of PCR negative patients and 48% of PCR-positive patients were male. While 56% of PCR-negative patients had chronic disease, this rate was 4% in PCR-positive patients (Table 1). When we evaluated the lung tomography findings, 66.70% of PCR-positive COVID-19 patients had typical (ground glass view) viral pneumonic infiltrates, 6.7% had atypical findings and 26.70% (n: 20) of them had no lung involvement.

When CRP, fibrinogen and D-dimer values were examined, it was found that in PCR- negative COVID-19 patients these values were statistically significantly higher than in PCR- positive COVID-19 patients (p<0.05). The decrease in WBC values was more prominent in the PCR-positive group (32%). In PCR-negative patients, neutrophil and MPV values were higher, and lymphocyte values were lower (p<0.05). In addition, no significant difference was found between the eosinophil and PLT values in both groups (p> 0.05) (Table 2,3).

Discussion

In thoracic tomography, a ground glass image may occur due to the presence of a small amount of fluid or cells in the alveoli, or a thickening of the wall in the alveoli. COVID-19 is one of the most common images, but it can also be observed in pulmonary edema, acute respiratory distress syndrome (ARDS), lung malignancies, idiopathic pulmonary fibrosis, interstitial lung diseases (such as pneumonia, silicosis, hypersensitivity pneumonia, and sarcoidosis) (Figures 1-2) [11,12].

During the pandemic process, the most important principles in our fight against COVID-19 are early diagnosis and initiation of appropriate treatment of suspected patients, and isolation and vaccination studies of cases that have come into contact with these patients. In order to avoid wasting time in emergencies, WHO recommends that pre-diagnosis with thoracic CT findings and subsequent confirmation of the diagnosis with RT-PCR is one of the most frequently used methods. For this reason, in most countries, in the presence of a suspicious (especially ground glass view) image on thoracic CT scan, COVID-19 is diagnosed, treatment is started until blood tests are taken and the patient is isolated. Generally, it has been observed that the PCR test becomes positive within an average of 2-8 days from the onset of the disease [13]. In a study conducted by Tanyeri, CT specificity was found to be 69% for COVID-19, and it was reported that, in suspicious cases, it would be more rational to perform a CT scan first [14]. Even if the PCR test is negative due to reasons (such as laboratory error or insufficient viral material in the sample), the person is considered a COVID-19 patient and his isolation continues with treatment. In the study conducted by Vannucci et al., the most accurate sampling method reported as broncho-alveolar lavage (BAL ). However, it is not a highly preferred method due to the risks during BAL (especially the risks of contamination and complications)[15]. In our study, we found that in PCR-negative COVID-19 patients with CT findings, some of the patients were negative despite repeating the PCR test two or three times. In our study, we found that the mean age of the PCR-negative group with CT findings was higher than that of the PCR-positive group, and that CRP, Fibrinogen and D-Dimer values were also higher, indicating that the risk exacerbation of the disease increases with advanced age.
In another study by Ai et al., PCR positivity was found in 68.80% of patients with suspected COVID-19, and lung involvement on CT was found in 88% of these suspicious patients. In addition, they found involvement in thorax CT in 97% of patients with a positive PCR result [16]. In our study, we found involvement in CT in 73% of the patients who were PCR positive. Chen et al. reported that, despite multiple tests for COVID-19, viral RNA could be shown only in the fifth PCR test in a patient with ground glass in the lungs [17].

In studies conducted, high CRP was detected in 60% of COVID-19 patients, and it was reported that it may increase in severe viral infection, viremia and viral sepsis [18,19]. In our study, CRP values were found to be increased in 92% of PCR-negative patients with CT findings and in 62.70% of PCR- positive patients (p<0.05). It has been observed in studies that D-dimer and fibrinogen values are increased in COVID-19 patients. This is considered a manifestation of disseminated coagulopathy and is considered to inform us about the severity and prevalence of COVID-19 [20]. In our study, in PCR-negative patients with CT findings, D-dimer values were significantly higher than in PCR- positive patients (1121.88 ng/mL vs 618.2 ng/mL, p <0.05). In negative patients, it was significantly higher than PCR positive (499.6 mg/dl vs 390.1 mg/dl, p <0.05). These findings show that COVID-19 disease is more common and more severe due to lung involvement.

Lymphopenia (absolute lymphocyte count is defined as <1.0×103/μL) is a frequently expected finding for COVID-19 infection and is observed in cases where the immunological response to the virus is reduced [19]. In our study, lymphopenia was more common in PCR-negative patients with CT findings (1.61×103/uL vs 1.72×103/uL, p <0.05). In a study conducted by Huang et al. on 41 patients, the rate of lymphopenia was found to be 63%, lung involvement was demonstrated by CT in all of these patients [21], and it was observed that this rate increased to 83% in patients requiring hospitalization [18]. Similarly, lymphopenia was observed more frequently in PCR-negative patients with CT findings in our study. This can be explained by the fact that the infection progressed more clinically. Lippi et al. reported in their study that more lymphopenia developed in patients who died due to COVID-19. Lymphopenia, CRP, D-dimer, prothrombin time, increases in troponin and creatine phosphokinase are considered to be poor prognostic factors [18].

In COVID-19 infection, the neutrophil count was found to be higher in PCR-negative patients with CT findings compared to PCR-positive patients (6.16×103/uL vs 4.08×103/uL, p<0.05). Studies have found that neutrophil counts increase in cases of bacterial superinfection [18]. In addition, MPV values used as one of the inflammatory markers are higher in PCR-negative patients with CT findings compared to PCR- positive patients (9.70/L vs 9.48/L, p <0.05). In a study conducted by Güçlü et al. on COVID-19 patients, it was found that the MPV values were high in these patients, and they even showed that an increase of 1 unit in MPV increased mortality by 1.76 times [22]. There are publications reporting that low eosinophil values may be observed in patients with COVID-19, and if these low values persist, the prognosis may be adversely affected [23]. In our study, we observed decreases in eosinophil counts in both groups, but we found that there was no significant difference in eosinophil counts between PCR-negative patients with CT findings and PCR-positive patients (0.106×103/ uL vs 0.063×103/uL, p> 0.05 ).

In our study, no significant difference was found in PDW values between PCR-negative patients with CT findings and PCR- positive patients (16.17 ratio vs 16.08 ratio, p> 0.05). Likewise, no significant difference was found between platelet counts (237.80 ×103/uL vs. 228.10×103/uL, p>0.05). It has been reported that thrombocytopenia may occur in severe COVID-19 infection [20]. In our study, platelet counts were within normal limits.

Conclusion

In our study, we found a high rate of deterioration of inflammatory signs and values related to coagulopathy in our PCR-negative patients with CT findings. This is due to the fact that COVID-19 disease has progressed clinically due to lung involvement in this group due to the diagnosis of CT involvement in all of our PCR-negative patient groups. Although the definitive diagnosis of the disease is made with the PCR test, it should not be overlooked that patients may remain PCR negative, and it should not be forgotten that thorax tomography findings are a good method for diagnosing this group.

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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Adem Durmaz, Duru Mıstanoğlu Özatağ. Comparison of PCR-negative patients with CT findings and PCR-positive COVID-19 patients. Ann Clin Anal Med 2022;13(1):25-29

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Short-term results in mid and low rectal cancer with laparoscopic and open surgery

Serdar Şenol 1, Servet Karagül 1, Oktay Karaköse 2

1 Department of Gastroenterological Surgery, 2 Department of Surgical Oncology, SBÜ Samsun Training and Research Hospital, Samsun, Turkey

DOI: 10.4328/ACAM.20827 Received: 2021-08-21 Accepted: 2021-10-07 Published Online: 2021-10-09 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):30-34

Corresponding Author: Serdar Şenol, Samsun Eğitim ve Araştırma Hastanesi, Gastroeneteroloji Cerrahi Kliniği, Samsun, Turkey. E-mail: serdarardaduru@gmail.com P: +90 362 315 15 00 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1193-1567

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Abstract

Aim: The aim of this study was to compare rectal cancer patients who underwent open and laparoscopic surgery in terms of their short-term surgical and oncological outcomes.

Material and Methods: We retrospectively evaluated data of 71 patients with mid and low rectal cancer who underwent elective curative laparoscopic and open total mesorectal excision between January 2017 and December 2019.

Results: The operative time was longer ( 192 min. vs 173 min., p=0.059), the estimated blood loss was less (75 ml vs 150 ml, p=0,03), and the length of incision was obviously shorter in the laparoscopy group ( 5 cm vs 18 cm, p=0.01). There was no mortality in any of the groups. The overall morbidity rate was 25% in the open group and 17.94% in the laparoscopy group (p=0.469). Revision surgery was needed in 9.38% of the patients in the open group, 12.8% in the laparoscopy group (p=0.648). In the laparoscopy group, the cause of revision surgery was anastomotic leak for all patients. The median lymph node number was higher in the laparoscopy group. There was no significant difference in terms of surgical margins, surgical methods, time of initiation of oral intake and first flatus, and hospital stay. During the follow-up period, 2 patients (6.25%) in the open group had a local recurrence, and five patients (12.8%) in the laparoscopy group had distant metastasis.

Discussion: Laparoscopic surgery is a safe and effective method that can be used in the treatment of mid-low rectal cancer.

Keywords: Laparoscopy, Morbidity, Mortality, Rectal Cancer, Total Mesorectal Excision

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Introduction

Rectal cancer is the second most common type of cancer in developed countries, with a male to female ratio of 2–3:1 [1]. Treatment for locally advanced rectal cancers is neoadjuvant chemoradiotherapy followed by radical surgery, including total mesorectal excision (TME). Laparoscopic surgery is steadily replacing open surgery because it involves less blood loss, smaller surgical incisions, faster recovery, and shorter hospital stay [2]. However, the adoption of laparoscopic surgery for rectal cancer has been slower due to the difficulty of pelvic dissection and resulting concerns about the ability to perform TME equivalent to open surgery [3]. The aim of this study was to compare short-term surgical and oncologic outcomes of patients who underwent open and laparoscopic surgery for the treatment of the mid and low rectal cancer.

Material and Methods

This retrospective study included rectal cancer patients who underwent surgery at the Department of Gastrointestinal Surgery and Surgical Oncology of Samsun Training and Research Hospital, from January 2017 to December 2019. Ethical approval for the study was obtained from the Samsun Training and Research Hospital Ethics Committee (no: 2019/3/8). We retrospectively evaluated data related to 71 patients who underwent elective curative laparoscopic or open total mesorectal surgery (TME). The laparoscopic and open surgery groups were evaluated in terms of age, sex, ASA score, body mass index (BMI), neoadjuvant chemoradiotherapy, history of abdominal surgery, anastomosis characteristics, preventive ostomy, pathological stage, rates of pathologic complete response after neoadjuvant therapy, evaluation of distal and circumferential resection margins, number of excised lymph nodes, operative time, intraoperative blood loss, time of initiation of oral intake, first defecation time, length of hospital stay, mortality, morbidity rates and causes, reoperation rate, median follow-up time, disease free survival, local recurrence, distant metastases.

Statistical Analysis

Data analysis was performed using the IBM SPSS Statistics version 21 (Armonk, NY, USA) package software. The normality of data distributions was evaluated using the Kolmogorov- Smirnov test. Since all data were nonnormally distributed, the median, minimum, and maximum values were used to summarize the data, and the Mann-Whitney U test was used for intergroup comparisons. Percentage values were compared between groups using the chi-square test.

Results

In this study, 71 patients were enrolled (32 patients in the open group and 39 patients in the laparoscopic group). Patient characteristics between groups are shown in Table-1. The groups showed no statistically significant differences in median age, sex, BMI, ASA score, previous abdominal surgery, neoadjuvant chemoradiotherapy.

Intraoperative and postoperative outcomes are shown in Table-2. There was no statistically significant difference between the groups in terms of surgical methods used. Although there was no difference between the groups, the rate of preventive ostomy was higher in the open surgery group, and surgery time was longer in the laparoscopy group. Estimated blood loss was less and length of incision was obviously shorter in the laparoscopic group (p=0.01). No significant difference was observed either in the time of initiation of oral intake or in the time of first flatus. There was no significant difference in median length of hospital stay. There was no mortality in any of the groups. The specific postoperative complication rate was 25% in the open surgery group [anastomotic leak, anastomotic stenosis, surgical site infection] and 17.94% in the laparoscopic surgery group [anastomotic leak, anastomotic stenosis, surgical site infection, pneumonia, pelvic abscess, evisceration]. In the open surgery group, 9.38% of the patients required revision surgery, the main reasons for which were anastomotic leakage and evisceration. This rate was 12.8% in the laparoscopic surgery group and the cause was anastomotic leak. The difference was not significant between the groups in reoperation rates or specific complications. All patients with anastomotic leak in our study were male, all had locally advanced rectal cancer, low anastomosis, and all but one received preoperative therapy. There was 1 patient in each group whose endoscopic polypectomy result was reported as invasive carcinoma with a positive surgical margin, but no tumor was detected upon examination of the main surgical specimen. In the open TME group, carcinoma in situ was detected in 2 patients. There were two stage 4 patients in each group, who underwent simultaneous open and laparoscopic liver metastasectomy. In the laparoscopic TME group, the rate of patients who received preoperative chemoradiotherapy was higher (48% vs. 36%). Based on whether they received preoperative chemotherapy, the results showed that within the group that received preoperative chemotherapy, patients who underwent open surgery had a higher rate of pathologic complete response, but the difference was not statistically significant. The median lymph node number was higher in the laparoscopy group. However, this difference was also not statistically significant. Within the subgroup that did not receive preoperative treatment, the lymph node number was again higher in the laparoscopy group. The difference was not statistically significant. CRM and DRM were negative in all patients in both groups (Table- 3).

The median follow-up time was 22 (6-36) months in the open group and 23 (6-36) months in the laparoscopic group. Median disease-free survival (DFS) was 26 (12-36) months in the open group and 24 (12-36) months in the laparoscopic group (p=0.98 ). During the follow-up, 3 patients in the open group and 4 patients in the laparoscopic group were lost. In the laparoscopic group, one patient died after 23 months in a traffic accident, and two patients died at 14 and 18 months due to disease. Three patients with liver metastases underwent metastasectomy at 17 and 18 months. Two of three patients, still alive had an overall survival (OS) of 23 months and the other 17 months. In the open group, one patient died at 10months and the other one died at 16 months due to acute cerebrovascular disease and pneumonia. Because of the local recurrence, two patients were operated at 12 and 4 months. They have been followed for 19 months and 32 months without any disease.

Discussion

Colorectal cancer is the third most common type of cancer worldwide and continues to be a major cause of morbidity and mortality. The use of minimally invasive surgical methods for the treatment of colon cancer has increased in recent years due to the growing evidence of equivalent short-term surgical and oncologic outcomes [3]. In our study, we aimed to assess our short-term surgical and oncological results for mid and low rectal cancer patients. At the same time, we aimed to evaluate overall and disease-free survival during the follow-up period. As noted in numerous studies [1,4-7], since the technique is more challenging to perform and surgeons have less experience in it, laparoscopic surgery is associatedwith a significantly longer operative times. In our study, the median operative time was longer in the laparoscopy group, although the difference was not statistically significant. Also, it has been reported [1,4,8] that operative time can be reduced as technical experience and the number of experienced surgeons increase. When our surgical results of the last year were compared with previous ones, it was seen that there was no significant difference between the median operative time [190 (120-240) min. vs193 (130-300) min, p =0,67] . This can be explained by the increasing complexity of cases and the natural difficulty of the technique of performing open or laparoscopic surgery. Despite its technical complexity, laparoscopic rectal cancer surgery may provide a more magnified view of the pelvic cavity compared to open surgery, which may facilitate resection of the mesorectum with a higher accuracy and greater ease [4]. According to our results, laparoscopic surgery provided significantly less blood loss, shorter length of incision. We believe that, especially in lower rectal cancers, the use of the laparoscopic approach facilitates intraoperative exploration, enables the detection and preservation of important anatomic structures, is associated with a smaller incision, less tissue damage, blood loss, which was also mentioned in different studies [1,4].

Although there was no significant difference in our study, complete regression rate (12-38%) after neoadjuvant chemoradiotherapy (nCRT) was higher in the open surgery group. Factors that predict pathologic complete response after nCRT in rectal cancers include different neoadjuvant therapeutic regimens [9-11], intervals between nCRT and surgery, histological type of tumor, signet ring cell histology, absence of circumferential involvement [9]. Due to the retrospective nature of our study and the application of preoperative medical treatments in different centers, possible reasons that might have an effect on the statistically insignificant difference in the open surgery group could not be evaluated.
In our study, the number of lymph nodes removed was higher in the laparoscopy group, both among patients who received and did not receive neoadjuvant therapy. Furthermore, no DRM (distal resection margin) or CRM (circumferential resection margin) involvement was detected in either group. This indicates that the higher number of lymph nodes removed from laparoscopic patients who received preoperative therapy cannot be completely explained by the relatively higher proportion of preoperative therapy and higher response rate in the open surgery group, and that laparoscopy does not have an adverse impact on short-term oncological outcomes. In a meta- analysis [2] comparing the short- and long-term outcomes of these surgical approaches after neoadjuvant therapy in rectal cancer, as well as in many articles comparing removed lymph nodes, CRM, DRM, it was reported that the outcomes were significantly better in the laparoscopic group [3] or were similar between the groups [2, 12-17].

At the same time, two randomized controlled studies [18,19] raised concerns about the oncologic equivalence of the groups. They were unable to demonstrate noninferiority of the laparoscopic method compared to the conventional method for locally advanced rectal cancer. This was attributed to the difficulty of performing rectal surgery in the pelvic space, which is deep and narrow, with straight, rigid instruments used in the laparoscopic method. It was stated that open surgery may be better for this difficult area [19,20]. Although our follow-up time was not enough to make a conclusion about long-term oncological results, during the follow-up, 2 patients (6.25%) in the OG had a local recurrence and five patients (12.8%) in the LG had distant metastasis. Laparoscopy effect on short-term oncological outcomes.
No significant difference was detected between the groups in terms of mortality, morbidity, and reoperation rates. The higher occurrence of anastomotic leaks in laparoscopic surgeries performed in the first 2 years may be attributed to experience. All patients with anastomotic leak in our study were male, all had locally advanced rectal cancer, low anastomosis, and all but one received preoperative therapy. Our results suggest that surgical experience, male gender, low anastomosis, locally advanced rectal cancer and preoperative therapy are factors that may increase the risk of anastomotic leak following laparoscopic rectal cancer surgery, as stated in different studies [21,22]. According to our results, especially in mid and lower rectal cancers, the use of the laparoscopic approach facilitates intraoperative exploration and enables the detection and preservation of important anatomic structures. This approach provides better surgical outcomes and does not have an adverse impact on short-term oncological outcomes, and also provides comparable results for surgical margins, local recurrence, and disease-free survival.

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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Serdar Şenol, Servet Karagül, Oktay Karaköse. Short-term results in mid and low rectal cancer with laparoscopic and open surgery. Ann Clin Anal Med 2022;13(1):30-34

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Comparison of the effectiveness of Bobath and Vojta techniques in babies with Down syndrome: Randomized controlled study

Erdogan Kavlak, Ayse Unal, Fatih Tekin, Ahmed Ahmed Hamood Al Sakkaf

Department of Neurological Rehabilitation, Pamukkale University, School of Physical Therapy and Rehabilitation, Denizli, Turkey

DOI: 10.4328/ACAM.20830 Received: 2021-09-03 Accepted: 2021-09-26 Published Online: 2021-09-29 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):35-39

Corresponding Author: Ayse Unal, Department of Neurological Rehabilitation, Pamukkale University, School of Physical Therapy and Rehabilitation, Denizli, Turkey. E-mail: pt.aunal@gmail.com P: +90 258 296 42 62 F: +90 258 296 44 94 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0959-5664

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Abstract

Aim: This study was performed to compare the effectiveness of two different early physiotherapy approaches in babies with Down syndrome (DS).

Material and Methods: A total of 23 babies with DS aged between 0-24 months were included in the study. The babies were randomly divided into two groups: the Bobath-therapy (BT) group included 12 babies (6 girls, 6 boys) and the Vojta-technique (VT) group included 11 babies (4 girls,7 boys). A total of 12 sessions of physiotherapy were applied to the babies twice a week for 6 weeks. All evaluations were done before and after therapy. The Alberta Infant Motor Scale (AIMS) was used for assessing motor development level of babies, the Beck Depression Scale (BDS) was used for assessing emotional status of mothers, and the Nottingham Health Profile (NHP) was used for assessing the quality of life of mothers of babies.

Results: Mean age of babies, AIMS, BDS and NHP scores were similar in both groups before the therapy (p>0.05). A significant improvement was detected in AIMS scores after therapy in both BT (p=0.001)and VT groups (p=0.001). The mean changes in the AIMS score between groups were 8.33±6.34 for BT, 7.27±3.46 for VT group (p>0.05). No statistically significant difference was detected between groups with regard to changes in AIMS (p=0.629), BDS (p=0.642) and NHP (p=0.726) scores.

Discussion: Early treatment methods, BT and VT approaches, both improved motor performance levels in infants with DS, as well as improved mothers’ emotional state and quality of life.

Keywords: Alberta, Down Syndrome, Infant, Mothers, Physical Therapy Modalities

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Introduction

Down syndrome(DS) which was first described in 1846 is characterized by 21st chromosome’s being three. Among all cases, 90-95% have regular type trisomy(47XX or XY+21), 4-6% have translocation(46XX) and 3-4% have mosaic type trisomy (47,+21). Likelihood of Down syndrome is reported in 1 in 600- 700 live births, depending on maternal age. This risk gradually increases after 35 years of age and reaches 2/70 in 40 years andabove[1].PhenotypeofDSischaracterizedbyintellectual impairment, short stature, heart diseases, digestive disorders and orthopedic anomalies accompanying with abnormal physical and neurological findings. Motor development of the children with DS trails that of peers beginning from early ages due to neurological disorders including hypotonia, delayed correction and balance reactions, reduction in velocity of the movements [2]. Therefore early intervention is of importance in cases with DS.Studies are available in literature proving the benefits of early intervention in children with DS [3,4]. Although various approaches are available which would facilitate motor development, increase muscle tone and develop balance of children with DS, Bobath therapy(BT) and Vojta technique(VT) are the most commonly used ones [5].

Vojta-based neuro-physiologic physiotherapy applications have begun between 1954 and 1969, and continued thereafter [5]. Many disorders of central and peripheral nervous system are effectively treated with this method besides the structural disorders of muscles and joints. The treatment method developed by Vojta was first used in treatment of the adolescents with cerebral palsy and in treatment of the babies with coordination disorder. VT has effects not only in motor development but also in whole body including vegetative and sensory-neural system [6].

BT which is among the most common treatment methods for developmental dysfunction was first used in treatment of the children with cerebral palsy(CP) and in treatment of many developmental disabilities including DS thereafter [7,8]. Bobath therapy is focused on normalization of hyper or hypotonic muscles, development of balance reactions and facilitation of movements [7].

Despite the presence of the studies investigating the effectiveness of Bobath and Vojta-based early intervention therapy in babies with DS separately, number of the studies comparing the effectiveness of these methods is insufficient. Only one study is available in literature during the recent 10 years [5].

We had two purposes in carrying out this study. The primary purpose of the present study was to compare the effectiveness of BT and VT on motor development of babies with DS aged 0- 24 months. As a reflection of the treatments, the secondary purpose was to investigated how the quality of life and emotional status of the mothers of the babies who received these treatments were affected.

Material and Methods

A total of 23 babies with DS aged between 0-2 years who met inclusion criteria were included in the study. Babies were randomized to two groups as BT(n=12) and VT(n=11). Inclusion criteria were being between 0 and 2 years, being diagnosed with DS and not having an additional neuro-motor disease. No cases were excluded as all 23 patients met inclusion criteria and completed treatment processes (Figure 1). Approval was obtained from Pamukkale University Ethics Committee of Non- interventional Clinical Researches prior to the study (approval number:60116787-020/66911). The study was registered at Clinical Trials.gov (NCT04536506;URL:www.clinicaltrials.gov). Measurements: Demographic data of the babies with DS(age,gender,history of surgery) and the mothers(age, education status etc.) were collected through a demographic data form. Alberta Infant Motor Scale (AIMS) was used for assessment of babies’ motor development performance. Emotional status of the mothers was evaluated by using Beck Depression Scale(BDS) and quality of life of the mothers was evaluated by using Nottingham Health Profile(NHP). All assessments were done before treatment and at the end of 6th week.

AIMS: AIMS is a tool which evaluates the infants from baby to independently walking children and measures delay in motor performance, enables families and clinicians to obtain data about motor performance of the infant,compares motor performance before and after therapy.The child is observed when performing spontaneous behaviors with a certain postural control.The scale measures weight transfer, posture and anti- gravity movements at supine, prone, sitting and standing positions with 58items. The child receives 1 point for the movements he/she can perform and 0 point for the ones that he/she cannot perform. It is a reliable test with norm reference and suitable for clinical use due to taking short time [9].

BDS: BDS is a scale used for evaluating emotional status of the mothers and it was arranged so as to include the symptoms of depression. Items of the scale were prepared based on clinical observations and data, not based on any hypothetical opinion. The Likert type scale is composed of 21symptom categories. Each symptom category is scored between 0 and 3 with the highest possible score of 63.Higher score indicates more severe depression [10].
NHP: NHP was used for assessment of quality of life of the mothers. This is a scale which is commonly used in clinical practice and includes 38 items that evaluate quality of life in 6 sections (pain,energy level, social isolation, emotional reaction, physical activity). Ratio of the “yes” answers is evaluated and each section is scored between 0 and 100 where 0 is the best and 100 is the worst score [11].

Interventions; Bobath Therapy (BT) and Vojta Technique (VT): A total of 23 cases were randomly allocated to two groups: BT and VT. Both groups received 45min of sessions twice weekly for 6weeks. BT was applied by the physiotherapists with minimum 5 years of experience. VT was applied by a Vojta therapist with 24 years of experience.

BT: An individual program was scheduled for each case following pre-assessment. It was targeted to enable normal posture, facilitation of corrective balance and protective responses and development of normal movement patterns [12]. Neuro-developmental techniques like approximation, taping and applying resistance to movements were used for increasing postural tone. Correction, balance and protective responses were facilitated at prone, supine, crawling, sitting and standing positions according to neuro-motor levels of the cases. Training for turning from prone to supine, from supine to prone position, reciprocal crawling and coming to sitting position by using trunk rotation were also given [13].

VT: Vojta proposes that postural reflex abnormalities that are present at newborn period may be corrected with VT and abnormal movement patterns may be exchanged with normal movement patterns. Same types of movements were detected to emerge by applying stimulus to certain points in newborns and spastic children. Vojta defined two main movements as “reflex crawling” and “reflex turning” [6]. VT is based on “reflex locomotion” and “forcing neural pathways”. The movements done in axial region of the body (trunk, head, thigh and shoulders) against resistance emerges as a special muscular energy that is spread to whole body.The kinesiologic content of the pattern usually shows organized and repetitive character depending on the initial position. These patterns are global reciprocal as in locomotion types like crawling and walking.The patterns of reflex locomotion are crawling and turning reflexes. Specific stimulation techniques like pressure and strain applied for 30-60 sec to specific points are used for facilitating these reflexes [6,14].

1.Reflex crawling, 2. First stage of reflex turning, 3. Second stage of reflex turning were used as treatment methods in VT. Main and auxiliary points were stimulated (pressure and strain) symmetrically in both sides of the body (right and left) [14]. Statistical analysis

We determined that 90% statistical power could be achieved with a 95% confidence level when at least 20 cases (at least 10 cases per group) participated in the study with a Cohen- classified effect size was 0.6 [5]. Data were analyzed by using SPSS 22.0 package program. Continuous variables were given as mean±standard deviation, categorical variables were given as number and percent. Normality distribution of the data was tested with Kolmogorov- Smirnov test. Independent sample

t test when parametric test assumptions were provided and Mann-Whitney U test when parametric test assumptions were not provided were used for comparison of independent groups. The paired sample t test when parametric test assumptions were provided and Wilcoxon paired sample test while the was used when parametric test assumptions were not provided were used in dependent group comparisons. The differences between categorical variables were analyzed using Chi-square test [15].

Results

A total of 23babies with DS were randomly allocated to two groups. Bobath therapy group consisted of 12 cases(5girls, 7boys) and Vojta technique group consisted of 11 cases(5 girls, 6 boys). Mean age was 13.50±7.22 months in BT group and 10.77±7.40 in VT group. Nine(75%) subjects in BT group and 8(72.7%) subjects in VT group had co-morbid conditions. Parents reported that 2(16.7%) subjects in BT group and 1(9.1%) subjects in VT group underwent surgery. Demographic and clinical characteristics of the patients are presented in Table 1.

Eight (66.7%) mothers in BT group and 8(72.7%) mothers in VT group were aged 35 years and above. While 6(50%) mothers were graduates of high school and 5(41.7%) mothers were graduates of elementary school in BT group, 4(36.4%) mothers were graduates of high school and 6(54.5%) mothers were graduates of elementary school in VT group. Demographic characteristics of the mothers are presented in Table 2.

Motor development (AIMS scores)

When pre-treatment AIMS scores were analyzed, mean score of BT group was 31.83±12.94 and mean score of VT group was 30.72±18.04. Groups were similar with regard to motor performance (p>0.05). When the change in motor performance was analyzed, statistically significant changes were detected after therapy both in BT (p=0.001) and VT groups(p=0.0001). When AIMS scores were compared at the end of the therapy, no difference was found between groups(p>0.05). In-group and inter-group comparisons of the groups with regard to motor performance levels are presented in Table 3.

Quality of life and emotional status of babies’ mothers

No difference was found between groups with regard to pre- treatment emotional status and quality of life of the mothers (p>0.05). When the changes in BDS and NHP scores were analyzed, statistically significant differences were detected in post-treatment BDS scores were compared to pre-treatment score both in BT group (p=0.002) and VT group (p=0.003). There was a difference between pre- and post-treatment results for NHP in both BT (p=0.018) and VT groups (p=0.018). When BDS and NHP scores were compared at the end of the therapy, no difference was found between groups(p>0.05).

Discussion

According to the results of our study which compares the effectiveness of BT and VT techniques that are applied as early intervention approaches in babies with DS, both BT and VT were found to improve motor performances of the children and thereby emotional status and quality of life of the mothers. Both approaches were detected to yield similar effects after therapy.

Many studies are available in literature investigating the effectiveness of early intervention approaches like various neuro-developmental treatment approaches, Vojta technique and sensory integration in children with DS [16-21]. Martinez and Garcia reported that physiotherapy methods that start in the early period and applied according to the requirements of the child with DS improve psychomotor development of the children [19]. The authors also emphasized the importance of family support for active participation of the child. In the study of Harris investigating the effect of BT on motor development of babies with DS, he divided the cases to two groups as BT group and control group [8]. While control group was provided only routine control, BT group was applied 3sessions of BT weekly during 9 weeks. The authors investigated development level by using Bayley Infant Development Scale and Peabody Motor Development Scale and reported that BT had a positive effect on motor development in cases with DS.

Malak et al. divided 79 patients with mean age of 6 years and 3 months into 3 groups as 0-3 years, 3-6 years and above 6years. All patients were applied one session of BT weekly during 2years and evaluated by using GMFM-88 and Motor Impairment Grading Scale, children in 0-3years were found to have a significant development in motor skills [20]. Similarly, Mahoney et al. applied BT 2sessions weekly during one year in a total of 50 patients (23 DS and 27 CP) with age of 14 months and detected that the cases with DS had improved motor development through Proportional Change Index [21]. Morais et al. reported that motivation and attention of the child also improved besides performance in children with DS [22]. In the study of Uyanık et al. comparing the effectiveness of various physiotherapy approaches in children with DS,they divided 45 children into 3 groups and applied sensory integration 3 days weekly for 3 months in Group 1, vestibular stimulation in addition to sensory integration in Group 2 and neuro- developmental treatment in Group 3. The authors concluded that these approaches were not superior to each other with regard to supporting motor development and the program should be arranged in accordance with the needs of the child [23].

In literature, only one study could be encountered comparing the effectiveness of BT and VT applied to babies with DS in the early period. However, not only babies with DS but also those with other nervous system pathology were included in this study.That study has revealed that both treatment approaches improved motor development in DS [5]. Consistently with literature, both BT and VT significantly improved motor skills of the cases following 6 weeks of treatment program as compared to pre-treatment skills. In addition to this study, we also questioned the quality of life and emotional status of mothers who care for babies.

Studies are available reporting that treatment approaches applied to children with DS had positive effects in emotional status of the family besides motor development of the children [18,24]. Shields et al. reported that participation of the family in physiotherapy applications improved the communication with the child and the family was affected positively during this period [24]. Our study has revealed that emotional status and quality of life of the mothers improved both after BT and VT. Our study is of importance for being a randomized controlled study comparing early intervention approaches in babies with DS. In conclusion, BT and VT were found to have similar effects with regard to development of motor skills in cases with DS below 2 years of age.

In conclusion, both BT and VT were found to be useful for developing motor skills and post-treatment effectiveness of the methods was found to be similar. They were also found to be effective for improving emotional status and quality of life of the mothers. The results of the study emphasize the importance of arranging treatment programs according to the needs of the children. And also, the present study is considered to contribute to literature which has limited reports concerning this issue. Our study will guide further studies. However, in order to fill the gap in the literature, further studies with larger sample sizes are needed to compare the effectiveness of different early intervention rehabilitation methods in DS babies.

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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Erdogan Kavlak, Ayse Unal, Fatih Tekin, Ahmed Ahmed Hamood Al Sakkaf. Comparison of the effectiveness of Bobath and Vojta techniques in babies with Down syndrome: Randomized controlled study. Ann Clin Anal Med 2022;13(1):35- 39

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How fentanyl and remifentanil affect neuromuscular block, intubation quality and hemodynamic response

Hızır Kazdal 1, Elif Bombacı 2, Neşe Aydın 3

1 Department of Anesthesiology and Reanimation, Faculty of Medicine, Recep Tayyip Erdoğan University, Rize, 2 Anesthesiology and Reanimation Clinic, Kartal Dr. Lütfi Kırdar Education and Research Hospital, İstanbul, 3 Anesthesiology and Reanimation Clinic, İstanbul Haydarpaşa Numune Education and Research Hospital, İstanbul, Turkey

DOI: 10.4328/ACAM.20832 Received: 2021-09-12 Accepted: 2021-10-04 Published Online: 2021-10-15 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):40-44

Corresponding Author: Hızır Kazdal, Department of Anesthesiology and Reanimation, Recep Tayyip Erdoğan University, Faculty of Medicine, İslampaşa Mah. Şehitler Cad., 53020, Merkez, Rize, Turkey. E-mail: hizir.kazdal@erdogan.edu.tr P: +90 505 474 53 54 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0759-4716

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Aim: Opioids suppress noxious autonomic reflexes and affect multiple parameters such as heart rate and blood pressure. The objective of this study was to compare the effects of fentanyl and remifentanil on hemodynamic changes, neuromuscular blockade and the quality of intubation.

Material and Method: Sixty patients were divided into three groups as remifentanil, fentanyl, and a control group. Patients’ demographics and hemodynamic parameters were measured before anesthesia induction, immediately after induction, before intubation, immediately after intubation and at 3 minutes and 5 minutes after intubation and compared between the groups. In addition, intubation and side effects were also analyzed.

Results: The mean SBP was remarkably lower in the remifentanil group checked against both fentanyl and control groups after induction and 5 minutes after intubation (for both, p<0.05). The mean DBP and MAP and HR values were statistically notably lower in the remifentanil group after induction, before and after intubation and at 3 and 5 minutes (for all p<0.05). Excellent-good intubation quality was succeeded in 17 (85%) patients in the remifentanil group and in 16 (80%) patients in the fentanyl group, with no notable difference between them.

Discussion: Opioids increase the quality of intubation and suppress the undesirable hemodynamic response to intubation by blocking the central integration of sensory pathways without affecting neuromuscular conduction. The administration of remifentanil as a 1.5 μg/kg bolus followed by a 0.3 μg/kg/min infusion was more effective in controlling the undesired hemodynamic responses induced by tracheal intubation and laryngoscopy.

Keywords: Fentanyl, General Anesthesia, Intubation, Laryngoscopy, Remifentanil

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Introduction

The vast majority of patients undergoing surgery under general anesthesia require intubation and laryngoscopy as mandatory processes. Physiopathological changes such as reflex increased in blood pressure, heart, rate and serum catecholamine concentration observed following endotracheal intubation are of paramount importance in anesthesia induction [1, 2]. These changes are thought to be due to the stimulation of tracheal and laryngeal tissues during the procedure [3]. Tachycardia and transient hypertension are commonly associated with tracheal intubation and laryngoscopy [4]. Tachycardia and hypertension may be insignificant in healthy persons, but are crucial, especially in patients with increased intracranial pressure and ischemic heart disease. Studies have stated the relationship between post-intubation hypertension and poor outcomes [5]. In addition, in susceptible individuals, these hemodynamic and catecholamine responses may result in morbidity, including myocardial infarction, cerebrovascular events, and acute heart failure [6].

Several approaches have been used to prevent hemodynamic and catecholamine stress responses due to endotracheal intubation and laryngoscopy, including intravenous and topical administration of lidocaine, the use of beta-adrenergic blockers, direct-acting vasodilators, inhalation agents and opioids [2, 7, 8]. Opioids are the most prevalent agents for antinociception during general and have been shown to suppress noxious autonomic reflexes and to affect multiple parameters such as electrocardiogram, respiratory rate, blood pressure and heart rate, [9].

Neuromuscular blockade facilitates endotracheal intubation and provides muscle relaxation required for general anesthesia in certain surgical operations. However, the best intubation conditions should be provided for the quality of muscle relaxation, especially in several conditions, including patients with severe liver, kidney and heart disease, and extreme ages that may lead to pharmacodynamic changes [10]. Peripheral nerve stimulation is commonly used to specify the degree of the neuromuscular blockade through tactile and visual assessment. When peripheral nerve stimulation is used, mortality and morbidity rates have been significantly reduced since the desired degree of neuromuscular blockade can be obtained. The objective of our study was to compare the effects of fentanyl and remifentanil on neuromuscular blockade provided by cisatracurium, hemodynamic changes induced by intubation and the quality of intubation.

Material and Methods

Study population

The study included 60 patients aged 18-65 years with ASA I-II status who were scheduled for elective operation under general anesthesia in the operating rooms of our hospital. Patients with cardiovascular, pulmonary, hepatic, renal, neuropsychiatric and endocrine diseases, pregnant and breastfeeding patients, substance users, those with atopic structure and difficult intubation and patients with a weight >35% or <20% of the ideal weight were excluded.

Data Collection

Patients’ demographic data such as gender, weight and age were recorded. Mean arterial pressure (MAP), oxygen saturation (SpO2), diastolic blood pressure (DBP), systolic blood pressure (SBP), heart rate (HR) values were measured before anesthesia induction (pre-induction), immediately after induction and before administration of cisatracurium (post-induction), before intubation (pre-intubation), immediately after intubation (post- intubation), 3 minutes and 5 minutes after intubation. Drug side effects such as hypotension (SBP<80 mmHg), arrhythmias, bradycardia (HR< 45 bpm), apnea (cessation of breathing for 15 seconds or longer), skin rash and muscle rigidity were also recorded.

Anesthesia Management

The routine monitoring was performed with ECG and non- invasive measurement of DBP, SBP, SpO2, HR and MAP. Neuromuscular monitoring was carried out with TOF-Watch® SX device (Organon Ltd.,Ireland). Two surface electrodes were placed on the right wrist for ulnar nerve stimulation. The distal electrode was placed 1 cm proximal to the wrist flexion, and the proximal electrode was placed 2-3 cm adjacent to the distal electrode. The negative output of the monitoring device was connected to the distal, and the positive output to the proximal electrode. An acceleration transducer, which will evaluate the adduction response of the thumb to the ulnar nerve stimulus, was placed on the large surface of the thumb with a plaster. The grade of neuromuscular block at the time of intubation (%), time to T1 90% suppression level (sec), maximum block (effect) onset time (sec) (T1 95%) and time to the maximum (complete) block (T1 100%) were measured and recorded.

The patients were randomly divided into three groups as remifentanil, fentanyl, and control groups. The remifentanil group was administered a bolus dose of 1.5 μg/kg in 30 seconds followed by 0.3 μg/kg/min infusion. The fentanyl group received a bolus dose of 3 μg/kg for 30 seconds, while the control group was given 10 mL of normal saline. After waiting for 20 seconds, thiopental sodium was given to all 3 groups at a dose of 5 mg/ kg within 45 seconds until the eyelash reflex disappeared. The peripheral nerve stimulator was calibrated with a single 1 Hz stimulus, and supramaximal stimulus threshold was detected. Cisatracurium at a dose of 0.15 mg/kg was applied within 5-10 seconds, 30 seconds after the administration of thiopental. The timer was then reset and the stimulator was operated in a single stimulus mode with a frequency of 0.1 Hz. After 120 seconds, the level of neuromuscular block was determined as a percentage, and the intubation was performed and evaluated within 10 seconds by another experienced anesthetist who was unaware of the groups. The quality of intubation was evaluated as excellent (easy tube passage without coughing, vocal folds relaxed and in abduction position), good (tube passage with mild coughing and/or resistance, vocal folds relaxed and in abduction position), poor (tube passage with moderate cough and/or resistance, vocal folds in moderate adduction position) or impossible (vocal cords in tight adduction position) as described by Viby-Mogensen et al. [11].

The breathing of the patients was supported with 100% oxygen during the induction phase. Controlled breathing was provided with 50% oxygen + 50% nitrous oxide within the first 5 minutes following intubation. Anesthesia was maintained with appropriate agents and the surgical intervention was started after 5 minutes.

Ethical Consideration

The study protocol was authorized by our hospital’s local committee before the start of the study. We would like to state that our study was carried out in accordance with the ethical principles of the Helsinki Declaration.

Statistical Analysis

We used SPSS version 20.0 (Statistical Package for Social Sciences, USA) to analyze the data collected during the study. To analyze the normality of the variables, the Kolmogorov- Smirnov test was used. One-way ANOVA, Mann-Whitney U test and independent sample t-tests were used for comparing normally distributed continuous variables, and the Kruskal- Wallis test for comparing the non-normally distributed variables between the groups, while Chi-square and Fisher Exact tests were used to compare categorical variables. Mean±standard deviation expression was used to express continuous variables and categorical variables as frequency and percentage, p<0.05 values were considered statistically notable.

Results

Sixty patients were randomly assigned to three groups (Remifentanil, Fentanyl, Control) with 20 patients in each. The mean age of the patients was 39.42±10.50 years. The mean age was 43.85±8.97 years in the remifentanil, 38.4±12.33 years in the fentanyl, and 36.00±10.19 years in the control group. The mean weight of the patients was found as 69.15±9.95 kg. The mean weight was 67.30±9.24 kg in the remifentanil, 69.90±9.18 kg in the fentanyl and 70.25±11.42 kg in the control group. No remarkable difference was found between the groups in terms of gender, age and weight (for all p>0.05).

No statistically notable difference between the groups when it comes to the levels of neuromuscular block at the time of intubation, time to T1 90% suppression level, maximum block (effect) onset time (T1 95%) and time to the complete block (T1 100%) (for all p>0.05). The neuromuscular blockade levels of the groups at different time points are given in Table 1.

No statistically notable difference was found in mean pre- induction SBP values between the three groups (for all p>0.05). The mean SBP was notably lower in the remifentanil group compared to both fentanyl and control groups post-induction and at 5 minutes after the intubation (for both, p<0.05). The lowest SBP values were found in the remifentanil group immediately post-induction, pre-intubation, immediately post- intubation, and at 3 and 5 minutes.
The mean DBP was statistically remarkably lower in the remifentanil group in comparison with both fentanyl and control groups immediately post-induction, pre-intubation, right after post-intubation, and at 3 and 5 minutes after intubation (for all p<0.05). The mean DBP values were remarkably lower in the fentanyl group compared to the controls in the measurements made at 3 and 5 minutes (both p<0.05). Systolic and diastolic blood pressure values over time according to the groups are expressed in Figure 1.

Statistically speaking, no significant difference was found between the three groups in terms of mean HR (for all, p>0.05). The mean HR was notably lower in the remifentanil group compared to other groups post-intubation (p<0.001), compared to the fentanyl group post-induction (p<0.05), and pre-intubation and compared to the control group at 3 (p<0.001) and 5 minutes (p<0.01). The mean HR value was notably lower in the fentanyl group compared to the controls at 3 and 5 minutes (both p<0.05) (Figure 3). The measurements of the SpO2 were similar in all groups at all time intervals (for all, p>0.05).

Accordingly, excellent-good intubation quality was achieved in 17 (85%) patients in the remifentanil group and in 16 (80%) patients in the fentanyl group. The disparity between these two groups was not statistically significant (p=0.904). Whereas impossible intubation was not observed in the remifentanil and fentanyl groups, 25% (n=5) of the intubations were assessed as impossible in the control group, and the disparity was significant compared to both the remifentanil (p=0.026) and control (p=0.047) groups.

When the side effects of the drugs were evaluated; three (15%) of the patients in the remifentanil group developed hypotension, while neither of the patients in this group developed bradycardia. Three (15%) patients in the remifentanil group and one (15%) patient in the fentanyl group developed apnea. Skin rash was observed in one (5%) patient in the control group, while muscle rigidity was seen in two (10%) patients in the fentanyl group.

Discussion

The use of intravenous opioids for anesthetic induction and neuromuscular monitoring has been reported to alleviate hemodynamic stress responses, including hypertension and tachycardia during general anesthesia [9, 12-14]. In our study, we compared the effects of remifentanil and fentanyl on the neuromuscular block induced by cisatracurium via peripheral nerve stimulation, hemodynamic changes and the quality of intubation.

De Kort et al. performed intubation using propofol 1-2 mg/kg as premedication and obtained good intubation in 85% and inadequate intubation in 15% of patients [15]. Karaman et al., provided excellent intubation in 19/20 (95%) of patients with fentanyl using the Viby-Mogensen score as in our study [16]. Abdelhalim et al. reported that 2 μg/kg fentanyl followed by 3 mg/kg propofol provided a higher rate of excellent intubation compared with 2 μg/kg fentanyl followed by 2 mg/kg propofol [17]. In our study, we used cisatracurium as a neuromuscular relaxation agent. Svalingam et al., obtained excellent intubation in 64%, good intubation in 32% and poor intubation in 4% of the patients with alfentanil 10 μg/Kg and suxamethonium 1 mg/Kg, without using muscle relaxant [18]. Although studies have been reported different rates of intubation quality,, high rates of excellent-good intubation indicate the benefits of using opioids for improving the quality of intubation.

Barclay et al. compared bolus doses of 1 μg/kg, 2 μg/kg and 4 μg/kg of remifentanil in a placebo-controlled study in preventing hemodynamic response to intubation [19]. They used propofol as a hypnotic agent and cisatracurium at a dose of 0.15 mg/ kg as a muscle relaxant during induction. They found that the 2 μg/kg dose of remifentanil completely suppressed the hemodynamic response to intubation, while the increased dose of 4 μg/kg did not provide any additional benefit, and node of the patients developed complications such as bradycardia, tachycardia, hypotension or hypertension [19]. The results of this study are in parallel with our findings.

Lee et al. reported significant decreases in SBP post-intubation compared to pre-induction with the use of remifentanil (p<0.001) [20]. A number of studies published in peer-reviewed journals have compared the effects of remifentanil and other agents on hemodynamic responses induced during general anesthesia. Habib et al. compared remifentanil bolus (0.5 over 30 seconds) followed by an infusion (0.1 μg//Kg/min) with alfentanil bolus (10 μg/kg over 30 seconds), and both regimens effectively suppressed the hemodynamic response to laryngoscopy and intubation [21]. Sezen et al. lowered blood pressure and heart rate through administration of remifentanil plus desflurane [22]. Tuncel et al. compared remifentanil and alfentanil infusions in abdominal surgery and reported that remifentanil better controlled intraoperative hemodynamic responses [23]. On the other hand, Farzi et al. found no notable difference between remifentanil and fentanyl in terms of hemodynamic parameters [24]. Although results of studies can significantly differ due to several factors, such as the opioids to be compared, other agents used for premedication and presence of neuromuscular relaxation. However, the results of our study and other studies usually indicate a marked superiority of remifentanil in terms of hemodynamic responses, including HR and blood pressure values.

Study Limitations

The main limitations of this study are that the study was carried out in a single center and the number of participants was relatively low. Nevertheless, we feel that the results we acquired will contribute to the existing literature on the effects of using opioids on hemodynamic responses induced by anesthesia induction.

Conclusion

The findings of our study showed that opioids increase the quality of intubation and suppress the undesirable hemodynamic response to intubation by blocking the central integration of sensory pathways without affecting neuromuscular conduction. The administration of remifentanyl as a 1.5 μg/kg bolus followed by a 0.3 μg/kg/min infusion did not provide a significant advantage in improving the quality of intubation compared to a 3 μg/kg bolus dose of fentanyl, but remifentanyl was more effective in controlling undesirable hemodynamic responses to laryngoscopy and tracheal intubation and therefore, it is worthy of promotion in clinical practice.

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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Hızır Kazdal, Elif Bombacı, Neşe Aydın. How fentanyl and remifentanyl affect neuromuscular block, intubation quality and hemodynamic response. Ann Clin Anal Med 2022;13(1):40-44

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Are tyrosine kinase inhibitors as effective as they are safe in renal cell cancer patients over the age of 65?

Arife Ulas 1, Fahriye Tugba Kos 2, Didem Sener Dede 3, Bulent Yalcin 3

1 Department of Medical Oncology, University of Health Sciences, Bursa City Education and Research Hospital, Bursa, 2 Department of Medical Oncology, University of Health Sciences, Ankara City Education and Research Hospital, Ankara, 3 Department of Medical Oncology, Yildirim Beyazit University, Faculty of Medicine, Ankara, Turkey

DOI: 10.4328/ACAM.20833 Received: 2021-08-28 Accepted: 2021-10-14 Published Online: 2021-10-24 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):45-49

Corresponding Author: Arife Ulas, Bursa City Education and Research Hospital, Dogankoy, 16110, Nilüfer, Bursa, Turkey. E-mail: drarifeulas@hotmail.com P: +90 505 251 96 23 Fax: +90 224 975 00 00 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2918-2592

Abstract
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Abstract

Aim: In the present study, we aimed to compare clinicopathological characteristics and survival results of young and elderly patients with renal cell cancer (RCC).

Material and Methods: Patients 65 years of age or older were classified into the elderly age group, while all others were classified into the younger age group. To determine the correlation between clinical and pathological parameters, the chi-square test or Fisher’s exact test was used. The Kaplan–Meier method was utilized to analyze the survival rate.

Results: The median duration of follow-up was 24 (1.0-240.0) months. In young patients, the median survival was found to be 51.0 (95% CI 20.7-81.2) months, while it was 26.0 (95% CI 6.4-45.6) months in the group of elderly patients (p=0.03). The median progression-free survival (PFS) was calculated to be 25.0 months (95% CI 18.5-31.4) in young patients, while it was 8.0 (95% CI 4.6-11.3) months in elderly patients (p = 0.02). No significant difference was found between groups in terms of clinicopathological characteristics and data on treatment side effects (p <0.05).

Discussion: Although there is no significant difference between the two groups of ECC patients in terms of clinicopathological characteristics, overall survival may be shorter in the elderly patient group due to the age factor. However, in the elderly group, PFS was found to be lower despite the use of TKI, which suggests that these drugs are not as effective in elderly patients as in younger patients in spite of the ease of oral intake and a safe side effect profile. Further studies, which will be carried out with elderly patients, may clarify this issue.

Keywords: Renal Cell Cancer, Elderly Patients, Tyrosine Kinase Inhibitors

Full Text

Introduction

Renal cell cancer (RCC) is commonly a disease of elderly patients, and its incidence is strongly associated with age. According to SEER data, 49% of patients with RCC were reported to be 65 years of age or over [1]. By 2030, the majority of the population will be over 65 years of age, and hence a decrease can be expected in the incidence of metastatic RCC in elderly patients [2].

Since aging is a natural process when natural physiological reserves are depleted, vulnerability and impairment of homeostatic balance results in a more rapidly progressive pathological condition and leads to serious health problems [3,4]. The treatment process of elderly patients diagnosed with cancer is more complex than that of younger patients. It has been stated that causes of high mortality in elderly patients include high incidence, inadequate antineoplastic treatment, decrease in organ functions, insufficient treatment tolerance, reduction in stem cell reserve and repairability and underutilization of protective methods [5,6]. Decreased PFS and the presence of comorbidites in elderly patients have led to their underrepresentation in clinical studies. Therefore, suggestions on the treatment of elderly patients with mRCC are usually based upon the data obtained from young patients enrolled in these studies, which may not be optimal for elderly patients, as many elderly patients are fragile, have age- associated organ dysfunction and have more than one medical comorbidity [7,8].

Within the last decade, the median survival of mRCC has increased to over 36 months with the approval of more than ten targeted treatments and immune checkpoint inhibitors [9]. These advances in treatment have indicated that metastatic renal cells carcinoma is a disease with the potential of being chronic and can be cured with the simultaneous and sequential employment of agents, which have varying mechanisms of action and toxic effects. Yet, as elderly patients are underrepresented in clinical studies, there is still a paucity of information on the benefits and toxic effects of these drugs. Therefore, we have yet to understand how to reach treatment targets in elderly patients, and hence selections of treatments and their sequence create a particular challenge for clinicians. Considering the growth in the elderly population all over the world, both the rate and the absolute number of patients having the disease will increase. Therefore, it is important to take into consideration the problems specific to the management of elderly patients. The aim of the present study was to analyze and evaluate the clinical characteristics, survival outcome, sunitinib treatment efficacy and toxicity data in young and elderly patients followed in our clinic.

Material and Methods

The present study retrospectively evaluated 100 patients followed and treated with the diagnosis of RCC in Medical Oncology clinic of Yıldırım Beyazıt University, Ankara Ataturk Training and Investigation Hospital between 2005-2014. The data of 100 patients included in the study were retrieved from patient files and recorded. The study was approved by the ethics committee of the Ankara Ataturk Training and Investigation Hospital.

Demographic characteristics of patients, presenting symptoms, ECOG performance status, smoking history, diseases, diagnostic method, histopathological characteristics and laboratory findings were recorded. Surgical treatment, cytokine treatment, tyrosine kinase inhibitors (sunitinib, sorafenib, pazopanib), other treatment modalities and survival outcomes were evaluated. The development of toxicity during treatment and dose alterations were recorded. Patients were staged according to the TNM criteria [10]. to Treatment response was assessed according to the RECIST (Response Evaluation Criteria in Solid Tumors) criteria, and side effects were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (Aes) version 4.0 (Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. May 28, 2009. Department of Health and Human Services; National Institutes of Health; National Cancer Institute. 2010; 14:3-4) [11]. Risk factors associated with shorter survival were evaluated according to the Memorial Sloan Kettering Cancer Center (MSKCC) risk classification [12].

Patients 65 years of age or older were classified into the elderly age group, while all others were classified into the younger age group. Overall survival (OS) was defined as the time from the date of diagnosis to death or final evaluation of the patient in the clinic. Disease-free survival (DFS) was defined as the time from the date of operation to the development of local recurrence or distant metastasis (months); and progression- free survival (PFS) was defined as the time from the onset of treatment to disease progression or development of distant metastases.

Statistical analysis

The data were analyzed with the SPSS 15.0 software program. Fisher and Chi-Square tests were used for nominal variables and numerical data. . The Kaplan–Meier method was utilized to assess survival rates, and comparisons were made with the log-rank test. Uni and multivariate analyses were performed with the Cox regression model. A p value <0.05 was considered statistically significant.

Results

Patient characteristics

The present study included 100 RCC patients with complete data. Patients were stratified into the young age group (≤65) and the elderly group (>65). The overall median age was 62 years (25.0-89.0), and 40% were over 65 years old. The median age was 71 years (66-89) in the elderly patient group, while it was 54 years (25-65) in the young patient group. The median follow-up period was 28.0 (2.0-240.0) months in young patients, while it was 20.5 (1.0-196.0) months in the elderly patient group.

The male/female ratio in patients was found to be 2.1. The number of patients at ECOG stage 0-1 was 87. The most common complaints at diagnosis were flank pain (31%) and hematuria (16%); 64.0 % of patients underwent radical nephrectomy, while 7% underwent partial nephrectomy. The number of patients diagnosed with biopsy was 28. In histopathological evaluation, 84 patients had clear cell and 16 patients had nonclear cell histology. The majority of the patients were at stage IV (55.0%). The most common sites of distant metastases were lungs (34%), bones (28%), and liver (14% ). Eleven patients underwent metastasectomy, of which, 4 patients underwent metastasectomy for lung metastasis, 3 for brain metastasis, 3 for surrenal gland metastasis and 1 for bone metastasis. According to the MSKCC criteria, 33 patients were in the favorable risk group, 36 in the medium and 31 in the unfavorable risk group.
No significant difference was found between the two patient groups with regard to clinicopathological characteristics, and hematological and biochemical parameters (P>0.05) (Table 1)

Treatment

Interferon treatment was given to 62 % of the patients. The number of patients receiving TKI after IFN was 49. Of these, 43 received sunitinib, 5 pazopanib and 1 sorafenib. Their mean age was 63 (27-78) years, with 67.4 % at the age of 65 or below. Patients taking sunitinib received a mean of 6.0 cures (1.0- 45.0) of treatment. During sunitinib treatment, the dose was reduced in 53.8% of patients and treatment was interrupted in 36.6%. The overall response rate was 68% and 53.8%, respectively in young and elderly patients, with no statistically significant difference (p=0.39).
Among side effects, hypothyroidism requiring treatment occurred in 30% of patients. Grade 3-4 toxicities included fatigue (34.9 %), anemia (27.9 %), rash on skin (16.3%), mucositis (18.8%), hand and foot syndrome (13.6%), neutropenia (7.0 %) and hypertension (4.6%). No significant difference was found between the two groups with regard to hypothyroidism (P=0.73) and other toxicities (P= 0.79) (Table 1). The rate of discontinuation of treatment due to adverse events was found to be similar in the two groups.

Survival

The median duration of follow-up was 24.0 months (1.0-240.0). During the follow-up period, 34 (56.7%) patients died in the young patients group, while 34 (85.0 %) patients died in the elderly group. The median overall survival was 51.0 (95% CI 20.7-81.2) months in the young patient group, while it was 26.0 (95% CI 6.4-45.6) months in the elderly group (p=0.03) (Figure 1). The median progression-free survival was 25.0 (95% CI 18.5-31.4) months in the former group, while it was 8.0 (95% CI 4.6-11.3) months in the latter group (p=0.02) (Figure 2).
In patients who received Sunitinib, the median GS was 30.0 months (95% CI 17.9-42.0), and the median PFS was 15 months (95% CI 3.4-26.6 ). During TKI use, disease progression occurred in 12 (44.4% ) patients in the young patient group, and in 10 (66.7%) patients in the elderly patient group. In young patients using sunitinib, mean PFS was 16 (95% CI 4.4- 28.6 ) months, while OS was 33.0 (95% CI 5.19-46.1) months. In elderly patients using Sunitinib, PFS was 7.0 (95% CI 4.1- 9.8) months, while OS was 21.0 (95% CI 2.6-39.3) months. In patients who received Sunitinib according to the MSKCC ( for sunitinib) criteria, in favorable, medium and unfavorable patients, median OS was respectively 102.0, 36.0 and 17.0 months (p<0.0001). In the above mentioned patients, median PFS was respectively 45.0 months (95% CI 1-99.3), 15.0 months (95% CI 1-33.9) and 6 months (95% CI 1.5-11.4) (p=0.05).

Discussion

In the present study, outcomes of an unselected patient population we followed in our daily practice were evaluated. In this retrospective study, it was established that improvement was obtained in survival in RCC carcinoma patients followed in a single center within a decade with the administration of TKIs following cytokine treatment. However, it was established that in elderly patients, OS and PFS were shorter than that in younger patients in spite of TKI treatment. In addition, no difference was found between the two groups in terms of toxicity patterns, which were tolerable in both.

The risk of toxicity and comorbidities are the most important factors in treatment selection in this elderly patient group. In the present study, in elderly individuals administered targeted treatment, treatment-associated toxicity, rates of serious toxicity, and therefore discontinuation of treatment were found to be similar to those in young patients. Likewise, in some previous studies, similar efficacy and tolerability rates were found in young and elderly patients [13,14]. In a metaanalysis, including six studies, the side effect profile was found to be comparable in young and old patients. However, side the effect profile was demonstrated to be higher than in earlier studies [13]. In a study performed with Japanese patients, the initial dose of sunitinib was maintained without cessation, and the importance of genetic alterations in sunitinib metabolism was emphasized [15]. In another Japanese study, the rate of treatment-associated toxicity, especially hematological one, was found to be very high in elderly patients, and accordingly, dose modification was carried out [16]. Maintaining adequate dose levels during the treatment process is the most important condition for treatment response [17,18]. The individualization of treatment in this manner may lead to marked changes in survival.

There are many additional factors influencing efficacy and toxicity in elderly patients; i.e. performance status, polypharmacy, nutrition, cognitive functions and socioeconomic status [19]. Various studies have indicated that immunological and genomic changes associated with aging may contribute to the pathogenesis of cancer and influence the efficacy of anti-cancer treatments [20]. These observations have revealed that some differences in the pharmacokinetics of anticancer treatment may partially contribute to the outcome of treatment. In the present study, when the overall study population was considered, the median OS and PFS were found to be higher compared to previous clinical studies. Yet, in the elderly patient group, OS and PFS were found to be shorter in spite of TKI treatment. In some studies, it has been suggested that elderly patients may respond better to sunitinib treatment [21,22]. In a study on tumor biopsies in RCC, an age-associated difference has been demonstrated in tumor vascularity, and it was shown that patients with clear cell tumors ≥ 65 years of age had a higher microvascular tumor density compared to patients <65 years of age. In addition, the activity of angiogenic markers was found to be different as well. In order to explain this, it was proposed that patients with higher vessel microvascularity may respond better to treatment, or density of vessels may be inversely proportional to tumor aggressiveness [21,22].

It has been observed that the prognosis gets better consistently in elderly patients, and the number of patients receiving both first line and second-line treatment is increasing. Recently, in randomized controlled studies on patients using (immune checkpoint inhibitors, ICIs) inhibitors and combination regimens, their efficacy has been demonstrated [23,24].

We believe that our low number of patients and the fact that majority of these patients were in the medium and low-risk group may have contributed to these results. The difference in the results of clinical studies may be due to differences in patient selection and duration and dose intensity of sunitinib treatment. However, as the current study was retrospective, dose intensity and detailed drug interactions could not be evaluated. Comorbidities increasing with age, low-performance level, and multidrug combinations may create problems in management. In elderly patients with RCC, it is important to informpatients about drug efficacy and treatment tolerance. Limitations of the present study include retrospective nature, small sample size, and inclusion of a heterogeneous population (stage, age, PFS, and metastatic site). Furthermore, it did not include immunotherapy-based therapies, which are currently standard treatments for mRCC, which is another limitation. The present study was carried out on a patient population followed in a single cancer treatment center, with homogenous treatment approaches and reference values for laboratory data, which may be considered a partial advantage. In addition, response evaluation was made with the same methods and similar approaches were used in side effect management, which is a further advantage.

In the near future, improvement in prognosis can be expected, especially with increased and longer-term use of ICI’s. It may also be hoped that better-individualized treatment strategies may be developed for elderly patients by the determination of key molecules via gene sequencing apart from conventional predictive factors determining the efficacy of drugs and prognosis in association with comorbidities.

Our results may be significant as they may guide clinicians and help predict prognosis, and monitorize treatment toxicity. In conclusion, in elderly patients with mRCC, it is important to describe the clinical determinants of outcome. Therefore, inclusion of elderly patients in studies at a higher rate and reporting of results stratified by age is necessary.

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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Arife Ulas, Fahriye Tugba Kos, Didem Sener Dede, Bulent Yalcin. Are tyrosine kinase inhibitors as effective as they are safe in renal cell cancer patients over the age of 65? Ann Clin Anal Med 2022;13(1):45-49

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The efficiency of transdermal oxygen wound therapy in lower extremity venous ulcers

Ozgur Altinbas 1, Mehmet Orkun Sahsivar 2

1 Department of Operating Room Services, Gaziantep University, Vocational School of Health Services, Gaziantep, 2 Department of Cardiovascular Surgery, Izmir Dr. Suat Seren Chest Diseases and Surgery Training and Research Hospital, Izmir, Turkey

DOI: 10.4328/ACAM.20835 Received: 2021-08-29 Accepted: 2021-09-28 Published Online: 2021-10-05 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):50-53

Corresponding Author: Ozgur Altinbas, Department of Operating Room Services, Gaziantep University, Vocational School of Health Services, Gaziantep, Turkey. E-mail: ozgur_altinbas@yahoo.com P: +90 505 657 05 77 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6819-2454

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Abstract

Aim: Despite improved healthcare quality and technological facilities, chronic venous ulcer is still an important health challenge all over the world. Although different treatment modalities are being used, the results are not satisfactory in many patients. The purpose of this study is to evaluate the efficiency of transdermal oxygen wound therapy in patients with lower extremity chronic venous ulcer due to deep venous insufficiency.

Material and Methods: Sixty-four patients with chronic venous ulcer related to deep venous insufficiency were enrolled in the study between 2017 and 2019. The patients were divided into two groups. Group 1 was the control group and received routine wound therapy, and Group 2 was the experimental group and received transdermal oxygen therapy additional to routine therapy. The status of the wound was evaluated between the groups.

Results: The number of patients with complete wound healing in the experimental group was statistically significantly higher than in the control group. In addition, the total mean area of the wound in the experimental group was significantly lower than in the control group.

Discussion: Transdermal wound oxygen therapy is an efficient treatment modality for patients with lower extremity chronic venous ulcers related to venous insufficiency.

Keywords: Transdermal Oxygen Therapy, Venous Insufficiency, Venous Ulcer, Wound

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Introduction

Venous ulcer is a serious clinical condition due to chronic venous insufficiency (CVI). It is the main reason of approximately 70% of chronic ulcers of the lower limbs [1]. Diabetes mellitus, sickle cell disease, rheumatoid arthritis, chronic osteomyelitis, peripheral vascular disease, skin tumor and vasculitis are other common reasons of chronic ulcers. Whereas some cases with venous ulcer may be idiopathic and some can be multifactorial [2]. Despite technological improvements in the field of medicine, it is still a big challenge to deal with venous ulcers worldwide [3].

Different advanced treatment modalities include supplemental systemic oxygen, hyperbaric oxygen treatments (HBOT), and locally performed transdermal wound oxygen therapy (TWOT) has been reported in the literature to treat chronic or ischemic wounds. TWOT has become popular among them recently due to increased patient comfort, decreased risk of oxygen toxicity, portability and efficiency [4].

In this study, we aimed to evaluate TWOT for the healing of chronic venous ulcers due to deep venous insufficiency.

Material and Methods

Between 2017-2019, sixty-four patients with lower extremity venous ulcer due to deep venous insufficiency were included in the study. Written informed consent was obtained from all participants and the clinical council of the related department approved this randomized controlled study protocol. The study was designed according to the Declaration of Helsinki. Patients were divided into two groups. Group 1 was the control group and Group 2 was the experimental group. The coin tossing method and the block randomization technique were used to determine the group of patients. The inclusion criteria were age over 18 years and the presence of grade 4 deep venous insufficiency and venous ulcer in one of the lower extremities, according to venous Doppler ultrasound results and physical examination. The exclusion criteria were any kind of cancer, pregnancy, peripheral vascular disease like diabetes mellitus, which can induce vascular complications, acute thrombophlebitis, wounds completely covered with eschar, ulcer due to Raynaud disease, wound with fistulae or deep sinus tracts where the end cannot be probed and deep venous thrombus. Thus, all patients underwent venous and arterial Doppler ultrasound of the lower extremities to determine venous insufficiency and the absence of venous thrombus and peripheral arterial disease. Demographic data of the patients were also recorded.
Group 1 consisted of 32 patients (males: 24, females: 8), and routine wound and venous insufficiency therapy included debridement and antibiotherapy, if necessary, venotonic drugs, lower extremity elevation and compression socks. The sample was taken from the patients who had suppurative and malodorous wounds, and the decision to prescribe antibiotherapy was made according to any bacterial growth. Group 2 consisted of 32 patients (males: 25, females: 7). TWOT was performed in addition to routine therapy, except for compression socks in this group. Compression socks could not be used in this group because of the location of the device (Figure 1). TWOT was applied to the area with ulcer to maintain continuous delivery of oxygen for 15 days. Initially, the site of the ulcer was debrided to remove impurities from the wound, area if necessary, then a disposable catheter was inserted into the wound site, thereafter wound dressing was applied using saline-soaked gauzed and the device was started for the treatment. This process was repeated three times and the total treatment lasted 45 days. The area of the wound was measured in square millimeters using a standard sterile graded clipper. The wound status was assessed before and every fifteen days after the beginning of the intervention. Accordingly, the wound status was evaluated four times: before the intervention, and fifteen days, thirty days, and forty-five days after the intervention.

Statistical Analysis

All values were shown as mean ± SD or percentage. The distribution of all variables was checked using the Kolmogorov– Smirnov test. The Mann–Whitney U test was used for data with abnormal distribution. Otherwise, the differences between the mean values of the two groups were analyzed using the unpaired Student’s t-test. The gender of the two groups was analyzed using the chi-square test. Pearson’s test was used to assess the correlations, but Spearman’s correlation analysis was performed in the correlation analysis of data with abnormal distribution. GraphPad Instat (version 3.05, GraphPad Software Inc., San Diego, CA, USA) statistical software was employed. Statistical significance was accepted at the level of 0.05.

Results

Between 2017 and 2019, a total of 64 patients were included in the study. The TWOT group consisted of 32 patients (males: 25 and females: 7) and the control group consisted of 32 patients (males: 24 and females: 8). The number of male patients was predominant in both groups, with a percentage of 75% in the control group and 78% in the TWOT group. There were no statistically significant differences in age, gender and wound area between the groups (Table 1).

Five patients in both groups required antibiotherapy for sensitive microorganisms detected in the wound sample for two weeks. There was no growth in control samples.
The number of completely healed ulcer, defined as complete epithelialization of the wound without drainage, was 28 in the TWOT group and only 1 in the control group. This difference was statistically significant according to the binominal test results (p<0.001).

The results of repeated wound area measurements on the fifteenth, thirtieth and forty-fifth days showed a statistically significant decrease in the TWOT group, however, the wound area did not differ significantly in the control group. Moreover, the total mean of wound area in the TWOT group was statistically significantly lower than the control group (Table 2).

Discussion

Venous ulcers are common disorders worldwide and various risk factors were defined for the development of this clinical condition, including a family history of chronic venous insufficiency, age 55 years and older, a history of thrombophlebitis or venous thrombus, physical inactivity, increased body mass index, skeletal or joint disease of lower extremities, a high number of pregnancies and venous reflux in the deep veins. The quality of life of patients with venous ulcer is generally affected negatively due to prolonged and unsatisfactory treatments. Severe complications like infection and malignant change can be observed [5].

The most common type of chronic lower extremity ulcers is venous ulcers, with 1% overall prevalence and up to 3% in the age of 65 years and over [6]. Venous ulcers of lower extremities are usually localized in the malleolar region, both in the lateral and medial sites of the ankle. However, they also occur in the infra and supra-malleolar regions of the foot and leg [7]. Venous hypertension due to venous reflux, varicose veins, postthrombotic syndrome and venous insufficiency are the most frequent causes of the lower extremity ulcers. The underlying mechanism of venous ulcer is tissue ischemia as a result of damage and destruction of capillaries that maintain nutrients and oxygen to the skin and subcutaneous tissues [8]. Coherent with the literature, all participants in our study had grade 4 deep venous insufficiency and ulcers on the lower extremities.

For lower extremity ulcers related to venous insufficiency, a variety of treatment regimens are used, including local dressings, topical and systemic agents, exercise, tissue products, compression therapy and ablation or surgery of the superficial venous incompetence [9]. None of the participants in our study had superficial venous insufficiency, thus ablation and surgery were not performed.
To understand the role of oxygen in wound healing, several modalities using oxygen have been explored in recent years, including supplemental oxygen therapy, HBOT and TWOT, as alternative methods in the treatment of chronic venous ulcers. Supplemental oxygen therapy is a kind of inhalation therapy performed using a nasal cannula or ventral mask to improve tissue oxygen concentration [10]. It is a cost-effective, easy and useful way to provide supplementary systemic oxygen, which has been shown to decrease the infection rate and be beneficial in the healing of wounds [11]. HBOT is another kind of systemic oxygen therapy that was initially used in the treatment of decompression sickness and CO2 poisoning. Subsequently, it began to be used in clinical situations such as burn, chronic wound and acute crush [12]. HBOT maintains increased oxygen dissolved in the circulating blood plasma, which results in an elevated oxygen concentration in tissues [13]. Besides the evidence of benefits in wound healing, HBOT has several disadvantages. The most serious side effect of the HBOT is tension pneumothorax, which can be life-threatening if unrecognized or untreated. Reversible myopia due to lens deformation, ear and sinus barotraumas, exacerbation of congestive heart failure, pulmonary edema, seizure and retinal damage are the other side effects of HBOT [14]. In addition, it is expensive, limits mobility and has an impact on the quality of life [15]. Other disadvantages of this therapy are access difficulties for the patients due to the limited number of healthcare centers that have HBOT units, and the intolerance to the therapy for medical reasons [14].

Thanks to developments in the area of wound care and research on more effective treatment methods for skin ulcers, TWOT was introduced in the literature as an alternative therapy using oxygen directly to the wound site. It concentrates oxygen to nearly 100% and continuously delivers it to the wound at a rate of 3 mL/h [16]. Direct application of oxygen to the wound bypasses the oxygen transport system, so an oxygen-rich wound bed environment can be achieved, which promotes healing [17]. All stages of wound healing include hemostasis, inflammation, proliferation, maturation, and remodeling, facilitated by oxygen through the release of several mediators and cytokines, which initiate angiogenesis, thrombosis, granulation tissue formation, and re-epithelialization [18]. In a study designed by Howard et al [14], the oxygen level under the normal skin surface area was 45-65 mmHg. Schreml et al [19] declared this level under chronic wound conditions as 5-20 mmHg, moreover 0-5 mmHg in the center of the wound, where the vascular supply is absent. Thus, an increased risk of infection and delayed wound healing may occur due to the anaerobic process. Directly applied oxygen to the ulcerative area helps prevent this uneventful situation by increasing the oxygen to the desired level.

Several studies were conducted in the literature on the use of TWOT. According to a study, which designed a controlled wound model in rabbits, significantly greater epithelial coverage was detected in the TWOT group when compared to the control group [20]. Tawfick et al [21] compared the efficiency of TWOT and conventional compression dressing therapy in patients with lower extremity venous ulcers. According to their study, the rate of completely healed ulcers was 80% in the TWOT group and 35% in the other group. Similarly, the proportion of completely healed ulcers was 87.5% in the TWOT group in our study. The efficiency of TWOT in recurrence of the completely healed venous ulcers was studied, and 3 of the 51 healed ulcers managed with TWOT showed recurrence signs, besides, the recurrence of completely healed ulcers managed by a compression dressing therapy was significantly higher with the rate of nearly 50% [22]. According to the study designed by Kaufmann et al [23] in patients with venous and arterial ulcers with the mean wound duration of 15 months, the reduction in wound area was 83%, and total closure of the wound was 47% in venous leg ulcers and 74% and 57% in arterial foot ulcers, respectively when using TWOT.

TWOT can be applied not only in chronic venous ulcer therapy, but also in chronic diabetic foot ulcers. Driver et al [24] declared in their study on 16 patients with chronic diabetic foot ulcers that wound site reduction was 87% in the TWOT group (n=9), and 46% (n=7) in the control group. Similarly, Hayes et al [25] emphasized that topical oxygen therapy promotes the healing of chronic foot ulcers due to diabetes mellitus.

In conclusion, TWOT is easy to use, safe, cost-effective method and promotes the healing of chronic wounds. In addition, TWOT provides therapy at home and hospital stay is not needed. Further studies are necessary to evaluate more of the effects of the TWOT.

Acknowledgment

The authors thanked Prof. Dr. Abdullah Tuncay Demiryurek for assessing the article in terms of the language grammar.

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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Ozgur Altinbas, Mehmet Orkun Sahsivar. The efficiency of transdermal oxygen wound therapy in lower extremity venous ulcers. Ann Clin Anal Med 2022;13(1):50-53

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Knowledge, attitude and practices of teledentistry during the COVID-19 pandemic in Southern Saudi Arabia

Siraj DAA Khan 1, Musleh Al-Garni 2, Hassan Hadi Al-Mutarid 3, Zabnan Masfer Al Bahri 3, Mahdi Hadi Al Salem 3, Saleh Manaa Al Mahaamed 3

1 Department of Pediatric Dentistry, Preventive Dental Sciences, 2 Department of Dental Public Health, Preventive Dental Sciences 3 Interns, Najran University, Faculty of Dentistry, Southern Saudi Arabia

DOI: 10.4328/ACAM.20840 Received: 2021-09-02 Accepted: 2021-10-08 Published Online: 2021-10-13 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):54-57

Corresponding Author: Siraj DAA Khan, Faculty of Dentistry, Najran University, KSA. E-mail: sdkhan@nu.edu.sa P: +96 617 542 79 60 Corresponding Author ORCID ID: https://orcid.org/0000-0002-7015-2232

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Abstract

Aim: The aim of this study was to assess the knowledge, attitudes and practice of teledentistry during COVID-19 among dentists in Southern Saudi Arabia.

Material and Methods: A questionnaire with 27 questions was constructed, validated and circulated electronically via social media channels like WhatsApp and by email to dentists from various fields in Southern Saudi Arabia. Data were collected and analyzed using the statistical software SPSS 23.0.

Results: Most of the respondents showed a positive behavior towards all domains of the questionnaire, including knowledge, attitude and practice of teledentistry. Out of 839 participants, 532 participants were familiar with this term, most of them (64.4%) were practicing it during the pandemic of COVID-19.

Discussion: It is an emerging technique that has the ability to improve the delivery of dental care diagnosis to communities with limited access or no access to specialists. As of today, there is a need for improvement in practicing it among the Saudi dental community.

Keywords: Telehealth, Teledentistry, COVID-19, Pandemic, Communication Technology, Information Technology

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Introduction

Thefieldofdentistry,alongwithotherdisciplinesofmedicine, has faced significant challenges with the spread of viral diseases [1]. COVID-19 is caused by a virus known as SARS- CoV-2. The transmission method of this virus between people is mainly through contact routes and respiratory droplets [2]. Based on the available evidence, WHO has suggested strict droplet-preventive and contact measures for healthcare workers dealing with COVID-19 patients, and also aerosol- generating procedures are observed in clinical settings as airborne. Countries all over the world have affirmed states of emergency, which transformed the delivery of dental services. Since that time, various demonstration projects relatied to oral health have been using telehealth.

The term telehealth is given to those public health services and deliveries that use communication technology for diagnosis, self-care, to expedite consultation, planning and scheduling treatment by a healthcare worker for distant patients. Teledentistry, a branch of telehealth, provides dental care service at a distance with the help of communication and information technology. All professional and legal obligations and current dental practice related to in-clinic care are also mandatory for teledentistry [3].

It is a type of telehealth that is particularly allocated to dentistry and uses ICT (information and communication technology), electronic medical records, the internet and digital photography for consultation, continuing or supervision education. It has the potential to develop the delivery of oral healthcare and access to underserved and rural areas [4]. Teledentistry has the ability to minimize overall costs and save resources of healthcare [5]. According to an Australian study, if teledentistry were applied for screening the risk of low caries in children, it could save up to 40 million dollars/year [6]. In addition, the psychological effect of anxiety and fear, as well as non-essential contact, can be reduced for both patients and healthcare workers [7].

There is a limited amount of literature addressing the attitudes and awareness of dental professionals towards teledentistry and its use in healthcare provision. Therefore, the aim and objective of this survey were to investigate the knowledge, attitude and practice of teledentistry, as well as the practice of teledentistry during the COVID-19 pandemic among Saudi dentists. We are sure that this survey will add great information to the present literature, especially in Southern Saudi Arabia.

Material and Methods

After taking approval from the Scientific Research Ethical Committee of Najran University, a questionnaire for this cross- sectional research was shared with dentists including dental undergraduates, dental interns, dental postgraduates, general dental practitioners and specialists from October 2020 to December 2020. A total of 839 people related to dental fields from Southern Saudi Arabia participated in this survey. The respondents were given a brief introduction about the purpose of the survey in electronic format. Afterward, the questionnaire was sent to them using a convenient sampling technique e.g. through social media via emails and WhatsApp. Participants involved in the direct dental care of patients were included. A total of 27 multiple choice questions were asked in the four-part survey; Part 1 included questions regarding demographic data; Part 2 included questions regarding knowledge of teledentistry; Part 3 included questions to assess attitudes towards teledentistry; Part 4 comprised questions about practicing it during COVID-19. The participants of the survey were questioned about their familiarity and attitude towards teledentistry and about practicing it in their dental practices. The dentists’ responses were summarized in Tables.

Statistical Analysis

Responses of the participants were analyzed for frequency.

Results

Demographic data

A total of 839 people from different fields of dentistry participated in this survey. Out of 839 respondents, 437 (52.1%) were male and 402 (47.9%) were female. Their qualification differed: 244 (29.1%): dental undergraduate, 220 (26.2%): general dental practitioner, 178 (21.2%): dental interns, 125 (14.9%) dental postgraduate, and 72 (8.6%) were dental specialist; 463 (55.2%) participants were from Abha, 127 (15.1%) from Najran and 249 (29.7%) from Jazan (Table 1). Knowledge about teledentistry

Five hundred thirty-two (63.4%) participants were familiar with the term teledentistry; 175 (20.9%) did not know it and 132 (15.7%) were not sure. Out of 664 respondents who knew teledentistry, only 248 selected Synchronous, Asynchronous, Mobile health, Remote patient monitoring as key modalities. Participants had different opinions on the use of teledentistry, as described in Table 1. Five hundred out of 664 thought that it was a technically difficult platform that required training and education. However, 61.6% understand that it can help in health education during and after the pandemic (Table 2a).

Attitude towards teledentistry

As compared to traditional examination, most people (289) thought that this technique is easier because it uses intraoral cameras, but is not accurate. One hundred forty-ninesaid it was neither easier nor accurate, and 226 participants found it easier and accurate. A large number of participants (50.9%) agreed that dentists are afraid of making inaccurate diagnosis through the use of teledentistry. The reasons for the lack of compatibility of healthcare professionals varied among the participants. Lack of training and expertise was the reason for 24.7% of participants, poor internet access for 37.5%, hardware shortage for 25.5 % and high cost for 12.3% of respondents; 59.5 % of participants agreed that teledentistry will increase the accessibility of specialists to rural and underserved communities. Four hundred dentists were ready to support a government initiative whereby patients could obtain advice via this technique (Table 2b).

Practice

Out of 664 participants, only 429 were seeing patients through teledentistry, of which 208, 84, 70 and 67 were using teleconsultation, telediagnosis, tele triage and tele monitoring respectively. The majority of participants (212) preferred telephone call and SMS; 56% found it very useful, however, some participants (20.8%) thought that it had too many legal issues, and 23.2% considered it limited. In the current pandemic situation, 375 dentists chose that the dental curriculum needs an update regarding teledentistry; 394 thought that it has gained more importance in the current situation than before; 417 participants understand that if not fully replaced, at least it can complement the existing compromised dental system (Table 2c).

Discussion

The concept of teledentistry was initially proposed by the American Army as part of the Total Dental Access Project in 1994. Nowadays, teledentistry is widely accepted in the fields of dental education, public awareness, and research activities within several dental disciplines.Teledentistry is an advanced technique for the delivery of health services that can help contact and triage patients, also facilitate discussion of the results of investigations and enable clinicians to give advice [8]. In the present study, 63.4% of the participants were familiar with it, which is higher than in the study by Almazrooa et al., which showed that 28.4% were familiar with the term teledentistry [9], and another study mentioned that only 7.23% of dentists know the concept of teledentistry, and the majority of respondents (98%) have never practiced it [10].

In the present study, most (56%) of the participants agreed that teledentistry is very useful, but 23.25% said it was very limited, and 20.8% thought it had too many legal issues, this number is quite higher than in the study by Boringi et al., in which only 4.19% of participants said that it had legal issues, and 28.13% of respondents believed it had limited application; and in the same survey, 50% agreed that it could help in health education of the masses [10]. The same results were found in the present study, in which the percentage of respondents was 61.6%.

The majority of respondents (59.9%) were sure that it will increase the accessibility of specialists to rural and underserved communities. A great number of dentists (67.6%) in a similar study also believed that it can be useful in improving access to oral health care [11].

In the present study, 62.8% of participants said that teledentistry could complement the existing compromised dental system, if not fully replaced during the COVID-19 pandemic. In this survey, 64.4% of dentists were practicing teledentistry, which is in accordance with a study by Almazrooa et al. that demonstrated that 50% of dentist had applied teledentistry in their clinical practice [9]. This method is ideal for limiting the movement of people in hospitals, because it prevents unnecessary contact of patients to asymptomatic carriers of COVID-19, including healthcare workers [12]. Adoption of telephonic consultations and virtual clinics in this pandemic situation will minimize the overcrowding of emergency rooms in hospitals and will also reduce unnecessary visits that increase the risk of disease transmission, and ultimately it prevent the shattering of healthcare systems [13].

Conclusion

Most of the participants were well aware about teledentistry and showed a positive attitude towards it. However, in terms of practicing it during this pandemic, further improvement is needed in dentists in Southern Saudi Arabia.

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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Siraj DAA Khan, Musleh Al-Garni, Hassan Hadi Al-Mutarid, Zabnan Masfer Al Bahri, Mahdi Hadi Al Salem, Saleh Manaa Al Mahaamed. Knowledge, attitude and practices of teledentistry during the COVID-19 pandemic in Southern Saudi Arabia. Ann Clin Anal Med 2022;13(1):54-57

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Impact of sars-COV-2 on the attitudes of patients with prosthodontic needs

Numan Tatar 1, Ayşe Karabaş 2

1 Department of Prosthodontics, Faculty of Dentistry, Inonu University, Malatya, 2 Department of Prosthodontist, Private Practise, Gaziantep, Turkey

DOI: 10.4328/ACAM.20841 Received: 2021-09-03 Accepted: 2021-10-21 Published Online: 2021-11-04 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):58-61

Corresponding Author: Numan Tatar, Department of Prosthodontics, Faculty of Dentistry, Inonu University, Malatya, Turkey. E-mail: numan.tatar@inonu.edu.tr. P: +90 422 341 01 05 / +90 422 341 63 03 F: +90 422 341 11 07 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3947-9007

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Aim: SARS-CoV-2 has caused a global pandemic that has negative consequences for many parts of life. To our knowledge, no study has assessed the effect of the SARS-CoV-2 pandemic on a possible delay in prosthodontic treatments because of a potential concern of contamination in individuals. Therefore, the purpose of this study was to assess this potential impact of fear, as well as oral health-related quality of life, in partially edentulous patients using questionnaires during the SARS-CoV-2 pandemic.

Material and Methods: A total of 135 partially edentulous patients (74 females and 61 males aged 18-70 years) participated in this study. A complete questionnaire consisting of general knowledge questions on SARS-CoV-2 and the OIDP scale, which evaluates the effect of oral status on daily activities were used in participants.

Results: Statistical analyzes showed that participants with a history of SARS-CoV-2 and/or who are aware of a member of their social circle with a history of the virus, and/or who is deceased, were unwilling to receive dental care during the pandemic. Most of the participants between the ages of 31 and 60 were more worried about the transmission of SARS-CoV -2 during dental treatment.

Discussion: Concerns about SARS-CoV -2 contamination of patients over 30 years of age may have a negative impact on oral health due to delayed prosthodontic treatments.

Keywords: SARS-CoV-2, Dental Treatment, Oral Health, Fear of Contamination

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Introduction

A new type of coronavirus SARS-CoV-2 has been detected in Wuhan in 2019 with potential findings of pneumonitis. It began as an epidemic through droplets transmission during coughing and sneezing, as well as breathing of infected individuals, and turned into a global pandemic [1]. Contamination with surfaces and fecal-oral transmission have also been reported [2]. Dentists have been reported to be at a higher contamination risk due to the intense aerosol and airborne particles that occur during their treatments [3]. Therefore, at the beginning of the pandemic, only emergency care was recommended to dentists, however, currently these cautions are being gradually removed for the prevention of oral diseases [4].

Threats of contamination during an epidemic have been reported to increase fear and stress in individuals [5]. Similarly, it is clear that SARS-CoV-2 has caused negative psychological outcomes, including worldwide fear due to the lack of effective vaccination to defeat SARS-CoV-2 worldwide [6 ,7]. Previously, anxiety levels due to SARS-CoV-2 in patients related to dental treatments have been stated in the literature. Dental patients have been reported not to have a willingness to attend dental appointments regardless of an emergency. However, patients undergoing orthodontic treatment have been stated to be more concerned about an extension of treatment duration [8]. In addition, previously, the anxiety status and willingness of the patients have been evaluated in dental patients who need to receive pedodontics [9] and orthodontic treatment [10]. However, to our knowledge, no studies have focused on anxiety levels or willingness and fear of contamination in patients requiring prosthodontic treatments. Therefore, the aim of this study was to compare people’s awareness of SARS-CoV-2 and the dental treatment approach, as well as the effect of this disease on oral and dental health by using demographic data.

Material and Methods

A total of 135 patients, including 74 female and 61 male patients between the ages of 18 to 70 years, who applied to the Department of Prosthodontics, Faculty of Dentistry, Inonu University and were partially edentulous, were involved in the study. Ethical approval for the study was obtained from (Blinded) University Clinical Research Ethics committee (#2020/966). All participants signed an informed consent form before participating in the study. Information about gender, age, marital and educational status, employment status, and the presence of any chronic diseases in patients was recorded. Questionnaires: Two different questionnaires have also been applied to patients including the general knowledge about SARS-CoV-2 and also the fear of contamination during dental treatments (Table 1-3). Questionnaire questions measuring information source, knowledge level, attitude towards coronavirus patients, risk knowledge, awareness, and demographic data were used in the study. In addition, Oral Impact on Daily Performance (OIDP) survey was used to monitor oral impact on daily activities for the last 6 months.

Statistical analysis: The obtained data were evaluated using commercially available software (SPSS 25.0, IBM, Chicago, IL, USA). The Kolmogorov-Smirnov test was used to determine the normal distribution of the data. Pearson’s Chi-square analysis,

Yates corrected Chi-Square analysis, and Cramer’s V-coefficient analysis were used for statistical analysis. The data were expressed as mean ± standard deviation. A P-value < 0.05 was considered statistically significant.

Results

The current study involved 74 females and 61 males. There were no significant differences between the ages of the male and female participants (p>0.05). Educational status was also similar in both genders (p>0.05).

Twenty-three of 135 participants (24.4%) found dental treatments to be risky in terms of SARS-CoV -2 transmission (p<0.01) (Table 1). Gender-based analysis results showed that male participants found dental treatments riskier in terms of SARS-CoV -2 transmission compared to females, however there was no significance (p>0.05) (Table 2). The presence or absence of someone infected with SARS-CoV -2 in their social circle did not influence the participants’ decisions with respect to the risk of SARS-CoV-2 transmission (p>0.05) (Table 1).

The majority of participants (23 males (51,1%), 45 (50%) females) thought that SARS-CoV -2 is the most dangerous disease in Turkey at the moment (p<0.01) and, the gender of participants did not affect the result (p>0.05) (Table 2). Participants between the ages of 18 to 30, which constitute 40% of the study participants, did not report dental treatments as risky in terms of SARS-CoV -2 transmission. In addition, only a limited number of (13.3%) participants in the 18-30 age group reported a higher risk due to dental treatments (Table 3). On the contrary, less than 8% of patients between the ages of 31 to 60 years thought that dental treatments were more likely in the transmission of SARS-CoV -2. Most of the participants in this age range (31-60) had higher concerns regarding SARS- CoV-2 transmission during dental treatments (p<0.01) (Table 2 and 3).

Discussion

The global outbreak of SARS-CoV-2 has affected many parts of life, including dental and medical treatments. Previously, the state of anxiety and willingness of patients towards pediatric [9] and orthodontic treatments [10] during the SARS- CoV-2 pandemic have been evaluated. However, to the best of our knowledge, this is the first assessment of patients in prosthodontic dentistry. Current results showed that the presence or absence of a person infected with SARS-CoV-2 in his or her social circle did not influence patients’ decisions about the risk of COVID-19 transmission. Furthermore, patients between the ages of 31 and 60 were more concerned about the transmission of SARS-CoV -2 during dental treatments.

The current study was carried out between July and October 2019, when SARS-CoV -2 was partially controlled and quarantine rules were partially lifted in Turkey. However, in this study, participants over the age of 30 still expressed anxieties about SARS-CoV -2 transmission . Similarly, Cotrin P, et al [10] also reported that at the onset of the pandemic in Brazil, although the number of cases was low, patients were concerned about SARS-CoV-2 transmission. This might be due to the fact that it becomes easier to obtain global information about the pandemic because of social media use, which is positively correlated with anxiety [11].

It has been reported that the SARS-CoV-2 pandemic affects orthodontic appointments [10]. Cotrin P, et al. [10] reported that females undergoing orthodontic treatment were more anxious compared to males in terms of SARS-CoV-2 transmission and less worried regarding treatment delay. In the current study, participants of both genders defined dental treatments as risky in terms of SARS-CoV -2 transmission. This could be due to the age differences between participants in the two studies. In addition, this difference may be due to the timing and type of treatment in the two studies.

It has been reported that patients postpone medical treatments because of contamination with SARS-CoV-2, which could later promote the risk of health problems in the near future [12]. A similar observation was also reported by Campagnaro R, et al. [9] that 86% of parents whose children had dental trauma during pandemic did not apply dental units, and 24.4% of parents canceled undergoing treatments of their children. In the current study, 73,3 % of the participants found prosthetic treatments risky during the pandemic. Therefore, it might be suggested that the fear of SARS-CoV-2 contamination during dental treatments may cause negative oral health outcomes. Conclusion:

In conclusion, SARS-CoV-2 has affected our lives in many different ways. Concerns about SARS-CoV-2 contamination of patients over 30 years of age may have a negative impact on oral health by delaying prosthodontic treatments.

Acknowledgment

We would like to thank Hilal Yağın for her kind assistance during statistical analysis.

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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12. Karacin C, Bilgetekin I, Basal BF, Oksuzoglu OB. How does COVID-19 fear and anxiety affect chemotherapy adherence in patients with cancer. Future Oncol. 2020;16(29):2283-2293.

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Numan Tatar, Ayşe Karabaş. Impact of sars-COV-2 on the attitudes of patients with prosthodontic needs. Ann Clin Anal Med 2022;13(1):58-61

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Emergency visits of otorhinolaryngology department during COVID-19 pandemic, Saudi Arabia, 2020

Saleh Mayoof Alosaimi 1, Abdulhamid Qaed A. Alenezi 2, Ghaida Hassan Alotaibi 3, Maha Othman S. Alsharif 3, Aeshah Dakhel Alrabie 3 Omar Mohammed B. Alruwaili 4

1 General Otolaryngology Consultant at AlHada Military Armed Forces Hospital, Taif, 2 Faculty of Medicine, Northern Border University, Arar, 3 Collage of Medicine, Taif University, Taif, 4 College of Medicine, Aljouf University, Sakakah, Saudi Arabia

DOI: 10.4328/ACAM.20842 Received: 2021-09-07 Accepted: 2021-09-30 Published Online: 2021-11-18 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):62-66

Corresponding Author: Omar Mohammed B. Alruwaili, Aljouf University, College of Medicine, Sakakah, Saudi Arabia. E-mail: Omruwaili@gmail.com P: +96 659 866 84 93 Corresponding Author ORCID ID: https://orcid.org/0000-0002-4955-427X

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Aim: In this study, we aimed to assess the frequency of patient emergency visits to the Otorhinolaryngology (ORL) Department during coronavirus COVID-19 pandemic and compare it with that before coronavirus COVID-19.

Material and Methods: A retrospective comparative study was performed at Al-Al-Hada Armed Forces Hospital, Taif (Saudi Arabia), and data regarding various diagnoses of ORL cases were collected from medical records of patients who visited/admitted to ORL-ED during the lockdown (Group 1) and those who visited/ admitted to ORL-ED before the pandemic (Group 2).

Results: Group 2 had a significantly higher percentage of cases who had no ENT-related disorders, hypertrophy inferior turbinate (HIT), stridor, obstructive sleep apnea (OSA), epistaxis and who had no complications, had general ENT, foreign body ingestion-aspiration, trauma, otology and who had more than one disorder and Group 1 had a significantly higher percentage of those having nasal obstruction, tonsil hypertrophy grade 3, had emergency head and neck cancer, had deep neck space infections and who had complicated.

Discussion: During coronavirus COVID-19 pandemic period, cold ENT visits were much less and foreign body ingestion remains the highest reason for ENT visits. Additionally, telemedicine has been shown to be effective in reducing ED visits during the pandemic period. Furthermore, older cases with chronic ENT problems who had regular follow-up ENT visits were less likely to visit ED during the pandemic.

Keywords: Emergency, Cases, Otorhinolaryngology, COVID-19, Pandemic, Taif

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Introduction

In March 2020, the World Health Organization (WHO) confirmed the outbreak of severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2) as a global pandemic and called it COVID-19; at that time, there were no clear therapies and vaccines available for disease control [1]. Consequently, health systems and medical centers were challenged by an emergency and disorganization [2].

COVID-19 created a burden in terms of complications that occurred directly during the crisis and lasted over a period of time [3]. However, it is clearly difficult to eliminate the disease, and the primary task is to maintain the situation under control [4]. Thus far, hospitals have decided to suspend all elective and referable procedures for both surgery and outpatient clinic visits [5]. Some clinical specialties were more vulnerable to serious problems owing to the organization of patient care [4]. Emergency care is an important department of any medical center [6]. During the COVID-19 pandemic, many governments implemented a lockdown and self-quarantine to counteract the outbreak of infection and decrease emergency visits during the COVID-19 pandemic [5]. In England, emergency department visits decreased by 49% [5, 7], and 50.2% of overall patient visits during this period were for endodontic treatment [8]. Otorhinolaryngology (ORL) Department is one of the specialties where urgent consultations are held. Patients attendance dropped significantly within the month following the onset of the COVID-19 pandemic, and many illnesses disappeared [9]. ORL emergencies are common among communities, and early diagnosis and management are important to reduce morbidity and mortality [10]. The head and neck perform multiple functions in critical areas of human health (including respiration, digestion, sensation, communication, and aesthetics) that can be threatened by ORL emergencies [11]. During an emergency, management priorities should focus on airways, breathing, circulation, and disability to decrease morbidity and mortality (American Academy of Otolaryngology Head and Neck Surgery Foundation. Primary care otolaryngology. 2011. Available at: https://www.entnet.org/wp-content/uploads/files/Oto-Primary- Care-WEB.pdf). ORL emergencies include: foreign bodies in the aero-digestive tract, deep neck space infections, epistaxis, and laryngotracheal trauma [12]. Obviously, foreign bodies in the aero-digestive tract are the most common emergency and require immediate intervention [6].

A previous study showed that there was a total reduction in ORL emergency visits by 73% during the COVID-19 pandemic [13]. Patients with general ORL symptoms (e.g., mild cases of epistaxis, cases of otology, cases of vertigo, uncomplicated cases of infection) showed statistically significant numbers and were empirically handled. There was no statistical decrease in swallowing cases of foreign bodies [13].

Specific strict measures were taken by the American Academy of Otolaryngology-Head and Neck Surgery (AAOHNS) during the COVID-19 pandemic, which included cancellation of all elective cases, converting all tracheotomies to percutaneous routes, keeping patients intubated for up to three weeks, limiting the OR personnel with teams involved in cases of suspected COVID patients, and all clinic patients had their follow-ups rescheduled or were offered telemedicine visits [14].

Very few studies have been performed to assess the ORL emergency visits in the world during the COVID-19 pandemic, and no study has been done in Saudi Arabia to assess this issue. Thus, this study aimed to find out the number of patients who visit the ORL Emergency Department during the COVID-19 pandemic, and compare it with that before coronavirus COVID-19 and assess its relationship to types of emergencies.

Material and Methods

Study design: A retrospective comparative study was conducted in Al-Hada Armed Forces Hospital.
Study population: The data were collected retrospectively about patients visited or admitted to the emergency ORL department. Ethical approval

Ethical approval for the study was obtained from Al-Hada Armed Forces Hospital research ethical committee on 12 August 2020. Register number H-02-T-078. Reference REC.T. 2020-08-468. Data collection: The data were collected from medical records of patients of all ages who visited or admitted to the emergency ORL department during the period of nationwide lockdown from February 2020 to May 2020 (Group 1), and from those visited or admitted to the same setting before the pandemic from October 2019 to January 2020 (Group 2). The exclusion criteria were all patients who visited the emergency department related to another specialty other than ORL and any patient diagnosed with a somatic disorder. Patients were classified into 9 ENT categories, according to the cause of a visit to the ORL emergency department (General ORL, foreign body ingestion-aspiration, trauma, vertigo, epistaxis, otology, emergency head and neck Cancer (including hemorrhage and airway compromise), deep neck infections, including supraglottic, and sialadenitis as well as insecure airway cases), and those having problems other than ENT.

Statistical analysis: Data were analyzed using (SPSS) version 25. Qualitative data were expressed as numbers and percentages, and the Chi-squared test (χ2) was applied to check the between variables. Quantitative data were expressed as mean and standard deviation (Mean ± SD), and the Mann-Whitney test was applied for non-parametric variables. A p-value of <0.05 was considered statistically significant.

Results

Table 1 shows that the mean age of the participants was 31.93 ± 18.24 years, and 64.9% were emergency cases who visited the Otorhinolaryngology (ORL) Department from October 2019 to January 2020. Of studied patients, 82% had more than one ENT disorder, and 5.9% had chronic tonsillitis as a risk factor related to the condition.

Table 2 shows that 97.7% of patients were admitted through the emergency department, 46.8% were known cases of any ENT diseases, and 66.7% had no medical or surgical history. Of them, 76.1% came with no complications and 8.6% came with nasal obstruction.

(Table 3) demonstrated that group 2 had a significant higher percent of those who had no ENT-related disorders, and who had no past medical or surgical history (p≤ 0.05). Group 1 had a significant higher percent of those who had nasal obstruction and tonsil hypertrophy grade 3 as a complication the patient

came with compared to group 2. While group 2 had a significant higher percent of those who had hypertrophy inferior turbinate (HIT), stridor, obstructive sleep apnea (OSA), epistaxis and who had no complications compared to group 1 (p≤ 0.05).

Figure 1 illustrated that Group 2 had a significantly higher percentage of patients with General ENT, foreign body ingestion-aspiration, trauma, otology and who had more than one disorder (p≤0.05), while Group 1 had a significantly higher percentage of patients who had emergency head and neck cancer (including hemorrhage and airway compromise), and who had deep neck space infections, including supraglottic, and sialadenitis as well as insecure airway cases) (p≤0.05).

Figure 2 illustrated that Group 1 had a significantly higher percentage of patients who were complicated cases compared to Group 2 (p≤0.05).

Discussion

During four months of the national lockdown owing to COVID-19, there was a 46% decrease in the number of ORL emergency department visits compared to the same period of the previous year. The reduction in trauma is due to the implemented measures taken during the lockdown. In addition, multiple patients may prefer to manage non-urgent conditions on their own or by remote communication with their otolaryngologists. In agreement with this, a recent study has documented a substantial decrease in ORL emergency consultations by 80.8% [9].

According to our study, most of the participants who attended the ORL emergency department had more than one ENT disorder that required urgent intervention, and epistaxis showed the most significant reduction. A study performed in northern Italy during the COVID-19 pandemic also showed that epistaxis had the highest reduction in the number of cases compared to previous years [5].
Epistaxis is reported to account for only 0.5% of all emergency department visits and up to one-third of all otolaryngology- related emergency department encounters. Inpatient hospitalization for aggressive treatment of severe nosebleeds has been reported in 0.2% of patients with nosebleeds [15].
In terms of admission, most cases were admitted through the emergency department, and there were fewer cases in the outpatient department. Therefore, a significant increase in the number of patients attending otorhinolaryngology department can be expected in the coming months that will require proper management. Most of the cases were known cases of ENT diseases; we speculate that this may be due to fear of contracting the virus. The same was recognized in a study performed in Italy; during the COVID-19 pandemic, only Emergency Department consultations were guaranteed in the ENT Department [5].
The results of this study revealed an overall reduction in the number of ORL emergency consultations during the pandemic. Another study observed the same reduction (by 80.8%) in the number of emergency visits during the nationwide lockdown from February 2020 to April 2020 [9].
This study determined that Group 1 had a significantly higher percentage of patients with comorbidities (e.g., HTN, DM, and thyroid disorders) and cancers compared to Group 2. This can be explained by the lockdown and governmental limitations, which were implemented to reduce infection transmission. In addition, the obtained results can be attributed to patients’ fear of contacting the COVID-19 infection because they are more susceptible to it than other people. Initial reports stated that coronavirus may be particularly dangerous for certain risk groups (e.g., people with chronic diseases), which forced people to adjust their risk perception and worries related to such information (WHO Director-General’s opening remarks at the media briefing on COVID-19 – 11 March 2020. Available at: https://www.who.int/director-general/speeches/detail/who- director-general-s-opening-remarks-at-the-media-briefing-on- covid-19—11-march-2020).
During the nationwide lockdown, the number of visits or admitted cases with conditions related to ORL (e.g., deviated nasal septum, chronic tonsillitis, allergic rhinitis, otitis media, and URTI) decreased. A study performed in Italy showed that the reduction was in the range of 80.2–88.9% under the same conditions during the period of nationwide lockdown [9]. In a previous study [9], there was a large unexplained reduction in epistaxis by 80.2%; while this study showed a 75% decrease in epistaxis during the pandemic.
In this study, patients from Group 1 accounted for a significantly higher percentage of those who had complications of tonsil hypertrophy grade 3 and neoplasm of the thyroid. The same was reported in a previous study performed in Greece, where patients with general ENT symptoms, mild epistaxis cases, otology cases, vertigo cases, and uncomplicated infectious cases showed a statistically significant reduction in the number of cases and were treated empirically [13].
When comparing emergency visits before and during the COVID-19 pandemic, we determined that most complaints during the ENT emergency visits prior to the COVID-19 pandemic were related to vertigo, epistaxis, head and neck emergency cancer, including hemorrhage and compromised airways. In contrast, during the COVID-19 pandemic, most visits were due to foreign body aspiration, trauma, and otology. Surprisingly, there was a reduction in head and neck emergency cancer cases. A similar study performed in Greece in 2020 showed that patients with general symptoms of ENT, mild cases of epistaxis, cases of otology, cases of vertigo, and uncomplicated infection cases showed a significant reduction, while there was no reduction in the foreign body aspiration cases [13].

Previous studies have determined that, regarding trauma cases, the lockdown was responsible for the reduction in these cases. Other reports revealed that there was a significant decrease in visits to emergency trauma departments [7]. Other studies reported lower volumes of trauma and injury cases caused by fights, vehicle accidents, ladder accidents, or incidents at work, school, and sport [16].

We believe that the different causes of emergency visits were present in each studied group. Firstly, during the pandemic, the symptoms of vertigo and mild epistaxis can be managed at home or telehealth, so in these cases, we noted a further reduction. Saudi Arabia (SA) experienced the use of telemedicine services during the previous epidemic of the Middle East respiratory syndrome (MERS) in 2012 [17,18]. During the COVID-19 pandemic, telemedicine through mobile applications has found effective tools to facilitate delivering healthcare to patients [19,20].

Limitations

The limitation of the present study is the cross-sectional nature that could assess the associations between variables without revealing the causal relationships.

Conclusion

During the COVID-19 pandemic period, cold ENT visits were much less, and foreign body ingestion remains the main reason for ENT visits. Additionally, the effectiveness of telemedicine in reducing ED visits during the pandemic period has been proved. Furthermore, older cases with chronic ENT problems who had regular follow-up ENT visits were less likely to visit ED during the pandemic.

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. Qian X, Ren R, Wang Y, Guo Y, Fang J, Wu Z-D, et al. Fighting against the common enemy of COVID-19: a practice of building a community with a shared future for mankind. Infect Dis Poverty. 2020;9(1):34-40.

5. Elli F, Turri-Zanoni M, Arosio AD, Karligkiotis A, Battaglia P, Castelnuovo P. Changes in the use of Otorhinolaryngology Emergency Department during the COVID-19 pandemic: report from Lombardy, Italy. Eur Arch Otorhinolaryngol. 2020;277(12):3525–8.

6. Yojana S, Mehta K, Girish M. Epidemiological profile of otorhinolaryngological emergencies at a medical college, in rural area of gujarat. Indian J Otolaryngol Head Neck Surg. 2012;64(3):218–24.

7. Thornton J. Covid-19: A&E visits in England fall by 25% in week after lockdown. BMJ. 2020;369:m1401.

8. Yu J, Zhang T, Zhao D, Haapasalo M, Shen Y. Characteristics of Endodontic Emergencies during Coronavirus Disease 2019 Outbreak in Wuhan. J Endod. 2020;46(6):730–5.

9. Gelardi M, Iannuzzi L, Trecca EMC, Kim B, Quaranta NAA, Cassano M. COVID-19: what happened to all of the otolaryngology emergencies? Eur Arch Otorhinolaryngol. 2020;1–2.

10. Yojana S, Mehta K, Girish M. Epidemiological profile of otorhinolaryngological emergencies at a medical college, in rural area of gujarat. Indian J Otolaryngol Head Neck Surg. 2012;64(3):218–24.

11. Helwany M, Rathee M. Anatomy, head and neck, palate. In: Stat Pearls. Treasure Island (FL): StatPearls Publishing; 2021.

12. Adedeji TO, Sogebi OA, Tobih JE. Pattern of otorhinolaryngological admissions via emergency unit in a suburban tertiary center. Int J Biomed Sci. 2015;11(3):146–51.

13. Sapoutzi M, Sideris G, Boumpa E, Papadimitriou N, Nikolopoulos T, Delides A. Variation in volumes and characteristics of ENT emergency visits during COVID-19 pandemic. Where are the patients? Acta Otorrinolaringológica Española. 2021; 11:1-10.

14. Balakrishnan K, Schechtman S, Hogikyan ND, Teoh AYB, McGrath B, Brenner MJ. COVID-19 pandemic: What every otolaryngologist-head and neck surgeon needs to know for safe airway management. Otolaryngol Head Neck Surg. 2020;162(6):804–8.

15. Tunkel DE, Anne S, Payne SC, Ishman SL, Rosenfeld RM, Abramson PJ, et al. Clinical practice guideline: Nosebleed (epistaxis) executive summary. Otolaryngol Head Neck Surg. 2020;162(1):8–25.

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Saleh Mayoof Alosaimi, Abdulhamid Qaed A. Alenezi, Ghaida Hassan Alotaibi, Maha Othman S. Alsharif, Aeshah Dakhel Alrabie, Omar Mohammed B. Alruwaili. Emergency visits of otorhinolaryngology department during COVID-19 pandemic, Saudi Arabia, 2020. Ann Clin Anal Med 2022;13(1):62-66

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Evaluation of platelet parameters in patients with gestational diabetes mellitus (GDM)

Fehmi Unal, Nil Atakul

Department of Obstetrics and Gynaecology, Istanbul Teaching and Research Hospital, Istanbul, Turkey

DOI: 10.4328/ACAM.20846 Received: 2021-09-05 Accepted: 2021-10-17 Published Online: 2021-10-25 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):67-71

Corresponding Author: Fehmi Ünal, Department of Obstetrics and Gynaecology, Istanbul Teaching and Research Hospital, 34098, Istanbul, Turkey. E-mail: unal.fehmi@gmail.com P: +90 212 459 60 00 Fax: +90 212 459 62 30 Corresponding Author ORCID ID: https://orcid.org/0000-0002-8182-2051

Abstract
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Abstract

Aim: Gestational diabetes mellitus (GDM) is the most common metabolic disease during pregnancy. In our study, we evaluated the role of platelet large cell ratio (PLCR) and immature granulocytes (%IG) in GDM.

Material and Method: Our study was conducted by retrospectively reviewing the records of 53 GDM patients between January 2019 and June 2020 at the clinics of Istanbul Training and Research Hospital. Thirty-eight healthy patients were included in the control group. GDM was diagnosed with 75g OGTT. The PLCR and IG% values obtained from the complete blood count of each patient performed in our hospital were studied.

Results: Gestational diabetes mellitus was detected in 53 of 91 patients included in the study. The mean age in the GDM group was higher than in the non-GDM (control) group (32.8±5.0 /26.9±5.0, p<0.001). There was no statistical difference between the groups in gestational week (GW), body mass index (BMI) and PLCR parameters. Both IG% and HbA1c values were statistically significantly higher in the GDM group than in the non-GDM group (0.6±0.2/0.5±0.1, p=0.002; 5.4±0.8/5.1±0.3, p=0.005, respectively). In the ROC curve analysis, the area under the curve (AUC) for the IG% value to predict the presence of GDM was 0.713 (0.606-0.821).

Discussion: This study investigated the values of PLCR and IG%, which are new inflammatory markers that have not been studied much, in GDM patients. We detected a statistically significant increase in IG% values in GDM patients and for the first time determined a cut-off value for this marker using ROC curve analysis.

Keywords: Gestational Diabetes Mellitus, Platelet Parameters, Immature Granulocyte

Full Text

Introduction

Gestational diabetes mellitus (GDM) is the most common metabolic disease in pregnancy [1] and is defined as carbohydrate intolerance first diagnosed during pregnancy [2,3]. It is estimated that 7% of all pregnancies are complicated by diabetes mellitus (DM), and 86% of these patients have GDM [2]. With the worldwide increase in obesity and sedentary lifestyle, the prevalence of DM is increasing [1]. The prevalence of GDM is also increasing with an increase in advanced-age pregnancies and obese patients [4]. Gestational diabetes mellitus affects both the mother and the fetus. It is associated with an increased risk of preeclampsia, premature rupture of membranes, dystocia, increased cesarean section rate, polyhydramnios, a large baby, and delayed fetal lung maturation [5]. In addition, women with GDM have an increased risk of developing type 2 DM later in life [1,2]. It is estimated that 50% of GDM patients will develop type 2 diabetes within 28 years after pregnancy [1].

Inflammatory markers have been observed at higher levels in GDM patients compared to normal pregnant women [6]. The development of GDM likely results from multiple factors that reduce insulin production by acting synergistically with the release of pro-inflammatory cytokines and impairment of pro-inflammatory signaling pathways [3]. Adiponectin, TNF- alpha, IL-6, alanine, branched-chain amino acids, adipocyte fatty acid-binding protein, and ferritin can be counted among the substances that have a high probability of influencing the development of GDM and will be used for GDM monitoring in the future [3]. It was pointed out that DM and, accordingly, GDM are associated with low-grade subchronic inflammation [7,8]. A complete blood count is a routinely ordered test at the initial evaluation of patients. It is well known that platelet parameters such as mean platelet volume (MPV), plateletcrit (PCT), platelet distribution width (PDW), which can be easily obtained from complete blood count, are associated with many inflammatory diseases and are used to monitor these diseases [4,9,10]. Supporting these data, changes in platelet parameters in GDM have been reported [11]. Platelet large cell ratio (PLCR) indicates the proportion of platelets larger than 12 fL. Normally, this proportion is 30% of the total platelet count. Large platelets are younger, contain more intracellular granules and, therefore have a greater thrombogenic potential [12]. It is ascertained that PLCR is mainly associated with MPV. This marker has also been found to be high in non-pregnant DM patients [10,13,14], but the situation in GDM patients remains uncertain.

The percentage of immature granulocytes (IG%) is an inflammatory marker seen in complete blood count. It has been reported that in inflammatory conditions, it rises much earlier than conventional parameters such as CRP [15,16]. Although some studies have found no association between GDM and %IG [17], there are still not enough studies on this topic. In our study, we aimed to elucidate the role of PLCR and %IG in GDM patients. Determining whether these inexpensive and easily obtained platelet parameters are valuable in the diagnosis of GDM patients is the main objective of our study.

Material and Methods

Our study was conducted by retrospectively reviewing the records of 53 patients diagnosed with GDM between January 2019 and June 2020 at the Obstetrics and Gynecology Outpatient Clinic of Istanbul Training and Research Hospital. The study patients were divided into two groups according to the presence of GDM diagnosis: the GDM group and the non- GDM group (healthy controls). Thirty-eight pregnant women who were monitored in our outpatient clinic, had no disease and a negative 75g oral glucose tolerance test (75g OGTT) were selected as a control group. GDM patients were then divided into two subgroups as insulin users and non-insulin users to compare relevant variables between them.

Gestational diabetes mellitus was diagnosed with 75g OGTT in accordance with the recommendation of IADPSG (International Association of Diabetes and Pregnancy Study Group). Patients were diagnosed with GDM if any of the fasting, first-hour and second-hour postload venous plasma glucose levels were equal to or higher than 92 mg/dL, 180 mg/dL and 153 mg/dL, respectively.

Patients diagnosed with pre-pregnancy DM, hypertension, renal disease, cardiovascular disease and neurological disease, and patients with a history of drug or substance use, the presence of infectious diseases, hematological diseases, immunological diseases and malignant diseases were excluded from the study. PLCR and IG% values obtained from the complete blood count of each patient performed in our hospital were studied. A complete blood count was performed with an automated hematology analyzer (XN 3000; Sysmex Corp., Kobe, Japan) from blood samples collected from taken from the patients’ antecubital veins. Other patient outcomes were evaluated based on patient records.

Ethical approval for the study was obtained from the Ethics Committee of Istanbul Training and Research Hospital (Decision No: 2465, Date: 10/07/2020). Since our study was retrospective, written informed consent could not be obtained from the patients.

Statistical analysis

All statistical tests were performed using the Statistical Package program for Social Sciences 25.0 for Windows (SPSS Inc., Chicago, IL, USA). The Kolmogorov-Smirnov or Shapiro-Wilk test was used to analyze the normality of the data. Normally distributed numerical data were expressed as mean ± SD, non- normally distributed parameters were expressed as median (25-75) percentiles, while categorical data were expressed as percentages. According to the data distribution, comparison of non-dependent numerical data was performed using Student’s t-test and/or Mann-Whitney U test. Similarly, the relationship between parameters was evaluated with Pearson’s or Spearman’s correlation analysis according to the normality of the data. The IG% value was analyzed using univariate logistic regression analysis to predict the presence of GDM in patients. Figure 2 was constructed using the probability value obtained from the logistic regression analysis. The specificity and sensitivity of the IG% value best predicting GDM was calculated using ROC analysis. A p-value of <0.05 was accepted as statistical significance to be bidirectional.

Results

Gestational diabetes mellitus was detected in 53 of 91 patients included in the study, and their clinical and demographic characteristics are shown in Table 1. When the mean age of the groups was compared, it was found that the mean age in the GDM group was higher than in the non-GDM (control) group (32.8±5.0 /26.9±5.0, p<0.001). There was no statistical difference between the groups in terms of gestational week (GW), body mass index (BMI) and PLCR parameters. Evaluation of IG% and HbA1c values revealed that both IG% and HbA1c values were statistically significantly higher in the GDM group than in the non-GDM group (0.6±0.2/0.5±0.1, p=0.002; 5.4±0.8/5.1±0.3, p=0.005, respectively) (Table 1).

Clinical and demographic characteristics of 22 (41%) insulin users with a GDM diagnosis and 31 (59%) non-insulin users were evaluated. There was no statistically significant difference in age, GW, BMI, PLCR, IG%, and HbA1c levels between insulin and non-insulin users. There was no statistically significant difference between the ages of insulin and non-insulin users (33.5±5.2, 32.3±4.9, p=0.373, respectively). Similarly, the weeks of gestation between the two groups did not differ statistically significantly (35.5±3.0 weeks for insulin users, 36.6±2.5 weeks for non-insulin users p=0,144). The mean BMI for insulin and non-insulin users were 31.8±4.4 and 30.4±7.2 (p=0,411), respectively. The PLCR values for insulin users (31.2±6.0) and non-insulinusers(32.3±4.5)werealsosimilar(p=0,476).The percentage of immature granulocytes was also similar between insulin and non-insulin users (0.6±0.2, 0.6±0.1, p=0.331, respectively). Lastly, HbA1c levels for insulin and non-insulin users were 5.6±1.0 and 5.3±0.4 (p=0.103), respectively.

The relationship between HbA1c value and IG% value was evaluated in all patients using Pearson’s correlation analysis. There was a statistically significant increase in the IG% value with increasing HbA1c value (r: 0.320/ p=0.002). A moderate correlation was found between the HbA1c value and the IG% value.

Similarly, the IG% value was examined using logistic regression analysis to predict the possibility of all patients having GDM. The relationship between the probability obtained from the regression analysis and the IG% value was recorded. The probability of participants having GDM for each IG% value was determined, as shown in Figure 1. Finally, the specificity and sensitivity of the IG% value for GDM diagnosis in pregnant women were evaluated using ROC analysis. In the ROC curve analysis, the area under the curve (AUC) for the IG% value was determined to predict the presence of GDM. The area under the curve (AUC) was measured as 0.713 (0.606-0.821). It was also found that the IG% value could predict the diagnosis of GDM with a sensitivity of 70% and a specificity of 61% at a cut-off value of 0.5 (Figure 2).

Discussion

This study investigated the PLCR and IG% values, which are new inflammatory markers that have not been studied much, in GDM patients. We detected a statistically significant increase in IG% values in GDM patients and for the first time determined a cut-off value for this marker using ROC curve analysis.

The relationship between DM pathogenesis and inflammation is a well-known matter that has been reported many times [3,7,10]. Jindal et al. [10] in their study highlighting the role of inflammation in the pathogenesis of DM detected that MPV, PDW and PLCR values were significantly higher in diabetic patients than in the control group. The role of inflammation has also been demonstrated in GDM patients, as in patients with type 2 diabetes.

Gomez et al. [18] in their review emphasized the similarities between type 2 diabetes and GDM, noting that in many studies, pro-inflammatory cytokines such as TNF-alpha and IL -6 were found to be high and anti-inflammatory cytokines such as IL -10 were found to be low. The same results were also reported by Catalano et al. [19]. In their published review, Khambule et al. pointed out that GDM risk factors such as age, obesity, and polycystic ovary syndrome are associated with chronic low-grade inflammation, and emphasized the need for new biomarkers [3], as the criteria for diagnosing and monitoring GDM have not yet been finalized. These authors indicated that inflammation-related markers such as adiponectin, TNF-alpha, and IL -6 could be used to diagnose and monitor GDM in early or late pregnancy [3].

In addition to the long-known effects of platelets in thrombus formation, they have also been believed to affect DM and GDM after it was understood that they play a role in the pathogenesis of inflammatory diseases [4]. Many studies have investigated the relationship between platelet parameters such as PCT, MPV, PDW and platelet-to-lymphocyte ratio (PLR) and GDM, with varying results [3,4,17]. Several studies have found an association between MPV and GDM [19,20]. Shahbaz et al. [4] revealed that PCT, MPV, PDW and PLR values among platelet parameters were higher in GDM patients and that PCT values achieved higher sensitivity and specificity than other parameters; however, PLCR and IG% parameters were not investigated in this study. On the other hand, Fashami et al. [22] determined that platelet count, MPV, PCT and PLR values were statistically significantly higher in GDM patients. Other studies have also found a relationship between the MPV value and GDM [23].

Aytan et al. [17], who investigated the PLCR and IG% values, which are the main parameters in our study, established no statistical difference in platelet parameters of GDM patients. These authors referred to publications reporting that platelet markers do not change in GDM patients [24]. In their study, they found that only nucleated red blood cell (NRBC) and red blood cell distribution width (RDW) values were significantly higher [17]. Our study concluded that the PLCR value did not differ significantly between GDM patients and the control group. However, IG% values were statistically significantly different between the GDM and control groups (p=0.002). To the best of our knowledge, the study by Aytan et al. [16] was the first to evaluate the IG% value in GDM patients. This marker has been reported to increase before conventional markers in inflammatory conditions [15]. It goes without saying that the patient group in the study by Aytan et al. mainly included 25- 26 weeks of gestation. The authors pointed out that GDM is a subclinical inflammatory state and that IG% is not useful in predicting GDM along with other platelet markers because it is a marker that increases in cases of more significant inflammation [17]. The mean gestational week in GDM patients in our study was 36 weeks. We speculated that the significantly higher IG% value in our study might be due to the fact that the inflammatory state in GDM patients progressed to a level that would affect these markers in later weeks. Accordingly, we hypothesized that IG% values, which Aytan et al. reported to be ineffective in predicting GDM in the early weeks of gestation, could be used in GDM monitoring in later weeks. By analyzing the ROC curve for IG%, we found that the cut-off value of 0.5 was predictive. Our study is the first to determine these values using the ROC curve for IG%, as far as we could detect.

In the present study, we also found that HbA1c values were higher in the GDM group, as expected, and IG% values increased with increasing HbA1c values. This suggests that there is a correlation between the severity of GDM and IG% levels. Insulin is preferred for blood glucose regulation in GDM patients [2]. Since insulin was started in patients with higher blood glucose levels who were thought to have more severe GDM, we investigated whether there was a difference between insulin users and non-insulin users with a GDM diagnosis. No significant difference was detected in age, gestational age, BMI, PLCR, IG%, and HbA1c values between insulin-using and non-insulin-using GDM patients.

Until more precise criteria for diagnosing and monitoring GDM are established, clinicians will continue to search for more effective and clearer criteria to predict and monitor GDM earlier. Inexpensive and routinely examined markers obtained by complete blood count provide valuable information about inflammation. As these markers are used in diagnosis, they may also be valuable in patient monitoring. As information on this topic accumulates, it will guide clinicians.

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. Khambule L, George JA. The Role of Inflammation in the Development of GDM and the Use of Markers of Inflammation in GDM Screening. Adv Exp Med Biol. 2019; 1134:217-42.

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Fehmi Unal, Nil Atakul, Evaluation of platelet parameters in patients with gestational diabetes mellitus (GDM). Ann Clin Anal Med 2022;13(1):67-71

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Could platelet mass index (PMI) be a new prognostic biomarker for COVİD-19?

Ugur Fahri Yurekli 1, Umran Liste 2, Burcu Ertunc 2, Mehmet Tercan 3, Mehmet Tahtabasi 4

1 Department of Medical Biochemistry, 2 Department of Medical Microbiology, 3 Department of Anesthesia and Reanimation, 4 Department of Radiology, Sanlıurfa Mehmet Akif Inan Education and Research Hospital, Sanlıurfa, Turkey

DOI: 10.4328/ACAM.20850 Received: 2021-09-10 Accepted: 2021-10-24 Published Online: 2021-11-05 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):72-75

Corresponding Author: Uğur Fahri Yürekli, Şanlıurfa Mehmet Akif İnan Eğitim ve Araştırma Hastanesi, 63100, Şanlıurfa, Turkey. E-mail: ugurrllab@gmail.com P: +90 532 777 93 99 Corresponding Author ORCID ID: https://orcid.org/0000-0002-7969-5196

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Aim: Although most patients with COVID-19 experience respiratory tract infections, severe reactions to the virus may cause coagulation abnormalities that mimic other systemic coagulopathies associated with severe infections, such as disseminated intravascular coagulation and thrombotic microangiopathy. Fluctuations in platelet markers, which are an indicator of the acute phase response for COVID-19, are of clinical importance. The aim of this study is to evaluate the relationship between disease severity and Platelet Mass Index (MPI) parameters in COVID-19 patients.

Material and Methods: This retrospective observational study was conducted with patients who were diagnosed with COVID-19 in a tertiary hospital. The study was continued with the remaining 280 patients. All laboratory data were scanned retrospectively from patient files and hospital information system.

Results: A very high positive correlation was found between PMI and PLT. The PMI value in women was significantly higher than in men. It was observed that PMI did not differ significantly in terms of mortality, intubation, CPAP and comorbidity. PMI vs. Pneumonia Ct Severity Score, biochemistry parameters (AST, CRP), hemogram parameters (WBC, HGB, HCT, MCV, LYM, MPV EO) and coagulation factors (aPTT and FIB) at various levels of positive/negative, weak and strong, and significant relationship was found. There was no significant relationship between hormone and D-dimer when compared with PMI.

Discussion: Although platelet count alone does not provide information about the prognosis of the disease, PMI may guide the clinician as an indicator of lung damage in seriously ill patients

Keywords: COVID-19, PMI, Biomarker

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Introduction

Although most patients with COVID-19 develop a respiratory tract infection, many patients with severe cases present with coagulation abnormalities that mimic other systemic coagulopathies associated with severe infections, such as disseminated intravascular coagulation (DIC) or thrombotic microangiopathy [1]. The prevalence of COVID-19 coagulation abnormalities is rising as more patients develop venous and arterial thromboembolic complications that may go unrecognized [2]. An acute-phase reaction can lead to an increase in platelet count during the inflammation process as part of the natural immune response [3]. Hospitalized patients with newly confirmed or presumptive COVID-19 infections should be tested for coagulation on admission, including D-dimer, prothrombin (PT), activated partial thromboplastin time (aPTT), fibrinogen, and platelet count, as these tests can provide useful prognostic information [4].

Evidence of abnormal coagulation parameters associated with COVID-19 appeared in early reports from China: baseline characteristics of the first 99 patients hospitalized in Wuhan indicated that 6% had an elevated aPTT, 5% had elevated PT, 36% had elevated D-dimer and increased biomarkers of inflammation, including interleukin-6 (IL-6), erythrocyte sedimentation rate, and C-reactive protein (CRP) [4]. Thrombocytopenia occurred in only 12% of patients; however, 5 (5%) patients developed other coinfections (1 bacterial, 4 fungal) and 4 (4%) developed septic shock [5]. Considering the lack of consensus on the use of prophylactic anticoagulants, a biomarker is particularly important for COVID-19 patients with elevated D-dimer levels, but without known thrombotic complications [6]. Nowadays, both platelet count and platelet size can be easily measured using automatic counting devices; however, only a few studies have evaluated the clinical importance of using fluctuations in platelet counts as an indicator of acute-phase response [7].

The aim of this study is to define the platelet mass index (PMI), which includes both platelet count and platelet volume and is an important indicator of platelet activity [8]. This study is also intended to provide guidance for clinicians in determining the need for prophylactic anticoagulants.

Material and Methods

The medical records of 280 patients diagnosed with COVID-19 following a real-time PCR (RT-PCR) test who were treated at the Mehmet Akif Inan Education and Research Hospital, Sanlıurfa, Turkey, between April 2020 and December 2020 were reviewed. This study was approved by the Ethics Committee of the Mehmet Akif Inan Education and Research Hospital and the Turkish Ministry of Health (HRU/21.06).

RT-PCR results, routine hemograms, and biochemical data of all patients treated in any clinic in our hospital who tested positive for COVID-19 were obtained from the hospital system. The patients’ hemogram parameters were measured automatically using a Sysmex xn1000 (Sysmex Inc., Japan). Biochemistry- Hormone-D-Dimer analysis Roche Cobas 8000. Coagulation was measured automatically with Sysmex cs2500 devices (Sysmex Inc., Japan).

PMI was calculated by multiplying the platelet count by the mean platelet volume (MPV):PMI = platelet count × MPV/103(fL / nL) [8].
All chest CT images were analyzed by a radiologist without access to clinical or laboratory findings, based on previously published studies of COVID-19 [9,10],

The 280 patients were divided into 3 groups, which were based on the clinical stages of COVID-19 defined by China’s Health Authority and the interim guidance of the World Health Organization: ordinary cases, severe cases, and critical cases [11, 12].

Statistics

The evaluation of the data was made with the SPSS 21.00 program. Descriptive statistics were used

Results

In total, 280 patients were included in the study. One hundred twenty- six (45.3%) of the patients were women, 152 (54.7%) were men. One hundred seventy-nine (64.4%) patients had additional diseases such as hypertension, diabetes, COPD (Chronic obstructive pulmonary disease). The ranges of biochemistry of patients, hormones, coagulation results are shown in Table 1. The age, hospitalization period of the patients included in the study ranged from 17 to 98, and the mean age was calculated as 60.4±17.2 years, between 1 and 42 days and the mean hospitalization period was 9.66±6.78 days, respectively.

According to the respiratory support status of the patients, 64 (23%) were intubated and 72 (25%) were using CPAP (Continuous Positive Airway Pressure). The pneumonia CT severity score of the patients was between 0-20 and the mean score was found to be 7.67±4.9.

When patients were examined according to their clinical severity score, it was seen that were 7.6% “Mild”, 55% “Common”, 33.8% “Severe” and 3.6% “Critical”.
PMI value in women is significantly higher than in men (p <0.05). It has been observed that PMI does not differ significantly in terms of mortality, intubation, CPAP and comorbidity (Table 2). As a result of the study, a positive, weak and significant relationship was found between PMI and Pneumonia Ct Severity Score (r=0.237; p<0.001). It was observed that there was no significant relationship between age, day of hospitalization, Clinical Severity Score and PMI (p>0.05) (Table 3)

For biochemical parameters: a negative, very weak and significant relationship between PMI and AST (r=-0.124; p=0.043) was found; A positive, very weak and significant relationship (r=0.123; p=0.045) was found between PMI and CRP (Table 1). There was no significant relationship between PMI and hormone results (Table 1).

For hemogram parameters: a positive, weak and significant relationship between PMI and WBC was found, (r=0.35); a negative, very weak (r<0.2) and significant relationship (p<0.05) between PMI and HGB, HCT, MCV, LYM and MPV was found; a positive, very weak significant relationship between PMI and EO, (r=0.13; p<0.05) was found; A very high (r=0.970; p<0.001) positive correlation was found between PMI and PLT (Table 1). For the coagulation parameter: a negative, very weak and significant relationship between aPTT and PMI (r=-0.139; p <0.05) was found; A positive, weak and significant relationship was found between PMI and FIB. (r=0.26, p <0.001) (Table 1). There was no significant relationship between PMI and D-dimer (Table 1).

Discussion

COVID-19 is most commonly associated with ARDS and hypoxemic respiratory failure [13]. Furthermore, thrombosis, including pulmonary embolism, venous thrombosis, and ischemic stroke, are common among severely ill patients [13]. Significant derangements in the coagulation cascade have been observed in critically ill COVID-19 patients, including elevated D-dimers, a relatively modest decrease in platelet count, and a prolongation of the prothrombin time [14]. Recent postmortem evaluation of COVID-19 patients has demonstrated severe endothelial injury with cellular death/apoptosis, and the presence of intracellular virus in the autopsy lung with thrombosis and small to middle- size pulmonary vessels. Clotting and vascular damage were also conformed in the alveolar capillary in COVID-19 [15]. In our study, it was observed that PMI was lower in the mortality group, but the difference between the groups was not statistically significant (p>0.05), and we found that PMI is correlated with the Pulmonary Ct Score. PMI may be a marker for lung injury. In COVID-19 disease, there are two types of coagulation problems. One of them is that COVID-19 infection produces a prominent elevation of fibrinogen and D-dimer/fibrinogen degradation products. This is associated with systemic hyper coagulability and frequent venous thromboembolic events (VTE). COVID-19 also leads to arterial thrombotic events (including strokes and ischemic limbs), as well as microvascular thrombotic disorders (as frequently documented at autopsy in the pulmonary vascular beds). COVID-19 patients often have mild thrombocytopenia and appear to have increased platelet consumption, together with a corresponding increase in platelet production [16]. Here, in our study, the fact that PMI was not correlated with D-dimer, patient age, comorbidities, and hospital stay, but was compatible with Pneumonia Ct Score, concluded that PMI may be an early marker of lung damage associated with arterial angiopathy rather than systemic hyper coagulability and VTE. However, PMI’s correlation with aPTT and fibrinogen suggests that it is also an indescribable indicator for systemic coagulation

In meta-analysis made, COVID-19 patients revealed that patients with severe disease had lower platelet counts than those with non-severe disease. According to this, the non- survivors had a much lower platelet count than the survivors [17]. In our study, positive correlation with PMI and platelet counts may be important in diagnosing patients with severe lung damage before entering the DIC period.

Although viral infection can be associated with thrombocytopenia due to a variety of causes [18], in a study by Yin et al, those with COVID-19 disease actually had high platelet counts compared to patients with severe pneumonia but without COVID-19, [19]. Some studies have shown there are significant intravascular platelet aggregates in COVID-19 autopsy lung specimens, located primarily in the inter alveolar capillaries and smaller vessels; the degree of platelet deposition is not more than is seen in other fatal pulmonary infections.

However, none of the COVID-19 patients assessed in their study were thrombocytopenic [16]. In our study, we did not find a low number of platelets in severe COVID-19 patients (Table 1, Mean/std deviation; 231,1±92.8). Although the platelet count alone does not provide information about the prognosis of the disease, PMI may guide the clinician as an indicator of lung damage in seriously ill patients.

PMI is calculated in automated hemogram devices; it should be kept in mind that it can be used in routine follow-up.

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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Ugur Fahri Yurekli, Umran Liste, Burcu Ertunc, Mehmet Tercan, Mehmet Tahtabasi. Could platelet mass index (PMI) be a new prognostic biomarker for COVİD-19? Ann Clin Anal Med 2022;13(1):72-75

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Comparison of postoperative clinical effects of erector spinae plane block and patient controlled analgesia in thoracotomy patients

Murat Bagdas, Ayşe Mizrak Arslan, Elzem Sen, Lutfiye Pirbudak

Department of Anesthesiology and Reanimation, University of Gaziantep, School of Medicine, Gaziantep, Turkey

DOI: 10.4328/ACAM.20852 Received: 2021-09-12 Accepted: 2021-10-11 Published Online: 2021-10-18 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):76-79

Corresponding Author: Elzem Sen, Department of Anesthesiology and Reanimation, University of Gaziantep, School of Medicine, 27310, Gaziantep, Turkey. E-mail: drelzemsen@gmail.com P: +90 532 784 21 51 Fax: +90 342 360 39 98 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3001-7324

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Aim: The aim of this study was to compare Erector Spinae Plane (ESP) block and Patient Controlled Analgesia (PCA) methods for postoperative analgesia in patients undergoing thoracotomy surgery in terms of clinical efficacy and complication.

Material and Methods: The study included 80 patients who had thoracotomy surgery, 40 of whom had ESP block (Group E) and 40 of whom had PCA (Group P). Demographic data were recorded. In Group E patients, ESP block was administered with 20 ml of 0.5% bupivacaine accompanied by ultrasound, patients in Group were administered 10 μg/ml of fentanyl with 2 ml/h baseline and 2 ml bolus doses with a 15-minute lock-up period. The VAS (Visual Analog Scale) and NRS (Numerical Rating Scale) scores of the groups, time of the first additional analgesia, total amount of additional analgesic consumed, and side effects (nausea-vomiting, pruritus) were recorded.

Results: VAS and NRS scores were significantly lower in Group E (p<0.05). The duration of initial analgesia demand in Group E was longer, and the total opioid consumption was significantly lower in Group E (p<0.05). The incidence of nausea, vomiting and pruritus was significantly lower in Group E than in Group P (p<0.05).

Discussion: The ESP block is an effective analgesic technique in patients undergoing thoracotomy surgery, providing lower VAS and NRS values and lower opioid consumption with minor side effects in comparison to PCA.

Keywords: Erector Spinae Block, Patient Controlled Analgesia, Postoperative Analgesia, Thoracotomy

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Introduction

A thoracotomy involves one of the most painful surgical incisions, and the resulting pain is one of the leading causes of decreased respiratory function. Decreasing this pain is of vital importance for the prevention of atelectasis and the facilitation of cough, and also for patient comfort [1].

The erector spinae plane block (ESP) technique was first defined by Forero et al. for blocking thoracic neuropathic pain, and since then there have been few studies on its use for postoperative analgesia in different surgical procedures [2,3]. In this technique, a local anesthetic (LA) is injected under the erector spinae muscle, and the LA is expected to be distributed cranially to three vertebral levels and caudally to four levels [4]. Another method of pain control is patient-controlled analgesia (PCA), which was first described by Sechzer in 1968 as an intravenous opioid application. A system in which the patient controls the dose of the analgesic drug was developed after the use of low doses of intravenous (IV) opioid applications was demonstrated to be superior to conventional methods [5].

The present study makes a comparison of the postoperative analgesic PCA and ESP block techniques in terms of clinical efficacy and complications in patients undergoing thoracotomy surgery.

Material and Methods

The present retrospective study was conducted in accordance with the principles of the Declaration of Helsinki and was launched following approval by the Local Ethics Committee (2019/447). After informed consent was obtained, the medical records of patients who had undergone routine PCA or US- guided ESP were accessed, and those aged 18–70 years and with an ASA score of I, II or III who underwent ESP block or PCA application as a postoperative analgesic technique following thoracotomy surgery, between March 1 and November 1, 2019 were included in the study. Patients with missing medical data were excluded from the study.

The patients were divided into two groups as Group E (ESP block) and Group P (PCA), with 40 patients in each group. Patients in Group E were placed in a lateral position following thoracotomy surgery, and the nerve block was applied before emergence from anesthesia. Sterile gloves were used and the puncture site was sterilized using 10% povidone iodine (Isosol®), in accordance with asepsis-antisepsis rules, and a sterile drape was applied. The ESP block was performed under USG guidance (GE Logiq E brand USG and Linear IO 4–12 MHz probe) with a 2–4 cm adjustable depth, at a frequency of 10–12 MHz. The probe was placed approximately 3 cm lateral to the T5 spinous process on the parasagittal plane, and an 85-mm block needle (Echoplex, 21G nerve block needle) was introduced through the skin using the in-plane approach. The trapezius, rhomboid and erector spinae muscles were passed through, and when the needle touched the transverse process (approximately 2.5–3 cm depth), a test dose of 1 ml of 0.9% NaCl was administered between the fascia of the erector spinae muscle and the transverse process of the vertebra, and the location of the needle and the cranio-caudal distribution were confirmed. The ESP block was subsequently applied with the administration of 20 ml of 0.5% bupivacaine into the erector spinae region. For

Group P, 10 μg/ml fentanyl in a 100 ml isotonic NaCl solution was prepared 45 minutes before the end of the operation, and was administered through a PCA device (CADD-Legacy® 6300 ambulatory infusion pump) at a 2.0 ml/h basic rate, with 15 minutes of lockout duration and 2.0 ml bolus doses.

All patients received 100 mg tramadol IV as a standard dose at the end of the operation, prior to awakening from the anesthesia. Then patients were transferred to the intensive care unit (ICU) for close monitorization. The VAS (visual analog scale) was applied to all patients (in which the patient was asked to indicate the appropriate level of pain [in mm] on a 100 mm scale of 0–100, in which 0 = no pain, and 100 = most severe pain) [6] and the NRS (numerical rating scale) (in which the patient reports the severity of pain on a scale in which 0 equates to no pain and 10 equates to the most severe pain) at postoperative hours 0, 1, 6, 12 and 24 [7]. Furthermore, the time of administration of the first analgesic and the requirement for additional analgesics, the total analgesic IV dosage over 24 hours, and the presence of nausea, vomiting, itching or shoulder pain were all recorded. Tramadol 100 mg IV was administered as an additional analgesic to patients with a VAS of 40–50 mm, and morphine 3 mg subcutaneously to patients with a VAS of >50 mm. Metoclopramide 10 mg IV was given to patients who developed nausea and vomiting.

Statistical Analysis

The minimum number of patients in each group required to achieve a difference of 1±1.48 units was determined as 36 as significant (α=0.05, 1-β=0.80). G power version 3.1 was used for the analysis of data. The Shapiro-Wilk test was used to evaluate the normal distribution of numerical variables; we have shown the numerical (quantitative) data by descriptive statistics as mean±SD and median (Q1-Q3) depending upon normality and nominal data as n (%). A two-group comparison of the normally distributed data was made using the Student’s t-test, while non-normally distributed were numerical variables using Mann- Whitney U test. Associations between categorical variables were tested with a Chi-square test. IBM SPSS Statistics for Windows (Version 22.0. Armonk, NY: IBM Corp.) was used for the analyses. P<0.05 was accepted as significant.

Results

A total of 80 patients were included in the study, with 40 patients assigned to each group. Of the total, 26.2% (n=21) were females and 73.8% (n=59) were males; the mean age was 50.90±15.28 years with an age range of 18–70 years; and the mean BMI was 24.36±5.39. No statistically significant differences were noted in the descriptive variables of the two groups (p>0.05) (Table 1).

Comparison of the MAP (Mean Arterial Pressure) in the two groups revealed statistically significantly lower values in Group E than in Group P at four measurement times other than at hour 0 (p<0.05).

Comparison of the VAS scores in groups E and P revealed p-values of 0.001 at hour 0, 0.005 at hour 1, <0.001 at hour 6, 0.004 at hour 12 and 0.003 at hour 24. Comparison of the NRS scores in Groups E and P revealed p-values of 0.003 at hour 0, 0.008 at hour 1 and 0.002 at hour 6. The VAS and NRS values were found to be statistically significantly lower in Group E than

in Group P at 0, 1 and 6 hours, and VAS values were found to be statistically significantly lower in Group E than in Group P at 12 and 24 hours (Table 2).
The difference between the two groups in the start time of morphine administration was statistically insignificant (p=0.072). The time of the first tramadol dose following the 100 mg standard tramadol administration was found to be later in Group E than in Group P, although not statistically significant (p=0.594).

The amount of morphine administered at postoperative hours 0, 1, 6, 12 and 24 was found to be statistically significantly lower in Group E than in Group P (Postoperative hour 0 [p=0.003], hour 1 [p=0.001], hour 6 [p<0.001], hour 12 [p=0.005] and hour 24 [p=0.002]). The total amount of tramadol consumed at hours 12 (p=0.043) and 24 (p=0.018) was found to be statistically significantly lower in Group E than in Group P (Table 3).
The number of patients with nausea and vomiting in the two groups was compared, and it was present in 20% (n=8) and 47.5% (n=19) of the patients in Groups E and P, respectively (p=0.009). Pruritus was observed in 15% (n=6) and 40% (n=16) of the patients in the E and P Groups, respectively (p=0.012).

Discussion

In this retrospective clinical study, we compared ESP block and PCA through an analysis of 80 patients undergoing thoracotomy surgery. It was found that the postoperative pain scores in patients who were applied the ESP block technique were statistically significantly lower than in those who were applied the PCA technique. Furthermore, additional analgesics were started later in the ESP block group, lower doses of additional analgesics were required, and incidences of nausea- vomiting and itching were lesser in this group of patients. In addition, when vital signs were evaluated, MAP values were within physiological ranges and were statistically significantly lower in patients with ESP block.

Various approaches to analgesia have been suggested for the management of acute post-thoracotomy pain, among which PCA is a common approach that has long been used for the resolution of pain, and allows the patient to self- administer the analgesic. Both non-opioid and opioid agents may be used in PCA applications. As a new interfascial approach, ESP block has recently been identified as a simple and safe alternative analgesic technique for post-surgical thoracic pain [8-10]. Tulgar et al. [11] reported ESP block to be an efficient and safe interfascial plane block when used as a part of a multimodal analgesia plan. Given the ease of the US-guided ESP block technique, the distance maintained from the pleura, neuroaxial and vascular structures, and the subsequent lower rate of complications, ESP block can be recommended for postoperative analgesia in patients who have undergone thoracic surgery. Its distribution to a large dermatomal area without the need for multiple injections is another advantage of this technique. Ciftci et al. [12] in their study evaluating the efficacy of ESP block after VATS applied an ESP block of 20 ml of 0.25% bupivacaine, while the control group received no such application. Comparison of the VAS scores revealed similar results to those recorded in the present study, with statistically significantly lower values identified in the ESP group than in the control group. He et al. [13] applied a block using 0.5% ropivacaine 20 ml in the ESP group, while no such application was made in the control group. Subsequently, the pain experienced by the patients, evaluated with a VAS, was statistically significantly lower in the ESP group than in the control group, which concurs with the findings of the present study.

Gurkan et al. [4] in their study evaluating the effect of ESP block on postoperative opioid consumption after breast surgery applied a block at the T4 level using 20 ml 0.25% bupivacaine in an ESP Group. NRS scores were found to be lower in the ESP block group than in the control group. In a study by Sharma et al. [14], ESP block was applied in the ESP group at level T5 using 0.5% ropivacaine in a dose of 0.4 ml/kg following a total mastectomy, while the control group did not undergo any intervention. Similar to the present study, patient-reported NRS values were statistically significantly lower in the group with ESP block than in the control group.
In a study by Yayik et al. [15], evaluating the efficacy of ESP block for postoperative analgesia in patients who had undergone lumbar spinal decompression surgery, ESP block of 20 ml 0.25% bupivacaine was applied to one group, while the other group received no intervention. The authors recorded a statistically significantly shorter time until the first request for additional analgesia in the ESP block group than in the control group, similar to the present study. Abu Elyazed et al. [16] applied a bilateral ESP block of 0.25% bupivacaine in a dose of 20 ml at level T7 in their study evaluating the effects of ESP block in patients who underwent open epigastric hernia repair. The mean duration until the first request for additional analgesia was 455 minutes and 30 minutes in the patients who underwent ESP block and the control group, respectively.

Yao et al. [17], in their study evaluating the effect of ESP block after VATS on the quality of postoperative healing, applied an ESP block to half of the patients in the form of 20 ml of 0.5% ropivacaine, and normal saline at the same level to the remaining patients as controls. Total opioid consumed was reported to be statistically significantly lower in the ESP group than in the control group in the first 24 hours. In a study by Seelam et al. [18] evaluating the efficacy of ESP block in post-mastectomy patents, the block applied in the ESP group was 30 ml 0.25% bupivacaine at level T3, while the control group received no block. The total postoperative morphine consumption in the study was similar to that reported in the present study, being statistically significantly lower in patients with ESP block.

The major side effects recorded in the present study were nausea-vomiting and itching, which were observed to be statistically significantly lower in the group with ESP block. The reason for the higher incidences of both side effects observed in the group with PCA in the present study was attributed to the greater amounts of opioids consumed [19,20]. In a study by Yao et al. [17] in which an ESP block was administered to the experimental group after VATS, the incidence of nausea- vomiting was found to be higher in the control group than in the ESP group.

Further extensive multicenter studies are needed to better understand the effects, indications and contraindications of this block.

Conclusion

ESP block was found to lengthen the duration of the requirement for first postoperative analgesic administration, to decrease the additional and total analgesic requirement, and to decrease the side effects associated with opioid analgesic use in patients who have undergone thoracotomy. We thus suggest ESP block as a good alternative to pain control following thoracotomy.

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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3. Tulgar S, Senturk O. Ultrasound guided Erector Spinae Plane block at L-4 transverse process level provides effective postoperative analgesia for total hip arthroplasty. J Clin Anesth. 2018; 44: 68.

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8. De Cassai A, Bonvicini D, Correale C, Sandei L, Tulgar S, Tonetti T. Erector spinae plane block: a systematic qualitative review. Minerva Anestesiol. 2019; 85:308-19.

9. Fiorelli S, Leopizzi G, Menna C, Teodonio L, Ibrahim M, Rendina EA, et al. Ultrasound-Guided Erector Spinae Plane Block Versus Intercostal Nerve Block for Post-Minithoracotomy Acute Pain Management: A Randomized Controlled Trial. J Cardiothorac Vasc Anesth. 2020; 34(9):2421-9.

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15. Yayik AM, Cesur S, Ozturk F, Ahiskalioglu A, Ay AN, Celik EC, et al. Postoperative Analgesic Efficacy of the Ultrasound-Guided Erector Spinae Plane Block in Patients Undergoing Lumbar Spinal Decompression Surgery: A Randomized Controlled Study. World Neurosurg. 2019; 126;e779-85.

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Murat Bagdas, Ayşe Mizrak Arslan, Elzem Sen, Lutfiye Pirbudak. Comparison of postoperative clinical effects of erector spinae plane block and patient controlled analgesia in thoracotomy patients. Ann Clin Anal Med 2022;13(1):76-79

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Effects of three different embedding media on the accuracy of different electronic apex locators: An in vitro study

Hamza Cudal 1, Bertan Kesim 1, Tuğrul Aslan 2

1 Department of Endodontics, Faculty of Dentistry, Nuh Naci Yazgan University, 2 Department of Endodontics, Faculty of Dentistry, Erciyes University, Kayseri, Turkey

DOI: 10.4328/ACAM.20854 Received: 2021-09-13 Accepted: 2021-10-11 Published Online: 2021-10-19 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):80-83

Corresponding Author: Bertan Kesim, Department of Endodontics, Faculty of Dentistry, Nuh Naci Yazgan University, Kuzey Çevreyolu Erkilet Dere Mah. Nuh Naci Yazgan Üniversitesi Yerleşkesi, Kocasinan, Kayseri, Turkey. E-mail: bertankesim@gmail.com / bkesim@nny.edu.tr P: +90 505 240 13 39 / +90 352 324 00 50 Fax: +90 352 324 00 04 Corresponding Author ORCID ID: https://orcid.org/0000-0001-9192-5487

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Abstract

Aim: In this study, we aimed to evaluate in vitro the measurement accuracy of three electronic apex locators (EALs) in three different embedding media.

Material and Methods: Thirty maxillary central incisors were included (N = 30). The specimens were decoronated at cement–enamel junction, and the soft tissues in root canals were removed. The samples were randomly divided into three groups (n = 10). The specimens were embedded in alginate (group A), gelatin (group B) and agar agar (group C), leaving the coronal 2 mm of teeth exposed. Electronic lengths (ELs) of root canals of samples were measured using Raypex 6 (VDW, Munich, Germany), Apex ID (SybronEndo, Glendora, USA) and Ipex 2 (NSK Inc., Kanuma, Japan). In all groups, actual length (AL) values subtracted from EL values, and EL–AL values were recorded.

Results: The EL–AL values for each embedding media were classified within an error range of ± 0.5 mm and ± 1 mm, and the chi-square (χ2) test was used to compare the percentage of acceptable measurements of three EALs (α = 0.05). The measurements of Raypex 6 in agar agar medium were statistically different compared with those in alginate and gelatin media, within the error margin of ± 0.5 mm (p < 0.05). Both in alginate and gelatin media, no statistically significant difference was observed in percentages of acceptable measurements with Raypex 6, Apex ID and Ipex 2 within two ranges of error (p > 0.05).

Discussion: Within the limitations of this study, alginate and gelatin can be used safely as embedding media in studies investigating the in vitro measurement accuracy of EALs.

Keywords: Apical Foramen, Root Canal, Alginate

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Introduction

The success of root canal treatment (RCT) is closely linked to the accurate determination of the working length [1]. Therefore, various ideas have been put forward to establish the apical termination of root canal preparation (RCP) and root canal filling. Theoretically, the cemento–dentinal junction (CDJ) has been proposed as the ideal apical limit of the RCP, which is the major exit point of the root canal system (RCS), and is also a structural and biological link between cementum and dentin in the roots of the teeth [2]. However, the CDJ is practically indistinguishable on clinical examination and can only be detected in histological sections, and the lower border of the CDJ shows wide variations within the root canal lumen [3]. Therefore, the apical constriction, which is the narrowest diameter of the root canal in the apical portion of the RCS, seems to be a more plausible anatomical landmark for the endpoint of endodontic treatment [4].

Radiographic methods have some limitations in determining the working length of RCP, such as lack of depth perception of two-dimensional vision, visual artifacts and superpositions in the images, inability to fully evaluate the variances in apical root anatomy [5], and radiation exposure. Contemporary electronic apex locators (EALs) have been introduced to overcome the limitations of radiographic methods, and most of these devices can locate the apical constriction with high accuracy [6, 7]. In previous studies, the measurement accuracy of different EALs has been extensively studied, both in vivo [8, 9] and in vitro [10, 11]. In vitro studies of EALs were performed using different electroconductive embedding media to simulate clinical conditions [12, 13]. These embedding media complete the required electrical circuit while mimicking periradicular tissues that adhere to the tooth roots and support the teeth. The effects of various embedding media, such as agar agar [14], gelatin [15] and alginate [16], on the accuracy of EALs have been investigated in previous studies. Therefore, this study aims to compare the effects of three tooth embedding media on the accuracy of three EALs.

Material and Methods

Thirty extracted human maxillary central incisors were used in the study. Care was taken to ensure that the selected teeth were single-rooted and had normal canal anatomy. Teeth with curved and calcified root canals and teeth with excessive tissue loss were excluded from the study. Apical patency was established by inserting a size 10 K-file (Dentsply Maillefer, Ballaigues, Switzerland) into the root canal until its tip was visualized in the apical foramen. The crowns of all samples were removed at the cement–enamel junction with a low- speed diamond saw (Metkon Instruments Inc., Bursa, Turkey) to set a standard reference point to determine the working length. Coronal flaring was achieved, and soft tissues in the RCS were removed using WaveOne Gold (tip 25, 0.07v taper; Dentsply Sirona, Ballaigues, Switzerland). The root canals were irrigated with 5 mL of 2.5% NaOCl (Werax, Izmir, Turkey) during the RCP. Prior to electronic measurement, the actual lengths (ALs) of root canals were determined using a size 25K-file (Dentsply Maillefer) until its tip became visible from the apical foramen under a dental operation microscope (Carl Zeiss Gmbh., Jena, Germany) at 10× magnification. The distance between the file tip and the stopper was measured with digital calliper (Insize Mini Digital Calliper; Istanbul, Turkey) with an accuracy of 0.01 mm. The samples were randomly divided into three groups of 10 samples each (n = 10). In group A, the specimens were embedded in alginate, with the coronal 2 mm of teeth left exposed. The electronic lengths (ELs) of the root canals of the samples were measured using Raypex 6 (VDW, Munich, Germany), Apex ID (SybronEndo, Glendora, USA) and Ipex 2 (NSK Inc., Kanuma, Japan). In groups B and C, specimens were embedded in gelatin and agar agar, respectively, and all procedures were repeated in the same manner as those in group A. In all groups, AL values were subtracted from EL values, and EL–AL values were recorded.

Statistical Analysis

All statistical analyses were performed using statistical software SPSS 22.0 (SPSS Inc., Chicago, IL, USA) (α = 0.05). The normality of the data was evaluated using the Shapiro–Wilk test, which revealed that all data were normally distributed (p > 0.05). Descriptive statistics (mean and standard deviation) of the EL–AL values for the different EALs tested in different embedding media were calculated (Table 1). The EL–AL values for each embedding media were classified within the error range of ± 0.5 mm and ± 1 mm. The chi-square (χ2) test was used to compare the percentage of acceptable measurements of the three EALs (α = 0.05).

Results

Table 2 shows the success rates of the three EALs in different embedding media within two ranges of error. The measurements of Raypex 6 in the agar agar medium were statistically different compared with those in the alginate and gelatin media, within the error margin of ± 0.5 mm (p < 0.05).

When using the error range of ± 0.5 mm in the agar agar test medium, the percentage of acceptable measurements of Raypex 6 was statistically significantly lower than that of Ipex 2 and Apex ID (p < 0.05). Both in the alginate and gelatin groups, no statistically significant difference was observed in the percentages of acceptable measurements of Raypex 6, Apex ID and Ipex 2 within two ranges of error (p > 0.05).

Discussion

Electroconductive media are needed to simulate periradicular tissues in in vitro studies of EALs. The most commonly used embedding media are alginate [17], gelatin [1], agar agar [18, 19] and saline solution [20]. In Baldi et al.’s study [12], saline solution was found to be the most unfavorable embedding medium that interfered with the accuracy of EALs. This is why we did not include the saline solution in the current study. According to Gordon et al. [21], apical constriction is located at an average distance of 0.5 mm from the apical foramen. Thus, the actual working length was calculated by visualizing the tip of a size 10 K-file through the apical foramen of each sample and then subtracting 0.5 mm from the length of the file. This method has been used in previous studies [13, 22]. During RCP, 2.5% NaOCl is one of the most frequently used root canal irrigation solutions. Several studies have reported that NaOCl did not affect the determination of working length using EALs [18, 23]. Thus, we used 2.5% NaOCl as the root canal irrigant in the present study.

In a previous study [13], high accuracy was demonstrated in the measurements of alginate-embedded samples using the Raypex 5, whereas the measurement accuracy of Dentaport ZX in alginate-embedded samples was statistically significantly low. In our study, the group A samples were embedded into alginate mass, and no statistically significant difference was found in the accuracy of the three EALs within two error margins (± 0.5 mm and ± 1 mm). These favorable results may be attributed to the fact that the working principle of all three EALs relies on two-frequency basis. Using the error range of ± 0.5 mm, the accuracy rates of the EALs were 90% for Raypex 6, 100% for Ipex 2 and 90% for Apex ID. Minor differences in the success rate of these EALs may be related to the variances in the apical anatomy of the samples; these minor differences were not statistically significant.

For Root ZX in gelatin-embedded samples, Baldi et al. [12] found an accuracy rate of 60% within the ± 0.5 mm range of error and 96.7% within the ± 1 mm range of error. In our study, all group B samples were embedded in gelatin, and there was no statistical difference in the measurement accuracy of the three EALs in the gelatin group (p > 0.05). The high-accuracy measuring capability of the contemporary EALs used in this study may be related to the working characteristics of these EALs using more than one frequency signal and the calculation manner of these EALs, which rely on impedances rather than resistances.

Marroquin et al. [19] investigated the effect of the size of root canal instruments on the accuracy of EALs using agar agar- embedded teeth samples. In the aforementioned study, although no statistically significant difference was found in the success rate of the EALs for the working length determination, the most accurate results were obtained using the Raypex 5 [19]. In the current study, when using the ± 0.5 mm range of error, the lowest success rate was found using Raypex 6 (40%) among the three EALs in teeth embedded in agar agar medium (p < 0.05). The conductivity of an electrolyte is affected by the density and mobility of the charge carriers [24]. A higher quantity of mobile charge carriers in a polymer electrolyte occurs as a result of the interaction between the salt and the polymer host [25]. Based on this information, the statistically significant lower accuracy rate of agar agar as an embedding medium may be associated with the unpredictable chemical properties of the agar molecule. No statistical difference was found in the measurement accuracy between Ipex 2 and Apex ID within a ± 0.5 mm range of error in the agar agar test medium (p > 0.05). This suggests that the technical specifications of Raypex 6 may not be suitable for use in agar agar test medium. Our study revealed that alginate and gelatin could be used safely with contemporary EALs as embedding media. However, there is a need for new studies to reassess the reliability of agar agar as a test medium, performed with modern EALs.

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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Hamza Cudal, Bertan Kesim, Tuğrul Aslan. Effects of three different embedding media on the accuracy of different electronic apex locators: An in vitro study. Ann Clin Anal Med 2022;13(1):80-83

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Serum vitamin D status in pediatric critical care

Gizem Kaynar Beyaz 1, Seher Erdoğan 2, Gürkan Atay 2

1 Department of Pediatrics, T.C Hatay State Hospital, Hatay, 2 Department of Pediatric Critical Care, Health Sciences University, Umraniye Training and Research Hospital, Istanbul, Turkey

DOI: 10.4328/ACAM.20855 Received: 2021-09-13 Accepted: 2021-10-12 Published Online: 2021-10-25 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):84-88

Corresponding Author: Gizem Kaynar Beyaz, Department of Pediatrics, Hatay State Hospital, Hatay, Turkey. E-mail: gizemkaynar@gmail.com P: +90 505 806 11 42 Corresponding Author ORCID ID: https://orcid.org/0000-0002-8294-9791

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Aim: Vitamin D deficiency (VDD) is a huge public health problem affecting people of all ages, races, and genders. Studies performed in pediatric intensive care units (PICUs) found a prevalence of VDD between 30% and 70%, and it was shown that VDD was related to a more severe disease course and a longer PICU stay. The aim of our study was to investigate the prevalence of VDD at PICU admission and its relationship between disease type, severity, and prognosis.

Material and Method: The medical records of pediatric patients aged 1 month-17 years who were admitted to PICU between March 2017 and March 2018 were retrospectively reviewed. The patients’ pediatric mortality risk score (PRISM), 25-hydroxyvitamin D(25(OH)vitD) level at admission, serum calcium (Ca), phosphorus (P), magnesium (Mg), and alkaline phosphatase (ALP) levels were recorded. Blood 25(OH)VitD level ≤20 ng/mL was defined as VDD. Patients with low 25(OH)VitD levels (≤20 ng/mL) were grouped as ‘Group-1’, those without (>20 ng/mL) were grouped as ‘Group-2’.

Results: Among the patients, 55 (56.7%) had VDD. The mean 25(OH)D level was 12.7 ng/ml in Group 1 and 27.8 ng/ml in Group 2. Patients in Group 1 had a greater age, body weight, and height, but BMI (body mass index) was not significantly different between both groups. The two groups also did not differ significantly with respect to race, gender, admission season, underlying disease, PRISM score, sepsis rate, vasoactive agent need, mechanical ventilation support, number of days on mechanical ventilation, number of days of PICU stay, and mortality rate.

Discussion: As the prevalence of VDD is high among pediatric critical care patients, it is important to perform screening and administer effective replacement therapy to these patients. We believe that assessment of the relationship between vitamin D and disease duration, severity, and prognosis, and determining optimal vitamin D dose, administration route, and safety profile through prospective controlled studies could affect morbidity and mortality rates.

Keywords: Vitamin D, Pediatric Intensive Care, Mortality, Illness Severity

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Introduction

VDD is a major public health problem affecting people of all ages, races, and genders. Previous studies have shown that VDD is endemic in both children and adults and is related to increased viral respiratory infections and sepsis [1,2]. A reduction in the incidence of influenza infections was observed among children receiving vitamin D replacement therapy [3]. It has been reported that the level of cathelicidin, an antimicrobial peptide, was lower particularly among adult patients with VDD suffering sepsis [4]. Studies conducted in PICUs revealed that the prevalence of VDD ranges between 30% and 70%, and VDD has been shown to correlate to a more severe disease course and a longer PICU stay [5-7].

Similar to the general population, most children with reduced consumption of certain foods and exposure to inadequate number of ultraviolet rays are also subject to vitamin D deficiency before disease onset. Critical disorders and some interventions (surgery, fluids, extracorporeal membrane oxygenation, cardiopulmonary bypass, plasma exchange) may markedly reduce 25(OH)D level. Hepatic, parathyroid, and organ dysfunctions (reduced hydroxylation) and increased tissue demand during catabolism, reduced endogenous production, and malabsorption due to intestinal edema also play a role in reduced 25(OH)D level [8].

Our study aimed to investigate the relationship between VDD’s prevalence at PICU admission and its relationship with disease type, severity, and prognosis among critically ill pediatric patients.

Material and Methods

The medical records of pediatric patients aged 1 month-17 years who were admitted to Health Sciences University, Umraniye Training and Research Hospital, Pediatric Intensive Care Unit between March 2017 and March 2018 were retrospectively reviewed. Patients with rachitism, postoperative cardiac patients, patients with missing information, and patients that stayed at PICU for less than 24 hours were excluded. The patients’ age (months), gender, admission diagnosis, underlying disorders, vasopressor need, septic status, intensive care unit stay, and days on mechanical ventilator were recorded. Pediatric mortality risk score (PRISM) calculated from the patients’ data in the first 24 hours, serum 25(OH) D level measured at admission, and serum Ca, P, Mg, and ALP levels were recorded. Prematurity is one of the important risk factors for vitamin D deficiency. Therefore, patients with a history of premature birth were excluded from the study. Vitamin D deficiency was defined as a 25(OH) D level < 20 ng/ml regardless of age group, therefore, patients were evaluated without subgrouping according to their age.

The 25(OH)D level was measured by the chemiluminescence method (Abbott Architect 2000). Serum 25(OH)D level ≤20 ng/ mL was defined as VDD (7,8,17,18,). The patients were grouped into two according to the blood l 25(OH)D levels. Patients with low 25(OH)D levels (≤20 ng/mL) were termed as ‘Group-1’, and those without (>20 ng/mL) as ‘Group-2’.

Sepsis was defined by the presence of systemic inflammatory response syndrome coupled with clinically or microbiologically documented infection. Statistical analyses in the study were carried out under three subtitles as descriptive, univariate, and multivariate analysis methods. Criteria of normal distribution were tested for numeric variables. Two independent study groups were compared using the Mann-Whitney U test and more than two independent groups using the Kruskal-Wallis test for non-normally distributed numeric variables. Categorical variables were compared with the Chi-square test between two independent groups. Multivariate analyses were carried out with Cox regression analysis for censored time-to-event data; a logistic regression model was used for dichotomized data structures used for mortality assessment; and multivariate linear regression analysis was used for assessment of quantitative vitamin D level. A two-sided hypothesis structure and a 5% Type-1 level of error were used for all statistical analyses. Data analyses were performed using the SPSS 21 (IBM Corp. in Armonk, NY, USA) software package.

This study was approved by Health Sciences University, Ümraniye Training and Research Hospital.

Results

Among the study population, 52 (53.6%) were females and 45 (46.4%) were males. The mean age of the study population was 58.2±39.1 months; the mean weight was 18.7±15.7 kg; the mean height was 98.0±32.4 cm; the median BMI was 16.6±3.7 (Table 1). The most common cause of PICU admission was acute respiratory failure (31, 32%), followed in descending order by neurological disorders (27, 27.8%) and infectious disorders (22, 22.7%); 37.1% of the patients had received vitamin D replacement.

Admissions most commonly occurred in fall (36.1%), followed in descending order by summer (25.8%), spring (23.7%), and winter (14.4%).
The incidence of sepsis was 66%; the rate of inotropic infusion was 21.6%; the proportion of patients receiving mechanical ventilation and respiratory support was 46.4%.

Among the patients, 87.6% were of Turkish nationality and 12.4% were foreigners. The mean duration of mechanical ventilation was 16.2±29.8 days; and the mean duration of intensive care unit stay was 15.8±23.8 days. Eighty-one (83.5%) patients were discharged and 16 (16.5%) patients were lost. Group 1 had a mean 25(OH)D level of 12.7 ng/ml and Group 2 had a mean 25(OH)D level of 27.8 ng/ml. Group 1 had a greater age, body weight, and height (p:0.021, p:0.003, and p:0.004, respectively). There was no significant difference with respect to BMI (p:0.130). The two groups showed no significant differences in race, sex, admission season, underlying disorder, PRISM score, sepsis rate, need for inotropic infusion, MV support, number of days of PICU stay, number of days of MV support, and mortality rate. Similarly, laboratory values were also similar between the two groups (p<0.05) (Table 2).

The patients were compared with respect to prognosis; significant differences were found with regard to sepsis status, need for inotropic infusion, need for respiratory support with MV, number of MV days, number of PICU days, PRISM score, and serum calcium level; however, there were no significant differences in 25(OH)D levels and other laboratory values (Table 3).

Discussion

In studies performed in pediatric intensive care units, the prevalence of VDD has been reported to be 30% to 70%. In a study from Turkey conducted by Aşılıoğlu et al [9], which comprised 205 pediatric intensive care unit patients, the prevalence of VDD was 58.5%. That study also reported that multivariate analysis revealed a significant correlation only between patient age and winter season; it also revealed that patients with VDD were older, heavier, and had a greater rate of vasopressor need, but both groups were similar with respect to PRISM score and mortality rate. In a study by Elmoneim et al [10], which was performed among pediatric critical care patients, a correlation was found between 25(OH)D level and duration of intensive care unit stay and number of days on mechanical ventilator, but no correlation existed between mortality and 25(OH)D level. We found a VDD prevalence of 56.7%. Similar to that study, we found no significant difference between the study groups with respect to duration of PICU and hospital stay, MV need, PRISM score, and mortality rate. Unlike that study, there was no correlation between VDD prevalence and seasons; the two groups showed no significant difference in vasoactive agent use.

In a large-scale pediatric trial, it was reported that VDD was more prevalent among overweight children than in slim peers[11]. In our study, the mean body weight of patients with VDD was significantly lower than that of patients with a normal 25(OH)D level. This stemmed from a lower mean age of patients with VDD.

In a study comprising 101 critically ill pediatric patients, it was shown that patients with VDD had a higher mean age and a greater need for ventilator and vasoactive agent need. Multivariate analysis showed a correlation between VDD and duration of PICU stay, prism and pelod score, fluid bolus and ventilation need, vasoactive agent use, and mortality [12]. Unlike literature data, our study did not show any correlation with the presence of sepsis, vasoactive agent needs, mechanical ventilation needs, the number of days on mechanical ventilation, the number of days at intensive care unit, and mortality. These differences were attributed to variations of study groups, sunlight exposure, diet, climate, and the status of vitamin D replacement, as well as genotype variations of proteins involved in vitamin D transport, metabolism, and function.

In a study performed in 2016 at PICU, VDD prevalence was reported as 57%. Patients with VDD were younger, mostly male, and had more prominent renal dysfunction. VDD prevalence was also higher among patients admitted for cardiopulmonary disease [10]. Our study similarly showed that patients with VDD were younger, but the two groups did not differ significantly with respect to gender distribution. As we did expect lower 25(OH) D level among patients undergoing cardiovascular surgery, we excluded such patients.

Hebber et al [13] compared 61 PICU patients and 46 control subjects. They reported that 60% of PICU patients had VDD; on the other hand, the corresponding rate among the control subjects was 30%. They also reported that there was no correlation between 25(OH)D level and disease score (prism, pelod), and added that patients with asthma had a 25(OH)D level of 16.9 ng/mL, while those without it had a 25(OH)D level of 18.7 ng/mL. While 50% of patients admitted in the fall and winter had VDD, those admitted in spring and summer had a prevalence of 30% (p:0.003). Our study revealed that the VDD prevalence was 53% among patients admitted in the fall and winter, and 50% in those admitted in the spring and summer, showing no statistical significance.

Another study reported from Canada showed a significant difference between 25(OH)D levels at ward and PICU admission and that found at discharge (72 nmol/L and 49 nmol/L) [14]. In an adult population, Yi et al. [15] similarly reported a reduction in 25(OH)D level at 10- and 35-days periods.

Another study published in 2014 found a 25(OH)D level of 11.7 ng/mL among critically ill pediatric patients. In 71.4% of the patients, 25(OH)D level was low, in 46.2% of patients there was hypocalcemia, and 61.2% had elevated ALP level. No change was observed in 25(OH)D levels during patients’ hospital stay. No correlation was found between the PIM 2 score and 25(OH)D level, and no significant difference was evident between 25(OH) D levels of survivors and deceased ones [16]. Our study revealed a 25(OH)D level of 20.3 ng/ml, and 56.7% of the patients had a low 25(OH)D level. Both groups showed no significant differences in serum calcium, ionized calcium, phosphorus, and alkaline phosphatase levels. However, we showed that each unit of increase in the P level increased VDD prevalence by 1.54 times, while each unit of increase in the ALP level decreased VDD prevalence by 0.1%.

McNally et al. [11], in a multicenter study conducted in Canada, reported that the level of a 25(OH)D level was 67-75 nmol/L among healthy children and 43 nmol/L among critically ill children. They also reported that 25(OH)D level was lower among patients who needed a catecholamine infusion, had hypocalcemia, received fluid resuscitation in excess of 40 ml/ kg, and needed mechanical ventilation. The authors stated that acute reduction of 25(OH)D level was physiologically more prominent than chronic reduction, which occurred due to affection of compensatory mechanisms by inflammation and multiorgan dysfunction during the critical disease process. Another study reported in 2013 by the same author revealed that pediatric patients undergoing cardiopulmonary bypass had a mean preoperative 25(OH)D level of 60 nmol/L, with 42% having VDD; in the postoperative period, the mean 25(OH)D level was reduced to 35 nmol/L, while the prevalence of VDD increased to 84% [17]. Low postoperative 25(OH)D level was correlated to increased catecholamine need, fluid need, and longer duration of mechanical ventilation. The marked reduction in 25(OH)D among patients undergoing elective cardiac surgery was attributed to dilution secondary to volume expansion [18]. We linked the lack of correlation between catecholamine need, duration of mechanical ventilation, and 25(OH)D level to the exclusion of patients undergoing cardiovascular surgery. Another study performed in 2016 at PICU in Spain found a VDD prevalence of 43.8% and a mean 25(OH)D level of 22.28 nm/ mL. The patients with VDD had a higher mean age, PRISM score, morbidity rate, and patent educational level; they had more common admissions in the spring and winter; they also had a longer PICU stay. The authors reported that VDD increased morbidity by a factor of 5.4 [19].

Saboktakin et al. [20], in 2016 investigated vitamin D status among critically ill children. They administered 300.000 U vitamin D IM to patients with VDD and designated the patients with normal 25(OH)D level as a control group. They compared groups with and without vitamin D replacement. The control group had a longer duration at intensive care, mechanical ventilation, and a greater need for vasoactive agent use; however, study group had higher mortality. The authors reported that an adequate level of increase in 25(OH)D level could not be attained despite vitamin D replacement during hospitalization, especially for deceased patients.

Cechi et al. [21], in a study of 170 adult patients with sepsis, septic shock, and trauma, found that 25(OH)D level was lower in the sepsis group (p<0.001); mortality was higher in the sepsis group, but there was no correlation between 25(OH)D level and mortality. Ponnarmeni et al. [22] reported a lower 25(OH)D level among critically ill pediatric patients with sepsis compared with healthy controls (49.25 vs 68.7 nmol/L).

Vitamin D plays an important role for the induction of antimicrobial response against pathogens in humans. Among individuals with VDD, it has been shown that macrophages could not attain optimal regulation of cathelicidin protein (LL- 37) production, and vitamin D replacement improved LL-37 response to infectious signals [23]. Jeng et al. [24] showed a positive correlation between 25(OH)D level and plasma LL-37. However, in a similar study conducted in 2012, 25(OH)D level and disease score showed no significant correlation; VDD risk was greater in asthmatic patients [25].

In conclusion, VDD prevalence is higher among critically ill pediatric patients. Since the role of vitamin D in bone development and immunity is known, it is important to screen critically ill children and prescribe an effective replacement. We believe that assessment of the relationship between vitamin D and disease duration, severity, and prognosis and determining optimal vitamin D dose, administration route, and safety profile through prospective controlled studies could affect morbidity and mortality rates.

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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Gizem Kaynar Beyaz, Seher Erdoğan, Gürkan Atay. Serum vitamin D status in pediatric critical care. Ann Clin Anal Med 2022;13(1):84-88

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Endometrial injury and fertility outcome on the day of oocyte retrieval

Nurettin Turktekin 1, Cemil Karakus 2, Ramazan Ozyurt 3

1 Department of Operating Room Services, Nisantası University, Vocational School, 2 Vocational School of Health Services, Beykent University, 3 Istanbul IVF-Center, Istanbul, Turkey

DOI: 10.4328/ACAM.20856 Received: 2021-09-14 Accepted: 2021-10-10 Published Online: 2021-10-13 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):89-92

Corresponding Author: Nurettin Turktekin, Nisantası University, Vocational School, Operating Room Services Department, Istanbul, Turkey. E-mail: drnturktekin@gmail.com P: +90 532 798 38 44 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8167-3124

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Abstract

Aim: In this study, we aimed to investigate the effect of mechanical endometrial injury, performed on the day of egg retrieval, on pregnancy rates in patients who underwent IVF/ICSI due to PCOS and planned total embryo freezing.

Material and Methods: Sixty women with PCOS scheduled for total embryo freezing due to the risk of ovarian hyperstimulation syndrome were included in the study. The participants were randomly divided into two groups as treatment and control, with 30 patients in each group. For patients in both groups, standard antagonist protocol for controlled ovarian stimulation was applied. The patients in the treatment group underwent endometrial scratching with a Pipelle cannula after egg collection. The patients in the control group (sham) were reached up to the fundus with a Pipelle catheter, but scratching was not performed. The primary outcome measures of the study were beta-hCG, clinical pregnancy rates (CPR), live birth rates (LBR), and miscarriage rates.

Results: There was no significant difference between the two groups in terms of the percentage of beta-hCG positive patients, clinical pregnancy and live births (p>0.05). Clinical pregnancy and live birth rates of both groups were recorded as similar. No significant difference was found between the injury group and the control group in terms of miscarriages rates. All of the pregnancies in the scratching group and control group were intrauterine localized and no ectopic pregnancy was encountered.

Discussion: Injury to the endometrium on the day of egg collection does not cause a significant increase in clinical pregnancy and live birth rates.

Keywords: Mechanical Endometrial Injury, Oocyte Retrieval Day, Clinical Pregnancy, Live Birth, Miscarriage

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Introduction

Intentional endometrial injury (i.e. endometrial scratching) during ART in patients with recurrent implantation failure results in an approximately two-fold increase in both implantation and pregnancy rates [1,2]. However, many studies and reviews reported that the effects of injury on fertility outcome are not clear, thus there is not enough scientific data to recommend its routine use [3,4]. In connection with this, it has been reported that injury is not beneficial in patients with first IVF/ICSI trials and in unselected infertile patient groups [5,6]. Despite all these moderate quality study results, approximately 80% of infertility practitioners apply injury to their patients [7]. In many studies, mechanical injury is performed in the midlutel phase of the cycle, and IVF/ICSI is performed in the next cycle. However, in addition to studies that apply injury in the follicular phase, there are studies that have injury in both phases and achieve successful results [7]. There are a limited number of studies investigating the effects of injury on the day of egg collection on fertility outcome. In all but one of these studies, it was reported that the injury on the day of egg collection did not have an additional effect on implantation and pregnancy rates. In one study, the devastating effect of mechanical endometrial injury on implantation and clinical pregnancy rates on the day of egg retrieval was mentioned [8].

Although it varies according to the patient’s phenotype, PCOS is the most common endocrine disorder with subfertility. The mechanisms leading to subfertility in PCOS are phenotypic features such as hyperandrogenemia, ovarian morphology, or ovulatory dysfunction. In addition, the endometrium of PCOS patients is more resistant to embryo invasion and placentation than healthy individuals [9,10]. In PCOS cases, it may be possible to make the endometrium receptive by mechanical endometrial injury. Ovarian hyperstimulation syndrome (OHSS) is a life-treating complication in patients undergoing IVF/ICSI for PCOS. To prevent the development of OHSS in this patient group, total embryo freezing is one of the most important preventive measures [11]. Patients planned for total freezing due to the risk of OHSS are an ideal study group to investigate the effect of mechanical injury in PCOS. Therefore, this study was aimed to investigate the effect of mechanical endometrial injury, performed on the day of egg retrieval, on pregnancy rates in patients who underwent IVF/ICSI due to PCOS and planned total embryo freezing due to the risk of OHSS.

Material and Methods

Sixty women with PCOS scheduled for total embryo freezing due to the risk of ovarian hyperstimulation syndrome were included in the study. The two groups did not differ significantly in age and BMI. Patients were diagnosed with PCOS based on the revised Rotterdam criteria, which require two of the following three manifestations: (1) oligo and/or anovulation, (2) clinical and/or biochemical hyperandrogenism, and (3) polycystic ovaries determined with ultrasonography. Participants were selected among patients who applied to our IVF-Center for infertility treatment between 2019-2021. The study was started after obtaining patient consent and approval from the local ethics committee. Participants were randomly divided into two groups: treatment and control groups, with 30 patients in each group. For patients in both groups, a standard antagonist protocol for controlled ovarian stimulation was applied. rFSH treatment was started on the 2nd or 3rd day of the cycle. The gonadotrophin-releasing hormone antagonist was started on the 5th or 6th day of stimulation. Recombinant hCG (Ovitrelle, Merck-Serono, 250 mg, Modugno, BA, Italy) treatment was initiated when at least three follicles with a diameter of 18-20 mm were detected on ultrasonographic evaluation. Oocyte pick- up was performed 35 to 36 hours after hCG administration, guided by trans-vaginal ultrasonography. All embryos were vitrified as previously described. The patients in the treatment group underwent endometrial scratching with a Pipelle cannula after egg collection. The patients in the control group (sham) were reached up to the fundus with a Pipelle catheter, but scratching was not performed. Women with Asherman’s syndrome, endometrial polyp, submucous fibroids, uterine septum or other congenital uterine anomalies, hydrosalpinx, or endometrioma were excluded. Participants with a history of hormonal medication or intrauterine contraception use within the past 12 months and those with a history of habitual abortion or endocrine disorders were also excluded.

Following the OPU procedure, the injury procedure was performed while the patient was still under anesthesia. The injury procedure was performed in accordance with the previous studies. The Pipelle catheter was introduced through the cervix into the uterine fundus. The piston of the Pipelle cannula was withdrawn to create negative pressure and suction. Then the catheter was pushed back and forth in the cavity and withdrawn. The procedure was repeated until most of the cavity was injured and the procedure was terminated by removing the catheter from the cavity. In the control (sham) group, the Pipelle catheter was advanced through the cervix to the fundus and then removed from the cavity, but no injury was made. Following artificial endometrial preparation, the embryos were thawed and their qualities were examined. One or two good quality embryo transfer was performed to the patients in both groups in the following cycle after mechanical endometrial injury. Micronized progesterone was initiated vaginally for luteal support. Three patients in the treatment group and 4 patients in the control group were not transferred because they had clinical and laboratory findings of OHSS. The primary outcome measures of the study were to evaluate beta-hCG, clinical pregnancy rate (CPR), live birth rate (LBR), and miscarriage rate. The clinical pregnancy rate is defined as evidence of a gestational sac, confirmed by ultrasound examination at the 4th week of transfer. The live birth rate is defined as delivery of a live fetus after 24 completed weeks of gestational age. Serum beta-hCG levels were measured in all patients on the 12th day of embryo transfer. The loss of fetus before 20 weeks of gestation was defined as miscarriage.

Statistical analysis

All data were analyzed using the Statistical Package for Social Sciences software 21.0 for Windows package software (SPSS, Inc., Chicago, IL, USA). All parameters studied in the treatment and sham groups showed normal distributions, which were confirmed by the one-sample Kolmogorov-Smirnov test. During the statistical evaluation, ANOVA tests for continuous variables and Pearson’s chi-square tests for categorical variables were used. If the frequencies were less than we expected, Fischer’s exact test was used. Data were presented as mean ± SD. CPR, LBR, miscarriage rates and beta-hCG positive cases were given as percentages. P<0.05 was used for determining statistical significance.

Results

Demographic and cycle characteristics of the patients are shown in Table 1. Baseline characteristics of both groups were similar. There was no significant difference between the groups in terms of age, BMI, basal FSH and LH levels, endometrial thickness, and infertility duration in the participants. Both the number of oocytes collected from patients in both groups and the number of transferred embryos were recorded as similar. Mechanical endometrial injury was successfully performed in all patients in the treatment group. No complications were detected, except for pain and short-term spotting. A single dose of antibiotic prophylaxis was administered to the participants before the procedure. All cases in the control group successfully underwent the sham procedure, and no complications developed. As shown in Table 1, there was no significant difference between the two groups in terms of the percentage of beta- hCG positive patients, clinical pregnancy and live births. Clinical pregnancy and live birth rates in both groups were recorded as similar. Similarly, no significant difference was found between the injury group and the control group in terms of miscarriages rates. All pregnancies in the scratching group and control group were intrauterine localized, and no ectopic pregnancy was encountered.

Discussion

Implantation failure remains on the agenda as a rate-limiting step in the follow-up of infertile patients. For infertile patient groups suffering from this problem, the most effective method currently available is to expose the endometrium to controlled injury. However, there is no consensus in studies on the effects of endometrial injury on clinical pregnancy rates. While most of the studies have reported a significant increase in pregnancy rates in the post-injury period [1,2], some studies have reported that endometrial injury does not have a positive effect on pregnancy rates [5,6] and may even have detrimental effects on reproductive outcomes if the wrong cycle is applied [8]. We can list the main reasons for the inconsistency between injury studies as follows: (i) the participants are not homogeneous, (ii) the phase in which the injury is applied is different in each study, (iii) the injury method is different, (iv) the injury is done once in some studies and more than one in some studies. In addition to all these disadvantages, routine use of the method is not recommended since it has not been clearly demonstrated by which biological mechanisms injury increases pregnancy rates. However, it continues to be widely used by many infertility practitioners despite the mysteries of its mechanism of action and the possible harmful consequences of the described method [2,7]. In most of the injury studies, the method was applied either in the follicular phase or the luteal phase, or in both phases. The method can be performed either as an outpatient with a Pipelle cannula or with a hysteroscopy- guided Novak curette or electro cautery [1,2,8]. It has been reported that the effect on the fertility outcome does not change significantly depending on the phase of the cycle or the method applied. However, at one stage of ART practice, an important opportunity arises to apply injury to the patient. There are four studies designed to determine whether causing endometrial injury to a patient under anesthesia on the day of egg retrieval is beneficial [8,12-14]. In three of them, the injury was performed during egg collection, and the remaining one was on the day of embryo transfer.

Our study is the fourth study in the literature investigating the effects of endometrial injury on fertility outcome on the day of egg collection. In the present study, unlike other studies, the participants consisted of a homogeneous patient group diagnosed with PCOS, and total embryo freezing was performed in all of our patients. All patients underwent frozen embryo transfer in the next cycle. The patients in our control group consisted of patients diagnosed with PCOS without endometrial injury. Since the participants in both groups were similar in terms of demographic characteristics and age, the results obtained were homogeneous and more objective when compared. Our study clearly showed that there was no significant difference between the two groups in terms of the percentage of beta-hCG positive patients, clinical pregnancy rates and live birth rates. Similarly, there was no significant difference between the two groups in terms of miscarriage rates.

Our results are consistent with three of the four studies when compared with other studies with egg total day injury. In all these three studies, beta-hCG positivity and pregnancy rates after injury on egg collection day and/or transfer day were reported similar to patients without injury. [12-14]. Only one study reported that ovarian total day injury significantly reduced implantation, clinical pregnancy, and ongoing pregnancy rates. However, in that study, embryo freezing could not be performed after injury, and fresh embryo transfer was applied on the second day [8]. In our study, total freezing was performed after egg collection, and frozen embryo transfer was performed in the next cycle. Therefore, it is not correct to compare the results of these two studies with each other.

When the previous three studies and our study are evaluated together, damage to to the endometrium on the day of egg collection does not cause a significant increase in pregnancy 92 rates and does not have a harmful effect [8,12-14]. As a result, the patient’s being under anesthesia or being a candidate for total freezing is not an opportunity for injury after egg collection. Since the injury to be done will not be beneficial to the patient in terms of fertility, it should not be processed. In light of these results, we can perhaps suggest that since interventions such as endometrial biopsy or polyp removal during egg collection do not affect pregnancy rates in the next cycle, such procedures can be performed if necessary.

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. Barash A, Dekel N, Fieldust S, Segal I, Schechtman E, Granot I. Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization. Fertil Steril. 2003;79(6):1317-22.

2. Lensen S, Sadler L, Farquhar C. Endometrial scratching for subfertility: everyone’s doing it. Hum Reprod. 2016;31(6):1241-4.

3. Zygula A, Szymusik I, Grzechocinska B, Marianowski P, Wielgos M. Endometrial injury for women with previous in vitro fertilization failure – does it improve pregnancy rate? Neuro Endocrinol Lett. 2016;37(6):419-26.

4. Ko JK, Ng EH. Scratching and IVF: any role? Curr Opin Obstet Gynecol. 2016;28(3):178-83.

5. Panagiotopoulou N, Karavolos S, Choudhary M. Endometrial injury prior to assisted reproductive techniques for recurrent implantation failure: a systematic literature review. Eur J Obstet Gynecol Reprod Biol. 2015;193:27-33.

6. Nastri CO, Lensen SF, Gibreel A, Raine-Fenning N, Ferriani RA, Bhattacharya S, et al. Endometrial injury in women undergoing assisted reproductive techniques. Cochrane Database Syst Rev. 2015;22(3):CD009517.

7. Li R, Hao G. Local injury to the endometrium: its effect on implantation. Curr Opin Obstet Gynecol. 2009;21(3):236-9.

8. Karimzade MA, Oskouian H, Ahmadi S, Oskouian L. Local injury to the endometrium on the day of oocyte retrieval has a negative impact on implantation in assisted reproductive cycles: a randomized controlled trial. Arch Gynecol Obstet. 2010;281(3):499-503.

9. Palomba S, Piltonen TT, Giudice LC. Endometrial function in women with polycystic ovary syndrome: a comprehensive review. Hum Reprod Update. 2021;27(3):584-618.

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11. Mourad S, Brown J, Farquhar C. Interventions for the prevention of OHSS in ART cycles: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2017;1(1):CD012103.

12. Bernard A, Schumacher K, Marsh C. Endometrial Scratch (Injury): Does Timing Matter? J Family Reprod Health. 2019;13(2):85-8.

13. Abate V, De Corato R, Cali A, Stinchi A. Endometrial biopsy at the time of embryo transfer: correlation of histological diagnosis with therapy and pregnancy rate. J In Vitro Fertil Embryo Transfer. 1987;4(3):173–6.

14. Ubaldi F, Bourgain C, Tournaye H, Smitz J, Steirteghem AV, Devroey P. Endometrial evaluation by aspiration biopsy on the day of oocyte retrieval in the embryo transfer cycles in patients with serum progesterone rise during the follicular phase. Fertil Steril. 1997;67(3):521–6.

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Nurettin Turktekin, Cemil Karakus, Ramazan Ozyurt. Endometrial injury and fertility outcome on the day of oocyte retrieval. Ann Clin Anal Med 2022;13(1):89-92

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Efficacy of intravenous lipid emulsion (ILE) in the treatment of acute aluminum phosphide toxicity at Alexandria Main University Hospital, Egypt

Heba Abdel Samie Mohamed Hussein 1, Dina Hassan Zidan 2

1 Department of Forensic Medicine and Clinical Toxicology, 2 Department of Critical Care, Faculty of Medicine, Alexandria University, Egypt

DOI: 10.4328/ACAM.20863 Received: 2021-09-19 Accepted: 2021-10-05 Published Online: 2021-10-16 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):93-97

Corresponding Author: Heba Abdel Samie Mohamed Hussein, Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Alexandria University, 239 Elhorya Road, Alexandria, Egypt. E-mail: hebaforensic@gmail.com P: +20 100 295 74 39 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0022-4640

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Aim: Aluminum phosphide (AlP) poisoning causes high mortality. The present study evaluated the efficacy of SMOFlipid in acute unstable cases of aluminum phosphide poisoning in the Intensive Care Unit of Alexandria Main University Hospital, Egypt.

Material and Methods: The study included 66 patients, divided into a case group who received SMOFlipid, as well as standard hemodynamic stabilization measures. They were collected prospectively during a ten-month period. The control group received the standard measures. Data of these patients were collected retrospectively from the patients’ files of the intensive care unit of Alexandria Main University Hospital during a one-year period.

Results: There was a significant decrease in the mortality rate in the case group (61.3%) compared with the control group (94.3%). Systolic and diastolic blood pressure showed significant increases after SMOFlipid infusion (p=0.019 and 0.017, respectively) compared with controls (p=0.006 for both variables). There was a significant increase in the level of bicarbonate after infusion of SMOFlipid compared to pre-infusion levels (p=0.006). Significant increases in the levels of liver enzymes, triglycerides, and bilirubin were observed after infusion of SMOFlipid compared to pre-SMOF levels (p= <0.001).

Discussion: SMOFlipid caused a significant decrease in mortality rate of unstable acute ALP poisoning. Hemodynamic as well as acid-base status improved after infusion.

Keywords: Aluminum Phosphide, Unstable Cases, Acute Toxicity, Intravenous Lipid Emulsion, SMOFlipid

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Introduction

Aluminium phosphide (AlP) is a toxic compound that causes high mortality after acute exposure via different routes. It is a kind of pesticide that is used to protect grains stored in stores [1]. As it is extremely toxic, easily accessible and low in price, it is considered a dangerous source of severe toxicity in developing countries. Exposure to AlP is mostly suicidal, unusually accidental and infrequently homicidal [2].

Each tablet of AlP contains 56% aluminium phosphide and 44% ammonium carbonate that is included in the tablet to avoid self-detonation of phosphine gas (PH3) released upon the exposure of aluminum phosphide to moisture. This lipid-soluble phosphine gas is the active constituent of the AlP tablet, which leads to oxidative stress with the formation of free radicals and inhibition of cytochrome oxidase [3-5].

Intravenous lipid emulsion (ILE) is a combination of long-chain fatty acids that has been utilized to offer essential fatty acids for cases that need parenteral nutrition (PN). At the same time, it is considered a solid basis of calories to decrease the required amount for PN [6,7].

However, ILE has non-nutritional applications as well. It can be used as a treatment for poisonings involving toxic agents that have lipid-soluble properties. Administration of intravenous (IV) lipid emulsion can help in the recovery of patients with cardiovascular collapse [8].

SMOFlipid is a white, homogenous, sterile, non-pyrogenic lipid emulsion for intravenous infusion. The lipid content of SMOFlipid is 0.20 g/ml and involves a combination of fish oil, medium-chain triglycerides (MCTs), soybean oil and olive oil. The mean essential fatty acid content in SMOFlipid is 35 mg/ ml (range 28 to 50 mg/ml) linoleic acid (Omega-6) and 4.5 mg/ml(rangeof3to7mg/ml)α-linoleicacid(Omega-3).The phosphate content is 15 mmol/l [9].

The fat emulsion generates a lipid sink, which attracts the toxic agent from the tissues into the lipid phase and separates it from the aqueous plasma, where it cannot produce its pharmacologic action [10].

However, existing endorsements for the use of lipid rescue as a treatment for lipid-soluble toxic agents have been obtained only from case reports and animal studies; there are no available data from wide-scale studies. Therefore, the present study aimed to evaluate the efficacy of intravenous lipid emulsion as a line of treatment for acute unstable cases of aluminium phosphide poisoning admitted to the Intensive Care Unit of Alexandria Main University Hospital, Egypt.

Material and Methods

Patients

The present study was conducted on 66 patients. They were divided into two groups: the case group and the control group. The case group received SMOFlipid according to the regimen described in detail in the methods section, in addition to the standard treatment presented for such cases. They were collected prospectively during ten months, from September 1, 2019 to the end of February 2020. The period from early March 2020 to late September 2020 was skipped due to the COVID-19 pandemic. Then, from the beginning of October 2020 to the end of January 2021, the cases were collected again.

During this period, 31 patients with acute AlP toxicity were hemodynamically unstable and admitted to the Intensive Care Unit of Alexandria Main University Hospital.
The control group included 35 patients who received the standard treatment for hemodynamically unstable AlP toxicity cases in the Intensive Care Unit. The data of these patients were retrospectively collected from the patients’ files of the Intensive Care Unit of Alexandria Main University Hospital from early September 2018 to the end of August 2019.

The current study included patients who received appropriate, high-quality supportive care, those for whom no further conventional therapy options were available, and patients who continued to be hemodynamically unstable or were in cardiopulmonary arrest (grade 3 of the poisoning severity score).

Patients with a history of hypersensitivity to fish, egg, soya or peanut protein or to any of the active ingredients or excipients, severe hyperlipidemia, and severe liver insufficiency were excluded from the study. In addition, the present study excluded cases with severe blood coagulation disorders, severe renal insufficiency without access to hemofiltration or dialysis, and general contraindications to infusion therapy, such as acute pulmonary edema, hypervolemia, and decompensated cardiac insufficiency.

Methods

In the current work, the patients in the control group received standard measures for such cases, depending on hemodynamic stabilization. These measures were as follows:
– Airway protection

– Breathing monitoring and endotracheal tube insertion and mechanical ventilation, if indicated
– Circulatory support: intravenous fluid administration, vasoactive drug infusion

– Sodium bicarbonate infusion to buffer metabolic acidosis
– Proton pump inhibitor to guard against stress-induced gastric ulcers
– Prophylactic anticoagulant after monitoring the coagulation profile
Data on heart rate, blood pressure, and bicarbonate level were collected from patients’ files on the second day after admission to the intensive care unit.
Patients in the case group were subjected to the following:
• Initial assessment and stabilization.
• SMOFlipid 20% (purchased from Fresenius Kabi Canada Ltd.) was administered as a bolus dose of 1.5 ml/kg over 1 minute followed by continuous infusion. The bolus dose was repeated every 5 minutes up to a total dose of 3 mL/kg. A maximum of two repeated doses were given until adequate circulation was restored. The bolus dose was followed by a continuous infusion of 0.25 ml/kg/min for 30 to 60 minutes. This rate was increased to 0.5 ml/kg/min in some cases if blood pressure decreased or when the clinical situation began to worsen. A total dose of 10 ml/kg was given [11].
• Close monitoring of signs of an allergic reaction during administration was performed.
• Heart rate, blood pressure, bicarbonate, serum triglycerides, liver function tests including serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) and bilirubin were measured on admission to the intensive care unit and on the second day after administration of SMOFlipid.
• Patients were monitored noninvasively using electrocardiogram (ECG) leads attached to monitors reflecting heart rate (Mindray, Dragger, GE).

• Blood pressure was measured manually with a sphygmomanometer.
• Bicarbonate levels were tested using a GEM 5000 blood gas analyser.

• Serum triglycerides and liver enzymes were measured using laboratory tests.

Ethical considerations

The Ethics Committee of the Alexandria Faculty of Medicine approved this study (IRB No: 00012098, FWA No: 00018699) and informed consent was obtained from the patients’ next of kin before conducting the study.

Statistical analysis

Data analysis was performed using the IBM SPSS software package version 20.0. (Armonk, NY: IBM Corp). The Kolmogorov- Smirnov test was applied to attest to the normality of the distribution of variables. Comparison of categorical variables was performed using the chi-square test. The Mann-Whitney test was applied to compare quantitative variables between two groups that were not normally distributed. At the same time, the Wilcoxon signed ranks test was used for comparisons between two periods for nonnormally distributed quantitative variables. Student’s t-test was performed to compare the two groups for normally distributed quantitative variables. Paired t-tests were assessed for comparisons between two periods for normally distributed quantitative variables. The significance of the obtained results was judged at the 5% level.

Results

The present study was conducted on 66 hemodynamically unstable patients with acute AlP toxicity. No significant difference was observed between the case and control groups with regard to gender and age (p=0.873 and 0.611, respectively). However, the mortality rate was significantly higher in the control group (p= 0.001) (Figure 1).

Hemodynamic and acid-base status: (Table 1)

Non-significant differences were noticed between cases (before SMOFlipid infusion) and controls regarding systolic blood pressure, diastolic blood pressure and heart rate (p=0.809, 0.660 and 0.846).

There were significant differences among cases before and after SMOFlipid infusion (p=0.019 and 0.017, respectively), and between cases (after SMOFlipid infusion) and controls in terms of systolic and diastolic blood pressure (p=0.006 for both variables).

A significant increase was observed in the level of bicarbonate among cases before and after SMOFlipid infusion (p=0.006). Follow-up parameters of the case group
Significant increases in the levels of liver enzymes, including SGOT and SGPT, triglycerides (TGs) and bilirubin, in the cases after SMOFlipid infusion compared with before infusion (p= <0.001). (Table 2)

Table 1. Comparison between the two studied groups according to hemodynamic and acid-base status

Relationship between ILE infusion and the outcome

Systolic blood pressure, diastolic blood pressure and bicarbonate levels were significantly higher survivors than in cases who died (p=0.003, 0.010 and <0.001). At the same time, the heart rate was significantly lower in the survivors than in the cases who died (p=0.043).

SMOFlipid infusion caused significant decreases in liver enzymes (SGOT and SGPT) and bilirubin in survivors compared with cases who died (p=<0.001, 0.001 and 0.004). Regarding the level of triglycerides, non-significant differences were notedinsurvivorscomparedtothecaseswhodied(p=0.269) (Table 3).

Discussion

Pesticide toxicity is a very common and challenging health problem as a method of self-poisoning, especially in developing countries, where its sale is not restricted. In Egypt, in recent years, toxicity due to the ingestion of rice tablets or aluminum phosphide (AlP) has become the most common method of suicide, especially in rural areas [12].

The exact mechanism by which AlP exerts its effects has not yet been known. Therefore, no specific antidote is available, and the treatment of such cases depends mainly on supportive measures. [13]

Many previous studies have attempted to develop new modalities for the treatment of cases of acute AlP toxicity, which depended mainly on decreasing acidity and avoiding contact with aqueous medium, such as using paraffin oil or coconut oil for gastric lavage instead of potassium permanganate. In addition, the use of coenzyme Q10 (CoQ10), which can recover cardiac functions by increasing the activity of cytochrome C oxidase, was also proposed for the treatment of acute AlP toxicity. These measures consecutively restore mitochondrial functions and ATP production and improve the contractility of the heart. Furthermore, CoQ10 can aid in improving the multiorgan dysfunction caused by acute AlP poisoning [14-16]. Another study carried out by Goharbari et al. (2018) concluded that oral liothyronine was effective in improving the hemodynamic status of patients with acute AlP poisoning [17]. However, when the patients continued to be hemodynamically unstable or developed cardiopulmonary arrest despite all the supportive measures employed, admission to the intensive care unit was mandatory. Infusion of intravenous lipid emulsion (ILE) has been proposed by many previous studies as a method that can generate a lipid sink, which attracts the lipophilic toxic agent from tissues into the lipid phase, where it becomes ineffective [10]. Although intravenous lipid emulsion (ILE) has been used primarily in the treatment of toxicity by local anaesthetics, its use has extended to include other lipophilic poisons.

The aim of the present study was to examine the efficacy of intravenous lipid emulsion as a treatment measure for unstable cases of acute aluminium phosphide poisoning admitted to the Intensive Care Unit of Alexandria Main University Hospital, Egypt.

The type of intravenous lipid emulsion used in the current study is SMOFlipid, a third-generation lipid emulsion that is considered ideal, with a well-adjusted and more natural composition of fatty acids. Moreover, SMOFlipid is metabolized approximately 40% faster than soybean oil emulsions [18].

The dose regimen of SMOFlipid infusion used in the current study, with a total dose of 10 mL/kg, was chosen according to the American Society of Regional Anaesthesia and Pain Medicine (ASRA) and the European Resuscitation Council (ERC) Guidelines on Resuscitation. This dose was considered safe and was recommended to avoid possible side effects of ILE, which are likely to occur after a dose of 60 ml/kg and mainly affect the liver and lung tissues [19].

The mortality rate in the present study, which is the primary outcome, was calculated in relation to the number of unstable patients with acute AlP poisoning admitted to the intensive care unit only, and not to the total number of cases admitted to the poison centre. There was a significant decrease in mortality in the case group (61.3%) compared with the control group (94.3%), which demonstrated that ILE infusion helped improve the outcomes of the cases. This mortality rate was lower than in many previous studies [15,20,21].

The current work showed significant increases in systolic and diastolic blood pressures in the case group after infusion compared to before infusion of ILE and in the control group. These improvements were associated with a significant decrease in the administered amount of vasoactive drugs, mainly noradrenaline, infused in the patients. At the same time,thecasegroup,afterinfusionofILE,showedasignificant increase in the level of bicarbonate compared to the level before infusion, and this rise was also reflected in the pH level, denoting improvement of the haemodynamic compromise and metabolic acidosis caused by acute AlP poisoning. In fact, cardiogenic shock is the main cause of mortality in AlP. This result coincided with the case report carried out by Baruah et al. (2015) [22], who reported positive outcomes of the two cases studied. They also reported that ILE is better than coconut oil since it eliminates the poison after its dissolution in the plasma. Regarding the follow-up investigations of the case group before and after SMOFlipid infusion, the current study showed significant increases in the levels of liver enzymes (SGOT and SGPT) and bilirubin. These differences could be explained by the hemodynamic instability of the patients leading to ischaemic hepatitis [23]. Once blood pressure was improved, we detected improvements in liver enzymes and bilirubin levels on daily routine follow-up examinations performed regularly. Additionally, the dose of SMOFlipid infusion applied in the current work was less than needed to induce the side effects of intravenous lipid emulsion [19].

Conclusion

The present study concluded that intravenous lipid emulsion (SMOFlipid) helped significantly decrease the mortality rate of hemodynamically unstable acute AlP poisoning cases. In addition, hemodynamic and acid-base status improved after infusion.

Recommendations

Further studies are recommended on larger numbers of acute AlP poisoned patients (both adults and children). At the same time, future studies are proposed to study the early initiation of ILE therapy in acute AlP poisoning.

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. Abdollahi M, Mehrpour O. Aluminum Phosphide. In: Wexler P, editors. Encyclopedia of Toxicology. 3rd edition. Oxford, UK: Academic Press; 2014. p.164- 6.

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17. Goharbari MH, Taghaddosinejad F, Arefi M, Sharifzadeh M, Mojtahedzadeh M, Nikfar S, et al. Therapeutic effects of oral liothyronine on aluminum phosphide poisoning as an adjuvant therapy: A clinical trial. Hum Exp Toxicol. 2018; 37(2) 107–17.

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Heba Abdel Samie Mohamed Hussein, Dina Hassan Zidan. Efficacy of intravenous lipid emulsion (ILE) in the treatment of acute aluminum phosphide toxicity at Alexandria Main University Hospital, Egypt. Ann Clin Anal Med 2022;13(1):93-97

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Do antiepileptic drugs cause premature atherosclerosis by disturbing lipid metabolism?

Neslihan Eskut 1, Cagla Soysuren 2, Gulec Mert Dogan 3, Gamze Tuna 4, Feriha Toksoz 5, Nazif Calıs 6, Mustafa Cetiner 7, Yasar Zorlu 8, Guldal Kirkali 9

1 Department of Neurology, University of Health Sciences, Izmir Bozyaka Education and Training Hospital, Izmir, 2 Department of Neurology, Menemen State Hospital, Izmir, 3 Department of Pediatric Radiology, Inonu University, Malatya Educational and Research Hospital, Malatya, 4 Department of Moleculer Medicine, Dokuz Eylul University, Institute of Health Sciences, Izmir, 5 Department of SACEM Life Tecnologies, Dokuz Eylul University, Technology Development Zone (DEPARK), Izmir, 6 Iskenderun Technical University, Faculty of Business and Management Sciences, Hatay, 7 Department of Neurology, Kutahya Health Sciences University, Kutahya, 8 Department of Neurology, University of Health Sciences, Izmir Tepecik Education and Training Hospital, Izmir, 9 Department Biochemistry, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey

DOI: 10.4328/ACAM.20820 Received: 2021-08-17 Accepted: 2021-09-21 Published Online: 2021-09-25 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):98-103

Corresponding Author: Neslihan Eskut, Bahar mah. Saim Çıkrıkcı Cad, No: 59, 35170, Karabağlar, Izmir, Turkey. E-mail: nespur@hotmail.com P: +90 505 443 22 05 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1882-8992

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Aim: The aim of this study was to evaluate susceptibility to atherosclerosis in epileptic patients on carbamazepine and valproic acid monotherapy with lipid profile, lipoprotein (a) (lp(a)), oxidized low-density lipoprotein (LDL), adiponectin, and carotid artery intima-media thickness measurements.

Material and Methods: Of the 108 patients with epilepsy included in the study, 64 (36 female, 28 male) were receiving valproic acid monotherapy and 44 (25 female, 19 male) were receiving carbamazepine monotherapy. The control group comprised 48 (30 female, 18 male) healthy participants. Liver and kidney function tests, cholesterol, triglycerides, LDL, high-density lipoprotein (HDL), lp(a), oxidized LDL, adiponectin, and common carotid (CCA) and internal carotid artery (ICA) intima-media thickness (IMT) were investigated in both the patient and control groups.

Results: Mean age was 32.34±12.41 years in the valproic acid group, 32.70±11.64 years in the carbamazepine group, and 35.81± 11.76 years in the control group. Liver and kidney function test results were normal in all groups. Cholesterol levels were lower in the valproic acid group than the other groups. HDL levels were higher in the carbamazepine group than other groups. Adiponectin levels were lower in the valproic acid group. In all groups, cholesterol and LDL levels were higher in individuals older than 50 years old. When the patients were evaluated according to the duration of drug use, cholesterol and LDL levels were higher in patients who had used drugs for more than 5 years in the valproic acid group. There were no differences between the groups for triglyceride, oxidized LDL, or lp(a) levels or CCA and ICA IMT.

Discussion: There are conflicting results in the literature regarding epilepsy and atherosclerosis associated with antiepileptic drug usage. In this study, no evidence was found of an increasing risk of arteriosclerosis associated with antiepileptic drugs by measuring lipids, lipoprotein, oxidized LDL, adiponectin levels, and CCA and ICA IMT. However, it is important to monitor lipid levels in the follow-up of patients with epilepsy, especially for patients requiring long- term antiepileptic therapy and also older patients.

Keywords: Epilepsy, Antiepileptic Drug, Atherosclerosis, Lipoprotein, Carotid Intima-Media Thickness

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Introduction

Atherosclerosis (AS) is the common pathological basis of several cardiocerebral diseases that may cause mortality and morbidity [1]. Epilepsy is a common neurological disorder that affects people of all ages, races, social classes, and geographical regions [2]. Epilepsy requires long-term or sometimes lifelong therapy. Several recent studies have been conducted to determine whether antiepileptic drugs (AEDs) increase the risk of atherosclerosis because of metabolic changes, in addition to their known side effects, but the results of these studies are conflicting [3-6]. Some of them have reported that long-term exposure to AEDs may play a pivotal role in the pathogenesis of atherosclerosis in patients with epilepsy [3, 7, 8].

Carotid intima-media thickness (IMT) is a representative measure of atherosclerosis. Evaluation of both common carotid artery (CCA) and internal carotid artery (ICA) IMT is an important marker in investigating atherosclerosis [9]. The first morphological changes of arterial walls can be visualized by B-mode ultrasonography. Assessment by carotid ultrasonography is noninvasive and useful in the risk assessment of future cerebral or cardiovascular events according to atherosclerosis [10].

The aim of this study is to evaluate susceptibility to atherosclerosis in epileptic adults on valproic acid (VPA) or carbamazepine (CBZ) monotherapy based on carotid artery IMT measurements and levels of serum lipids, lipoprotein (a) (lp(a)), oxidized low-density lipoprotein (ox-LDL), and adiponectin.

Material and Methods

Study Population

This cross-sectional and case-control study included consecutive patients admitted to an epilepsy outpatient clinic. The participants were evaluated at the University of Health Sciences İzmir Tepecik Education and Research Hospital. Patients older than 18 years with disease duration of at least 1 year were included. Presence of ischemic stroke, history of cardiac or peripheral vascular disease, diabetes mellitus, pregnancy, smoking, renal or hepatic failure, and hormone replacement therapy were exclusion criteria. Written consent was obtained from the participants. The study was conducted according to the ethical principles suggested in the Declaration of Helsinki and the study protocol was approved by the institutional review board.

We initially enrolled 124 patients with epilepsy. Of those 124 patients, 6 had diabetes mellitus, 3 had coronary artery disease, 1 was pregnant, 1 was using hormone replacement therapy, and 5 were smokers. Those individuals were excluded from the study and a total of 108 patients with epilepsy, 64 of whom received VPA monotherapy and 44 of whom received CBZ monotherapy, were included. Forty-eight healthy participants were also enrolled as a control group. Demographic data including sex and age, duration of epilepsy, type and frequency of seizures, and duration of treatment were recorded. To investigate the effect of the duration of antiepileptic therapy on IMT, lp(a), ox- LDL, adiponectin, LDL, total cholesterol (TC), and triglyceride (TG) levels, two subgroups (duration of therapy ≤5 years and >5 years) were established for the VPA and CBZ groups. Biochemical Analysis

Following an overnight fasting period, blood samples were obtained between 8 and 10 AM before patients took their morning doses of AEDs. The blood sample to be used for lp(a), ox-LDL, and adiponectin analysis was immediately separated by centrifugation after being obtained. The supernatant was removed and stored at -85 °C until assayed.

The TC, TG, high-density lipoprotein (HDL) cholesterol, and serum concentrations of biochemical markers of liver and renal functions such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), urea, and creatinine (Cr) were measured by enzymatic colorimetric method using commercial kits (Olympus Diagnostica GmbH, Hamburg, Germany), while LDL cholesterol was estimated using the Friedewald equation (LDL = TC – (HDL + TG/5)).

Serum lp(a), ox-LDL, and adiponectin concentrations were measured by enzyme linked immunosorbent assay method using commercial kits (respectively, AssayPro, St. Charles, MO, USA; BIOMEDICA GmbH & Co. KG, Vienna, Austria; BioVendor GmbH, Heidelberg, Germany).

Intima-Media Thickness (IMT) Measurements

Examination of carotid artery IMT was performed by the same radiologist, who was blinded to the clinical and laboratory data of the participants. Ultrasonographic examinations (Nemio XG SSA; Toshiba, Tokyo, Japan) were performed with a linear band 7.5-MHz transducer. Patients were in a supine position during the examination, with the head slightly extended and rotated to the other side. The CCA IMT was measured 2 cm proximal to the bifurcation and the ICA IMT was measured 1 cm distal to the bifurcation. Measurements were made bilaterally and the far wall was evaluated. The mean of two sides for CCA and ICA was used.

Statistical Analysis

Statistical analyses were performed using SPSS 15.0 for Windows (SPSS Inc., Chicago, IL, USA). The Kolmogorov- Smirnov test was used to determine whether each variable was normally distributed. Descriptive statistics including means, standard deviations, minimum values, and maximum values of the variables were computed. Subgroup analyses of parametric variables were performed using the independent samples t-test, while analyses of non-parametric variables were performed using the chi-square test. Analyses of parametric variables among these three groups were performed using one-way analysis of variance (ANOVA) followed by the post hoc Bonferroni test for multiple comparison. Finally, subgroup analyses for carotid artery IMT, age, and duration of treatment were performed using the non-parametric Mann-Whitney U test. Values of p<0.05 were considered statistically significant.

Results

Sixty-four patients were on VPA monotherapy (28 male, 36 female) and 44 were on CBZ monotherapy (19 male, 25 female). Forty-eight healthy controls (18 male, 30 female) were also enrolled in the study. Mean age was 32.34±12.41 years in the VPA group, 32.70±11.64 years in the CBZ group. and 35.81±11.76 in the control group. There was no statistically significant difference between the gender distributions and mean ages of the groups (p>0.05). The demographic characteristics of the participants are shown in Table 1.
Liver and kidney function test results were normal in all groups. Although the values were within the normal range, GGT levels were significantly higher in the CBZ group (p<0.01).
The mean TC level was significantly lower in the VPA group than the other groups (p=0.01). HDL levels in the CBZ group were significantly higher than in the other groups (p=0.03). When all participants were evaluated by age, TC and LDL levels were significantly higher in participants older than 50 years (p=0.011 and p=0.006, respectively). There were no significant differences between the groups in terms of TG, lp(a), or ox-LDL levels (p=0.41, p=0.3, and p=0.82, respectively). The mean levels of lp(a) were 32.28 mg/dL in the control group, 30.97 mg/dL in the VPA group, and 37.34 mg/dL in the CBZ group. In all groups, the lp(a) levels were higher than 30 mg/dL, which is considered the threshold value for increased risk of early atherosclerosis. In the VPA group, adiponectin levels were significantly lower (p=0.03). The results of serum lipid profile, liver and kidney function tests, and serum lp(a), ox-LDL, and adiponectin levels of the patient groups and the control group are given in Table 2 together with statistical comparisons between these groups. There was no statistically significant difference between groups in terms of CCA and ICA IMT (p=0.58 and p=0.42, respectively). The mean CCA and ICA IMT values for the three groups and intergroup comparisons are shown in Table 3. No significant differences were found between the CBZ subgroups in terms of IMT, lp(a), ox-LDL, adiponectin, LDL, TC, or TG levels (p>0.05). However, patients on VPA monotherapy for longer than 5 years had higher TC and LDL levels (p<0.05) (Table 4).

Discussion

Atherosclerosis is a disease of large and medium-sized arteries and is characterized by endothelial dysfunction, vascular inflammation, and changes in IMT [11]. Many recent studies have examined whether AEDs increase the risk of atherosclerosis because of metabolic changes, in addition to their known side effects, but the results of these studies are contradictory [3-5]. There are few reports about the effect of AED treatment on serumlipidprofileandlipoproteinsintheadultpopulation[3-6, 12-14]. Elevated levels of serum TC, LDL [5, 6, 12, 14], and HDL were reported in pediatric patients receiving CBZ monotherapy [5, 6, 12]. In a prospective study, Verroti et al. reported that alterations in serum lipids and lipoproteins were transient [5]. Most studies in the literature reported alterations in serum lipids and lipoproteins with CBZ therapy, but Hamed et al. and Sözüer et al. did not demonstrate significant alterations in serum levels of TC, LDL, or TG in CBZ, VPA, polytherapy, or untreated groups [3, 14]. However, HDL levels were significantly lower in these groups when compared with a control group [3]. Several studies showed decreased TC [6, 12, 15], LDL [12, 15], and HDL [3, 12] levels during VPA treatment. Conversely, some studies reported similar values between the VPA group and control group for TG [3, 5, 13, 14], HDL [5, 6, 13, 14], LDL [3, 5, 13, 14], and TC [3, 5, 12-14] levels.

In this study, TC levels were significantly lower in the VPA group than the CBZ and control groups. HDL levels in the CBZ group were significantly higher than those in the other groups. There was no significant difference in TG levels between groups. These results indicate that other features such as genetics, dietary habits, or lifestyle factors might have more contributive effects on the lipid profile than AEDs.

In the literature, lp(a) has been identified as an independent risk factor for vascular disease and subjects with lp(a) values above 30 mg/dL have an increased risk of developing early atherosclerotic disease [16]. While lp(a) levels are mainly under genetic control and are less affected than other lipoproteins by age, sex, weight, and diet, there are a few exogenous factors, such as physical exercise, estrogen therapy, and end- stage renal failure, that affect lp(a) serum concentrations [17]. Data regarding AEDs and their effects on lp(a) levels are controversial and most previous studies were performed among pediatric populations. Voudris et al. reported elevated lp(a) levels in pediatric patients [18], whereas Verroti et al. showed no significant difference between the control group and pediatric epileptic patients receiving long-term CBZ or VPA [12]. In another study, elevated lp(a) levels were not statistically significant [4]. On the other hand, an increase in serum lp(a) concentrations was reported by Schwaninger et al. in adult epileptics receiving AED therapy. However, for half of those patients, a combination of different AEDs had been administered [19].

Several possible mechanisms have been proposed to explain the increase in lp(a) levels, such as the effect of renal functions on the catabolism of lp(a), the enzyme-inducing characteristics of CBZ, and AED-induced alterations in the synthesis of lp(a) [19]. There was no significant difference in levels of lp(a) between the VPA, CBZ, and control groups in our study. However, lp(a) levels in all three groups were higher than 30 mg/dL. There was no liver or renal dysfunction that affected the synthesis or metabolism of lp(a) in any of these groups. However, LDL levels were significantly lower in the VPA group than in other groups. We suggest that receiving AEDs did not affect the lp(a) levels and high levels exceeding the threshold value in all groups can only be explained by genetic predisposition.

Ox-LDL plays a role in the pathogenesis of atherosclerosis and can be a predictor for atherosclerosis in the absence of conventional risk factors such as hypertension, smoking, diabetes mellitus, and dyslipidemia [20]. It is widely accepted that oxidative modification of LDL is involved in the development of atherosclerotic lesions through the formulation of macrophage- derived foam cells and/or through pro-inflammatory effects on vascular cells [21]. This is the first step in the formulation of atherosclerotic plaque. There are few studies about the effect of AED treatment on ox-LDL [3, 22, 23]. It was reported that ox- LDL is associated with subclinical atherosclerosis [24]. Hamed et al. demonstrated unbalanced oxidative stress/antioxidant disequilibrium in both treated and untreated epileptic patients. Their study also identified reduced HDL and elevated ox- LDL levels [3]. On the other hand, Yıldız et al. investigated the effect of VPA, CBZ, and VPA-CBZ combination therapy on LDL oxidation, paraoxonase activity, thyroid hormones, and arterial distensibility (by carotid-femoral pulse wave velocity) in epileptic children; similar levels of ox-LDL and paraoxonase activity were reported in epileptic patients and control subjects. They showed increased carotid-femoral pulse wave velocity in epileptic children using CBZ and VPA. In addition, a correlation was found between pulse wave velocity, VPA, and thyroid- stimulating hormone levels [23]. In this study, there was no significant difference in terms of ox-LDL levels between the VPA, CBZ, and control groups. Although oxidant/antioxidant parameters were not evaluated in this study, due to the absence of elevated LDL levels and decreased HDL levels, we would not expect to find a difference in ox-LDL levels.

Adipose tissue is generally considered an endocrine organ, which releases various factors into the circulation system. Adiponectin is one of the adipocytokines and plays a protective role against diabetes and atherosclerosis. Research has shown that hypoadiponectinemia is associated with obesity, insulin resistance, cardiovascular disease, dyslipidemia, hypertension, and metabolic syndrome [25]. In addition, adiponectin has antiatherogenic properties, as shown by its capacity to inhibit monocyte adhesion to endothelial cells and macrophage-to- foam cell transformation [26]. There are a limited number of studies investigating the association between alteration of adiponectin levels and AED usage. Greco et al. reported that epileptic patients who gained weight had lower adiponectin levels and it was concluded that the decrease in adiponectin levels was the result of negative feedback inhibition as a consequence of increased fat mass [27]. It has also been reported that VPA inhibits adiponectin expression through the inhibition of histone deacetylases resulting in an increased gluconeogenesis process [28]. Despite similar BMIs and male/ female ratios, adiponectin levels were significantly lower in the VPA group than the other groups in our study.

The IMT of the intracranial part of the carotid arteries is accepted as a measurable indicator of atherosclerosis. The coronary, carotid, and femoral arteries have similar laminar flows. Carotid arteries are preferred in atherosclerosis assessment, as they are easily screened [29]. Carotid IMT measurement by ultrasound is a cheap, reliable, and repeatable method [30]. Previous studies have investigated the association of the use of AEDs and IMT values of the carotid arteries, but results are conflicting. Hamed et al. investigated CCA IMT measurements in epileptic patients using AEDs and drug-free patients. For the first time, they reported increased CCA IMT in both groups of epileptic patients regardless of drug use status. A greater increase in the CCA IMT was observed in the CBZ group. In the same study, an increase in vascular risk factors such as homocysteine, fibrinogen, malondialdehyde, and ox- LDL levels was shown together with a decrease in HDL and total antioxidant capacity. Considering these parameters, it was emphasized that epilepsy itself and/or AED therapy exposes the individual to atherosclerosis risk [3]. Tan et al. assessed 195 epileptic patients (60 of them receiving monotherapy) and 195 healthy participants and found higher CCA IMT values in the epileptic participants compared to the healthy controls. They found no difference between those taking VPA, liver enzyme inducer AEDs (phenytoin, phenobarbital, and carbamazepine), and polytherapy. The authors attributed the difference between the control group and patient group not to drug use but to the epilepsy itself and the oxidative stress arising from seizures. The same study noted higher CCA IMT levels in males and attributed that result to lifestyle factors [8]. On the other hand, a few studies have demonstrated no increase in CCA IMT [31-33]. Tokgoz et al. investigated changes in insulin, some adipocytokines, and carotid artery IMT, comparing pretreatment values and values obtained 6 and 12 months after the beginning of treatment [32]. In the review conducted by Lai et al., it was reported that AED usage was associated with CA IMT in patients with epilepsy, and especially among adult patients. In particular, CBZ and VPA may be related to a significant increase in CA IMT [34].

In this study, similar mean values of CCA IMT and ICA IMT were found among the patient and control groups. We reassessed the patient groups by developing two subgroups (duration of therapy ≤5 years and >5 years). There were no significant differences in terms of mean IMT, lp(a), ox-LDL, adiponectin, or TG levels, while patients using VPA for longer than 5 years had higher TC and LDL levels. In the CBZ subgroups, no significant differences were found between mean CCA IMT, ICA IMT, lp(a), ox-LDL, adiponectin, or TG levels.

This study has some potential limitations. The sample size is relatively small and may have resulted in limited statistical power. The cross-sectional design of the study is another limitation. Despite these limitations, our study is valuable for having taken advantage of testing atherosclerotic markers together with the lipid profile, ox-LDL, lp(a), adiponectin, and carotid artery IMT within a single work.

In conclusion, according to biochemical analysis and carotid IMT measurements, no significant result that could be interpreted as an increase in atherosclerosis risk was found regarding AED usage, except for high TC and LDL levels among patients using VPA for longer than 5 years. It is important to monitor lipid levels during the follow-up of patients with epilepsy, especially those patients who require long-term antiepileptic therapy and also older patients.

Scientific Responsibility Statement

The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

Animal and human rights statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

Funding: None

Conflict of interest

None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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Neslihan Eskut, Cagla Soysuren, Gulec Mert Dogan, Gamze Tuna, Feriha Toksoz, Nazif Calıs, Mustafa Cetiner, Yasar Zorlu, Guldal Kirkali. Do antiepileptic drugs cause premature atherosclerosis by disturbing lipid metabolism? Ann Clin Anal Med 2022;13(1):98-103

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The Stigmatizing Effect of Tuberculosis Disease

Burcu Korkut 1, Nergiz Sevinç 2

1 Department of Community Health Center, Karabuk Provincial Health Directorate, 2 Department of Public Health, Faculty of Medicine, Karabuk University, Karabuk, Turkey

DOI: 10.4328/ACAM.20825 Received: 2021-08-19 Accepted: 2021-11-27 Published Online: 2021-12-02 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):104-108

Corresponding Author: Burcu Korkut, Karabük Provincial Health Directorate Community Health Center, 5000 Houses 75. Year District, 20. Cad, No:4, 78020, Karabük, Turkey. E-mail: dr.burcutezcan@hotmail.com P: +90 537 063 16 27 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0296-9144

Abstract
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Abstract

Aim: This study aimed to measure the level of stigmatization using tuberculosis-related stigma (TRS) scale in healthy individuals and in patients with tuberculosis (TB) and to evaluate the factors affecting stigmatization.

Material and Methods: This cross-sectional survey study included healthy individuals (aged 18-75 years) admitted to Community Health Centre and patients with TB (aged 18-75 years) admitted to Tuberculosis Control Dispensary in Karabuk City of Turkey between July 2021 and October 2021. A questionnaire consisting of two parts, in which the first part included questions about sociodemographic characteristics and the second part included questions of Tuberculosis-Related Stigma (TRS) scale for the assessment of level of stigmatization, was applied to both healthy individuals and patients with TB using a face-to-face survey technique.

Results: The study included 360 healthy individuals (mean age: 45.46±12.90 years, female 65.3%) and 120 patients with TB (mean age, 41.15±16.42 years, male 60.8%). The mean total TRS scale score in healthy individuals was 18.60±4.18; those aged 36-53 years, those who were employed, and those living in the village had significantly higher TRS scale scores (p<0.05 for all). The mean total TRS scale score in TB patients was 19.72±3.20; those aged 18-35 years, single patients, those employed, and those with high- income level had significantly higher TRS scale scores (p<0.05 for all).

Discussion: The current study revealed that the level of stigma was higher in patients with TB. Additionally, it was thought that preventing stigma in TB patients would positively affect the treatment process.

Keywords: Stigma, Tuberculosis, Survey

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Introduction

Tuberculosis (TB) is a worldwide public health crisis. According to the 2019 report of the World Health Organization (WHO), TB affects around ten million people globally each year and is one of the top ten causes of mortality (available at: https://www. who.int/publications/i/item). The incidence of TB is 0.044% in Asia, 0.025% in Africa, 0.0029% in the Americas, and 0.0025% in Europe [1]. According to the Tuberculosis Control Dispensary (TCD) 2019 report, the incidence of TB in Turkey was 15.3%; 60.9% of the patients had pulmonary TB, 57.7% were males, 33.3% were over 65 years old, and 7.8% were relapse cases (available at: https://hsgm.saglik.gov.tr/depo/birimler / tuberkuloz_db/raporlar).

The causative agent of TB is Mycobacterium tuberculosis which is usually transmitted through the air. Among people with TB infection, 5-15% are at risk of developing TB at some point in their lives [2]. The disease affects the lungs at a rate of 65- 70% [3]. Some diseases such as acquired immunodeficiency syndrome (AIDS), diabetes mellitus, chronic renal failure, some types of cancers, drug and alcohol addiction, tobacco use, and silicosis can lead to TB by impairing the immune system [4]. Unintentional emotions, thoughts, and actions of healthy individuals in society against people diagnosed with infectious diseases, such as TB, aimed at reducing their social status and standing, are referred to as “stigmatizing” behaviors [5]. It is known that 27-80% of patients with TB worldwide are subject to stigmatization in their family, social and work environment. Psychological trauma caused by stigmatizing behaviors can lead individuals to quit their job, divorce, dropout of education, and suicide [6]. It has been noted that some patients with TB who have the fear of stigmatization conceal their disease, start their treatment late, or do not receive treatment at all, which all result in high mortality [7].

Concealing the disease due to fear of stigmatization makes it impossible to take social measures for preventing transmission, accelerates the spread of the disease, and causes an increase in TB incidence [8]. Thus, for reducing morbidity and mortality rates in TB and for preventing its transmission to healthy individuals, early diagnosis and starting timely treatment are critical [9]. It is of great importance to raise awareness of populations towards TB about modes of transmission, disease duration, precautions to be taken, treatment process, and the importance and necessity of regular use of medicines [10]. It is thought that studies on this topic would play an essential role in reducing transmission, providing positive treatment outcomes, and increasing motivation, hope, and quality of life for individuals with TB. Accordingly, the current study aimed to measure the level of TB-related stigmatization using the TB- related stigma (TRS) scale in healthy individuals and in patients with TB and to evaluate the factors affecting stigmatization.

Material and Methods

This cross-sectional survey study was conducted in Karabuk Province of Turkey between July 2021 and October 2021 on newly diagnosed TB patients (n=123, aged 18-75 years), who were admitted to the TCD, and on healthy individuals (n=367, aged 18-75 years), who were admitted to the Community Health Center (CHS). Resistant cases in which the infection did not become negative despite more than six months of therapy and those having relapses were excluded. The healthy group was formed from those having a family member diagnosed with TB and/or working in a health-related field. All participants were included in the study without being sampled. Ten participants (7 healthy participants and 3 patients with TB) who incorrectly completed the study questionnaire were excluded. The study was approved by the Ethics Committee of Non-Interventional Clinical Researches of Karabuk University (No: E-77192459- 050.99-48904 Subject: 2021/608) and Karabuk Governorship Provincial Health Directorate (No: 98024045-604.01.02). All participants were informed about the study and their written informed consent was obtained.

A questionnaire consisting of two parts was applied to both healthy individuals and patients with TB using a face-to- face survey technique. In the first part of the questionnaire, all participants were asked seven general questions about sociodemographic characteristics. In the second part, healthy individuals were asked 11 questions forming factor 1, and TB patients were asked 12 questions forming factor 2 of the Tuberculosis-Related Stigma (TRS) scale.

Tuberculosis-Related Stigma (TRS) scale

The TRS scale was first developed by Van Rie et al. [11], and the validity and reliability analysis of the Turkish version of the scale was performed by Küçük Şapçıoğlu (Küçük Şapcıoğlu E. Validity and reliability study of the tuberculosis-related stigma scale in Turkish population [Thesis]. İzmir: Ege University Institute of Health Sciences; 2012). Both factors of the TRS scale are 4-point Likert type scales, and each statement in the scale is scored from 0 to 3 (for positive questions: 0 points for “strongly disagree”, 1 point for “disagree”, 2 points “agree”, and 3 points for “strongly agree”). There are no reverse-scored questions on the scale. For both factor 1 and factor 2 of the TRS scale, higher scores indicate higher levels of stigma and/ or stigmatization. The lowest and highest scores obtained from the TRS scale were 0 and 33, respectively, for factor 1 (healthy individuals) and 0 and 36 for factor 2 (patients with TB). Cronbach’s alpha coefficients for factor 1 and factor 2 of the TRS scale were 0.88 and 0.82, respectively (Küçük Şapcıoğlu E. Validity and reliability study of the tuberculosis-related stigma scale in Turkish population [Thesis]. Izmir: Ege University Institute of Health Sciences; 2012).

Statistical Analysis

Data analyses were performed using the IBM SPSS Statistics for Macintosh, Version 25 (IBM Corp., Armonk, NY, USA). Descriptive statistics were expressed as frequency, percentage, mean, and standard deviation, minimum-maximum (min-max). The Kolmogorov-Smirnov test was used to test the normality of quantitative data. The Mann-Whitney U and Kruskal-Wallis tests were used to determine whether the dependent variables fit the normal distribution. Statistical significance was set at a p-value of <0.05 for all analysis methods.

Results

This cross-sectional, survey study included 360 healthy individuals (mean age, 45.46±12.90 years, female 65.3%) and 120 patients with TB (mean age, 41.15±16.42 years, male 60.8%). The distribution of healthy individuals and patients with TB according to their sociodemographic characteristics is presented in Table 1.
The mean TRS scale score was 18.60±4.18 (min-max, 9.0- 29.0) in healthy individuals. In these individuals, while sex, marital status, educational level, and income level did not have a significant effect on the level of stigmatization (p>0.05, Table 2), age, employment status, and place of residence had significant effects (p<0.05; Table 2).

In patients with TB, the mean TRS scale score was 19.72±3.20 (min-max, 14.0±27.0). In patients with TB, while age, marital status, employment status, and income level had a significant effect (p<0.05, Table 3), sex and educational status did not affect the level of stigmatization (p>0.05, Table 3).

Mean TRS scale scores of TB patients who experienced guilt (21.55±1.66), anxiety (22.00±1.26), fear (19.37±2.20), and sadness (19.03±2.35) were significantly higher than the mean score of those without these feelings (17.66±1.58, 18.34±2.15, 16.76±1.98, and 16.00±.00, respectively) (p<0.05, Table 3). However, no significant difference was determined between the mean scores of patients with and without the feeling of loneliness (19.02±2.60 and 18.26±1.55, respectively; p>0.05; Table 3).

Discussion

In the current study, which evaluated the stigma levels of healthy individuals and patients with TB, the TRS scale score was found as 18.60±4.18 and 19.72±3.20 in healthy individuals and in patients with TB, respectively. Accordingly, the stigma level was determined as moderate in both groups.

In the study conducted in a university hospital by Bayraktar and Khorshtd (2017) the stigma level in healthy individuals was reported as low with a mean TRS scale score of 13.87±6.26 [12]. In the current study, the stigma level was lower due to the fact that healthy individuals included in the study might also have relatives diagnosed with TB. Wynne et al. (2014) studied 360 healthy individuals in Uganda and found that 47% of them had highly stigmatizing attitudes towards patients with TB [13]. Bati et al. (2013) studied 422 healthy individuals with TB in rural areas in Ethiopia and found that 59.2% of healthy individuals had high levels of stigma towards TB patients [14]. The higher level of stigma associated with infectious diseases in the countries with a low level of education, such as Uganda and Ethiopia, can be explained by the fact that stigma is more common in underdeveloped societies. Crispim et al. (2017) assessed the stigma of TB patients and found a scale score of 83.1±0.2 [15]. The reason for the differences in stigmatization scores in the literature is thought to be due to the fact that different scales are used in the studies and the studies are carried out in different geographical regions and cultural environments.
Bayraktar and Khorshtd (2017) measured the level of stigma in TB patients and found that the mean TRS scale score was 11.08±5.50 [12]. In our study, the stigma score in TB patients was found to be moderate (19.72±3.20), and TB patients were observed to feel more stigmatized. Öztürk (2018) used the Stigma Scale in Patients with Tuberculosis (SSPT) and found a mean score of 69.6±12.6 [5]. In our study, when examining patients with TB, the mean TRS scale score was 19.72±3.20 (min-max, 14.0±27.0). Açıkel and Pakyüz (2015) found that the stigma score of the patients with pulmonary TB was above average (83.79±7.42) in 74.4% of the patients [16]. Baltacı et al. (2021) used SSPT and determined the stigma score of 53.6% of TB patients to be above average (71.86±10.13) [17]. The SSPT developed by Sert (2010) (Sert H. Determination of stigma levels and affecting factors in patients with tuberculosis [Doctoral Thesis]. Istanbul Marmara University Institute of Health Sciences; 2010) was used in the studies by Öztürk [5], Açıkel and Pakyüz [16] and Baltacı [17]. In all three studies, more than half of the participants with TB reported that they experienced high levels of stigma due to TB. The higher stigma scores found in these studies compared to our results could have resulted from the difference in socio-demographic characteristics such as residence place, educational level, employment status, and gender of the participants. Crispim et al. (2017) used the Brazilian version of the TRS scale and reported the stigma score of TB patients as 62.7±0.2 [15]. Both healthy and TB individuals participated in this research, and it was found that the stigma level of the ill individuals was higher than that of the individuals with tuberculosis. On the other hand, in the present study, stigma scores were higher in individuals with TB likely due to ethnic differences.

Jittimanee et al. (2009) found that 65% of the human immunodeficiency virus (HIV)-infected TB patients experienced high levels of stigma in Thailand [18]. Stigmatization of AIDS patients ranks first and TB patients ranks second worldwide. It is thought that this situation arises from the lack of knowledge about infectious diseases in society; the factors such as ways of transmission, duration, and methods of protection against these diseases. We think that TB patients being co-infected with HIV significantly increase the rate of stigmatization.

In the current study, the evaluation performed on the emotional states of the TB patients revealed that 30% of the patients felt guilty, 13.3% felt anxious, 56.7% felt fearful, 93.3% felt sad, and 75% felt lonely. The mean TRS scale scores of TB patients who experienced guilt (21.55±1.66), anxiety (22.00±1.26), fear (19.37±2.20), and sadness (19.03±2.35) were significantly higher than the mean score of those without these feelings (17.66±1.58, 18.34±2.15, 16.76±1.98, and 16.00±.00, respectively). Bayraktar and Khorshtd (2017) found that among individuals with TB, 33.9% experienced guilt, 12.8% experienced anxiety, 14.7% experienced fear, 44% experienced sadness, 5.5% experienced pessimism, and 9.2% experienced anger [12]. Moreover, Ünalan et al. (2008) determined that 75.5% of their patients experienced acceptance, 43.4% experienced sadness, and 28.6% experienced fear, pessimism, anxiety, and anger [19]. In addition, Dhingra and Khan (2010) demonstrated that 60% of 1977 patients in India experienced anxiety, pessimism, restlessness, and anger [20].

According to Datiko et al. (2020), individuals stigmatized owing to TB had pessimistic feelings such as fear, anxiety, loneliness, and sadness in Ethiopia. Although the rates of emotions arising from stigma in TB patients differ from the results of the current study, they are similar in content. The difference in the percentage of feelings is thought to depend on factors such as education level, income level, place of residence, level of knowledge about TB, isolation from the social environment, abandonment, or job loss [10].
In the current study, 60.8% of our patients were male. Similarly, in the study by Datiko et al. (2020) on stigmatization in TB in Ethiopia, the rate of male patients was 57.8% [10]. The average age of TB patients in the current study was 44.86±16.3 years, and 40% of the patients were aged between 18-35 years. In a study on stigmatization of TB patients by Baltacı et al. (2021), it was found that the mean age of patients was 46.96±14.21 years, and the age range was between 34-47 years [17]. The current study and other available studies indicate that TB is common in similar gender, mean age, and age range. Additionally, in the current study, 54.2% of TB patients reported their financial situation as “poor”. In their study, Bayraktar and Khorshtd (2017) found that 69.7% of TB patients described their economic status as moderate [12]. The difference between the studies may be due to the differences in socioeconomic levels and self-report of income levels by the patients. In our study, the residential area where the TB disease was the most prevalent was urban (53.3%). Similarly, Mis and Karasungur (2016) also reported that 52.1% of their TB patients lived in the city center in Van Province [21]. These findings may be due to the fact that people living in the city centre do not register at health centers due to the fear of stigmatization, and thus they are late for treatment. The evaluation of the educational level of the TB patients in the current study revealed that the literacy rate was 90%. Similarly, Bayraktar and Khorshtd (2017) found the literacy rate to be 89.1% [12]. Based on the above-mentioned data, to the best of our knowledge, the findings of the socio- demographic characteristics of TB patients in other studies are mainly similar to the findings obtained in the current study. The current study was conducted in a single center and TB patients did not want to participate in the survey due to fear of stigma, all of which can be considered limitations of the study. The lack of sufficient number of studies on the level of stigma in healthy individuals can be considered a strength of the study. Conclusion

The present study demonstrated that the level of stigma towards TB individuals was higher in TB patients than in healthy individuals with both groups having moderate levels. The average TRS scale scores of individuals diagnosed with TB who experienced feelings of guilt, anxiety, fear, and sadness were significantly higher than those who did not experience these feelings. While age, employment status, and place of residence had significant effects on stigma level in healthy individuals, age, marital status, employment status, and income level had significant effects on stigma level in patients.

The adverse effects of stigmatization were identified in the current study and it was emphasized that individuals diagnosed with TB should be isolated from society as long as they are contagious and should follow treatment regularly. In addition, basic information was provided to end social isolation after eliminating the contagion, emphasizing both the individualistic and societal importance of the issue. TB patients experiencing guilt, fear, and sadness should receive psychological counseling from health care professionals. It is considered useful for instructors to favor active education methods such as role- playing from an early age so that healthy individuals can empathize with stigmatized TB patients.

Scientific Responsibility Statement

The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

Animal and human rights statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

Funding: None

Conflict of interest

None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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Burcu Korkut, Nergiz Sevinç. The Stigmatizing Effect of Tuberculosis Disease. Ann Clin Anal Med 2022;13(1):104-108

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Comparison of manual compression with a new bioabsorbable vascular closure device in percutaneous peripheral procedures

Emced Khalil

Department of Cardiovascular Surgery, Ordu University Training and Research Hospital, Ordu, Turkey

DOI: 10.4328/ACAM.20864 Received: 2021-09-19 Accepted: 2021-12-20 Published Online: 2021-12-23 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):109-113

Corresponding Author: Emced Khalil, Department of Cardiovascular Surgery, Ordu University Training and Research Hospital, Bucak Mah., No: 94/1, 52200, Altinordu, Ordu, Turkey. E-mail: emjedkhalil@gmail.com Corresponding Author ORCID ID: https://orcid.org/0000-0003-1050-2656

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Abstract

Aim: The aim of this study was to see how well a new bioabsorbable vascular closure device (VCD) performs in comparison with manual compression (MC) for access-site hemostasis in patients undergoing percutaneous peripheral procedures.

Material and Methods: This retrospective cohort study was carried out by examining the files of patients who underwent vascular intervention for peripheral artery disease at Ordu University Training and Research Hospital between February 1, 2019, and January 31, 2020. The cases were divided into two groups according to the method of achieving access-site hemostasis (MC or VCD).

Results: The patients’ mean age was 64.81 ± 11.03 years, and 75.3% were males. There were 41 cases in the MC group and 40 cases in the VCD group. The frequency of hyperlipidemia in the VCD group was significantly higher than in the MC group (65.0% vs. 31.7%, p = 0.003). Time to hemostasis (TTH), time to ambulation (TTA), and length of hospital stay were significantly greater in the MC group than in the VCD group (p<0.001 for all). No major complications were observed in the VCD group, whereas 5 (6.2%) patients in the MC group developed complications (p = 0.023).

Discussion: The use of VCD appears to be associated with shorter TTH, TTA, and length of hospital stay, and major complications were less frequent in the VCD group.

Keywords: Percutaneous Administration, Vascular Closure Device, Hemostasis, Ambulation, Peripheral Arterial Disease

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Introduction

Manual compression (MC) is the gold-standard method for obtaining hemostasis after vascular interventional operations, but it is well established to be problematic for patients due to extended immobilization and the need for prolonged application of inguinal pressure [1]. This situation has motivated the research and development of vascular closure devices (VCDs) to decrease adverse effects and shorten the time to ambulation (TTA) [1]. The application of MC for hemostasis after femoral arterial puncture involves strong compression at the puncture site (around 15 minutes) and bed rest (extending to half a day). In addition to patient-related problems such as extended hospitalization and loss of time for hospital staff, MC has been associated with rebleeding risks [1].

VCDs have been demonstrated to be effective alternatives to MC in many patient groups (4) including anticoagulation recipients and those with repeat procedures. In a randomized comparison of VCD and MC in recipients of diagnostic procedures, VCD was found to shorten the time to hemostasis (TTH) and TTA. It has been shown that high-puncture antegrade approach to the femoral artery increases groin hematoma and retroperitoneal bleeding risks, while low punctures have been linked to the development of arteriovenous fistula and pseudoaneurysms [2]. Studies investigating VCDs in antegrade femoral punctures have shown that these devices are safe and reliable options [2]. However, there are few studies in the literature examining the use of VCD after a retrograde approach from the popliteal artery. Thus, the aim of this study was to compare a bioabsorbable VCD (Angio-seal VCD) with MC in terms of efficacy in providing hemostasis at the access site in patients undergoing percutaneous peripheral operations.

Material and Methods

This retrospective cohort study was carried out by examining the files of patients who underwent vascular intervention for peripheral artery disease at Ordu University Training and Research Hospital between February 1, 2019, and January 31, 2020. Ethical approval for the study was obtained from Ordu University Clinical Research Ethics Committee (No 2021/111). Patients

Patients were excluded from the study using the following criteria:
• Acute coronary artery disease or upper extremity artery disease

• Diagnosis of uncontrolled hypertension (blood pressure 180/110 mmHg) at closure
• Previous vascular grafting or femoral vascular surgery or diagnostic procedures in/from the same site

• Pre-existing platelet disorder, bleeding disorder (abnormal platelet count or international normalized ratio), systemic disease, or skin infection at the site
• Fluoroscopically observable calcium deposits, atherosclerotic lesions, or previously placed stents within a distance of 1 cm (distal or proximal) from the puncture site due to the possibility of complicating VCD application

Vascular interventions were performed on 155 patients during the study period, 81 of whom met the inclusion criteria. The cases were divided into two groups according to the application of post-procedural hemostasis, and there were 41 patients in the MC group and 40 patients in the VCD group.
Variables
The parameters examined in the study were as follows: patient characteristics (age, gender, body mass index [BMI], comorbidities, smoking status), procedure-related features (type of approach [antegrade, retrograde], localization [femoral, popliteal], and sheath size), and post-procedural clinical features (TTA, TTH, length of hospital stay and complications). Procedure and application of hemostasis

All patients underwent magnetic resonance imaging (MRI) angiography or computed tomography (CT) angiography before the intervention. At least 5000 IU of heparin was administered to the cases during the procedure, and low-molecular-weight heparin (LMWH) was applied after the procedure. Additionally, clopidogrel and cilostazol were prescribed after procedures when deemed necessary according to the lesion and the treatment applied.

As a new bioabsorbable device, the Angio-seal VCD (St. Jude Medical, Minnetonka, Minnesota) is applied using three major components: a collagen plug, an intra-arterially-deployed absorbable polymer anchor, and a suture applied under the skin. The collagen plug is squeezed between the suture and the anchor to facilitate hemostasis with the pressure provided by the whole structure. It is supplied in two sizes: 6-F and 8-F [2]. There were no requirements for Doppler ultrasonography (USG) in femoral artery punctures. However, popliteal artery punctures were always performed under Doppler USG guidance. Femoral angiographies were taken after completion of the interventional operations. The patients underwent VCD after its application was designated as a procedure that is covered by insurance (according to various criteria discussed below). Before the coverage was accepted by insurance, all patients had undergone MC. Procedures for the application of the Angio-seal VCD were carried out in the interventional radiology department right after treatment.

After confirmation of insurance coverage and at the time of the angioplasty operation, all patients were assessed for the possibility of Angio-seal VCD application. Patients with severely calcified femoral arteries and those with multiple plaques did not undergo Angio-seal application. Depending on the severity of the procedure and the material to be used, 6-F or 7-F sheaths were placed. The median (interquartile range, IQR) VCD size was 8 (6 – 8) mm. All patients received the same type of Angio-seal. Briefly, the guidewire of the Angio-seal device was routed through the 6-F sheath, and the vascular sheath was withdrawn under manual compression. The sheath of the Angio-seal device was then inserted into the artery over the previously placed guidewire (A), and the anchor was carefully placed in the appropriate position (B). Finally, closure with the anchor and suture was achieved by squeezing the arterial plug towards the arterial wall (C, D) (Figure 1).

In the MC group, manual compression was applied for 10-20 minutes, and then a sandbag was placed to exert sufficient pressure for 4 hours. The cases were mobilized 8 hours later as a standard procedure. Sandbags were not used in the VCD group, only a compressive bandage was applied. Hemostasis was achieved in the femoral artery immediately after the procedure.

Hemostasis evaluation and clinical follow-up

Successful closure with the Angio-seal VCD was defined through confirmation of the following: placement of the plug, extraction of the delivery system, and hemostasis within 5 minutes. In all patients with device failure, TTH was greater than 5 minutes. Manual compression was required in two VCD patients who underwent the procedure using the femoral retrograde approach because the VCD was unsuccessful with this particular approach. These two cases were excluded from the study. CT angiography or color-coded duplex sonography was used to assess puncture site problems. No complications were identified in any of the patients (Figure 2). TTH was defined as the time from the removal of the introducer sheath until hemostasis was achieved. The time to ambulation (TTA) was considered as the period from the withdrawal of the introducer sheath to the patient being able to stand and walk 20 feet without reappearance of bleeding.

All related complications were noted in both the MC and Angio-seal VCD groups, including re-bleeding at the operation site. Femoral pulses of both lower extremities were examined before the intervention, shortly after, and during recovery. On the first postoperative day, patients were examined for the development of ecchymosis, swelling, mass infection, or murmur at the intervention site, and palpation was performed. Major complications (ecchymosis or hematoma larger than 6 cm, pseudoaneurysm, arteriovenous fistula, and retroperitoneal hemorrhage) and minor complications (ecchymosis or hematoma smaller than 6 cm) were recorded. Additionally, patients who had undergone baseline duplex USG were subjected to follow- up ultrasound examination of the site on the 30th day after intervention.

Statistical analysis

The software SPSS version 21.0 was used to perform all statistical analyses (IBM, Armonk, NY). The normality of distributions was checked via the Shapiro-Wilk test. Data are presented as the mean ± standard deviation (SD) or median (1st – 3rd quartile range [IQR]) for continuous variables according to the normality of distributions and as frequency (percentage) for categorical variables. Normally distributed continuous variables were compared using an independent-sample t-test, while non- normally distributed variables were compared with the Mann- Whitney U test. The distribution of categorical variables was examined using chi-squared tests. Two-tailed p-values less than 0.05 were considered statistically significant.

Results

The mean age of the study group was 64.81±11.03 years, and 75.3% of the cases were males. There were 41 cases in the MC group and 40 cases in the VCD group. The frequency of hyperlipidemia in the VCD group was significantly higher than in the MC group (65.0% vs. 31.7%, p=0.003). No significant difference between the groups was found in terms of other comorbidities, age, gender, BMI, and smoking status (p>0.05 for all) (Table 1).

In the MC group, TTH (Figure 3) and length of hospital stay were significantly longer than in the VCD group (p<0.001 for all). No major complications were observed in the VCD group, but 5 (6.2%) patients in the MC group had major complications: retroperitoneal hemorrhage, AV fistula, embolism in the lower extremity, ecchymosis + hematoma (>6cm), and pseudoaneurysm. The frequency of major complications was significantly higher in the MC group than the VCD group (p= 0.023). All 9 minor complications recorded in the two groups were defined as ecchymosis + hematoma (Table 2). Two of the patients in the MC group received blood transfusions.

Discussion

The disadvantages or shortcomings of MC application are well described and include patient-related problems (related to groin pressure and extended bed rest), intensive workload for medical personnel, and longer hospitalization. The advantages of VCDs, including the Angio-seal VCD, are earlier vascular sheath removal, swift hemostasis, earlier ambulation, shorter hospitalization, and decreased staff workload [3]. This study revealed that TTA, TTH, and length of hospital stay were significantly shorter with the use of VCD, and major complications were significantly less frequent.

Cox et al. recently performed a systematic review of 34 randomized controlled trials comparing VCD and MC applications [3]. They also found that TTH, TTA, and length of hospital stay were significantly shortened with the use of VCD in comparison to MC. Noori et al. also described similar findings in another systematic review of 34 articles [4]. Wong et al. found that VCD use significantly decreased mean TTH (4.4 min vs. 11.6 min) and mean TTA (2.5 h vs. 5.0 h) [5]. Similarly, a randomized controlled study reported that TTA, TTH, and hospitalization durations were lower in the Angio-seal group. Considering the results of our study, which are compatible with previous studies, VCD is quite advantageous in terms of clinical outcomes in comparison to MC. In our study, the most prominent finding was thought to be the shortening of TTH, which is a benefit that is associated with the shortening of TTA and length of hospital stay. Therefore, VCD application can be more beneficial than MC, especially with respect to decreased TTA and patient-related advantages [6].

Another important finding of our study was that no major complications were observed in these patients, although minor ecchymosis + hematoma was observed in a few cases in the VCD group. In the VCD group, acute arterial occlusion and pseudoaneurysm were not identified. The low complication rate in our study is consistent with prior research [7]. In contrast, 12.2% of the MC group had major complications.

Previous studies on this subject have reported different results in terms of complication rates. First, we examined the results that are compatible with our study. Vaitkus et al. found a lower risk of vascular complications with VCD use (except for hematoma development) in their 5000-patient meta-analysis of access site complications. With the 6-Fr EXOSEAL system, Schmelter et al. showed a high success rate of 96%, fewer vascular problems (7%), and no severe complications.

In a prospective study including the records of nearly 13,000 consecutive patients from 2002 to 2007, fewer vascular complications were found with the use of VCD than MC in “appropriately selected patients undergoing diagnostic and therapeutic cardiac catheterizations [8]. In some studies, researchers have observed no significant variations in the incidence of complications across the groups. For instance, two recent systematic reviews have shown that the frequency of complications was similar in MC and VCD groups. Furthermore, VCD and MC were shown to have similar rates of periprocedural or access site complications [9]. Specifically, in a study comparing Angio-seal and MC, Alshehri et al. showed that the frequency of major complications did not change significantly between the groups, while the frequency of minor complications was significantly increased in the MC group [10].
Nonetheless, it has also been reported that complications increase with VCD use. In a study comparing Angio-seal and MC applications after endovascular interventions in peripheral artery disease, Fokkema et al. reported that the use of Angio- seals increased the risk of developing any complications (especially hemorrhage), regardless of other parameters. The authors emphasized that the Angio-seal system should be used carefully as it can increase the complication rate [11]. Similarly, there are different studies reporting an increase in complications with VCD methods [12]. It is thought that the different results reported in the studies may have been caused by differences in VCD devices and the experience of the practitioner.

Important limitations of our study include the fact that this is a retrospective study (therefore there was no randomization of groups) and it involved only a single center. Furthermore, a single type of VCD (St. Jude Medical, Minnetonka, Minnesota) with limited size options (6-F and 8-F) was used, thus it could not be compared to other devices. When discussing other studies, our comments were made with respect to the comparisons with MC, and the differences that may occur due to brand or model differences were not taken into consideration. Thus, the present arguments and inferences cannot be generalized to other types of VCDs. Although the frequency of hyperlipidemia was different between the groups, it is believed that this difference did not affect the results of our study.

Conclusion

With the utilization of the Angio-seal VCD, we found that TTH, TTA, duration of hospitalization, and major complication frequency were decreased in comparison to those with MC. After peripheral vascular interventions, the Angio-seal VCD appears to be a safe and effective method of arteriotomy closure, as demonstrated by our findings in patients undergoing single closure of percutaneous femoral and popliteal access. Nevertheless, in future studies, it would be useful to compare different VCD devices with a large number of cases.

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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Emced Khalil. Comparison of manual compression with a new bioabsorbable vascular closure device in percutaneous peripheral procedures. Ann Clin Anal Med 2022;13(1):109-113

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Impact of rem-related obstructive sleep apnea therapy on anxiety, depression and daytime sleepiness

Ayşegül Altıntop Geçkil 1, Hilal Ermiş 2

1 Department of Pulmonary Medicine, Faculty of Medicine, Malatya Turgut Ozal University, 2 Department of Pulmonary Medicine, Faculty of Medicine, Inonu University, Malatya, Turkey

DOI: 10.4328/ACAM.20963 Received: 2021-11-21 Accepted: 2021-12-15 Published Online: 2021-12-18 Printed: 2022-01-01 Ann Clin Anal Med 2022;13(1):114-118

Corresponding Author: Ayşegül Altıntop Geçkil, Department of Pulmonary Medicine, Faculty of Medicine, Malatya Turgut Ozal University, 44330, Malatya, Turkey. E-mail: aysegul.altintop@gmail.com Corresponding Author ORCID ID: https://orcid.org/0000-0003-0348-3194

Abstract
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Abstract

Aim: Obstructive Sleep Apnea (OSA) is characterized by repetitive episodes of complete or partial upper airway obstruction during sleep. Patients who slept at least 30 minutes in REM sleep, total apnea-hypopnea index (AHI)>5 and REM AHI/NREM AHI>2 are defined as REM-related OSA. We investigated the efficacy of treatment on anxiety, depression and daytime sleepiness in REM-related OSA.

Material and Methods: A total of 110 patients with REM-related OSA participated in the study. Patients were divided into two groups; the treatment group consisted of patients who received treatment (n:38) and the non-treatment group who refused to receive treatments (n:72). Of the 38 patients treated, 33 had mild disease and 5 had moderate disease. Sixty-seven of the 72 patients who did not receive treatment had mild disease and 5 had moderate disease. Both groups completed the HADS (Hospital Anxiety-Depression Scale), ESS (Epworth Sleepiness Scale) questionnaires. SPSS was used for data analysis. Results were expressed as mean and standard deviation. T-test and chi-square tests were performed to compare cases. A p- value <0.05 was considered statistically significant.

Results: There was no statistically significant difference between the groups, in terms of age, gender, height, weight, and body mass index (BMI). No statistically significant difference was found between the two groups in terms of polysomnography parameters AHI, REM AHI, arousal index, periodic leg movement (PLM) index, sleep latency, REM latency, minimum oxygen saturation (SPO2), and cumulative percentage of time spent at saturation below 90%. HADS- Anxiety, HADS- Depression and ESS scores were significantly higher in the non-treatment group in comparison to the treatment group (p=0.011, p=0.016, p=0.005, respectively).

Discussion: The results of our study showed that treatment has positive effects on anxiety, depression and daytime sleepiness, which are indicative of the quality of life in patients with REM-related OSA.

Keywords: REM-Related OSA, Anxiety, Depression, Treatment, APAP

Full Text

Introduction

Obstructive sleep apnea (OSA) is a syndrome characterized by recurrent episodes of partial (hypopnea) or complete (apnea) upper respiratory tract obstruction during sleep [1]. The REM (rapid eye movement) sleep covers 20-25% of all sleep time. During this stage of sleep, cardiorespiratory disorder, respiratory control disorder, and irregular ventilation occur [2]. Therefore, in patients with OSA, the number and duration of obstructive respiratory events increase as a result of severe oxygen desaturation during REM sleep.

Patients who slept at least 30 minutes of REM sleep, total apnea hypopnea index (AHI) > 5, REM AHI / NREM AHI≥ 2, NREM AHI <5 are defined as REM-related OSA [3]. REM-related OSA was described in 1996 by Kass et al. and constitutes 10-36% of all OSA cases. REM-related OSA is more common in mild to moderate OSA [4].

REM-related OSA has been associated with more severe cardiovascular side effects than classic OSA. In the Wisconsin Sleeping Cohort, it was reported that REM-related OSA was associated with hypertension [5]. Another study found that OSA patients with a longer duration of obstructive apnea had more severe hypertension compared to patients with a shorter apnea duration [6]. Furthermore, REM-related OSA was associated with type 2 diabetes [7]. Sleeping disorders are important risk factors for the development of depression. Gupta et al. showed an increased prevalence of OSA in people with and post-traumatic stress disorder and major depressive disorder [8]. REM-related OSA was associated with anxiety and depression [9]. The clinical significance of REM-related OSA has been underestimated and under-investigated for a long time and therefore it remained untreated. As a result, there are limited data on the efficacy of REM-related OSA therapy. Therefore, in our study, we planned to investigate the efficacy of treatment on anxiety, depression and daytime sleepiness in patients with REM-related OSA.

Material and Methods

Patients who applied to the Sleep Disorders Center of the Inonu University and Malatya Training and Research Hospital between 2017 and 2018 were evaluated retrospectively. All patients who underwent polysomnography were informed about the planned study before the procedure. It was explained that the data will be used in the study. The patients were asked whether they accepted voluntary participation or not, and a consent form was obtained from them if they agreed. The study was in accordance with the Helsinki Declaration, and it was approved by the Ethics Committee of the Medicine Faculty of Inonu University (issue:2018/22-4).

Additionally, patients with REM sleep time less than 30 minutes, total sleep activity less than 70%, and diagnosed with COPD or asthma were excluded from the study. Patients with a history of depression and antidepressants use were not included in the study.

A total of 110 patients with REM-related OSA were enrolled in the study. Patients were divided into two groups; the treatment group consisted of patients who received treatment (n:38) and the non-treatment group consisted of patients who refused to receive treatments (n:72). The group receiving treatment

consisted of patients who had been receiving treatment for at least six months as of the date of the survey. Both groups completed the HADS (Hospital Anxiety-Depression Scale), and ESS (Epworth Sleepiness Scale) questionnaires. Polysomnography (PSG): Patients were evaluated using a 55-channel polysomnography (Alice 6 ® Sleepware, Philips Respironics, PA, USA) system. Sleep recordings were analyzed according to the guidelines published by the American Academy of Sleep Medicine (AASM) [10].

AHI was obtained by dividing the sum of the apnea and hypopnea numbers by the sleep duration in hours. Sleep stages were scored as N1, N2, N3, and REM sleep. The REM latency is the time before the first REM phase. The desaturation index was defined as a 3% reduction in oxygen saturation (SPO2) from baseline, with the minimum SPO2 being the lowest SPO2 recorded overnight.

Hospital Anxiety-Depression Scale: HADS consists of two subscales, one of which consists of seven items measuring anxiety and the other seven items measuring depression, which are scored separately. The questionnaire consists of 14 parameters. The Likert scale was used (usually 3 points, often 2 points, sometimes 1 point, never 0 points). Total scores ≥10 are considered positive for anxiety, and scores ≥7 are considered positive for depression.

Epworth Sleepiness Scale: We used the Epworth Sleepiness Scale as it is a questionnaire used to evaluate daytime sleepiness in patients with sleep disorders. It is an 8-item questionnaire with scores between 0 and 24. A score of 10 or higher on the Epworth Sleepiness Scale is an indicator of excessive daytime sleepiness.

Statistical analysis: SPSS was used for data analysis. Results were expressed as mean and standard deviation. T-test and chi- square tests were performed to compare cases. A p-value <0.05 was considered statistically significant.

Results

A total of 110 patients with REM-related OSA were included in the study. Of the 38 patients who received treatment, 33 had mild disease and 5 had moderate disease. Sixty-seven of the 72 patients who did not receive treatment had mild disease and 5 had moderate disease.

Twenty-one patients received APAP (Automatic Positive Airway Pressure Therapy), 15 patients received surgery (nasal surgery, tonsillectomy), 1 patient used an oral appliance treatment, and 1 patient received APAP treatment after nasal surgery. The treatment group consisted of patients who used APAP for a minimum of 4 hours per day and used APAP in more than 70% of the sleep time over 6 months after the initiation of the treatment. The daily duration of the usage of APAP device was checked by analyzing the recorded data. Gender, age, weight, height and body mass index (BMI) of all patients were recorded. There was no statistically significant difference between the two groups in terms of gender, age, height, weight and BMI. No statistically significant difference was found between the two groups in terms of polysomnography parameters AHI, REM AHI, PLM (periodic leg movement) index, arousal index, REM latency, sleep latency, minimum SPO2, and desaturation index (Table 1). Anxiety score was significantly higher in the non-treatment group in comparison to the treatment group (p=0.011). Depression score was statistically significantly higher in the non-treatment group in comparison to the treatment group (p=0.016). The ESS score was significantly higher in the non-treatment group in comparison to the treatment group (p=0.005) (Table 2).

Discussion

In our study on REM-related OSA patients, anxiety, depression and ESS scores were significantly higher in the non-treated group. Currently, CPAP (Continuous Positive Airway Pressure Therapy) treatment is the gold standard method for the management of OSA [11]. Although CPAP treatment is recommended for patients with moderate to severe OSA (AHI>15/h), it is also recommended in patients when the symptoms are prominent and/or cardiovascular or cerebrovascular risk factors and severe oxygen desaturation during the night are present, even if OSA is mild (AHI: 5-15/h). However, general precautions (weight loss, non-supine position, alcohol and sedatives to avoid, treatment of concomitant diseases, etc.), oral appliance treatment, and nasopharyngeal surgery are also alternative treatment methods in suitable patients [12]. Actually, CPAP treatment is symptomatic therapy. Therefore, it is important to maintain adherence to CPAP, to estimate CPAP compliance before starting the treatment, and to use intensive interventions in patients who are not eligible for CPAP use. Various studies have shown that the severity of the disease, the degree of daytime sleepiness before treatment, gender, age, and PAP pressure are clinical determinants of adherence to CPAP use [11,12]. Although CPAP treatment has high efficacy, currently, the major problem with CPAP treatment is that a significant proportion of patients does not accept CPAP or have low compliance with treatment. Compliance rates vary between 29% and 81%. Although there are differences in the definition of compliance with CPAP therapy, patients who use CPAP more than 70% of the night and 4 hours per night are generally regarded as compliant [13]. It has been shown that oral appliance treatment reduces AHI and improves oxygenation at night [14]. In patients who cannot tolerate CPAP may also be considered as a treatment option. In a study conducted with an oral appliance, the treatment showed similar efficacy in REM-related and NREM-related OSA patients in terms of therapeutic efficacy [15]. Oral appliance treatment therapy, which can reduce daytime sleepiness, may be recommended for the treatment of patients with mild-to- moderate OSA. One of the treatment modalities in OSA is surgical treatment. Surgical interventions may be an option in patients who cannot tolerate CPAP and may be used as an alternative method in selected patients. In a multi-center study by MacKay et al, patients with moderate to severe OSA who failed CPAP have undergone palate and tongue surgery. Six months after the surgical operations performed on these patients, it was shown that patients experienced significant improvement in AHI and daytime sleepiness [16]. The most appropriate patients for either oral appliance therapy or surgical treatment are those with simple snoring or mild OSA. Surgical interventions can also be used in patients who cannot tolerate or accept CPAP treatment, even if they have moderate or severe OSA. Surgical treatment and oral appliance treatment can be considered as an alternative treatment for OSA patients in patients who do not want to use a CPAP device due to aerosolization during the COVID-19 pandemic period. REM phase of sleep accounts for about a quarter of the total sleep time in healthy adults, and is mostly intensified in the second half of the sleep period. NREM sleep accounts for about 80% of total sleep. Regardless of being REM-related or not, patients with OSA experience more severe respiratory events during REM sleep [17]. Therefore, REM-related OSA is treated with APAP because patients with REM-related OSA require relatively lower pressure over a long period of total sleep and higher pressures during the REM sleep period. In addition, fluctuations in pressure due to disproportionate distribution of respiratory events during sleep are one of the most important factors that may affect CPAP compliance. Since the recommended 4-hour treatment for CPAP therapy may not be sufficient in REM-related patients due to the fact that REM sleep is seen especially towards morning, it may also be necessary to use the device for a longer period of time. REM-related patients are reluctant to use CPAP because they are mainly mild-moderate. In these patients, suggesting oral appliance treatment or surgical treatment seems to be appropriate to improve treatment compliance. In a study evaluating CPAP treatment, the presence of REM-related OSA was shown to be an independent risk factor affecting CPAP compliance. They claimed that CPAP treatment compliance was better in normal OSA than REM-related OSA and the REM AHI / NREMAHI ratio was the most important factor affecting compliance [18]. In a recent study, twenty REM-related OSA patients who were given APAP treatment were followed up for a year in terms of quality of life. Patients were evaluated with ESS, FOSQ, psychomotor vigilance test reaction time (PVT-RT), and Depression Anxiety Stress Scales (DASS-21) questionnaires at 1, 3, 6, and 12 months after treatment, and APAP treatment reduced daytime sleepiness and increased quality of life [19]. The results of these studies are similar to the results of our study.

Sleep studies have shown that depression is associated with altered sleep architecture and REM sleep disturbance. Increased REM duration, increased REM intensity, and shortened REM latency, have been considered biological markers of depression [20]. Insomnia, which is correlated with depression, is seen in 39-58% of OSA patients. It has also been reported that 80% of patients with depression suffer from insomnia [21]. In a study investigating the effect of insomnia, REM-related OSA and normal OSA patients were compared with the ESS and Pitsburg Sleep Quality Index (PSQI), and as a result, high PSQI was found in REM-related female patients, and no difference was found between the groups in terms of ESS [22]. Koc et al in their study with patients with similar AHI, showed that morning headache was more common in the group with high AHI in the REM period compared to those with a lower, and daytime sleepiness was higher in the group with a morning headache [23]. In a meta- analysis, Sanchez et al., concluded that treatment with CPAP or oral appliance treatment in OSA was superior to placebo for the treatment of depressive symptoms [24]. In a review by Povitz et al., it was shown that use of both CPAP and oral appliance treatment for OSA treatment resulted in improvements in depressive patients [25].

The patients in our study were statistically similar in terms of age, gender, BMI and polysomnography data in both groups. However, there were some limiting factors. The cases were screened retrospectively. There was no standardization of the environment the patients lived in and the emotional situation they experienced during the study period, and there was no objective evaluation of other conditions that could cause depressive mood was done.

Conclusion

The results of our study showed that treatment has positive effects on anxiety, depression and daytime sleepiness, which are indicative of the quality of life in patients with REM-related OSA. Encouraging patients to receive treatment and assuring continuity will decrease sleep deprivation while improving the quality of life. Although, it is still not possible to eliminate OSA using a single method or a combination of multiple methods, it may be possible to define the patient’s needs and increase the compliance with the treatment of OSA by patient-targeted approaches with participation of patients in all processes. Further studies with larger series are needed to support these results.

Scientific Responsibility Statement

The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

Animal and human rights statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. 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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Ayşegül Altıntop Geçkil, Hilal Ermiş. Impact of rem-related obstructive sleep apnea therapy on anxiety, depression and daytime sleepiness. Ann Clin Anal Med 2022;13(1):114-118

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