February 2021
Study of the effects of spinorphin on painful diabetic neuropathy: A behavioral study in vivo
Erkan Cakmak
Department of Internal Medicine, Adıyaman University Training and Research Hospital Internal Diseases Clinic, Adıyaman, Turkey
DOI: 10.4328/ACAM.20475 Received: 2021-01-08 Accepted: 2021-01-25 Published Online: 2021-01-30 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):208-211
Corresponding Author: Erkan Cakmak, Department of Internal Medicine, Adıyaman University Training and Research Hospital Internal Diseases Clinic, Adıyaman, Turkey. E-mail: drerkan_23@hotmail.com P: +90 505 311 20 80 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0442-0630
Aim: Diabetic neuropathy is one of the chronic complications of diabetes. Our aim in this study is to examine the effects of spinorphine on painful diabetic neuropathy in vivo. Material and Methods: Seventy-five three-week rats were used. The first group was determined as a healthy control group (n = 15). Then, diabetic animals were grouped into subassemblies following induction in rats induced streptozotocin and diabetes. Groups were created using rat as follows: First group: Healthy control group, Second group: Diabetic control group (group to be given spinorphine solvent) (n = 15), Third group: DM + SP0.1 group (group to be applied 0.1 mg / kg spinorphine) (n = 15), Fourth Group: DM + SP1 group (group to be applied 1 mg / kg spinorphine) (n = 15) and Fifth group: DM + SP5 group (group to be applied 5 mg / kg spinorphine) (n = 15).Results: When the diabetic control group and the healthy control group were compared in terms of the pain threshold values, a statistically significant dif-ference was found (P <0.05). This result was considered significant in regards to the development of neuropathy (P <0.05). The pain threshold values in DM + SP0.1 and DM + SP1 groups had no statistically significant differences compared with the diabetic control group (P> 0.05). Discussion: This study, found spinorphine to be effective at doses of 5mg/kg or higher and when administrated intraperitoneally in the acute antinociceptive treatment of painful neuropathy in diabetic rats.
Keywords: Diabetic neuropathy; Hot plate; Spinorphine
Introduction
Diabetes mellitus (DM) is a chronic, metabolic disease, which is accompanied by disorders of carbohydrate, lipid and protein metabolism, especially hyperglycemia arising from disorders of insulin secretion, insulin activity, or both, and accompanied by accelerated atherosclerosis and microvascular and macrovascular complications [1, 2].
Various pathogenetic mechanisms play a role in the development of diabetes. These are other causes of pancreas β cell destruction and insulin resistance, which leads to absolute insulin deficiency [3, 4]
Many mechanisms have been proposed in the pathogenesis of diabetic neuropathy. These are metabolic processes that cause direct nerve injury, endoneurial microvascular damage, autoimmune inflammation, and decreased neurotrophic support [5, 6].
Spinorphine is a protein substance that was first isolated from the bovine spinal cord. Spinorphine shows its antinociceptive effect by inhibiting the enzyme fractionation enkephalin [7]. In animal studies related to spinorphine, it has been reported to provide strong antinociception when administered intraventricularly and intrathecally. As a result of these studies, it was found that spinorphine is an important agent in the metabolism of enkephalin in the spinal cord and thus in the modulation of pain [8].
In this study, it was analyzed whether different doses of spinorphine were effective when administrated intraperitoneally in the acute antinociceptive treatment of painful neuropathy in diabetic rats.
Material and Methods
Experimental Animals
Approval was obtained from the Animal Experiment Ethics Committee before the commencement of the study. In the experimental study, 75 BALB-C male rats with an average weight of 30 grams (30 ± 5 g) for at least 8-weeks were used. In Experimental Research Unit (FÜDAM) Animal Laboratory of Firat University, the temperature of the environment where the rats are kept is constantly between 22-25˚C and the animals were followed during 12 hours of light and 12 hours of darkness. The rats were specially prepared in an environment with a ventilation system and were fed in cages cleaned every day. Feed was given in a special steel trough, and water was given as normal tap water in stainless steel ball feeding bottles. The experimental animals were fed with specially prepared rat feeds in the form of pellets.
Diabetes induction
In this part of the study, 150 mg/kg STZ (Streptozocin, Zanosar, Pharmacia, France) by insulin injection of 26 gauge because of the induction diabetes in 60 rats was administered as a single dose by intraperitoneal (ip) injection [9] solubilized (pH: 4,5) in 0.4 ml (0,1M) sodium-citrate buffer. One week later, rats whose postprandial blood glucose exceeded 400 mg/dl as a result of measurement on the glucometer device by being taken blood from the tail vein were considered diabetic [10]. ACCU-CHEK Go (Roche) was used as a blood glucose meter. A drop of fresh blood taken from the tail of the experimental animal was absorbed into the strip of the blood glucose meter, and then, after 10 seconds, the blood glucose level was displayed on the device screen. Measurement of blood glucose level on these devices was performed by the “glucose-oxidase peroxidase” method [11].
Streptozocin is protected from light because it has the structure of N- (Methylnitrosocarbamoyl) -α-D-glucosamine. The pH of the environment was kept at 4-4.5 for optimum stability since it has decomposed rapidly at neutral pH. Therefore, while solubilising streptozocin, citrate buffer was used. Both insulin-dependent and insulin-independent diabetes have been induced by injuring pancreatic β cells [12].
Experimental Groups
The study consists of 5 groups.
1st group (n = 15): Healthy control group.
Following induction in rat induced diabetes using STZ (approximately 4th week); diabetic animals were separated into subgroups (n = 60).
2nd Group (n = 15): Diabetic control group (the group to be administered with spinorphine solvent).
3rd Group: DM + SP0.1 group (n = 15): The group to be administered low doses of spinorphine (Spinorfine with 0.9% saline at a dose of 0.1 mg/kg by solubilising within the physiology was administered by injecting).
4th Group: DM + SP1 group (n = 15): Group to be administered spinorphine at a median dose (Spinorfine with 0.9% saline at a dose of 1 mg/kg by solubilising within the physiology was administered by injecting).
5th Group: DM + SP5 group (n = 15): Group to be administered the maximum dose of spinorphine (Spinorfine with 0.9% saline at a dose of 5 mg/kg by solubilising within the physiology was administered by injecting).
Hot Plate Test in Diabetic Rats
Pain threshold values in study and control animals were analyzed using the hot plate test two weeks after the induction of diabetes. The ground temperature of the hot plate analgesimeter was set to 50 ± 0.5 ° C to create thermal hyperalgesia. While the animal was kept in this closed area, the chronometer was started. Observing the experimental animal, when forming a reaction such as pulling its nails, preening its nails due to pain, or jumping, the chronometer was stopped and withdrawal latency value was obtained in seconds.
Before starting pain threshold studies, animals were enumerated by means of marking the tails of the animals in all groups. First of all, control records of all groups were taken 15 minutes before injection and the time of injection was considered as 0 minutes. Following the injection, pain threshold values were measured at 15th, 30th, 45th, 60th, 120th and 180th minutes. It was taken care that the people who performed antinociceptive behavioral experiments did not have information about the blood glucose level of the rat.
Statistical Analysis
The average and standard deviation values of the data obtained in the study were calculated. SPSS 22.00 computer package statistics program (SPSS Inc., Software Chicago, IL, USA) was used in preparation of statistics. The Kruskal-Wallis and Mann-Whitney U tests were used in the analysis. A p-value <0.05 was considered significant.
Results
Before starting the experimental studies, in order to minimize the problems that may occur, all groups underwent a period of adaptation to the environment and hot-plate test for a week. Initially, pain threshold values were determined before the rat was not injected. Following these procedures, the animals in the control group were injected with saline, and (n = 15) physiological study group, respectively; Low doses of spinorphine (0.1mg/kg), median dose spinorphine (1mg/kg) and maximum dose spinorphin (5mg/kg) were administered by injection. The time of injection was accepted as 0 minutes. Since the half-life of spinorphine (t1/2) is 20 min, pain threshold values in all groups were measured with a hot plate device at 0th, 15th, 30th, 45th, 60th, 120th and 180th minutes, and their records were taken.
Pain threshold values of the healthy control group, were as follows: -15th minute: 16.18 ± 0.3, 0th minute: 16.55 ± 0.30, 15th minute: 17.25 ± 0.34, 30th minute: 16.89 ± 0.13, 45th minute: 15.48 ± 0.17, 60th minute: 17.67 ± 0.17, 120th minute: 16.09 ± 0.24 and 180th minute: 15.91 ± 0.20 seconds (Table 1). Pain threshold values of the diabetic control group, were as follows: -15th minute: 22.95± 0.88, 0th minute: 23.62 ± 0.97, 15th minute: 23.10 ± 0.84, 30th minute: 23.52 ± 0.97, 45th minute: 23.62 ± 0.69, 60th minute: 22.25± 0.89, 120th minute: 24.02 ± 0.83 and 180th minute: 23.76 ± 0 91 seconds (Table 1). A statistically significant diference was found when comparing the pain threshold values between the healthy control group and the diabetic control group, (p<0.05).
Pain threshold values in the DM + SP0.1 group, were recorded as follows: 22.36 ± 1.14, 22.25 ± 1.11, 21.82 ± 1.02, 20.48 ± 0.10, 21.35 ± 1.13, 21.05 ± 0.84, 21.15 ± 0.98, 21.13 ± 0.73 and 20.55 ± 0.38 seconds (Table 1). Pain threshold values in the DM + SP1 group, were determined as follows: 22.42 ± 0.80, 21.79 ± 0.94, 22.43 ± 0.94, 22.77 ± 1.13, 22.16 ± 0.95, 21.71 ± 0.85, 21.63 ± 0.92 and 21.38 ± 0.76 seconds (Table 1). Pain threshold values in DM + SP5 group, were determined as follows: 20.02 ± 1.16 sec, 20.58 ± 0.86 sec, 21.33 ± 0.22 sec, 23.12 ± 0.96 sec, 23.22 ± 0.10 sec, 21.53 ± 0.77 sec, 21.31 ± 0.83 sec and 21.44 ± 1.45 sec (Table 1). When comparing the pain threshold values measured at 30 and 45 minutes in the DM + SP5 group with the pain threshold values at -15, 0, 15, 60, 120 and 180 minutes, a statistically significant difference in acute antinociceptive effect on painful diabetic neuropathy was found (p <0.05).
Discussion
The hot plate test in the evaluation of neuropathic pain threshold is an indirect and in vivo method and the evaluation is made quantitatively. It has been reported that pain threshold reactions contribute to obtaining indirect information about diabetic neuropathic pain [13, 14,15].
The fact that it has an antinociceptive effect against painful stimuli has indicated the necessity of testing the activity possibilities of this agent in the acute treatment of neuropathic pain. For this reason, there are various studies in the literature [16-17].
Spinorphine and other enkephalin hydrolyzing enzyme inhibitors are highly promising therapeutic agents for antinociceptive therapy. Especially in recent years, the antinociceptive effects of these agents have been examined and reported. The most important advantages of these antinociceptive agents are that both are stronger than opioids and do not have side effects caused by opioids [18].
In a study carried out by Honda et al. [19], the effects of spinorphine on allodynia on thermal and mechanical nociception in rats in vivo were investigated. They demonstrated that intrathecal administration of spinorphin in a dose-independent manner inhibited intrathecal nociception causing allodynia. In addition, they found that spinorphine caused prolongation of the antinociceptive effect created by leu-enkephalin when administered intracerebroventricularly. Still in this study, they applied spinorphine intracerebroventricularly and all in all found that spinorphine did not change both the mechanical and thermal pain threshold. In this study, they stated that when administered intrathecally, spinorphin exerts its antinociceptive and antiallodynic effect by inhibiting the enzymes that break down enkephalin.
Nishimura et al. [20] administered spinorphin in to the monkey brain at 50-200 mcg doses intraventricularly in an animal study they conducted. At the end of the study, they found that spinorphine showed antinociceptive activity in a dose-independent manner. They considered from this effect of spinorphine to inhibit enzymes that hydrolyze enkephalin with a high affinity and potently, and they expressed that spinorphine is an important neuromodulator for enkephalin metabolism in the spinal cord [20].
Jung et al. [21] demonstrated that the antinociceptive effect of spinorphine, an endogenous peptide, is associated with inhibition of the enzymes that hydrolyze enkephalin, in particular, non-competetive and selective antagonism at the ATP-dependent human P2X3 receptors.
Yamomoto et al. [7] applied spinorphine intraventricularly to the monkey brain in a study they conducted. As a result of the study, they considered the antinociceptive effect of spinorphine in inhibiting the destruction of enkephalin. They showed that enkephalin has played a role in a highly complex pain modulation mechanism in the spinal cord. They reported that enkephalin is rapidly fractioned by endogenous enzymes and therefore it is ephemeral; spinorphin shows its antinociceptive effect by inhibiting the enzymes that hydrolyze enkephalin, especially DPP III. There are very few studies in the literature regarding the antinociceptive effect of spinorphine, and in these studies [7, 8, 19], they applied spinorphine to the monkey brain intraventricularly and intrathecally in a total dose range of 50-200 mcg. and the antinociceptive effect was obtained after thirty minutes. In this study, spinorphine was administered at a dose of 5 mg/kg as the highest dose and intraperitoneally. It has been determined that spinorfine does not show the antinociceptive effect at low doses, such as 0.1mg/kg and 1mg/kg and when administered intraperitoneally. However, when administered at a high dose such as 5mg/kg, it showed an antinociceptive effect when measured after 30 and 45 minutes (p <0.05). When applied at this dose, the antinociceptive effect was observed at 60, 120 and 180 minutes (p> 0.05). In accordance with the results obtained in previous studies on spinorphine, and also, in our study, the antinociceptive effect was obtained when administered at high doses. The half-life of spinorphine of 20 minutes has explained the observation of antinociceptive effect at 30 and 45 minutes when administered at a dose of 5 mg/kg and the termination of antinociception after 60 minutes.
In current studies on spinorphine, spinorphine was administered centrally such as intraventricular and intrathecal administration. Intraperitoneal administration was tried for the first time in this study, and a positive response was obtained in high dose administration. This result is important for the effectiveness of peripheral administration of spinorphine.
Limitations
Our study has several limitations. A wider group of rats could be used. Spinorphine could be given after a certain period of time after diabetes developed in rats. Thus the effect of complications could be seen more clearly. However, as rat losses may increase in this condition, it was not considered appropriate. A comparison of spinorphine with another molecule actively used in the treatment of diabetic neuropathy could be done. Thus, we could see the effect of spinorphine on diabetic neuropathy more clearly. However, the current situations are not included in the project due to high costs.
Conclusions
In conclusion, in this study, it was determined that spinorphine was effective in the acute antinociceptive treatment of painful diabetic neuropathy. To induce an acute antinociceptive effect of spinorphine, it should be used in doses of at least 5mg/kg or higher. There is no antinociceptive effect at lower doses. The antinociceptive effect appeared as of 30 minutes and disappeared after 60 minutes. In consideration of all these findings, spinorphine is seen as a promising agent for the acute antinociceptive treatment of painful diabetic neuropathy.
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. Yenigün M. Her Yönüyle Diabetes Mellitus (All Aspects of Diabetes Mellitus). 2nd ed. İstanbul: Nobel Tıp Kitabevi; 2001. p.237-43.
2. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997; 11-20.
3. Foster DW. Diabetes Mellitus. Wilson JD, Fauci A, Braunwald E, Isselbacher KJ, Martin JB, Kasper DL, Hauser SL, Longo DL, editors. Harrison’s Principle of Internal Medicine. 14th ed. New York: Mc Graw Hill Companies; 1998. p.2060-80.
4. Davon A. Marcus. Chronic pain. A primary Care Guide to Practical Management, 2nd ed. Totawa, NJ: Human Press; 2005. p.114-15.
5. Ertaş M. Nöroloji. A. Emre Öge (editör). İstanbul Üniversitesi İstanbul Tıp Fakültesi Yayınları Nobel Kitabevi; 2004. p.617-18.
6. Devor M. Sodium channels and mechanisms of Neuropathic pain. J Pain. 2006; 7(Suppl. 1):S3-12.
7. Yamamoto Y, Ono H, Ueda A, Shimamura M, Nishimura K, Hazato T. Spinorphin as an endogenous inhibitor of enkephalin-degrading enzymes: roles in pain and inflammation. Curr Protein Pept Sci. 2002; 3:587-99.
8. Nishimura K, Hazato T. Isolation and identification of an endogenous inhibitor of enkephalin-degrading enziymes from bovine spinal cord. Biochem Biophys Res Commun. 1993; 194:713-19.
9. Christianson JA, Ryals JM, Johnson MS, Dobrowsky RT, Wright DE. Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice. Neuroscience. 2007; 145:303-13.
10. Wang Z, Dohle C, Friemann J, Green BS, Gleichmann H. Prevention of high- and low-dose STZ-induced diabetes with -glucose and 5-thio-D-glucose. Diabetes. 1993; 42:420-8.
11. Vitros DT. II Operator’s Manual Book. USA: Johnson and Johnson Company; 2003. p.324-49.
12. Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res. 2001; 50:536-46.
13. Piercy V, Banner SE, Bhattacharyya A, Parsons AA, Sanger GJ, Smith SA, et al. Thermal, but not mechanical, nociceptive behavior is altered in the Zucker Diabetic Fatty rat and is independent of glycemic status. J Diabetes Complications. 1999; 13:163-9.
14. Klitgaard H, Matagne A, Gobert J, Wülfert E. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. Eur J Pharmacol. 1998; 353:191-206.
15. McMahon SB, Cafferty WB. Neurotrophic influences on neuropathic pain. Novartis Found Symp. 2004; 261:68–92.
16. Robert H, Alec B, Miroslav B, John T. Pharmacologic management of neuropathic pain. The J of Pain. 2007; 132:237-51.
17. Junichi H, Yukio Y, Hisasi K, Kinya N, Tadahiko H. Identification of Dipeptidyl Peptidase III in Human Neutrophils. BBRC. 2000; 273:393-7.
18. Sato H, Kimura K, Yamamoto Y, Hazato T. Activity of DPP III in human cerebrospinal fluid derived from patients with pain. Masui 2003; 52:257-63.
19. Honda M, Okutsu H, Matsuura T. Spinorphin, an endogenous inhibitor of enkephalin-degrading enzymes, potentiates Leu-enkephalin-induced anti-allodynic and antinociceptive effects in mice. Jap J Pharm. 2001; 87:261-7.
20. Nishimura K, Ono H, Ueda A, Shimamura M, Nishimura K, Hazato T. Spinorphin as an endogenous inhibitor of enkephalin-degrading enzymes: roles in pain and inflammation. Curr Protein Pept Sci. 2002; 3:587-99.
21. Jung KY, Moon HD, Lee GE, Lim HH, Park CS, Kim YC. Structure-activity relationship studies of spinorphin as a potent and selective human P2X(3) receptor antagonist. J Med Chem. 2007; 50:4543-7.
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The effect of sufi music on sedation in patients under spinal anesthesia during orthopedic surgery
Ali Akdoğan, Mahmut Arslan, Nesrin Erceyes
Department of Anesthesiology and Critical Care, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
DOI: 10.4328/ACAM.20472 Received: 2021-01-07 Accepted: 2021-01-26 Published Online: 2021-01-29 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):204-207
Corresponding Author: Ali Akdogan, Karadeniz Technical University, Faculty of Medicine, Department of Anesthesiology and Critical Care, 61080, Trabzon, Turkey. E-mail: draliakdogan@yahoo.com P: +90 (462) 377 57 41 F: + 90 (462) 325 53 98 Corresponding Author ORCID ID: https://orcid.org/0000-0001-7592-3844
Aim: Music is the preferred method of sedation due to its noninvasive nature, affordable cost, and easy application. In this study, we aimed to compare music therapy with a control (non-music) group in terms of perioperative sedation requirements, anxiety levels, and patient satisfaction starting from the preopera-tive period in patients who underwent orthopedic surgery under spinal anesthesia.Material and Methods: This study was carried out prospectively with 50 patients in the ASA I-II risk group, aged 18-60 years and will undergo elective non-oncological orthopedic surgery. Patients taken to the preparation room were randomly classified into two groups. Propofol (FRESENIUS-Germany) infusion was started at 1 mg/kg/hour in patients who underwent spinal anesthesia in the operation room. The Bispectral Index Monitor™ (BIS) was used to verify sedation. Hemodynamic data and BIS values were recorded preoperatively (t1) and during spinal anesthesia (t2). Perioperative values were recorded at the 5th, 15th, 30th, 60th minute (t3, t4, t5, t6) and postoperative 30th minute (t7). Results: There was no statistically significant difference between patients’ demographic characteristics and the duration of surgery. Although lower values were detected in the music group in terms of heart rate (HR) and mean arterial pressure (MAP) at all times, the difference between the groups was not statistically significant. When evaluated in terms of BIS scores, significantly lower values were recorded in the music group at all times. When Ramsey Sedation Scores were compared, while high scores were obtained at t2 and after in the music group at all times, the results at t5, t6, t7 times were found to be significantly higher.Discussion: Our study showed that listening to Sufi music starting from the preoperative period has positive effects on anxiety. Considering the negative ef-fects of anxiety on the experience of anesthesia and operation success, it can be said that the more frequent use of a non-invasive method such as music can reduce the anxiety of the operation.
Keywords: Music therapy; Spinal anesthesia; Turkish sufi music; Perioperative anxiety
Introduction
Spinal anesthesia is more frequently used today as it reduces intraoperative blood loss, has less common side effects such as prolonged sedation, nausea-vomiting, respiratory depression that we encounter in general anesthesia, reduces morbidity in high-risk patients, and its analgesic effect continues in the postoperative period [1]. In the preoperative period, anxiety is a natural process, and many methods are used to prevent this situation. It is known that anxiety negatively affects patients in the perioperative period [2,3]. It has been reported that the sounds of the surgical team and surgical instruments or spinal anesthesia in the operation room increase patient anxiety [2]. This situation can become stronger, particularly in orthopedic surgeries, where surgical tools such as hammer and drill are frequently used.
In the studies conducted, the effectiveness of non-pharmacological methods used in reducing the preoperative anxiety in patients has been investigated with various studies. Among these methods, giving information preoperatively, showing a short film about the surgery and the hospital, and having pediatric patients wear a mask accompanied by their family can be counted [4,5]. It has been shown that anxiety and postoperative pain are less in elderly patients who receive perioperative psychological support and music [6].
Music is a more acceptable sedation method than other pharmacological methods because of its noninvasive nature, cost-effectiveness, and easy application [7,8]. In addition to the limited number of studies on spinal anesthesia and music, researches have been conducted in existing studies by making patients listen to the music of their choice, favorite music, or classical music. In our country, studies on music date back to much older times. Particularly in Turkish-Islamic civilizations, there are works showing that Sufi Music was commonly used in the treatment of various psychiatric diseases and in hospitals. However, today, there are a limited number of studies in which Sufi Music is used for treatment and rehabilitation [9].
In this study, we aimed to compare music therapy with a control (non-music) group, starting from the preoperative period and continuing in the perioperative period, in terms of perioperative sedation requirements, anxiety levels, and patient satisfaction in patients who underwent orthopedic surgery under spinal anesthesia.
Material and Methods
This study was carried out prospectively in 50 patients in the ASA I-II risk group, aged 18-60, who will undergo elective non-oncologic orthopedic surgery, with the approval of the local ethics committee and informed consent from the patients. The exclusion criteria were identified as those who have hearing loss, are professional music practitioners, are using medications that can affect the hypothalamo-hypophyseal and sympathetic system. In addition, patients who did not like this type of music and stated that they did not want to listen were not included in the study. New patients were recruited in place of patients who were excluded for any reason to reach the planned sample size.
Patients who were taken to the preparation room 30 minutes preoperatively were randomly classified into two groups as the music group (Group M) and the control group (Group K). The software on the “www.randomizer.org” website was used for randomization. Hemodynamic data and RSS (Ramsey Sedation Scale) values of the patients were noted in the preparation room (t1). The patients in Group M were made listen to works from Turkish Sufi Music Hüseyni Mode with an mp3 player (SONY NVZ-B172), using headsets. The patients were told to adjust the volume of the music according to their preferences. An oxygen mask was worn on both group (M) and group (K), and oxygen was given at a rate of 3lt/min. Both groups received the 0.08 mg/kg midazolam (Zolamid, DEFARMA-Turkey) intravenously (IV) and given with a slow bolus. Patients were monitored and started to wait. Patients sedated with midazolam in the anesthesia preparation room were taken to the operation room 30 minutes later.
The patients who were transferred to the operating room and whose electrocardiography (ECG), non-invasive blood pressure, and peripheral oxygen saturation were monitored were made to continue to inhale 3 lt/min of oxygen with a face mask. Covidien Bispectral Index Monitor™ (BIS) (Medtronic Minimally Invasive Therapies, Minneapolis, MN) was used to confirm moderate sedation in both groups (65-75). Propofol (FRESENIUS-Germany) infusion was started to the patients at a rate of 1 mg/kg/hour with the perfuser. Spinal anesthesia was provided to the patients, who were in the lateral decubitus position, by intrathecal administration of 2.5 ml 0.5% bupivacaine with a 25 gauge needle at the L3-4 or L4-5 level. Surgery was initiated when the appropriate block-level occurred in patients who were controlled with motor block modified Bromage score and a sensory block pinprick test. Hemodynamic data and BIS values were recorded preoperative (t1) and during spinal anesthesia (t2). Perioperative 5th, 15th, 30th, 60th minute (t3, t4, t5, t6) and postoperative 30th minute (t7) values were recorded.
Obtained data were evaluated using the “SPSS for Windows 13.0” software. The data were expressed as a percentage, mean ± standard deviation. In the comparison of the data obtained by measurement, data conforming to the normal distribution were compared with the “Student t- test”, and the data not conforming to the normal distribution with the “Mann-Whitney U” test. P <0.05 was considered a significant result.
Ethics committee
The study protocol was approved by the Karadeniz Technical University ethics committee (2012/132).
Results
A total of 61 patients were included in the study. Since 2 patients had hearing loss, and 4 patients had to be switched to general anesthesia, and 5 patients who did not want to participate in the study were excluded. Data were analyzed for 50 patients (Figure 1).
No statistically significant difference was found between the demographic characteristics of the patients whose age, gender, body mass index (BMI), ASA scores, and duration of surgery were evaluated (Table 1).
Although lower values were detected in the music group in terms of heart rate (HR) and mean arterial pressure (MAP) at all times, the difference between the groups was not statistically significant (p=0.538) (Figure 2).
When Ramsey Sedation Scores were compared, while high scores were obtained in the music group at all times at t2 and after, the results at t5, t6, t7 times were considered to be significantly higher (p=0.019, p = 0.047, p = 0.012, respectively) (Figure 3).
Discussion
This prospective, randomized and controlled study was conducted after ethics committee approval was obtained. The main finding of the study is that the respiratory rate and BIS values are significantly lower and RSS is significantly higher in the music group. No significant difference was found between the heart rate count, mean arterial pressure, and saturation values at the measurement times.
Different rates of anxiolysis have been achieved in studies using non-pharmacological methods to reduce anxiety due to anesthesia or surgery. The sedative effect of music therapy and particularly classical Turkish music has been known for many years. Our study has shown that classical Turkish music can be helpful in reducing anxiety in patients undergoing orthopedic surgery under spinal anesthesia.
Surgery anxiety depends on many factors. In adult patients, many factors related to anesthesia, surgical procedure, postoperative pain thought and postoperative rehabilitation process affect anxiety. The high level of anxiety negatively affects the success of the surgery, patient comfort, and patient satisfaction. Although pharmacological premedication can be used to combat anxiety non-invasive, pleasant methods should be preferred. The primary and side effects of the agents used for pharmacological premedication may cause undesirable results.
Although the use of music in medicine dates back many years, music has been studied frequently in recent years to prevent anxiety due to reasons such as being non-invasive, cheap, and having no side effects. The effect of music on all classifications of patients, from intensive care patients who are followed up with a mechanical ventilator, to patients under spinal anesthesia, from the pediatric age group to the elderly population, is investigated [6,10-12].
Although music genres, age groups, sample sizes, clinical situations, and situations that cause anxiety are different, the effect of music therapy on reducing anxiety is generally mentioned.
The assessment of anxiety is difficult due to the presence of confounding factors, differences in past experiences, and personality factors. Various questionnaires have been conducted to understand whether the level of anxiety is immediate or general. The relationship between state- and trait anxiety has been tried to be evaluated in the questionnaires. The evaluations made, although their validity has been proven for the society studied, raise questions in terms of their objectivity.
The disadvantages of pharmacological methods used to reduce anxiety are respiratory and hemodynamic adverse effects and the possibility of extra anxiety caused by the procedure.
In studies where music was used to deal with anxiety, no difference was found between hemodynamic and respiratory data of the patients [1,13,14]. In a study investigating the effects of music, silence, and ambient noise, no difference was found between the number of respiration. In our study, no difference was found between the heart rate, mean arterial pressure, and peripheral oxygen saturation of the patients, and their respiratory rate was lower in the music group at all times. Despite the difference in respiratory rates, the saturation values of the patients did not change. The difference between the respiratory numbers in our study can be attributed to the more anxiolytic effect of traditional Sufi music we use.
The effects of the modes used in traditional Turkish music on the human psyche have been known for many years. And Farabi has described in his works what mode of this music genre has what kind of effects. According to these results, which are mostly based on experience, the Hüseyni mode music we made our patients listen to in our study, is known for its effects of peace, tranquility, comfort, and sleep.
The bispectral index is an EEG parameter and it is an approved method that can show the anesthetic effect. It offers clinicians the opportunity to objectively evaluate the sedative and hypnotic effects of anesthetic medications. In our study, the distinction between BIS values has an important place in eliminating subjective data.
In a study investigating the sedative effects of music in patients undergoing septorhinoplasty with a methodology similar to our study, significant BIS score changes were detected in the music group [15]. The BIS data in our study are compatible with the aforementioned study.
In another study investigating the effect of music, white noise, and ambient noise on propofol consumption in patients who underwent spinal anesthesia in patient-controlled sedation, propofol consumption was found to be significantly lower in the music group, and no significant difference was encountered between patients [16]. In our study, the patients evaluated with the Ramsey sedation scale had higher perioperative 30th and 60th minute and postoperative 30th-minute sedation scores than the control group. In the studies aforementioned, in which the level of anxiety was evaluated subjectively, conflicting results with our study were considered normal.
It is obvious that it is difficult to achieve standardization in studies conducted with music. There are many confounding factors in the planning and implementation of the study. The absence of a purification of ambient sounds (silence), called the white noise group in our study, and the non-standardization of sound intensity can be considered a shortcoming. In further studies, we believe that it is possible to clarify how much, what intensity, and which type of music can be used by investigating different types of music, different surgical types, and different sound intensities.
Our study showed that making listen to traditional Sufi music from the preoperative period to the perioperative and postoperative period has positive effects on anxiety. Considering the negative effects of anxiety on the experience of anesthesia and operation success, it can be said that the more frequent use of a non-invasive method such as music can reduce the anxiety of the operation.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
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) Stoelting RK, editors. Epidural and Spinal Anesthesia, Clinical Anesthesia, 5th ed. Philadelphia: Lipincott Williams & Wilkins; 2006.p. 691-717.
2) Lepage C, Drolet P, Girard M, Grenier Y, DeGagné R. Music decreases sedative requirements during spinal anesthesia. Anesth Analg. 2001;93(4):912-6. DOI: 10.1097/00000539-200110000-00022.
3) Lautenbacher S, Huber C, Schöfer D, Kunz M, Parthum A, Weber PG, et al. Attentional and emotional mechanisms related to pain as predictors of chronic postoperative pain: a comparison with other psychological and physiological predictors. Pain. 2010;151(3):722-31. DOI: 10.1016/j.pain.2010.08.041.
4) Soltner C, Giquello JA, Monrigal-Martin C, Beydon L. Continuous care and empathic anaesthesiologist attitude in the preoperative period: impact on patient anxiety and satisfaction. Br J Anaesth. 2011 May;106(5):680-6. DOI: 10.1093/bja/aer034.
5) Jlala HA, French JL, Foxall GL, Hardman JG, Bedforth NM. Effect of preoperative multimedia information on perioperative anxiety in patients undergoing procedures under regional anaesthesia. Br J Anaesth. 2010;104(3):369-74. DOI: 10.1093/bja/aeq002.
6) Fortier MA, Blount RL, Wang SM, Mayes LC, Kain ZN. Analysing a family-centred preoperative intervention programme: a dismantling approach. Br J Anaesth. 2011;106(5):713-8. DOI: 10.1093/bja/aer010.
7) Wang Y, Dong Y, Li Y. Perioperative Psychological and Music Interventions in Elderly Patients Undergoing Spinal Anesthesia: Effect on Anxiety, Heart Rate Variability and Postoperative Pain. Yonsei Med J. 2014 55(4): 1101-5. DOI: 10.3349/ymj.2014.55.4.1101
8) Koch ME, Kain ZN, Ayoub C, Rosenbaum SH. The sedative and analgesic sparing effect of music. Anesthesiology. 1998 Aug;89(2):300-6. doi: 10.1097/00000542-199808000-00005. PMID: 9710387
9) Kukreja P, Talbott K, MacBeth L, Ghanem E, Sturdivant AB, Woods A, et al. Effects of Music Therapy During Total Knee Arthroplasty Under Spinal Anesthesia: A Prospective Randomized Controlled Study. Cureus. 2020 ;12(3):e7396. DOI: 10.7759/cureus.7396.
10) Han L, Li JP, Sit JW, Chung L, Jiao ZY, Ma WG. Effects of music intervention on physiological stress response and anxiety level of mechanically ventilated patients in China: a randomised controlled trial. J Clin Nurs. 2010;19(7-8):978-87. DOI: 10.1111/j.1365-2702.2009.02845.x.
11) Ilkkaya NK, Ustun FE, Sener EB, Kaya C, Ustun YB, Koksal E, et al. The effects of music, white noise, and ambient noise on sedation and anxiety in patients under spinal anesthesia during surgery. J Perianesth Nurs. 2014;29(5):418-26. DOI: 10.1016/j.jopan.2014.05.008.
12) Kain ZN, Caldwell-Andrews AA, Krivutza DM, Weinberg ME, Gaal D, Wang SM, et al. Interactive music therapy as a treatment for preoperative anxiety in children: a randomized controlled trial. Anesth Analg. 2004;98(5):1260-6. DOI: 10.1213/01.ane.0000111205.82346.c1.
13) Zhang XW, Fan Y, Manyande A, Tian YK, Yin P. Effects of music on target-controlled infusion of propofol requirements during combined spinal-epidural anaesthesia. Anaesthesia. 2005;60(10):990-4. DOI: 10.1111/j.1365-2044.2005.04299.x.
14) Wang SM, Kulkarni L, Dolev J, Kain ZN. Music and preoperative anxiety: a randomized, controlled study. Anesth Analg. 2002;94(6):1489-94. DOI: 10.1097/00000539-200206000-00021.
15) Ganidagli S, Cengiz M, Yanik M, Becerik C, Unal B. The effect of music on preoperative sedation and the bispectral index. Anesth Analg. 2005;101(1):103-6. DOI: 10.1213/01.ANE.0000150606.78987.3B.
16) Brunges MJ, Avigne G. Music therapy for reducing surgical anxiety. AORN J. 2003;78(5):816-8. DOI: 10.1016/s0001-2092(06)60641-8.
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Ali Akdoğan, Mahmut Arslan, Nesrin Erceyes. The effect of sufi music on sedation in patients under spinal anesthesia during orthopedic surgery. Ann Clin Anal Med 2021;12(2):204-207
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Evaluation of knowledge and attitudes of radiology department workers about artificial intelligence
Isil Yurdaisik 1, Suleyman Hilmi Aksoy 2
1 Department of Radiology, Istinye University Medical Park Gaziosmanpasa Hospital, 2 Department of Radiology, Hisar Intercontinental Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.20453 Received: 2020-12-24 Accepted: 2021-01-25 Published Online: 2021-01-28 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):186-190
Corresponding Author: Isil Yurdaisik, Department of Radiology, Istinye University Medical Park Gaziosmanpasa Hospital, Cukurcesme Street No: 57-59 Gaziosmanpasa, Istanbul, Turkey. E-mail: mdisilyurdaisik@gmail.com P: +90 212 979 30 00 F: +90 212 979 30 00 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8316-1229
Aim: The objective of this study was to investigate the knowledge and attitudes of radiology department workers through a survey.Material and Methods: In this study, the opinions and attitudes of physicians, residents and technicians working in radiology departments of various hospitals and medical students in our university about AI were collected through a survey conducted between 01/07/2020 and 12/08/2020 and analyzed through a survey.Results: The response rate of the survey was 25.3%; 47.1% of the participants reported that they have enough knowledge about AI applications in general, while only 25% stated that they hadsufficient knowledge about AI applications in radiology. Among all participants, 35.3% thought that AI applications would negatively affect the profession of radiologists, while 30.3% thought that these applications would have positive impacts; 51.9% of the participants think that AI applications will save time for radiologists. The rate of participants who were concerned about the advances in AI was 16.1%. Discussion: Further similar studies should be conducted on this issue in order to obtain more detailed information and contribute to the literature. We believe that our results will be guiding for further comprehensive studies on the opinions of radiology department workers about the use of AI in the field of radiology.
Keywords: Artificial intelligence; Radiology department; Imaging; Healthcare workers
Introduction
Artificial intelligence (AI) is defined as computers that behave in the ways that previously thought to require human intelligence and have significant potential to considerably improve radiology, assist patients and reduce costs [1]. AI (decision trees, support vector machines, neural networks, etc.) is currently used in the discussion of a wide range of medical imaging problems, such as imaging segmentation (detection of the limits of a targeted object) [2], registration (visual alignment of anatomic parts on single or multimodality images) [3], and the detection and classification of formations/structures (grouping subgroup medical information) [4]. AI methods are superior in the recognition of complex patterns in imaging data and providing quantitative evaluation rather than qualitative assessment. AI softwares offer high-resolution input images and segmentation mapping.
Radiology workers obtain information from medical images. AI provides further information by extending this specialty to provide better and completely new predictions. It is predicted that the results obtained from images will be interpreted by human radiologists in cooperation with intelligence and autonomous machines. Although machines can make mistakes, they are likely to make more efficient and consistent decisions than humans. In some cases, the machines will contradict human radiologists and will be proven to be accurate. AI imaging interpretation will affect the reporting and communication of the results [5]. AI leads to superintelligence, which is defined as “intelligence that significantly exceeds the cognitive performance of humans almost in every field”. As said by Hawking et al. “Success in creation of AI will be the greatest success in the history of humanity. However, unfortunately, this can be the last until we do not learn how to prevent it” (available at: https://futurism.com/hawking-creating-ai-could-be-the-biggest-event-in-the-history-of-our-civilization). It is predicted that AI will be increasingly used in the medical field, affecting decision mechanisms and reducing human errors and cost in near future. This is more prominent in the radiology field, where the potential for using AI is much higher. Analysis of the thoughts of radiology department workers would provide contributions to the development and use of more efficient AI applications.
To our knowledge, although there are numerous studies on the opinions of healthcare workers about the use of AI in various medical areas, we could not find such a study in the field of radiology. Therefore, the objective of this study was to investigate the knowledge and attitudes of radiology department workers through a survey.
Material and Methods
In this study, the opinions and attitudes of physicians, residents and technicians working in radiology departments of various hospitals and medical students in our university about AI were collected through a survey conducted between 01/07/2020 and 12/08/2020 and analyzed.
Ethics committee approval was obtained from Istinye University non-invasive ethics committee for the study. Ethics committee approval number: 75, received on 15/09/2020.
Survey
The survey form used in this study was prepared by the researcher by screening the relevant literature. The survey form was conveyed to potential participants via the Internet and announced via Whatsapp and social media. The survey forms were filled in through face-to-face interviews with the faculty students. It took about 15 minutes to complete each form. The survey forms were conveyed to a total of 807 potential participants. A total of 260 persons replied to the survey, and a total of 56 persons with missing responses or those from other departments were excluded from the study. The forms of the remaining 204 persons were reviewed and analyzed.
The survey consisted of 22 questions. The first 5 questions included socio-demographic data (gender, age group, affiliation, duration of experience and subspecialty), while the remaining 17 questions measured the knowledge and attitudes of the participants about AI. In the survey, questions 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 21 were scored with the Likert-5 scale, and pointed as strongly agree: 1, agree: 2, undecided: 3, disagree: 4 and strongly disagree: 5. In addition, the survey involved two open-end questions. These questions inquired whether there were AI applications in the institution where the participant was working and her/his opinion on the areas where AI would be beneficial in the radiology department.
The questions about AI in the survey are given in Table 1.
In the analysis of the obtained data, continuous variables are expressed as mean ± standard deviation, and the categorical variables are expressed in frequency and percentage.
Results
A total of 204 participants responded to the survey. The response rate of the survey was 25.3%. Forty-five of all participants (22.1%) were radiologists, 56 (27.5%) were residents, 38 (18.6%) were technicians, and 65 (31.9%) were medical faculty students. One hundred twenty-two of the participants (59.8%) were female and 82 (40.2%) were male. When age groups of the participants were examined, 101 (49.5%) were aged 18-29 years, 66 (32.3%) were aged 30-39 years, 27 (13.2%) were aged 40-49 years, 8 (3.9%) were aged 50-59 years and 2 (1%) were ≥ 60 years old group. The distribution of the age groups of participants by positions is given in Figure 1.
When affiliations of the participants were examined, 113 (55.3%) were working in a university hospital, 56 (27.5%) in a training and research hospital and 35 (17.2%) in a private hospital. The distribution of participants by affiliations is shown in Figure 2.
Duration of experience in radiology departments was analyzed. Accordingly, the duration of the experience was found as 0-5 years in 135 (66.2%), 5-10 years in 28 (13.7%), 10-20 years in 25 (12.3%) and ≥ 20 years in 16 (7.8%) participants. The distribution of participants according to the duration of the experience is shown in Figure 3.
When the answers given to the questions evaluating opinions and attitudes of the participants about AI were examined, 47.1% of the participants reported that they have enough knowledge about AI applications in general, while only 25% stated that they have sufficient knowledge about AI applications in radiology. Among all participants, 35.3% thought that AI applications will negatively affect the profession of radiologists, while 30.3% thought that these applications will cause positive impacts; 22.5% of all participants believed that in establishing a diagnosis AI will be superior over radiologists in near future. The rate of participants who thought that AI will completely replace radiologists was only 6.3%.
Among the participants, 51.9% think that AI applications will save time for radiologists. The rate of participants who stated that they will assume the legal responsibility of imaging results provided by AI was only 5.3%. Of all participants, 12.2% were reported that they will always use AI when making medical decisions in the near future. Among the participants, 54.9% thought that new physician candidates should choose specialty areas where AI can not dominate. The rate of participants who were concerned about the advances in AI was 16.1%. The distribution of survey answers by professional positions is given in Table 2.
Discussion
One of the mottos of radiology residents is: “The more images you see, the more examinations you report, the better you get”. In recent years, imaging has evolved from projection images such as radiographies toward more complex and data-rich tomographic images such as ultrasound (US), CT, tomosynthesis, positron emission tomography and MRI. Radiologists have been reduced to only imaging analysts, while the interpretation of findings was left to other physicians. This is dangerous not only for the radiologist, but also for the patients. Non-radiologists can be completely aware of the clinical situation, but they have no radiologic knowledge. In this case, AI emerges as an opportunity for the improvement of radiology. However, since AI is a relatively new technology, the opinions and attitudes of healthcare workers on this issue show significant variability.
In this study, the opinions and attitudes of radiology department workers and medical faculty students were examined for the first time in the literature. The majority of AI experts think that the developments of this technology will increase the effectiveness of healthcare in the medical field and diagnostic accuracy and will reduce the workload of physicians [6-8]. In recent years, increasing access to health data and the rapid development of big data analysis methods have allowed successful AI applications in every area of medicine [9]. However, the debate is ongoing in the literature about the use of AI in medicine and particularly in the field of radiology. AI is highly resource-dependent, and the development and deployment of AI requires great data and skills. These resources are not evenly distributed, and this may lead to denial of access to potential benefits from AI by some countries, regions and subgroups [10]. In addition, today physicians are legally responsible for poor patient outcomes. It is unclear who will be responsible for poor outcomes of AI in the future [11].
Radiology has always been the specialty that used the most digital information and adopted computer science for the first time [12]. Medical imaging has been the most commonly searched area in AI, and the number of publications on AI have risen to 700-800 from 100-150 in the last decade [12, 13]. More than 50% of the AI studies in radiology are on MRI and CT followed by neuroradiology, musculoskeletal, breast, cardiovascular, urogenital, lung and abdominal issues [12].
In general, AI programs that are being developed include image detection, segmentation, and precise information linking genomic and imaging data [14].
In our study, 80.9% of participants thought that they have sufficient knowledge about AI applications, while this rate was only 41.7% in participants thinking that they have sufficient knowledge about AI applications particularly in the field of radiology. In a survey study by Oh et al. from Korea, opinions of 669 physicians were collected. Only 5.9% of participants reported that they are familiar to AI [15]. Our different results might be due to the different number of participants and including only the workers of the radiology department.
In the present study, 77.9% of the participants reported that AI will completely replace radiologists in near future. This also explains the concerns of participants about AI applications. In fact, 56.9% of the participants stated that they were concerned about AI. Different results have been reported in the studies in the literature on AI in different issues. For example, in an international survey study by Sarwar et al., attitudes and perspectives of 487 pathologists were evaluated. The participants were asked about whether AI will replace pathologists in near future. Among he participants, 38% reported that AI can not affect employability, while 42.4% stated that AI would create new positions, increasing employment. In the same study, only 17.6% of the participants reported that AI may replace themselves [16]. Again in a survey conducted among psychiatrists in the Duke University and Harvard Medical Faculty, only 4% of the participants stated that AI may replace themselves [9]. In a survey study by Oh et al., 35.4% of Korean physicians thought that AI would replace physicians [15]. In a study by Blease et al. from the UK, the opinions of family physicians were evaluated, and participants reported that cAI is not likely to replace physicians in the near future [15]. In the same study, the majority of the participants (94%) reported that technology can not provide emphatic care as or better than physicians [17].
On the other hand, there are studies in the literature reporting that physicians support AI applications. In a survey study by Hoek et al. opinions of 59 radiologists, 56 surgeons and 55 medical faculty students on AI were investigated [18]. In this study, the majority of participants reported that AI should be included as a support system in radiology. Among students who reported that they do not prefer the radiology department as a specialty, 26% stated AI as a reason. In our study, 70.1% of the participants thought that new physician candidates should choose specialty areas where AI can not dominate. This rate was found as 92.3% among medical faculty students.
Study Limitations
This study has some limitations. First, the number of participants is relatively small. In addition, our results can not be generalized since only radiology department workers were included. Finally, we could not include questions in the survey to directly measure the knowledge of the participants about AI. However, as a strength, our study is the first in the literature to investigate the opinions and attitudes of radiology department workers towards AI.
Conclusion
AI applications show deployment in the field of radiology with commercially existing products. This fact does not mean progression toward a situation where physicians are not needed, but instead, it reinforces clinical decision making. However, healthcare workers in radiology departments have intense concerns that AI will replace them in near future. Increasing the awareness of radiology department workers is important for the contribution of the development of AI applications in the field of radiology. In this study, the opinions and attitudes of radiology workers on AI were investigated and analyzed. We think that further similar studies should be conducted on this issue in order to obtain more detailed information and contribute to the literature. We believe that our results will be guiding for further comprehensive studies on the opinions of radiology department workers about the use of AI in the field of radiology.
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. Kohli M, Prevedello LM, Filice RW, Gei JR. Implementing Machine Learning in Radiology Practice and Research. Am J Roentgenol. 2017;208(4):754-60.
2. Sharma N, Aggarwal LM. Automated medical image segmentation techniques. J Med Phys. 2010;35(1):3-14.
3. Wyawahare MV, Patil PM, Abhyankar HK. Image registration techniques: an overview. Int J Signal Process. Image Process Pattern Recognit. 2009;2(3):11–28.
4. Deepa SN, Devi BA. A survey on artificial intelligence approaches for medical image classification. Indian J Sci Technol. 2011;4(11):1583–95.
5. Erickson BJ, Korfiatis P, Akkus Z, Kline TL. Machine Learning for Medical Imaging. Radiographics. 2017;37(2):505-15.
6. Parish JM. The Patient Will See You Now: The Future of Medicine is in Your Hands. J Clin Sleep Med. 2015;11(6):689-90.
7. Obermeyer Z, Emanuel EJ. Predicting the Future – Big Data, Machine Learning, and Clinical Medicine. N Engl J Med. 2016;375(13):1216-19.
8. Kohane IS, Drazen JM, Campion EW. A glimpse of the next 100 years in medicine. N Engl J Med. 2012;367(26):2538-9.
9. Tasdogan AM. Knowledge, Attitudes and Perspectives of Anesthesiologists on Artificial Intelligence. EJMI. 2020; 4(1):1-6.
10. Geis JR, Brady AP, Wu CC, Spencer J, Ranschaert E, Jaremko JL, et al. Ethics of Artificial Intelligence in Radiology: Summary of the Joint European and North American Multisociety Statement. J Am Coll Radiol. 2019;16(11):1516-21.
11. Schönberger D. Artificial intelligence in healthcare: A critical analysis of the legal and ethical implications. Int J Law Inf Technol. 2019; 27:171–203.
12. Pesapane F, Codari M, Sardanelli F. Artificial intelligence in medical imaging: threat or opportunity? Radiologists again at the forefront of innovation in medicine. Eur Radiol Exp. 2018;2(1):35.
13. Jiang F, Jiang Y, Zhi H, Dong Y, Li H, Ma S, et al. Artificial intelligence in healthcare: past, present and future. Stroke Vasc Neurol. 2017;2(4):230-43.
14. Liew C. The future of radiology augmented with Artificial Intelligence: A strategy for success. Eur J Radiol. 2018;102:152-6.
15. Oh S, Kim JH, Choi SW, Lee HJ, Hong J, Kwon SH. Physician Confidence in Artificial Intelligence: An Online Mobile Survey. J Med Internet Res. 2019;21(3):e12422.
16. Sarwar S, Dent A, Faust K, Richer M, Djuric U, Van Ommeren R, et al. Physician perspectives on integration of artificial intelligence into diagnostic pathology. NPJ Digit Med. 2019;2:28.
17. Blease C, Bernstein MH, Gaab J, Kaptchuk TJ, Kossowsky J, Mandl KD, et al. Computerization and the future of primary care: A survey of general practitioners in the UK. PLoS One. 2018;12:13:e0207418.
18. Hoek E, Diederichs M. Engineering and hydraulics in jointed rock masses. Int J Rock Mech Min Sci. 2006;43:203-15.
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Isil Yurdaisik, Suleyman Hilmi Aksoy. Evaluation of knowledge and attitudes of radiology department workers about artificial intelligence. Ann Clin Anal Med 2021;12(2):186-190
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The effect of positive end-expiratory pressure on optic nerve diameter in patients undergoing craniotomy operation
Ozlem Sezen 1, Kemal Tolga Saracoglu 1, Tahsin Şimşek 1, Banu Cevik 1, Evren Aydoğmuş 2
1 Department of Anesthesiology and Reanimation, University of Health Sciences, Kartal Dr.Lutfi Kırdar City Hospital, 2 Department of Neurosurgery University of Health Sciences, Kartal Dr. Lutfi Kırdar City Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.20469 Received: 2021-01-06 Accepted: 2021-01-22 Published Online: 2021-01-25 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):199-203
Corresponding Author: Ozlem Sezen, Department of Anesthesiology and Reanimation, University of Health Sciences, Kartal Dr.Lutfi Kırdar City Hospital, Istanbul, Turkey.E-mail: drozlemsezen@hotmail.com P: +90 216 441 39 00 GSM: +90 532 391 82 98 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2144-9224
Aim: In this study, we aimed to investigate the effect of PEEP on changes in intracranial pressure with the guidance of ultrasonographic measurement of the optic nerve, in patients who underwent craniotomy operation in the supine position.Material and Methods: A total of 60 patients evaluated as ASA I-II and who were scheduled for craniotomy operation in the supine position under elective conditions were included in the study. Following routine monitorization of anesthesia induction, patients were provided with 1 mcg/kg iv fentanyl, 3 mg/kg iv thiopental sodium, 0.6 mg/kg iv rocuronium. Anesthesia maintenance was then provided with 2% sevoflurane and remifentanil (0,05-2 mcg/kg/min) infusion to keep BIS between 40 and 65. Patients in Group I received a 5 cmH2O PEEP, while those in Group II received 0 cmH2O PEEP. Patients’ HR, SAP, DAP, MAP, end-tidal carbon dioxide (ETCO2), SpO2, Ppeak, Pmean, minute volume, Tv expiratory, ONSD values were measured at following time-points: T0-before anesthesia induction, T1-after the dura is opened, T2-immediately before the dura is closed, T3-before extubation.Results: There was no statistical difference in hemodynamic parameters ( SAP, DAP, MAP ) between the two groups (p>0.05). ONSD was similar between both groups at all time points except for T2 results . The mean ONSD at T2 was significantly higher in Group I (p=0.04). Ppeak and Pmean were significantly higher in Group I at all time points (p<0.05).Discussion: We investigated the effect of PEEP on the optic nerve sheath diameter and its indirect effect on intracranial pressure; we revealed that two differ-ent PEEP levels did not create a difference.
Keywords: Intracranial pressure; PEEP; Optic ultrasound
Introduction
Intracranial hypertension may negatively affect patient outcomes in the perioperative period, as it leads to cerebral ischemia. On the other hand, the use of positive end-expiratory pressure (PEEP), recruitment maneuvers and prone position in order to prevent atelectasis in the intraoperative period may cause undesirable effects on cerebral physiology by decreasing cerebral venous return and mean arterial pressure. In addition, lung-sparing ventilation targets (airway plateau pressure <28-30 cmH20, driving pressure <14 cmH20 or delta-transpulmonary pressures <10–12 cmH20) may cause hypercarbia, leading to changes in intracranial pressure [1]. It has been shown that continuous PEEP applications lower cerebral blood flow and cerebral perfusion pressure both in healthy volunteers and patients with cerebral damage [2]. However, recent studies have noted positive changes in intracranial pressure (ICP) in patients who received PEEP. PEEP opens collapsed alveoli, improving oxygenation. In this way, end-expiratory alveolar collapse is prevented, intrapulmonary shunting is reduced, functional residual capacity is increased, and the risk of developing complications such as ventilator mediated pneumonia or pulmonary damage is decreased in patients under general anesthesia [3].
The optic nerve, which is part of the central nervous system, is surrounded by a subarachnoid space containing the dural sheath and cerebrospinal fluid (CSF). Intense adhesion between the optic nerve and its sheath is observed in the posterior part of the nerve in the optic canal. However, the sheath is less adhered to the nerve in the anterior part and especially in the retrobulbar segment of the optic nerve, and is surrounded only by orbital fat. For this reason, the retrobulbar optic nerve sheath can be flexible and expanded in the case of increased pressure in the CSF [4]. Ultrasonographic measurement of the optic nerve sheath diameter (ONSD) is a simple, non-invasive and safe technique for evaluation of ICP. ONSD can be obtained by axial measurement 3 mm behind the optic nerve head using optical imaging performed with transorbital sonography [5] (Figure 1).
In this observational study, we aimed to investigate the effect of using PEEP on changes in intracranial pressure with the guidance of ultrasonographic measurement of the optic nerve, in patients who underwent craniotomy operation in the supine position.
Material and Methods
This prospective one-way, randomized controlled study was conducted after the approval of the Institutional Ethics Committee (decision no: 2019/514/147/3) according to the ethical principles outlined in the Helsinki Declaration and Guidelines for Good Clinical Practice. Written informed consent was obtained from all the participants.
Study population
A total of 60 female and male patients aged over 18 years, evaluated as ASA I-II and scheduled for craniotomy operation in the supine position under elective conditions were included in the study.
Exclusion criteria
Patients who had a surgical operation related to the optic nerve, those with a history of drug allergy, glaucoma or increased intraocular pressure, pregnant patients and those with retinal detachment were excluded from the study.
Anesthesia procedure
All patients were routinely monitored in the operating room with electrocardiography (ECG), noninvasive blood pressure, pulse oximeter (SpO2) and bispectral index (BIS). Patients’ heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure were measured and recorded. In order to capture the best view between the retrobulbar echogenic adipose tissue and vertical hypoechoic band, a linear ultrasound probe running at 7.5 MHz (Toshiba Aplio 50 XV USG device) was inserted in the gel at the transverse plane horizontally, 3.0 mm behind the optic nerve by taking care not to apply pressure to the eyeball, and ONSD measurement was made and recorded while the eyelid was closed. Following preoxygenation, anesthesia induction was provided with 1 mcg/kg iv fentanyl, 3 mg/kg iv thiopental sodium, and 0.6 mg/kg iv rocuronium. Anesthesia maintenance was then provided with 2% sevoflurane and remifentanil (0,05- 2 mcg/kg/min) infusion to keep BIS between 40 and 65. Patients in Group I received a 5 cmH2O PEEP, while those in Group II received 0 cmH2O PEEP.
Data collection
Patients’ HR, SAP, DAP, MAP, end-tidal carbon dioxide (ET CO2), SpO2, Ppeak, Pmean, minute volume ve Tv expiratory and ONSD values were measured at following time-points: T0- before anesthesia induction, T1- after the dura is opened, T2- immediately before the dura is closed, T3- before extubation.
Statistical Analysis
Results obtained in this study were statistically analyzed with IBM SPSS Statistics software version 22.0. The t-test was used in the comparison of the descriptive statistical parameters (mean, standard deviation, minimum and maximum values) between the two groups, and a one-way ANOVA test was used in multiple comparisons. P- values <0.05 were considered statistically significant.
Chiu et al. found reference ONSD values as 4.5 mm and maximum values as 5.1 mm [6]. As a result of the power analysis made, taking alpha error as 0.05, beta error as 0.20 and effect size as 0.70; the required minimum number of patients was calculated as 26 patients per group, 52 patients in total. Considering the possible losses during the study period, 30 patients per group, 60 patients in total were included in the study.
Results
A total of 60 patients were recruited in the study. Patients’ characteristics are shown in Table 1. No significant difference was found between the groups in terms of HR, SAP, DAP, MAP and SpO2 values measured at T0 (before anesthesia induction), T1 (after the dura is opened), T2 (immediately the dura is closed) and T3 (before extubation) time points (p>0.05).
ONSD was similar between both groups at all time points except for the results at T2. The mean ONSD at T2 was significantly higher in Group I (p=0.04). In the intragroup comparison, ONSD was significantly lower at T1 and T2 time points compared to before induction in both groups (p<0.001). ONSD dropped by 1.08 mm at T1 compared to before induction in both groups. ONSD was 1.19 mm lower at T2 in Group I, while this value was 1.35 mm in Group II. ONSD was significantly lower at T3 compared to T0 in Group I (p<0.001), while there was no significant difference between these time points in Group II (p=0.075). ONSD dropped by an average of 0.47 mm at T3 in Group I, while this value was 0.33 in Group II (Table 2).
When among respiratory parameters EtCO2, Ppeak, Pmean, minute volume and Tv expiration were evaluated, Ppeak and Pmean were significantly higher in Group I at all time points (p<0.05), but no significant difference was observed between the groups in terms of the other parameters (Table 3).
Whereas a statistically significant correlation was found between ONSD and mean arterial pressure values measured at T0 (before anesthesia induction) and T2 (immediately before the dura was closed) (p=0.02), no significant correlation was found between parameter measurements in Group II.
Discussion
Measurement of optic nerve sheath diameter is quite adequate and well-standardized compared to other complex ultrasonographic measurement methods, and the results can be readily measured again for check. Tayal et al. [7] showed that physicians who had no ocular ultrasonography experience previously became qualified by performing 25 ONSD measurements. There may be a risk of subjective data measurement depending on the person who performs the measurement. Therefore, in our study, all measurements were made by the same person experienced in ONSD measurement. In this way, we tried to standardize the increase and decrease of the measurements. Blaivas et al. reported that they have used ocular USG in adult patients in the emergency department with suspicion of elevated intracranial pressure. They suggested this method as a rapid, bedside and noninvasive way of determining increased intracranial pressure in case of alterations in the level of consciousness [8].
Normal ICP varies between 7 and 15 mmHg in adults in the supine position. ICP over 15 mmHg is considered abnormal, and over 20 mmHg is considered pathological. Increased ICP during anesthesia may be seen with laryngoscopy, pneumoperitoneum a high PEEP, upright Trendelenburg position, low anesthesia status and extubation [9].
Muench et al. [10], investigating the effect of different PEEP levels (0-10 cmH2O) on intracranial pressure, cerebral oxygenation, regional cerebral blood flow and systemic hemodynamic variable, and found that increased PEEP caused significant decreases in mean arterial pressure and cerebral blood flow. However, the authors stated that the change in cerebral blood flow was essentially dependent on the change in mean arterial pressure, and brain perfusion did not impair when mean arterial pressure kept stable.
In a retrospective study investigating patients with severe neurologic injury (GCS<9) who required ICP monitoring, no significant correlation was found between PEEP or ICP or cerebral perfusion pressure (CPP), except for patients with severe pulmonary injury. In the multivariate analysis of patients with severe pulmonary injury, each 1 cmH2O increase in PEEP was found to be correlated with a 0.31 mmHg increase in ICP (p=0.04) and 0.85 mmHg decrease in CPP (p=0.002) [11].
In our study, a 5 mmHg PEEP was applied in Group I, while no PEEP was administered in Group 2. Increased PEEP values were not needed, as there was no change or deterioration in the situation related to respiratory functions, and in conclusion, deep and prolonged hypotension was not noted in any patient. HR, SAP, DAP, MAP and SpO2 values were within normal limits at all time points, and in both groups, the differences were not statistically significant. This normotensive situation provided stable perfusion pressure, while there was a difference between the groups only in ONSD measurements at T2 (immediately before the dura is closed) time point. However, we think that this was not at a level that can create a clinical impact.
On the other hand, in a prospective study including 21 intensive care patients with normal and abnormal lung compliance, the effects of increases in PEEP on central venous pressure (CVP), CPP, ICP and cerebral compliance were studied. In patients with normal compliance, increased PEEP caused an increase in CVP and a decrease in mean arterial pressure and CPP, while ICP and cerebral compliance did not change. Whereas, in patients with low compliance the increase in PEEP did not create any change in the variables [12].
In a prospective, single-center study including 499 patients with brain injury, including subarachnoid hemorrhage, it was reported that low tidal volumes and higher PEEP caused mechanic ventilation duration to drop to 12.6 days from 14.9 days and a 90-day length of stay in intensive care unit on average [13]. In a multi-center study on patients with acute cerebral injury, including subarachnoid hemorrhage, low tidal volume (<7 ml/kg), moderate PEEP (6-8 cmH2O), and early extubation protocol were associated with mortality and a decrease in the number of invasive ventilation free days [14]. In a single-center study examining the relationship between lung-sparing ventilation and ICP, ICP values of 12 subarachnoid hemorrhage patients with hypercapnia (PaCO2 50-60 mmHg) who were ventilated with lung- sparing ventilation modes were not higher than ICP values of the patients with a PaCO2 value of 40 mmHg [15].
In a study by Mehrpaur et al. [16], ONSD measurement with ultrasonography was demonstrated as an effective non-invasive method for the determination of intracranial hypertension. Rajajee et al. [17], measured ONSD in a group of 536 patients with head trauma, ischemic stroke and cranial tumors, and found that increased ICP values were correlated with the changes in ONSD. Again in the same study, the optimal cut-off value for ICP >20 mmHg was reported as 4.8 mm for both eyes with 86% sensitivity and 94% specificity rates. Hamilton et al. found that with an increase in ICP for every 1 mm Hg, ONSD increased by 0.0034±0.0003 mm [18].
Special attention is recommended in the adjustment and monitoring of airway pressures and minute ventilation when mechanical ventilation is required in patients with brain injury [19] because, regardless of the ventilation adjustment, according to the basic conditions of cerebral autoregulation, it can affect ICP positively or negatively in a neurocritical patient depending on the final results on PaO2 and ICP.
In our study, Ppeak and Pmean (5 cmH2O PEEP) were significantly higher at all time points in Group I (p<0.05); however, there was no significant difference between the groups in terms of the other respiratory parameters. Furthermore, there was no significant difference between the groups in terms of ONSD value except for the T2 time point.
In a study investigating the effect of upside- down position on ICP in awake and anesthetized rabbits, it was shown that after a small increase, ICP gradually increasedin the first 12 hours in the awake rabbits, whereas ICP gradually decreased in the 8 hours following a marked increase in the anesthetized rabbits. This indicated that fluid shift and venous expansion have at least as much effect as impairment of cerebral venous drainage on the increase of ICP [20]. Accordingly, it can be predicted also in humans that ICP will increase faster in an anesthetized patient compared to an awake one. Therefore, the anesthetic agent to be chosen should provide sufficient cerebral perfusion pressure, while ICP should not cause fluctuations in cerebral blood flow and cerebral oxygen demand. Sujata et al. [21] compared the effects of propofol on ONSD and ICP, and Chui et al. [6] effects of propofol and volatile anesthesia in craniotomy procedures. Both studies showed that the effects on brain relaxation score were similar, despite the fact that the mean ICP values were lower and CPP values were higher with propofol maintenance. In our study, balanced anesthesia was achieved in all patients in the supine position with sevoflurane, and no significant difference was found between the group in ONSD except for the T2 time point.
In a recent study, Robba et al. evaluated the changes in ICP caused by the prone position or PEEP in patients undergoing spinal surgery and showed that prone position and PEEP >8 mmH2O increased the mean ONSD value [22]. On the other hand, a high PEEP level has been shown to create an important difference in ICP when applied in ARDS patients with cerebral damage [23]. However, it is not known which PEEP level is the most appropriate for patients with acute brain injury [24].
Although invasive ICP measurement remains the gold standard, these methods (Doppler and ONSD) can be easily used in patients with hemostatic disorders when invasive devices are not indicated (such as mild traumatic brain injury) [25].
Study Limitations
Minimum limit values of the optic nerve sheath diameters that show the increase in ICP are not clear, as specified in previous studies. However, previous studies have shown that ONSD is correlated with ICP and can be used in the determination of ICP in various clinical situations.
Another limitation is the risk of subjective data that may occur during the measurement and depend on the person who measures the values.
Conclusion
In this study, in which we investigated the effect of PEEP on the optic nerve sheath diameter and its indirect effect on intracranial pressure, we revealed that two different PEEP levels did not create a difference. Ultrason guided ONSD is a noninvasive monitoring tool for a brain- protective ventilation strategy in neurocritical patients in need of mechanical ventilation when invasive monitoring of ICP is not indicated, can not be accessed, or contraindicated.
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. Corradi F, Robba C, Tavazzi G, Via G. Combined lung and brain ultrasonography for an individualized ‘’ brain-protective ventilationstrategy’’ in neurocritical care patients with challenging ventilation needs. Crit Ultrasound J. 2018;10:24
2. Yiallourou TI, Odier C, Heinzer R, Hirt L, Martin BA, Stergiopulos N, et al. The effect of continuous positive airway pressure on total cerebral blood flow in healthy awake volunteers. Sleep Breath 2013;17(1):289–96.
3. Corradi F, Robba C, Tavazzi G, Via G. Combined lung and brain
ultrasonography for an individualized “brain-protective ventilation strategy” in neurocritical care patients with challenging ventilation needs. Corradi et al. Crit Ultrasound J. 2018;10:24.
4. Hayreh SS. Pathogenesis of optic disc edema in raised intracranial pressure. Prog Retin Eye Res.2016;50:108-44.
5.Geeraerts T, Duranteau J, Benhamou D. Ocular sonography in patients with raised intracranial pressure: the papilloedema revisited. Crit Care. 2018;12(3):150.
6. Chui JH, Mariappan R, Mehta J, Manninen P, Venkatraghavan L. Comparison of propofol and volatile agents for maintenance of anesthesia during elective craniotomy procedures: systematic review and meta-analysis. Can J Anaesth. 2014; 61(4):347–56.
7. Tayal VS, Neulander M, Norton HJ, Foster T, Saunders T, Blaivas M. Emergency department sonographic measurement of optic nerve sheath diameter to detect findings of increased intracranial pressure in adult head injury patients. Ann Emerg Med. 2007; 49(4):508–14.
8. Blaivas M, Theodoro D, Sierzenski P. Elevated intracranial pressure detected by bedside emergency ultrasonography of the optic nerve sheath. Acad Emer Med. 2003;10(4):376-81.
9. Kim EJ, Koo B, Choi SH, Park K, Kim MS. Ultrasonographic optic nerve sheath diameter for predicting elevated intracranial pressure during laparoscopic surgery: a systematic review and meta-analysis. Surg Endosc. 2018;32(1):175–82.
10. Muench E, Bauhuf C, Roth H, Horn P, Phillips M, Marquetant N, et al. Effects of Positive End-Expiratory Pressure on Regional Cerebral Blood Flow, Intracranial Pressure and Brain Tissue Oxygenation. Crit Care Med. 2005; 33(10):2367–72.
11. Boone MD, Jinadasa SP, Mueller A, Shaefi S, Kasper EM, Hanafy KA, et al. The effect of positive end-expiratory pressure on intracranial pressure and cerebral hemodynamics. Neurocrit Care. 2017;26(2):174-81.
12. Caricato A,Conti G, Della Corte F, Mancino A, Santilli F, Sandroni C, et al. Effects of PEEP on the intracranial system of patients with head injury and subarachnoid hemorrhage: the role of respiratory system compliance. J Trauma. 2005;58 (3):571-6.
13. Roquilly A, Cinotti R, Jaber S, Vourc’h M, Pengam F, Mahe PJ, et al. Implementation of an evidence-based extubation readiness bundle in 499 brain-injured patients. a before-after evaluation of a quality improvement project. Am J Respir Crit Care Med. 2013; 188(8): 958-66.
14. Asehnoune K, Mrozek S, Perrigault PF, Seguin P, Dahyot-Fizelier C, Lasocki S, et al. A mult-faceted strategy to reduce ventilation-associated mortality in brain-injured patients. The BI-VILI project. A nationwide quality improvement project. Intensive Care Med. 2017;43(7):957-70.
15. Petridis AK, Doukas A, Kienke S, Maslehaty H, Mahvash M, Barth H, et al. The effect of lung-protective permissive hypercapnia in intracerebral pressure in patients with subarachnoid haemorrhage and ARDS. A retrospective study. Acta Neurochir. 2010;152(12):2143-5.
16. Mehrpour M, Torshizi FO, Esmaeeli S, Taghipour S, Abdollahi S. Optic nerve sonography in the diagnostic evaluation of pseudopapilledema and raised intracranial pressure: a cross-sectional study. S Neurol Res Int. 2015; DOI:10.1155/2015/146059
17. Rajajee V, Vanaman M, Fletcher JJ, Jacobs TL. Optic nerve ultrasound for the detection of raised intracranial pressure. Neurocrit Care. 2011;15(3):506–15.
18. Hamilton DR, Sargsyan AE, Melton SL, Garcia KM, Oddo B, Kwon DS, et al. Sonography for determining the optic nerve sheath diameter with increasing intracranial pressure in a porcine model. J Ultrasound Med. 2011; 30(5):651–9.
19. Rajajee V, Riggs B, Seder DB. Emergency neurological life support: airway, ventilation, and sedation. Neurocrit Care. 2017; 27(Suppl. 1):S4–28
20. Tatebayashi K, Doi M, Kawai Y. Changes of intracranial pressure during head-down tilt in anesthetized and conscious rabbits. J Gravit Physiol 2002;9(1):101-2.
21. Sujata N, Tobin R, Tamhankar A, Gautam G, Yatoo AH. A randomised trial to compare the increase in intracranial pressure as correlated with the optic nerve sheath diameter during propofol versus sevoflurane-maintained anesthesia in robot-assisted laparoscopic pelvic surgery. J Robotic Surg. 2019; 13(2):267-73.
22. Robba C, Bragazzi NL, Bertuccio A, Cardim D, Donnelly J, Sekhon M, et al. Effects of prone position and positive end-expiratory pressure on noninvasive estimators of ICP: a pilot study. J Neurosurg Anesthesiol. 2017; 29(3):243–50.
23. Mascia L, Grasso S, Fiore T, Bruno F, Berardino M, Ducati A. Cerebro- pulmonary interactions during the application of low levels of positive end-expiratory pressure. Intensive Care Med. 2005; 31(3):373–9.
24. Young N, Rhodes JK, Mascia L, Andrews PJ. Ventilatory strategies for patients with acute brain injury. Curr Opin Crit Care. 2010;16(1):45–52.
25. Robba C, Cardim D, Sekhon M, Budohoski K, Czosnyka M. Transcranial Doppler: a stethoscope for the brain-neurocritical care use. J Neurosci Res. 2018;96(4):720–30.
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Ozlem Sezen, Kemal Tolga Saracoglu, Tahsin Şimşek, Banu Cevik, Evren Aydoğmuş. The effect of positive end-expiratory pressure on optic nerve diameter in patients undergoing craniotomy operation. Ann Clin Anal Med 2021;12(2):199- 203
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Is sternum fracture a concerning clinical situation?
Özlem Güler 1, Fatoş Kozanlı 2
1 Department of Emergency Medicine, Kahramanmaraş Sütçü İmam University Faculty of Medicine, 2 Department of Thoracic Surgery, Kahramanmaraş Sütçü İmam University Faculty of Medicine, Kahramanmaraş, Turkey
DOI: 10.4328/ACAM.20461 Received: 2020-12-31 Accepted: 2021-01-14 Published Online: 2021-01-19 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):195-198
Corresponding Author: Özlem Güler, Kahramanmaraş Sütçü İmam University, Faculty of Medicine, Department of Emergency Medicine, 46040, Onikişubat/Kahramanmaraş, Turkey. E-mail: ozlemguler81@yahoo.com P: +90 533 413 13 25 F: +90 (344) 300 10 37 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1444-7730
Aim: In this study, it was aimed to investigate the demographic characteristics of the patients diagnosed with sternum fracture (SF) admitted to our hospital in the last year, the treatments applied, and the etiological factors causing SF.Material and Methods: Fifty-six patients diagnosed with SF as a result of blunt trauma were retrospectively analyzed. Only cases with blunt trauma and SF were included in the study.Results: A total of 56 cases, 34 males (60.8%) and 22 females (39.2%), who had thoracic trauma and SF together were included in our study. In 33 (58.8%) cases, a motor vehicle accident was the mechanism with the highest rate of trauma. Rib fracture was most commonly accompanied by SFs in 28 cases (50%). The most common extra-thoracic additional organ injury was extremity fracture at various levels, which was confirmed in 13 cases (23.2%). Twelve (21%) patients with isolated SF were kept under observation in the emergency department and provided with pain relief. These patients were recommended to come for control 5 days later and were discharged. The number of cases we applied medical treatment was 50 (89.2%). There were no deaths directly related to SF.Discussion: Sternum fracture due to trauma indicates that the trauma is severe. Cases must be evaluated in terms of additional organ injury. Mortality occurs especially in patients with multiple trauma and for reasons other than thoracic. Patients with isolated non-complicated, non-displaced SF do not need hospi-talization if there are no additional organ injuries or uncontrolled pain.
Keywords: Blunt thoracic trauma; Hemothorax; Pneumothorax; Sternum fracture
Introduction
Thoracic trauma constitutes approximately 10% of all trauma cases admitted to emergency services [1]. Thoracic injuries constitute approximately 25% of post-traumatic deaths [2]. Sternum fractures (SF) are observed in 3% to 8% of blunt traumas [3]. Most (> 95%) SF recover with conservative treatment. Surgical fixation is indicated in cases of fracture instability, displacement, or nonunion of the fracture [4]. Severe chest pain, shortness of breath, persistent cough, and paradoxical movement of the chest wall may be observed due to unstable or displaced fractures in a few cases [5]. Injuries that can be observed due to SF are more important than the fracture itself [6]. Various outcomes such as pleural effusion, hemothorax, pneumothorax, pericardial effusion, pneumomediastinum, and retrosternal hematoma may occur after SF[1].
There is no consensus regarding the evaluation and the treatment algorithm of SF cases [7]. While lateral chest radiography is sufficient to make a diagnosis, SF can sometimes be overlooked in this examination during the first evaluation of traumatic cases. In the case of localized pain and tenderness on physical examination, the condition of the sternum should be evaluated with serial radiographs [8].
This study aimed to investigate the demographic characteristics of the patients diagnosed with SF admitted to our hospital in the last year, the treatments applied, and the etiological factors causing SF.
Material and Methods
Our study was conducted in accordance with the Declaration of Helsinki and approval was obtained from the institutional clinical research ethics committee (approval date: 27/05/2020, decision no: 2020/10). The files of patients over the age of 18 who applied to the emergency medicine department of a tertiary referral hospital with blunt trauma were reviewed retrospectively. Fifty-six patients who were diagnosed with SF as a result of blunt trauma between May 2019 and May 2020 were analyzed. Only cases with blunt trauma and SF were included in the study.
The patients who did not have a history of blunt trauma and were under 18 years of age were excluded. Also, cases without SF were not included in the study. Information about our cases was accessed through the electronic data recording system of our hospital. Age, gender, trauma mechanism, localization of SF, physical examination findings, accompanying other organ injuries, treatment modalities, length of stay at the hospital, and treatment results were determined.
Posteroanterior and lateral chest radiographs were obtained for all patients following their physical examination at the first admission to our emergency department. Those with an indication were evaluated with computed tomography of the thorax. Electrocardiography (ECG) and echocardiography (ECHO) were performed in all patients with SF, and their cardiac enzyme values were studied. The ECG and cardiac enzyme values of patients with isolated, non-displaced, non-complicated SF have been studied again at intervals of 12-24 hours. Patients with normal cardiac enzyme levels and ECG findings were not hospitalized. The appropriate analgesics were prescribed to them and they were called for control 5 days later. Patients with complicated SF were hospitalized and treated in appropriate clinics considering the degree of their additional organ injuries.
Statistical analysis
Statistics program for social sciences 20 (SPSS 20) was used for statistical analysis. Numerical data were given as mean ± standard deviation, and categorical variables as frequency and percentage. The Chi-square test was used for categorical data in comparisons between groups. The t-test or Mann Whitney U tests was used for comparison of numerical data between groups. Spearman’s correlation analysis was used to determine the correlation. A p- value <0.05 was considered statistically significant.
Results
A total of 56 cases, 34 males (60.8%) and 22 females (39.2%), who had thoracic trauma and SF together were included in our study. The mean age of our cases was 56.6 ± 19.3 (18-100) years. In 33 (58.8%) cases, the mechanism with the highest rate of trauma was a motor vehicle accident (Table 1).
When we summed up falling from trees and animal bumps under one heading, the name of an agricultural accident, we found that it was the highest rate of injury mechanism after traffic accidents with a rate of 23.2%.
We evaluated our cases with no pathological findings other than SF as isolated SF, and cases with additional organ injury as complicated SF. There was no injury other than SF in 16 (28.6%) of our cases. Other accompanying injuries are listed in Table 2. We found that rib fracture was the most commonly accompanied by SFs in 28 cases (50%). Less frequently, lung contusion was determined in 12 cases (21.4%), hemothorax in 9 cases (16%), pneumothorax in 6 cases (10.7%), hemopneumothorax in 5 cases (8.9%), minimal pericardial effusion in 1 case (1.8%). The most common extra-thoracic additional organ injury was extremity fracture at various levels and confirmed in 13 cases (23.2%). Afterward, we found that 9 cases (16%) had intracranial injuries and 3 cases (5.4%) had intraabdominal organ injuries.
Forty (71.4%) of our cases had corpus, 12 (21.5%) had manubrium, 4 (7.1%) had both corpus and manubrium fractures. There were 43 (76.8%) patients with displaced SF and 13 (23.2%) patients with non-displaced SF.
Twelve (21%) patients with isolated SF were kept under observation in the emergency department for not more than 24 hours. The fractures of these patients were non-displaced, cardiac enzymes, ECG, and ECHO findings were normal at the time of the first application. Since the ECG, ECHO, and cardiac enzymes of these patients were within normal limits, which were studied at intervals of 12-24 hours, it was not deemed necessary to hospitalize them. Patients whose pain relief was provided were recommended to come for control 5 days later and were discharged.
A chest tube was inserted in 6 (10.7%) of our cases due to hemothorax, pneumothorax, and hemopneumothorax. The number of cases we applied medical treatment was 50 (89.2%). In none of our cases, surgical stabilization was required.
The mean length of hospital stay for patients with SF was 5.5 ± 5.6 days. The average length of hospital stay according to the mechanism of trauma is given in Table 3. When the patients were grouped according to the mechanism of trauma, there was a statistically significant difference between the groups in terms of length of stay at the hospital (p = 0.005). It was found that the subjects who had a motorcycle accident (p = 0.030) and out-of-vehicle traffic accident (p = 0.013) were hospitalized for a longer time than the subjects who fell from their level. The mean length of hospital stay was 7.71 ± 7.09 days in patients with extra-thoracic injuries and 4.81 ± 4.96 days in those with thoracic injuries. The length of hospital stay was similar in patients with and without extra-thoracic injuries (p = 0.165).
The frequency of additional organ damage was found to be similar (P = 0.079) among the groups according to the mechanism of trauma. There was no correlation between age and the length of hospital stay (r = -0.087, p = 0.525). The mean age was different in the trauma groups (p = 0.039). The mean age for falling off his/her own level was 73.28 ± 18.15 years and 50.12 ± 16.33 years for in-vehicle traffic accidents. The average age in the group for falling off his/her own level was higher than vehicle traffic accidents (p = 0.046).
Five (8.9%) of the cases with SF died. The causes of death were intracranial injury in 4 (75%) cases and fat embolism due to multiple extremity fractures in 1 (25%) case. There were no deaths directly related to SF.
Discussion
Sternum fractures are often caused by thoracic trauma and/or direct blows to the sternum. The most common cause is traffic accidents [7]. In accordance with the literature, 58.8% of SF was caused by motor vehicle accidents in our study. We learned that all of our cases were brought in due to an in-vehicle traffic accident were wearing seat belts. There are many studies reporting that seat belts increase the possibility of SF in motor vehicle accidents. However, considering the severity of the trauma in traffic accidents, we think that SF caused by wearing seat belts is a small cost for survival.
Studies have revealed that SFs are located in the corpus sterni at a rate of 77%-89% [3,9]. The rate of corpus sterni fractures was 71.4% similar to those in our study.
One of the most important factors determining morbidity in SFs is additional organ injuries [10]. Sternum fractures may be accompanied by myocardial contusion, tracheobronchial, pulmonary and vascular injuries, and flail chest depending on the severity of the trauma [11]. In a series of 200 cases done by von Garrel et al., rib fractures were found to accompany SF with a rate of 10.5% [9].
Unlike the literature, the SFs were primarily accompanied by rib fractures with a rate of 50% in our study, hemothorax, pneumothorax, and hemopneumothorax, which frequencies vary between 3% and 20%, are other pathologies accompanying SF [9,12]. In accordance with the literature, hemothorax was found in 16% of the cases, pneumothorax in 10.7%, hemopneumothorax in 8.9%, and tube thoracostomy was applied to 10.7% of them. There were no cases that required surgical fixation.
Due to the possibility of myocardial damage in SFs, cardiac monitorization, ECG, cardiac enzyme and protein (CK-MB and troponin I) level measurements should be performed at 12 and 24 hours [13]. We followed all our cases at the 12 and 24 hours with the cardiac enzyme, ECG, and ECHO considering the literature recommendations. We decided that hospitalization was not necessary for 12 (21%) of our non-displaced, isolated SF patients who had no pathological findings in their ECG, ECHO, and cardiac enzymes. However, we called these cases for control 5 days later. There was no morbidity related to SF in any of the patients discharged. We did not find any case series that were externalized similar to our study in the literature. We found that 24-hour observation was sufficient in cases with isolated, non-displaced SF. We think that the cost is reduced with this approach.
The average length of stay at the hospital in patients with SF is between 2-10 days in the literature [14,16]. The average length of stay at the hospital in our study was 5.5 ± 5.6 days similar to the literature. Some studies reported that the length of stay at the hospital varies statistically significantly with accompanying injuries, while others reported that there is no significant relationship between additional injuries and length of stay at the hospital [12,16]. We found that additional organ injury did not significantly increase the length of stay at the hospital. The low number of patients with additional organ injuries in our study is a limiting factor for this result.
Study Limitations
The main limitations are the low number of patients with additional organ injuries, being a single-center and retrospective nature of the study..
Conclusions
Sternum fracture due to trauma indicates that the trauma is severe. Cases must be evaluated in terms of additional organ injury. The cardiac enzyme, ECG, and ECHO examinations should be performed for cardiac injury evaluation. The prognosis of isolated SFs is quite good. Mortality occurs especially in patients with multiple trauma and for reasons other than thoracic. Patients with isolated non-complicated, non-displaced SF do not need to be hospitalized if there is no additional organ injury or uncontrolled pain. It will be appropriate to treat accompanying injuries in SFs that require hospitalization. If there is no accompanying injury, follow-up and analgesic treatment are sufficient.
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. Ulusan A, Karakurt O. Cardiac findings of sternal fractures due to thoracic trauma: A five-year retrospective study. Ulus Travma Acil Cerrahi Derg. 2018;24(3):249-54. DOI: 10.5505/tjtes.2017.01336.
2. Cobanoglu U, Hiz O, Sayir F, Ediz L, Sehitogullari A. Traumatic and Atraumatic Sternal Fractures: Analysis of 13 Cases. Turk Toraks Derg. 2012;13:146-51.
3. Athanassiadi K, Gerazounis M, Moustardas M, Metaxas E. Sternal fractures: retrospective analysis of 100 cases. World J Surg. 2002;26(10):1243-6. DOI: 10.1007/s00268-002-6511-5.
4. Klei DS, de Jong MB, Oner FC, Leenen LPH, van Wessem KJP. Current treatment and outcomes of traumatic sternal fractures-a systematic review. Int Orthop. 2019;43(6):1455-64.DOI: 10.1007/s00264-018-3945-4.
5. Zhao Y, Yang Y, Gao Z, Wu W, He W, Zhao T. Treatment of traumatic sternal fractures with titanium plate internal fixation: a retrospective study. J Cardiothorac Surg. 2017;12(1):22. DOI: 10.1186/s13019-017-0580-x.
6. Kumbasar U, Tokat AO, Karasu S, Cakmak H, Tokat S, Uzun HA, et al. Sternal Fractures: Retrospective Analysis of 55 Cases. J Ankara Univ Fac Med. 2012; 65 (2):125-8.
7. Turhan K, Cakan A, Ozdil A, Cagirici U. Traumatic sternal fractures: diagnosis and management. Ege Journal of Medicine. 2010; 49(2):107-11.
8. Al-Qudah A. Operative treatment of sternal fractures. Asian Cardiovasc Thorac Ann. 2006;14(5):399-401. DOI: 10.1177/021849230601400510.
9. Von Garrel T, Ince A, Junge A, Schnabel M, Bahrs C. The sternal fracture: radiographic analysis of 200 fractures with special reference to concomitant injuries. J Trauma. 2004;57(4):837-44. DOI: 10.1097/01.ta.0000091112.02703.d8.
10. Aydogmus U, Sonmezoglu Y, Kocaturk CI, Cansever L, Ozdemir S, Bedirhan MA. The Diagnosis and Treatment of Traumatic Sternal Fractures. Eurasian J Pulmonol. 2009;11(2):74-7.
11. Fullerton DA, Grover FL. Blunt trauma. In: Pearson GF, Deslauries J, Hiebert CA, McKneally MF, Ginsberg RJ, Urschel HC (Eds). Thoracic Surgery. 1st ed. Philadelphia: Harcourt Brace Company; 1995.p.1555-60.
12. Wiener Y, Achildiev B, Karni T, Halevi A. Echocardiogram in sternal fracture. Am J Emerg Med. 2001;19(5):403-5.DOI: 10.1053/ajem.2001.24463.
13. Velissaris T, Tang AT, Patel A, Khallifa K, Weeden DF. Traumatic sternal fracture: outcome following admission to a Thoracic Surgical Unit. Injury. 2003;34(12):924-7. DOI: 10.1016/s0020-1383(02)00415-1.
14. Ciriaco P, Casiraghi M, Negri G, Gioia G, Carretta A, Melloni G, et al. Early surgical repair of isolated traumatic sternal fractures using a cervical plate system. J Trauma. 2009;66(2):462-4. DOI: 10.1097/TA.0b013e31814b2c5e.
15. Knobloch K, Wagner S, Haasper C, Probst C, Krettek C, Vogt PM, et al. Sternal fractures are frequent among polytraumatised patients following high deceleration velocities in a severe vehicle crash. Injury. 2008;39(1):36-43. DOI: 10.1016/j.injury.2007.07.007.
16. Potaris K, Gakidis J, Mihos P, Voutsinas V, Deligeorgis A, Petsinis V. Management of sternal fractures: 239 cases. Asian Cardiovasc Thorac Ann. 2002;10(2):145-9. DOI: 10.1177/021849230201000212.
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Özlem Güler, Fatoş Kozanlı. Is sternum fracture a concerning clinical situation? Ann Clin Anal Med 2021;12(2):195-198
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Augmentation of cerclage wire strength with a basic knot technique: A biomechanical study
Ertuğrul Şahin 1, Ahmet Karakaşlı 2, Bora Uzun 3, Hasan Havıtçıoğlu 2
1 Department of Orthopaedics and Traumatology, Kemalpaşa State Hospital, 2 Department of Orthopaedics and Traumatology, Dokuz Eylul University, Faculty of Medicine, 3 Department of Biomechanics, Dokuz Eylul University, Health Science Institute, Izmir, Turkey
DOI: 10.4328/ACAM.20456 Received: 2020-12-26 Accepted: 2021-01-11 Published Online: 2021-01-15 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):191-194
Corresponding Author: Ertuğrul Şahin, Kemalpaşa State Hospital, Orthopaedics and Traumatology Clinic, 35730, Kemalpaşa, Izmir, Turkey. E-mail: ertugrulsahinn@hotmail.com P: +90 +90 506 808 22 69 / +90 232 878 80 30 Corresponding Author ORCID ID: https://orcid.org/0000-0002-8509-3570
Aim: Loosing of cerclage wire is a common problem in the fixation of fractures and alternative techniques are required to provide more strength cable systems. The aim of this study was to evaluate the benefit of an additional knot to the cable system to increase durability and strength of wire Material and Methods: Twelve artificial bone fragments were bisected thoroughly in the coronal plane. Two mm diameter CoCr Dall Miles were used in two groups; the first group was the sleeve group (n=6) and the second group was the sleeve + knot group (n=6). All cables were once looped around the saw bone with positioning the sleeve at the beaded end of the cable, and the tensioner knob was used to create tension to 90 lb/in2 (62,05 N/cm2). In the sleeve + knot group, one more simple knot was performed with conventional surgery skill, and the two ends of cerclage wire were put into the tensioner knob to create tension again. Mechanical tension testing was performed at a velocity of 20mm/min. Axial tension force was applied until failure. The maximum force and displacement values were recorded at the failure point.Results: There was a significant difference in the mean rank of applied force between the sleeve and sleeve + knot groups (p=0,025). However, there was no statistical difference in the amount of displacement between the two groups (p=0,378). The ratio of force/displacement displayed a significant difference between the two groups, it was shown that the sleeve + knot group was more durable than the sleeve only group (p=0,01).Discussion: Adding a knot to the cable system increases the durability and strength of the cable system by approximately %40. These findings showed that adding a knot to the cable-domino system had decreased the possibility of loosening and fixation failure.
Keywords: Augmentation; Biomechanics; Cerclage wire; Dall miles; Knot; Sawbones
Introduction
Cerclage wiring, a basic surgical technique, has been used in many areas of orthopedic surgeries, especially to help or support the fixation of fractures mainly long bones and periprosthetic fractures. In the past, many materials such as titanium alloy, chrome-cobalt, stainless steel were used for cable systems [1].
Documentation of the first use of cerclage wire dates back to 1775 [2]. It has become an option in different areas such as fixation of unstable intertrochanteric, acetabular, periprosthetic fractures of femur, humerus, elbow, revision total hip arthroplasties in combination with other implants [3-9]. In recent years, the use of cerclage wire has increased as a result of the increase of periprosthetic fractures, and in this situation there is increasing interest in the cerclage wire techniques, which provide augmentation and make fixation more stable. Surgeons try to overcome the insufficiency and stability of cerclage by using different techniques and adding other implants such as Steinman pins [10], external plaster cast [9]. Since simple cerclage wiring alone is related to high failure rates, fixing the rigidity is very important [11]. Therefore, researchers are focusing on the factors that affect yield and breaking load, fatigue strength because the best way to measure mechanical strength is to evaluate yield and breaking loads. Fatigue strength is also useful for the measurement of the strength of cerclage wire [1].
The multifilament cable was first used for the fixation of the greater trochanter osteotomy in total hip arthroplasty by Dall and Miles [12].The widely used Dall Miles cables are made of stainless steel multifilament and are twice as strong as surgical chrome wire [10,13] . Other beneficial effects of multifilament cables are preventing kinking, which is widely accepted as a risk factor for breakage of cable, making control of tension degree easier [6,13,14]. However, surgeons also encounter failure of multifilament cables because of the patient’s biologic factors (bone quality, comorbidities, life qualities), the surgeons’ insufficiency about instruments stability, and also wire itself can fail.
In literature, the best cerclage wire configuration is still unclear. This study compared the failure of a load of conventional and our augmentation technique by detecting the strength point value when displacement had occurred.
Material and Methods
Study groups
No animal or human studies were carried for this study so there was no need for ethical approval. Twelve artificial bone fragments (Sawbones, fourth-generation composite, item no: 3403 medium–left ) cut from the femur diaphysis model were used. The diameter and length of all sawbones were the same and were approximately 2 cm and 10 cm respectively. These fragments were bisected thoroughly in the coronal plane. Twelve CoCr Dall Miles (Med – Tıp, İzmir, Turkey) 2 mm diameter cable systems were used in two groups; the first group was the sleeve group (n=6) and the second group was the sleeve + knot group (n=6), focusing on 2 different cerclage wiring techniques. All cables were once looped around the saw bone with positioning the sleeve at the beaded end of the cable, and the tensioner knob was used to create tension to 90 lb/in2 (62,05 N/cm2) [15]. The sleeve was crimped with crimp tool. These procedures were the same for the two groups. In the sleeve + knot group, one more simple knot was performed with conventional surgery skill, and the two ends of cerclage wire were put into the tensioner knob to create tension again. Under tension, the two ends of the cable were cut using a cable cutter (Figure 1).
Mechanical testing
Mechanical testing was performed on a test system (Shimadzu Autograph AG-IS 5kN, Japan) with a 5 kN load-cell. The half of the saw bone fragments were mounted separately on two metallic half-cylinders forming a full cylinder. Each metal half-cylinder was fastened to a frame. The upper frame was fixated to the load cell of the system using a Schanz screw passing through all the holes in the frame and load cell. The lower frame was rigidly fixated to the base platform of the actuator. Both half metal cylinders mediatized and saw bone fragments were put on these cylinders to provide contact to each other (Figure 2). The cables were looped around the two cortical half shells, passed into the sleeve, tensioned and cut and manually pretensioned. Mechanical tension testing was performed at a velocity of 20 mm/min. Axial tension force was applied until failure occurred (Figure 3). The maximum force and displacement values were recorded at the failure point when the applied force suddenly dropped.
Statistical analysis
We used the SPSS software (SPSS 26; SPSS, Chicago, USA) for statistical analysis. The ratio of maximum force and displacement was used to evaluate failure between the groups. In the analytical evaluation, the Mann-Whitney test was applied to evaluate the differences in the mean ranks of the two groups because the comparison of these two groups provided nonparametric conditions. The significance was defined as p < 0.05.
Results
All saw bone models were broken at the failure point. The amount of applied force leading to the initiation of the break of the saw bone models and the displacement of half shell pieces at the moment of break are shown in Table 1. There was a significant difference in the mean rank of applied force between the sleeve and the sleeve + knot groups (p=0,025) (Table 2). The Sleeve + knot group needed much more force to catastrophically destroy the cable system than only sleeve group. But no statistical difference in the amount of displacement between the two groups was seen (p=0,378) (Table 2). When we look at the force/displacement ratio, we found a significant difference between two groups: the sleeve + knot group was more durable than the sleeve only group (p=0,01) (Table 3). No failure or loosening of cable in the crimp happened.
Discussion
In this study, we investigated that adding a simple knot technique to the standard procedure of the cable system made it more strength and stable biomechanically. In this setup, the saw bone fragments were transformed into half-shells by cutting in the coronal plane, and these pieces were mounted on metal bars to create separation under our control and measure the applied force and the amount of displacement. We defined the failure point as the applied axial loading exceeded the centripetal force of the wire around the saw bone. There may be seen loosening in the cerclage wire system after fixation of the fracture during the postoperative period [16-19]. In this study, we think this problem could be reduced with a simple knot. It was seen that adding a knot to cable – domino fixation system increased the stability by approximately 40% more strength.
The most common places of failure on the wire are usually at stress risers (knots, twists, or kinking areas). The site of failure is usually located at potential stress risers [1]. In our study, we added an extra knot on the sleeve part of the cable. Thus, we think this adding knot spread the stress area to a wider area, and this may help resist more strongly. We cut our wire just near the knot under the tension of the device. Therefore, we might lose our tension after cutting, but even though the sleeve + knot group is superior to only the sleeve group. This study showed us that a device that protects against tension after cutting wire is needed in this area.
We have made knots by hand first and then used a tensioner device to create tension on the knot. This is compatible with other studies. Harnroongroj et al. [20] found that stiffness was related to the tightening of the construct; they found that to achieve the best stability, 200 N tension cerclage wire was needed. Wähnert et al. [21] found that twisting under tension was beneficial for the installation of pre-tension.
Cutting the wire causes a significant loss of tension. Which part of wire is cut, also effects the tension, within the twist at the end of the wire [21]. Rook et al. [22] investigated first the twisted wire and then cutting below the breakage, in addition, without breakage, to reach the precise stable long-term tension, the strength of the wire is as important as fracture reduction and bone-to- bone contact. In this study, we proved that adding a basic knot method significantly enhances the load resistance of the cerclage and improves the cerclage fixation.
The limitation of this study is that, in normal human physiology, the cable system always exposures cyclic loading by dynamic forces. Accordingly, the reason of failure is fatigue. But we perform force from the center to the periphery by increasing continuously until broken down. This shows us strength and durability. We defined failure of the system when it broke. In the literature, Lenz et al. [23] defined more than 3 mm axial displacement, Talbot et al. [24] defined displacement of 10 mm, or the point where applied force suddenly dropped by 10%. The point of only catastrophic failure of each system was determined. We also dealt only with centripetal force with axial loading.
Conclusion
This knot technique is very simple and fast. In our biomechanical study, we showed that only adding a knot to a cable system increases the durability and strength of the cable system by approximately 40%. These findings showed that adding a knot to the cable-domino system decreased the possibility of loosening and failing of fixation. There will be some advantages in clinical use considering the difficulties, especially in fixation of periprosthetic fractures, complex fractures using screws.
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. Dall DM. A biomechanical and clinical review: The Dall – Miles cable system. In: Sofue M, Endo N, editors. Treatment of Osteoarthritic Change in the Hip Joint Preservation or Joint Replacement. Shinano, Japan: Springer; 2007. p. 239–43.
2. Craig NJA, Sivaji C, Maffulli N. Subtrochanteric fractures: A review of treatment options. Bull Hosp Jt Dis. 2001; 60(1): 35–46.
3. Grimsrud C, Monzon RJ, Richman J, Ries MD. Cemented hip arthroplasty with a novel cerclage cable technique for unstable intertrochanteric hip fractures. J Arthroplasty. 2005; 20(3): 337–43.
4. Lin HH, Hung SH, Su YP, Chiu FY, Liu CL. Cerclage wiring in displaced associated anterior column and posterior hemi-transverse acetabular fractures. Injury. 2012; 43(6): 917–20.
5. Han KJ, Lee DH, Bang JY. Do cerclage cables delay the time to bone union in patients with an unstable humeral shaft fracture treated with intramedullary nails? Yonsei Med J. 2017; 58(4): 837–41.
6. Müller T, Topp T, Kühne CA, Gebhart G, Ruchholtz S, Zettl R. The benefit of wire cerclage stabilisation of the medial hinge in intramedullary nailing for the treatment of subtrochanteric femoral fractures: A biomechanical study. Int Orthop. 2011; 35(8): 1237–43.
7. Angelini A, Battiato C. Combination of low-contact cerclage wiring and osteosynthesis in the treatment of femoral fractures. Eur J Orthop Surg Traumatol. 2016; 26(4): 397–406.
8. Kulkarni SG, Babhulkar SS, Kulkarni SM, Kulkarni GS, Kulkarni MS, Patil R. Augmentation of intramedullary nailing in unstable intertrochanteric fractures using cerclage wire and lag screws: a comparative study. Injury. 2017; 48(Suppl. 2): 518–22.
9. Angelini A, Battiato C. Past and present of the use of cerclage wires in orthopedics. Eur J Orthop Surg Traumatol. 2015; 25(4): 623–35.
10. Liu A, O’Connor DO, Harris WH. Comparison of cerclage techniques using a hose clamp versus monofilament cerclage wire or cable. J Arthroplasty. 1997; 12(7):772–6.
11. Dennis MG, Simon JA, Kummer FJ, Koval KJ, DiCesare PE. Fixation of periprosthetic femoral shaft fractures occurring at the tip of the stem: A biomechanical study of 5 techniques. J Arthroplasty. 2000; 15(4):523–8.
12. Dall DM, Miles AW. Re-attachment of the greater trochanter. The use of the trochanter cable-grip system. J Bone Joint Surg Br. 1983; 65(1):55–9.
13. Kraus MJ, Nowakowski AM. Cerclage Breakage in Trochanteric Revision – High Risk for Hip Endoprosthesis? Acta Chir Orthop Traumatol Cech. 2017; 84(2):138–40.
14. Codesido P, Mejía A, Riego J, Ojeda-Thies C. Cerclage Wiring Through a Mini-Open Approach to Assist Reduction of Subtrochanteric Fractures Treated with Cephalomedullary Fixation: Surgical Technique. J Orthop Trauma. 2017; 31(8): 263–8.
15. Ménard J, Émard M, Canet F, Brailovski V, Petit Y, Laflamme GY. Initial tension loss in cerclage cables. J Arthroplasty. 2013; 28:1509–12.
16. Shin WC, Moon NH, Jang JH, Jeong JY, Suh KT. Technical note and surgical outcomes of percutaneous cable fixation in subtrochanteric fracture: A review of 51 consecutive cases over 4 years in two institutions. Injury. 2019; 50(2): 409–14.
17. Klinge SA, Vopat BG, Daniels AH, Bariteau JT, Rubin LE, Limbird R. Early catastrophic failure of trochanteric fixation with the dall-miles cable Grip System. J Arthroplasty. 2014; 29(6):1289–91.
18. Kim JW, Park KC, Oh JK, Oh CW, Yoon YC, Chang HW. Percutaneous cerclage wiring followed by intramedullary nailing for subtrochanteric femoral fractures: A technical note with clinical results. Arch Orthop Trauma Surg. 2014; 134(9):1227–35.
19. Meyer DC, Ramseier LE, Lajtai G, Nötzli H. A new method for cerclage wire fixation to maximal pre-tension with minimal elongation to failure. Clin Biomech. 2003; 18:975–80.
20. Harnroongroj T. Twist knot cerclage wire: The appropriate wire tension for knot construction and fracture stability. Clin Biomech. 1998; 13(6):449–51.
21. Wähnert D, Lenz M, Schlegel U, Perren S, Windolf M. Cerclage handling for improved fracture treatment. A biomechanical study on the twisting procedure. Acta Chir Orthop Traumatol Cech. 2011; 78(3):208–14.
22. Rooks RL, Tarvin GB, Pijanowski GJ, Daly WB. In Vitro Cerclage Wiring Analysis. Vet Surg. 1982; 11:39–43.
23. Lenz M, Perren SM, Richards RG, Mückley T, Hofmann GO, Gueorguiev B, et al. Biomechanical performance of different cable and wire cerclage configurations. Int Orthop. 2013; 37(1):125.
24. Talbot M, Zdero R, Schemitsch EH. Cyclic loading of periprosthetic fracture fixation constructs. J Trauma. 2008; 64 (5):1308.
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Ertuğrul Şahin, Ahmet Karakaşlı, Bora Uzun, Hasan Havıtçıoğlu. Augmentation of cerclage wire strength with a basic knot technique: A biomechanical study. Ann Clin Anal Med 2021;12(2):191-194
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The correlation between knee osteoarthritis and the ABO blood group system in a Turkish population
Yüksel Uğur Yaradılmış 1, Bahtiyar Haberal 2, İsmail Demirkale 1, Murat Altay 1
1 Department of Orthopaedics and Traumatology, University of Health Sciences, Keçiören Health Practice and Research Center, 2 Department of Orthopaedics and Traumatology, Başkent University Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.20337 Received: 2020-09-08 Accepted: 2020-10-22 Published Online: 2020-10-23 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):181-185
Corresponding Author: Yüksel Uğur Yaradılmış, Pınarbaşı M Afacan S No 18/12, Keçiören, 06380, Ankara, Turkey. E-mail: ugur_yaradilmis@outlook.com P: +90 5327697802 Corresponding Author ORCID ID: https://orcid.org/0000-0002-7606-5690
Aim: This study aimed to determine the validity of the relationship between primary knee osteoarthritis and the ABO blood group system in the Turkish popula-tion and whether ABO group system could be a risk factor for early-onset knee osteoarthritis or revision surgery.Material and Methods: A retrospective examination of the data of 2752 patients who underwent knee arthroplasty surgery in our clinic between 2011 and 2019 was carried out. A total of 2436 primary knee osteoarthritis (PKO) patients underwent total knee arthroplasty (TKA) surgery and 206 patients underwent revision knee arthroplasty (RKA). A control group was formed of 22350 individuals aged >40 years from the same geographical region. The frequency of the ABO subgroups (A, B, O, AB) was compared between the primary knee osteoarthritis group and the control group. In addition, ABO subgroups (A, B, O, AB) were determined in the group of patients aged <65 with knee osteoarthritis (early-onset knee osteoarthritis) or revision group.Results: In the PKO group, the female to male ratio was 8:1, and the mean age was 67.2±8 years. The most significant relationship between blood groups and osteoarthritis was found in Group A (p=0.001). Group AB had a significant but low relationship (p=0.002). However, no statistically significant difference was found between age <65 years and >65 years of age (p=0.642). In comparison with the PKO group and RKA, Group A in the revision group was seen at a statistically significantly higher rate (p=0.043). Discussion: Group A blood group was found to be associated with both primary knee osteoarthritis and revision knee arthroplasty.
Keywords: Knee; Osteoarthritis; Blood group; Revision
Introduction
Osteoarthritis of the knee is a chronic degenerative disease with increasing prevalence with aging [1]. Osteoarthritis (OA) develops with the action of proinflammatory cytokines such as IL-1β and TNF-α, leading to a deterioration in chondrocyte metabolism [2, 3]. An increasing number of studies have reported the relationship between ABO blood group type and proinflammatory cytokines and the systemic inflammatory response [4].
The ABO blood group system, which is the most commonly used system in the classification of human blood, is based on hereditary features determined by the presence or absence of A and B antigens in red blood cells, tissue cells, saliva, and body fluids. The basis of the ABO blood group system was first defined by the Australian physician Landsteiner, and the Czech psychologist Janski, independently of each other in the first decade of the 20th century [5]. ABO antigens have been associated primarily with tumor disease, cerebrovascular and cardiovascular diseases, infection, and inflammatory diseases [6]. Previous studies have reported an association between blood groups and orthopaedic diseases such as musculoskeletal injuries and hip fractures [7,8]. These findings suggest that the genes and enzymes in the ABO system have pleiotropic roles.
A recent study by Li et al, conducted in Guangzhou city in China, is the only study in the literature to report the relationship between primary knee osteoarthritis (OA) and ABO blood groups. The study of a large patient sample included radiological grading and showed the frequency and severity of primary knee OA in ABO blood groups [9]. However, the frequency of ABO blood groups is known to be affected by many factors, and different frequencies are seen between communities and countries [10].
In knee arthroplasty, two patient groups are of importance: a) OA with onset at a young age and b) revision knee arthroplasty with major complications accompanying the inflammatory process. As Li et al. have stated that there could be a relationship between the ABO blood group system and gonarthrosis, naturally that there could be a relationship with early-onset OA or revision arthroplasty.
The aim of this study was to determine the validity of the relationship between the ABO blood group system and primary knee OA in the Turkish population and to investigate whether the ABO blood group system could constitute a risk for early knee OA or the need for revision surgery.
Material and Methods
Study design
A retrospective examination of the data of 2752 patients who underwent knee arthroplasty surgery in our clinic between 2011 and 2019 was carried out. After the exclusion of patients with inflammatory osteoarthritis, tumor disease, and age <40 years, a total of 2642 patients who underwent primary and revision surgery were included in the study. A total of 2436 patients evaluated as grade 3 and 4 according to Kellgren and Lawrencegrading system with persistent complaints of pain despite conservative treatment underwent primary knee arthroplasty surgery. Revision knee arthroplasty (RKA) was applied to 206 patients and the revision burden was determined as 7.4%. The control group was a representative subset of the local population, aged >40 years from the same geographical area. The ABO blood group types were determined at the Blood Centre of the Başkent University Hospital. Approval for the study was granted by the Başkent University Hospital and all study procedures were performed in accordance with the ethical standards laid down in the Declaration of Helsinki. The ethics committee approval was obtained by the University of Health Sciences of Turkey affiliated hospital of Keçiören HPRC with the following 59. meeting on 15.05.2020, reference number: 43278876-929.
Determination of the ABO blood group
The ABO blood groups were tested using the standard agglutination method. The ABO blood group test is routine for patients of surgical departments, and is also performed for patients from other departments when needed. The determination of the ABO blood group types for the patient group in the study was performed in the clinical laboratory of Keçiören Health Practice and Research Hospital Blood Centre and for the control group in the Başkent University Hospital Blood Centre.
Knee osteoarthritis and ABO group
The frequencies of the ABO subgroups (A, B, O, AB) were compared between the primary knee osteoarthritis (PKO) group (n:2436) and the control group (n:22350), and risk groups for knee OA were investigated. The relationship with age and gender was determined with regression analysis. The PKO group was separated into two age groups as <65 years (n:1092) and > 65 years (n:1340) to determine the early onset of OA. The groups were compared to determine the relationship between ABO subtype and early onset OA. The details of the patient groups are shown in Figure 1.
Revision surgery and variables
Risk factors for revision surgery were determined as age, gender, comorbidity, and ABO blood group. To determine the relationship between the ABO blood group system and revision surgery, the ABO subtypes were compared between the PKO and RKA groups. To determine the relationship between septic revision and the ABO blood group system, the ABO subtypes were compared between the RKA septic cases and the RKA non-septic cases. Other risk factors for revision surgery that were investigated were determined as age, gender and comorbidity. The number of comorbidities was determined. The PKO and RKA groups were compared in respect of age, gender, and comorbidities.
Statistical analysis
Data obtained in the study were analyzed statistically using SPSS v.22 software with a 95% confidence interval. Qualitative data were stated as frequency distribution, and quantitative data were stated as mean, minimum, and maximum values. The χ2 test was applied to categorical data, and the Student’s t-test was applied to quantitative data. Normality of data distribution was tested with the Shapiro-Wilk test. Inter- and intra-observer reliability was assessed using the interclass coefficient. The PKO group and control group were compared in respect of the ABO blood group system using logistic regression analysis. The age and comorbidity values of the patients in the PKO and RKA groups were evaluated with the Mann-Whitney U test. Gender and ABO blood group types of the PKO and RKA groups were compared using the Chi-square test. A value of p<0.05 was accepted as statistically significant.
Results
Demographic data of the patients and the control group
The primary knee osteoarthritis (PKO) group comprised 2436 patients with a gender ratio (F:M)- of 8:1, and a mean age of 67.2±8 years (range, 43-88 years). The control group comprised 22350 individuals with a gender ratio (F:M) of 1.2:1, and mean age of 57.4±10.36 years (range, 40-98 years). The Mann-Whitney U test showed that the mean age of the PKO group was statistically significantly older (p<0.001). As a result of the Chi-square test, the rate of female gender was determined to be statistically significantly higher in the PKO group (p<0.001) (Table 1).
Primary knee osteoarthritis and ABO subtype
In the PKO group, the blood group distribution was as follows: Group A: 1092 (44.8%), Group B: 404 (16.6%), Group O: 762 (31.3%) and Group AB: 176 (7.2%). In the control group, the blood group distribution was as follows: Group A: 9668 (43.2%), Group B: 3890 (17%), Group O: 6705 (30.4%) and Group AB: 2080 (9%) (Figure 2). The difference between the ABO subtypes was determined to be statistically significant (p=0.000). As a result of logistic regression analysis, the frequency of blood group A was determined to be high and group AB was low (A: p=0.001, B: p=0.145, O: p=0.345, AB: p=0.002). No statistically significant difference was determined between the two age subgroups of the PKO group (p=0.642) (Figure 3).
Revision knee arthroplasty and ABO subtype
In the revision group of 206 patients, the ABO subtypes were as follows: Group A: 107 (51.7%), Group B: 32 (15.6%), Group O: 59 (28.3%) and Group AB:8 (3.9%). In comparison with the PKO group, Group A in the revision group was seen at a statistically significantly higher rate (p=0.043) (Table 2). The RKA group was separated as septic (n:89, 43%) and non-septic (n:116, 57%) cases, and no significant difference was observed between the groups in respect of the ABO blood group types (p=0.644) (Table 2).
Revision knee arthroplasty and risk factors
The RKA group comprised of 182 females and 24 males with a mean age of 71.1 years (range, 42-93 years). In comparison with the PKO group, a statistically significant difference was observed in respect of mean age (p<0.05), and the gender distribution was similar to the higher rate of females (p=0.746). The mean number of comorbidities was 3.2±1.3, which is significantly higher than in the PKO group (p=0.000). Age and comorbidity were determined to be risk factors for revision surgery.
Discussion
The outcomes of this study demonstrated that blood group A is seen at a higher rate and Group AB is seen lower rate in PKO in the Turkish population in the comparison of ABO blood group distribution in the PKO group and the control group. There was also seen to be a significant difference in the ABO blood group distribution between the PKO group and the RKA group with blood group A seen at a higher rate in the revision group.
ABO blood group type has been associated with several diseases for osteoarthritis and primarily with abdominal cancers and cardiovascular diseases [5]. In 1975, Lourie et al. evaluated the association between ABO blood group and primary hip OA in a retrospective case-control study. Compared with the control group, the proportion of patients with blood group O was lower in the case group [11].
In a more specific group of patients with femoral head avascular necrosis (AVN), Yang et al. examined the relationship with ABO blood group [12]. Since it is known that there is a relationship between the ABO blood group type and venous thrombus diseases, Yang et al. focussed on the relationship with AVN [13]. Although no direct relationship was determined between AVN and ABO blood group, a more rapid progression of AVN in patients with blood group A was seen. Interestingly, there are different studies in the literature that have examined the association of ABO blood groups with orthopedic pathologies such as Achilles tendon rupture and rotator cuff arthropathy [14, 15].
Primary knee OA is a multifactorial disorder associated with the same factors such as age, female gender, obesity, osteoporosis, hypermobility, and hyperuricemia [2]. The only study in the literature related to primary knee OA and ABO blood groups was published in 2019 by Li et al. Although a statistically significant difference was observed in knee OA in the AB blood group, it was also noted that there was no significant difference between the patient and control groups in respect of the frequency of AB blood group (patient group: 9.7% AB, control group:7.8% AB). In the current study, as in the Li et al.’s study, a relationship was found between ABO blood groups and primary knee OA. Although the most important finding was that blood group A was associated with knee OA, it was also determined that blood group AB was seen less in the knee OA group (patient group: 44% group A, control group: 43.2% group A; patient group:7.2% group AB, control group: 9% AB). Based on this, it can be understood that the results of this study strengthen the relationship between OA and ABO blood groups, and it was concluded that differences may be seen between different populations. In the study by Li et al., although A B antigens in the joint synovium were not included in the histological section of the study, a close relationship was shown between H antigen and LeY antigen [8]. This histological finding also strengthens the hypothesis and results of both studies.
The distribution of blood groups shows variability between countries [9]. Group B is common in Asia, especially in southern India. Group A is common throughout the world but the highest incidence is seen in Australian Aborigines and Semitic races. In England, the blood group distribution of Groups A, B, O, and AB is 45%, 9%, 43% and 3%, respectively [9]. The Italian Blood Donation Association reported that the national distribution of Groups A, B, O, and AB is 32.02%, 14.10%, 50.63% and 3.25%, respectively [10]. Li et al. reported the Guangzhou Blood Centre control group to be 27.3% group A, 26.5% group B, 38.4% group O and 7.8% group AB [8]. The control group in the current study was determined as 43.2% group A, 17.4% group B, 30.2% group O, and 9% group AB. These results demonstrate that the relationship between blood group and disease must be evaluated at the community level.
Blood group A is common in the Turkish population. According to the data of 5 million people reported by the Turkish Red Crescent, blood group distribution is as follows: A: 42.5%, B:15.8%, O: 32.2%, and AB:7.6% [10]. In a study on 288,469 subjects by Ergün et al., conducted in a similar location to that of the current study, the blood group rates were found to be as follows: A: 44.62%, B: 15.45%, O: 32.24%, and AB: 7.69% [16]. The comparison of the study and control group of this study and two large groups of data are shown in Table 3. The fact that blood group A was most common in the PKO group of the current study shows consistency with the data of these other two studies. Previous studies in the literature have shown an association between blood group A and disease [17-19]. In studies determining the relationship between ABO blood groups and osteoporosis, with the exception of group O, a relationship has been shown with osteoporosis [ 17, 18].
In a study of hip fractures, Buckwalter et al. reported increased fracture incidence in the A blood group [19]. Kuru et al. also examined the relationship between hip fractures and ABO blood groups, and determined a relationship between extracapsular fractures and blood group A. In that study by Kuru et al., not only the relationship between disease and ABO blood groups, but also the relationship between the ABO group system and length of hospital stay and blood transfusion was examined [10].
Unlike other studies in the literature, significant differences were found in the revision arthroplasty group of the two groups that received a lot of attention in the current study (early-onset OA and revision arthroplasty). A new finding in the revision arthroplasty group was the significant relationship between revision surgery and blood group A (p=0.043). A relationship was found between the revision arthroplasty group and ABO blood groups, and risk factors were determined as age, comorbidities, and blood group A. It has been stated that the combination of the inflammatory process with septic revision is inevitable, but this situation may not be expected for non-septic patients. However, the study by Loria et al. changes this view as it showed that an increase in inflammatory cytokines within the joint in non-septic patients could cause inflammation in non-septic patients [20]. The combination of inflammatory symptoms with revision arthroplasty can be explained by the relationship of ABO blood groups with revision arthroplasty. Other risk factors for revision arthroplasty found in this study were age and comorbidities, which is consistent with the literature [21].
The other group of importance in the PKO group was the group with advanced OA determined at a young age. The early onset of PKO not only diminishes the quality of life of the patient at a young age but also leads to a severe treatment process. Genetic studies of OA at a young age have come to prominence. While some studies have reported that there may be a relationship between OA and genomes (CALM 1), others have determined no relationship with genomes (ADAM12, GDF5) [22, 23]. Nevertheless, in genome studies, the relationship of genes and populations is mentioned. In the current study, while the distribution of ABO blood groups was similar in the younger patient group and those aged >65 years, the blood group was seen as a risk factor for the early onset of OA (p=0.664).
By keeping the number of participants high in both the patient and control groups in the current study, it was aimed to achieve high reliability of the results and to reduce the effects of the variables. A limitation of the study is the retrospective design and the fact that the details were taken from medical records. There is a need for further studies including more patients in the revision group and the support of a study including genetic patterns.
In conclusion, the results of our study determined a relationship between blood group A and both knee OA and revision knee arthroplasty. However, our study found a low relationship between the AB group and knee OA. Nevertheless, the relationship between the ABO blood group system and osteoarthritis can show variations between populations.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Henrotin YE, Bruckner P, Pujol JP. The role of reactive oxygen species in homeostasis
and degradation of cartilage. Osteoarthritis Cartilage. 2013;11(10):747–55. DOI: 10.1016/s1063-4584(03)00150-x
2. Dennison E, Cooper C. Osteoarthritis: epidemiology and classification. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH (eds). Rheumatol. 2003, 3rd ed. Edinburgh: Mosby; p. 1781-91.
3. Emre F, Başak AM, Aslantaş B, Ertaş ES, Öztürk R, Aytekin MN. Effects of PRP and HA injections with intervals on pain and function in knee OA. Ann Clin Anal Med. 2020. DOI: 10.4328/ACAM.20185
4. Pare G, Chasman DI, Kellogg M, Zee RY, Rifai N, Badola S. Novel association of ABO histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women. PLoS Genet. 2008 ;4(7):e1000118. DOI: 10.1371/journal.pgen.1000118.
5. Lederer SE. Bloodlines: blood types, identity, and association in twentieth century America. The Journal of the Royal Anthropological Institute. 2013;19:S118–29. DOI: 10.1111/1467-9655.12019.
6. Anstee DJ. The relationship between blood groups and disease. Blood. 2010;115(23):4635–43. DOI: 10.1182/blood-2010-01-261859.
7. Kujala UM, Järvinen M, Natri A, Lehto M, Nelimarkka O, Hurme M, Finne J. ABO blood groups and musculoskeletal injuries. Injury. 1992; 23(2): 131-3.
8. Uzoigwe C, Smith RP, Khan A, Aghedo D, Venkatesan M. Association of ABO blood group with fracture pattern and mortality in hip fracture patients. Ann R Coll Surg Engl. 2014; 96(6): 442–5. DOI:10. 1308/003588414X13946184902604.
9. Li C, Ouyang N, Wang X, Liang A, Mo Y, Li S, et al. Association between the ABO blood group and primary knee osteoarthritis: A case-control study. J Orthop Translat. 2019; 21:129-35. DOI:10.1016/j.jot.2019.08.003
10. Kuru T, Olcar HA. Relationship between the AB0 Blood System and Proximal Femoral Fracture Patterns in the Turkish Population. Biomed Res Int. 2020;2020:1834525. DOI:10.1155/2020/1834525
11.Lourie JA. Is there an association between ABO blood groups and primary osteoarthrosis of the hip? Ann Hum Biol. 1983;10(4):381–3.
12. Yang SY, Zeng LY, Li C, Yan H. Correlation between an ABO Blood Group and Primary Femoral Head Necrosis: A Case-Control Study. Orthop Surg. 2020;12(2):450-6. DOI:10.1111/os.12628
13. Spiezia L, Campello E, Bon M, Tison T, Milan M, Simioni P, et al. ABO blood groups and the risk of venous thrombosis in patients with inherited thrombophilia. Blood Transfus. 2013; 11(2): 250–3.
14. Leppilahti J, Puranen J, Orava S. ABO blood group and Achilles tendon rupture. Ann Chir Gynaecol. 1996;85(4):369-71.
15. Doo-Hyung L, Han-Dong L, Yoon SH. “Relationship of ABO blood type on rotator cuff tears.” PM R 2015;7(11):1137-41.
16. Ergün A, Yardımcı S. Türkiye Genelinde ABO Kan Grupları ve Rh Faktörünün Dağılımı (Distribution of ABO blood group and Rh factors in Turkey). Ankara Üniversitesi Tıp Fakültesi Mecmuası/ The Journal of Ankara University Faculty of Medicine. 1993;46(3):527–33.
17. Choi JW, Pai SH. Associations between ABO blood groups and osteoporosis in postmenopausal women. Ann Clin Lab Sci. 2004;34(2):150–3.
18. Lu BB, Li KH. Association between ABO blood groups and osteoporosis severity in Chinese adults aged 50 years and over. J Int Med Res. 2011;39(3):929–33. DOI: 10.1177/147323001103900327.
19. Buckwalter JA, Turner JH, Raterman L, Tidrick RT. On the etiological role of heredity in fractures. Surgical Forum. 1957;7:610–14.
20. Loria MP, Dambra P, Moretti B, Patella V, Capuzzimati L, Cavallo E, et. al. Role of cytokines in gonarthrosis and knee prosthesis aseptic loosening. J Orthop Sci.2014; 9(3): 274-9.
21. Koenig K, Huddleston JI, Huddleston H, Maloney WJ, Goodman SB. Advanced age and comorbidity increase the risk for adverse events after revision total hip arthroplasty. J Arthroplasty. 2012;27(7):1402-7.e1. DOI: 10.1016/j.arth.2011.11.013
22. Shin MH, Lee SJ, Kee SJ, Song SK, Kweon SS, Park DJ, et al. Genetic association analysis of GDF5 and ADAM12 for knee osteoarthritis. Joint Bone Spine. 2012;79(5):488-91. DOI: 10.1016/j.jbspin.2011.10.016
23. Mototani H, Mabuchi A, Saito S, Fujioka M, Iida A, Takatori Y, et al. A functional single nucleotide polymorphism in the core promoter region of CALM1 is associated with hip osteoarthritis in Japanese. Hum. Mol Genet. 2005;14(8): 1009-17.
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Yüksel Uğur Yaradılmış, Bahtiyar Haberal, İsmail Demirkale, Murat Altay. The correlation between knee osteoarthritis and the ABO blood group system in a Turkish population. Ann Clin Anal Med 2021;12(2):181-185
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Post-traumatic cerebral infarction (PTCI), an institutional experience
Vikas Chandra Jha, Neeraj Jha
Department of Neurosurgery , All India Institute of Medical Sciences,Patna, India
DOI: 10.4328/ACAM.20221 Received: 2020-05-26 Accepted: 2020-06-26 Published Online: 2020-08-02 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):144-149
Corresponding Author: Vikas Chandra Jha, Department of Neurosurgery , All India Institute of Medical Sciences,Patna, India. E-mail: drvikaschandrajha@aiimspatna.org P: 07389831560 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0080-061X
Aim: In this study, we aimed to assess effect of less studied risk factors associated with the development of post-traumatic cerebral infarction (PTCI) as severe systemic injury apart from head injury, length of stay on mechanical ventilation in ICU, sepsis, coagulopathy, DVT together with common risk factors as age, GCS severity, etc. and significance of bedside tool as TCD to detect it earlier and its implication in final clinical outcome in such cases.Material and Methods: 400 patients of head injury treated in our department between July 2018 to July 2019 were included in the study. 28 patients were diagnosed with PTCI. Risk factors for development of PTCI were analysed. Utility of TCD in early detection and clinical management of PTCI was assessed.Results: PTCI was observed in 7 % (28/400) of patients. Among risk factor analysis age (p=0.029), initial Glasgow coma scale score≤8 (p<0.028), decompres-sive craniotomy (p=0.023) and prolonged ICU stay (0.031) and TCD parameters as MCA velocity≥200cm/s (p≤0.028), PCA velocity≥70cm/s (p=0.025) were significantly associated with PTCI than without it on multivariate regression analysis. Mortality was lower in PTCI cases detected earlier (p<0.09) together with earlier clinical improvement (p<0,009) in neurological features in comparison to cases detected late.Discussion: Prolonged length of stay on a mechanical ventilator with poor GCS is a significant risk factor for the development of PTCI and early detection with a bedside tool as TCD helps in planning management better with a significant improvement in short-term mortality and clinical improvement in such cases.
Keywords: Head injury; PTCI; Risk factors; TCD; Institutional experience
Introduction
Preventions and risk factors of one of the uncommon secondary brain injuries whose incidence is 1.9-40 % are not well known. Few risk factors as old age, GCS <8 are commonly reported in the literature but other risk factors as a severe systemic injury associated with head injury, length of stay in ICU, sepsis, MODS (multiple organ dysfunction), coagulopathy, DVT, etc. should also be considered especially in the cases having polytrauma because these factors may be contributory in development of PTCI. We have tried to analyze the effect of the above-mentioned risk factors on the development of PTCI and the significance of such a bedside tool as TCD to detect it and also tried to evaluate the effect of aggressive management in clinical outcomes in such cases in the present study.
Material and Methods
We reviewed 400 head injury cases admitted to our department from July 2018 to December 2019 at our institute. We included cases of all age groups and all grades of head injury and well-demarcated area of hypodensity on NCCT head subsequent to admission, but not the cases with a documented history of the past cerebrovascular accident with brain infarct.
Detailed written informed consent was taken at the time of enrolment for this study from the patient/next of kin/guardian / to use the information and their data for teaching and clinical research purposes. Institutional ethical clearance number IEC/2020/1250.
The diagnosis of cerebral infarction was made on non-enhanced CT based on a well-demarcated region of low attenuation conforming to an arterial vascular territory. Cases were further evaluated for PTCI on magnetic resonance imaging (MRI) by visualization of a well-demarcated region, in an arterial vascular distribution, of low signal on T1-weighted images, high signal on conventional T2-weighted or fluid attenuation inversion recovery sequences, and of high signal on diffusion-weighted images, indicating diminished perfusion, associated with a corresponding decrease in signal on the apparent diffusion coefficient map. Cerebral infarctions were classified as watershed infarctions when they were located between the long penetrating cortical and striatocapsular branches (deep watershed infarction), in the supply area terminating in periventricular white matter (terminal zone infarction), or in border zones between the anterior and middle cerebral artery (MCA) or between the posterior and MCA (anterior or posterior border zone infarction, respectively). We reviewed all CT scans, MRIs, and cerebral angiograms identified as positive for infarction. A diagnosis of cerebral infarction was revised if follow-up studies indicated that the findings were actually related to evolving contusions, artifact, or were inconsistently visualized. Patient demographics (age, sex), injury specifics and clinical data (Abbreviated injury score (AISS>3)), length of stay (LOS) in the intensive care unit (ICU), and the hospital were analyzed. Cases with AISS>3 were included in it as it indicates severe injury requiring surgical management which could have aggravated secondary brain injury by causing hypovolemia, shock, etc. and there was less chance of interobserver variation in score >3. The incidence of PTCI, mortality rates, and site(s) of infarctions were ascertained. The following risk factors were evaluated: age, abbreviated injury score (AIS), admission GCS, the performance of decompressive craniectomy, coagulopathy, abbreviated injury score (AIS), length of stay (LOS) in intensive care unit (ICU) and hospital. The difference in mortality and clinical benefit was compared in PTCI cases that were detected earlier than late detected.
PTCI detected within 10 days was labeled early and detected thereafter as late, since the cumulative frequency graph revealed 70% of cases detected within 10 days, and in the majority of the studies, these cases were detected within 3 weeks.
Improvement in clinical features, measured on GCS on follow up, was labeled as an improvement.
Continuous variables were expressed as mean ± standard deviation (SD) and were compared using independent t- tests. Categorical variables were expressed as number (percentage) and were compared with the Chi-square test or the Fisher exact test, as appropriate. Multiple logistic regressions were used to identify PTCI-related factors that are helpful in recovery. Factors with a P- value <0,5 in the univariate analysis, were entered into the multivariate analysis. SPSS (Version 20.0; IBM Corp, Armonk, NY) was used for statistical analysis.
Results
In this study, 6.5 % (26/400) of cases were detected to have PTCI after sustaining a head injury. Cases of less than 60 years were detected to be less prone to develop PTCI as compared with cases ≥60 years, and there was a significant difference in incidence in these two groups (p=0.029) (Tables 1 and 3). Male cases were slightly more common as compared to female cases to develop it (m:f, 1:3). Severe head injury GCS≤8 (Figure 1) was significantly more prone to develop it (P=0.028) but cases with PTCI were also found with moderate head injury 34.61 % (9/26) (Figure 2) as well as mild head injury 7.6 % (2/26). The mass effect in the form of midline shift ≥0.5mm was significantly associated with the development of PTCI, and cases with a herniating brain who had undergone decompressive craniotomy were detected to have more chance of developing it, as 42.5% of head injury cases (17/40) who had undergone this procedure developed PTCI (p≤0.012), compared to only 3.33% of head injury cases (12/360) who were managed conservatively. Other associated systemic injuries, as measured on abbreviated injury score (AIS≥3), were contributing to the development of PTCI, a positive correlation coefficient (0.126) was found with the development of PTCI but its association was not significant (p≤0.536). Among other factors, the length of stay on a mechanical ventilator (MV) was significantly associated with the development of PTCI (Tables 1and 3) that caused prolongation of stay in ICU and hospital.
The cases who developed PTCI were repeatedly screened with a bedside tool such as transcranial Doppler, which revealed significant association of detecting it with middle cerebral artery (MCA) blood flow velocity ≥150cm/s (p-value≤ 0.014) and posterior cerebral artery (PCA) blood flow velocity ≥70cm/s (p-value ≤0.012) (Table-2). These entire features correlate with stenosis in the path of vessels compressed by the herniating brain, dissection or thromboembolic phenomenon. These findings on Doppler were labeled as positive findings on TCD and its sensitivity and specificity to detect PTCI were found to be 97% and 84% with area under the curve (AUC) 0.859 and p-value of 0.016, suggesting good predictive value to detect PTCI (Figure 3).
All the factors which were found to have a significant association with the development of PTCI on univariate regression analysis were subjected to multivariate regression analysis. Only age ≥60 years (p=0.029), GCS ≤8 (p=0.028), length of stay on a mechanical ventilator (p=0.028) were significantly associated with the development of PTCI (Table 3).
Clinical improvement in 72.7% of cases (8/11) detected early by a bedside screening tool (TCD) and confirmed on CT of the head, showed a significantly good recovery compared to 23.5% of cases (4/17) in which it was detected late (p-0.011). We found a significant difference in short-term mortality in 18.18% of cases (2/11) detected earlier as compared to 82.35% of cases (13/17) detected late (p=0.003). Cases with PTCI had follow-up of 12±9.87 (SD) months and cases without it had follow-up of 14.24±16.567 (SD) months (Table-1).
Discussion
Posttraumatic cerebral infarction is a known secondary entity after traumatic brain injury and often associated with poor prognosis. Its incidence in the present study is similar to other studies which reported its incidence in the range between 1.9 and 10.4% [1-3]. The reason of the observed variation may be due to different groups of case selection, as few studies have included cases of both severe and moderate head injuries, and few had only cases of severe head injury. Different studies have suggested a significantly higher incidence of severe head injuries compared to moderate head injury cases. In this study, we have noticed PTCI in all severity grades of head injury, as it was also detected in cases of moderate and mild head injury. Inclusion of moderate and mild head injuries is necessary to detect more cases for its better management.
Cases having head injury were common in age group < 60 years compared to > 60 age group, incidence of PTCI was significantly higher in aged>60 years with increased mortality, as observed in this study and other studies, probably because this age group is more predisposed for the presence of atherosclerosis of vessels, brain atrophic changes leading to more shearing stress and to severe cerebral vascular injury together with other associated comorbid diseases.
PTCI cases were detected as early as 3rd day in this study and as late as 1.5 months, but the majority of cases were detected within 2 weeks, which is on the lower side compared to other studies, where the majority of the cases had been found within 3 weeks and above [2-4]. The appearance of well-demarcated area of hypodensity in particular vascular distribution suggests PTCI, which is commonly caused by mass effect with herniation of brain and compression of vessels underlying the tentorial margin, falx cerebri, and compression against bony margin. In our study, there are cases with no features of brain herniation and mass effect on CT and clinically belong to moderate and mild head injury [5-7]. These findings can be explained by pathological mechanisms such as vasospasm, vascular dissection with a thromboembolic phenomenon, etc. for which repeated examination with bedside tools like transcranial Doppler helps detecting PTCI early as in this study, compared to other studies [8-10]. Clinically, in cases with secondary deterioration in sensorium and other diminishing clinical features, we should be suspicious of PTCI together with post-traumatic hydrocephalus, post-traumatic seizures, brain edema, etc.
In cases admitted in the emergency ward, there are cases with polytrauma, in which venous embolism as DVT, PE, peripheral arterial embolism are less common entity, but its contribution to the development of PTCI should not be ignored [11, 12]. This is one of the first articles taking into consideration the severity injury score of other systems as abdomen, chest, limbs, and pelvis. On analysis of associated injuries of other systems which may be as risk factor for the development of PTCI but its significance could not be proved as they were found in less number in the present study. Few studies suggested significantly higher ICU LOS, hospital LOS, and days on a mechanical ventilator compared to the case without the above-mentioned risk factors in thromboembolic phenomena [11-12]. Cases that require prolonged mechanical ventilator support have itself many factors associated with it which can contribute to the development of brain infarct as a thromboembolic phenomenon, impaired perfusion pressure, cerebral compliance change due to frequent change in intracompartmental pressure change of chest and cranium, etc. In this study significant association between development of PTCI and prolonged mechanical ventilation was found which creates a vicious cycle of prolonged ICU stay and hospital stay so the effort to minimize this cycle is imperative in such cases.
There is variability in detecting PTCI using CT of the head but a high index of suspicion keeps PTCI as one of the factors for no improvement or deterioration neurologically, and using bedside tools like transcranial Doppler and frequent CT of the head at regular intervals can help us detect this pathology earlier as in the present study [8-10]. Increased MCA blood flow velocity, higher PCA blood flow velocity, higher Lindegaard ratio, and pulsatile index raise the suspicion of vascular compression either due to raised intracranial pressure (ICP), brain herniation, arterial dissection, thromboembolic phenomenon, etc. TCD may play a role in monitoring the early development of cerebral vasospasm after traumatic subarachnoid hemorrhage (SAH) and cases with impending vascular occlusion due to brain herniation and the early or delayed development of increased ICP following traumatic brain injury (TBI). This is achieved by frequent monitoring with TCD which is a relatively low-cost, risk-free, bedside available, and high temporal resolution device, and suitable for the emergency setting. Significant limitations to the clinical utility of TCD in TBI include limited spatial resolution, assumptions made regarding the vessel diameter on TCD, operator dependence, and in patients who do not have an adequate acoustic temporal window for insonation [9-11]. Despite all these limitations, it is quite useful as in our study with good predictive value. Administering Calcium channel blockers in such cases with clinical suspicion of vaso occlusive phenomena had been reported in cases with head injury admitted in the emergency ward and found helpful in few studies, but cerebral protectant as nimodipine is not proven in posttraumatic infarct cases with vasospasm, but we have administered in cases with PTCI, and good clinical improvement in early detected cases were found [13-18].
In studies, the timing of decompressive craniotomy was a significant risk factor for the development of PTCI. These studies suggested that brain tissues and vessels passing through the bony defect are compressed by the dural and bony margin, leading to further cascade of congestion and edema. Larger craniectomy may influence the development of PTCI. The optimal timing for decompressive craniectomy is crucial to prevent the occurrence of PTCI or decrease its severity [18-22]. Although decompressive craniotomy is done for impending brain herniation and to prevent a cascade of cycle causing vascular compression as of PCA territory in uncal herniation leading to PCA territory infarct, its association with PTCI has been documented in several studies [19-21]. Decompressive craniectomy is mainly done for significant mass effect with raised ICP and it has been found to decrease mortality in many studies. The size of craniotomy and timing of decompressive craniectomy is always a matter of discussion and different authors have different opinions. Even few authors have reported increased association of larger decompressive craniotomy with PTCI proposing dura and bone to produce a constrictive effect on bulging brain but the majority of studies have differing opinions as wider decompressive craniotomy lowers ICP better and can help in reducing the development of PTCI. These varying opinions may indicate towards decompression of lesion, contusion, and hematoma to minimize the constricting effect of bone and dura around the bulging brain at the site of decompression, but early decompression as in the present study, was found beneficial after being detected on TCD and impending infarct was found on CT of the head [20-22].
Factors responsible for the development of post-traumatic cerebral infarction, such as raised intracranial pressure, decreased cerebral perfusion pressure, adequate size of decompressive craniotomy, as early as possible, with adequate lesionectomy, cerebral protectant together with calcium channel blockers, have been uniformly reported in the majority of studies, to be beneficial to prevent the development of PTCI. The treatment of PTCI lies in prevention. Avoidance of hypotension and hypoxemia is crucial to prevent the occurrence of PTCI. The availability of bedside tools as transcranial Doppler is very helpful as described in the literature, to identify features of raised ICP, spasm, etc. The use of cerebral protectants together with nimodipine and timely decompressive craniotomy helped in improving clinical outcome. These findings are also motivating factors for increasing the use of DSA in cerebral injury case and judicious use of intraarterial cerebral protectants, such as Nimodipine, as done in spontaneous cerebral vasospasm causing delayed ischemic neurological deficits, the role of which can be further explored after early detection of PTCI.
Conclusion
Prolonged length of stay on a mechanical ventilator with poor GCS is a significant risk factor for the development of PTCI and early detection using bedside tool such as TCD help in planning management better with significant improvement in short-term mortality and clinical improvement in such 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
1. Server A, Dullerud R, Haakonsen M, Nakstad PH, Johnsen UL, Magnaes B. Post-traumatic cerebral infarction. Neuroimaging findings, etiology and outcome. Acta Radiol. 2001; 42(3):254-60.
2. Tawil I, Stein DM, Mirvis SE, Scalea TM. Posttraumatic cerebral infarction: Incidence, outcome, and risk factors. J Trauma. 2008; 64(4):849-53.
3. Tian HL, Geng Z, Cui YH, Hu J, Xu T, Cao HL, et al. Risk factors for posttraumatic cerebral infarction in patients with moderate or severe head trauma. Neurosurg Rev. 2008; 31(4):431-7.
4. Sato M, Tanaka S, Kohama A, Fujii C. Occipital lobe infarction caused by tentorial herniation. Neurosurgery. 1986;18(3):300-5.
5. Rothfus WE, Goldberg AL, Tabas JH, Deeb ZL. Callosomarginal infarction secondary to transfalcial herniation. AJNR Am J Neu-roradiol. 1987; 8(6):1073-6.
6. Robertson SC, Lennarson P, Hasan DM, Traynelis VC. Clinical course and surgical management of massive cerebral infarction. Neurosurgery.2004; 55(1):55-61; discussion 61-62.
7. Schievink WI, Mokri B, O’Fallon WM. Recurrent spontaneous cervical-artery dissection. N Engl J Med. 1994; 330(6):393-7.
8. Zubkov AY, Pilkington AS, Bernanke DH, Parent AD, Zhang J. Posttraumatic cerebral vasospasm: clinical and morphological pre-sentations. J Neurotrauma; 1999; 16(9):763-70.
9. Fatima N, Shuaib A, Chughtai TS, Ayyad A, Saqqur M. The role of Transcranial Doppler in Traumatic Brain Injury: A Systemic Review and Meta-Analysis. Asian J Neurosurg; 2019; 14(3):626-33.
10. Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery.1980; 6(1):1-9.
11. Lichte P, Kobbe P, Almahmoud K, Pfeifer R, Andruszkow H, Hildebrand F, et al. Trauma Register DGU. Post-traumatic thrombo-embolic complications in polytrauma patients. Int Orthop. 2015;39(5):947-54.
12. Franchini M, Mannucci PM. Association between venous and arterial thrombosis: clinical implications. Eur J Intern Med. 2012 ; 23(4): 333–7.
13. Martin NA, Doberstein C, Zane C, Caron MJ, Thomas K, Becker DP. Posttraumatic cerebral arterial spasm: transcranial Doppler ultrasound, cerebral blood flow, and angiographic findings. J Neurosurg. 1992;77(4):575–83.
14. Oertel M, Boscardin WJ, Obrist WD, Glenn TC, McArthur DL, Gravori T, et al. Posttraumatic vasospasm: the epidemiology, severity, and time course of an underestimated phenomenon: a prospective study performed in 299 patients. J Neurosurg. 2005;103(5):812–24.
15. Sahuquillo J, Robles A, Poca A, Ballabriga A, Mercadal J, Secades JJ. A controlled, double-blind, randomized pilot clinical trial of nicardipine as compared with a placebo in patients with moderate or severe head injury. Rev Neurol. 2000;30:401–8.
16. Compton JS, Lee T, Jones NR, Waddell G, Teddy PJ. A double blind placebo controlled trial of the calcium entry blocking drug, nicardipine, in the treatment of vasospasm following severe head injury. Br J Neurosurg. 1990;4:9–15.
17. The European Study Group on Nimodipine in Severe Head Injury. A multicenter trial of the efficacy of nimodipine on outcome after severe head injury. J Neurosurg. 1994; 80(5):797–804.
18. Eberle BM, Schnuriger B, Inaba K, Gruen JP, Demetriades D, Belzberg H. Decompressive craniectomy: Surgical control of traumatic intracranial hypertension may improve outcome. Injury. 2010;41(9):894-8.
19.Su TM,Lan CM,Lee TH,Shih FY,Hsu SW,Lu CH. Posttraumatic Cerebral Infarction After Decompressive Craniectomy for Traumatic Brain Injury: Incidence, Risk Factors and Outcome; Turk Neurosurg. 2017; DOI: 10.5137/1019-5149.JTN.20761-17.1.
20.Tian HL, Geng Z, Cui YH, Hu J, Xu T, Cao H, et al. Risk factors for posttraumatic cerebral infarction in patients with moderate or severe head trauma. Neurosurg Rev. 2008; 31(4):431- 7.
21. Ham HY, Lee JK, Jang JW, Seo BR, Kim JH, Choi JW. Post- traumatic cerebral infarction: Outcome after decompressive hemicraniectomy for the treatment of traumatic brain injury. J Korean Neurosurg Soc. 2011: 50(4):370-6.
22. Honeybul S. Complications of decompressive craniectomy for head injury. J Clin Neurosci. 2010: 17(4):430-5.
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Vikas Chandra Jha, Neeraj Jha. Post-traumatic cerebral infarction (PTCI), an institutional experience. Ann Clin Anal Med 2021;12(2):144-149
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Decreased annexin a2 (anxa2) levels in children with atopic dermatitis: A case-control study
Himmet Haluk Akar 1, Yakup Çağ 2, Mehmet Yaşar Özkars 3, Mikdat Yıldız 4
1 Department of Pediatric Immunology and Allergy, University of Health Sciences, Kanuni Sultan Süleyman Training and Research Hospital, Istanbul, 2 Department of Pediatrics, University of Health Sciences Kartal Dr. Lütfi Kırdar Training and Research Hospital, Istanbul, 3 Department of Pediatric Immunology and Allergy, Kahramanmaraş Sütçü İmam University School of Medicine, Kahramanmaraş, 4 Department of Pediatrics, Batman Maternity and Child Health Hospital, Batman, Turkey
DOI: 10.4328/ACAM.20236 Received: 2020-06-09 Accepted: 2020-07-11 Published Online: 2020-07-19 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):172-175
Corresponding Author: Himmet Haluk Akar, İstanbul Health Sciences University, Kanuni Sultan Süleyman Training and Research Hospital, Department of Pediatric Immunology and Allergy, İstanbul, Turkey. E-mail: himmetakar@gmail.com GSM: +90 532 516 67 84 Corresponding Author ORCID ID: https://orcid.org/0000-0002-7266-5445
Aim: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in children. The pathogenesis of AD has not been clearly understood. The role of annexin A2 (ANXA2), which is an anti-inflammatory mediator, has not been investigated in the pediatric population with AD. The aim of this study is to investigate serum ANXA2 levels in children with AD. Material and Methods: Three groups were enrolled in this study; an SPT-Pos group (skin prick test positive 25 subjects with AD), an SPT-Neg group (skin prick test negative 25 subjects with AD), and a control group (27 healthy subjects). The serum ANXA2 levels were measured using enzyme-linked immunosorbent assay (ELISA). Results: We observed significantly lower serum ANXA2 levels in the disease group than in the control group [0.53 (range 0.14 – 4.38) pg/mL vs 0.94 (range 0.40 – 8.74) pg/mL, respectively; p = 0.01], especially in the SPT-Post group. However, there was no correlation among the parameters of ANXA2, IgE, eosinophil counts. Discussion: ANXA2 may have the role of an anti-inflammatory mediator in the pathogenesis of AD in children. The ANXA2-associated pathways may be con-sidered in the development of novel therapeutic approaches for the treatment of patients with AD.
Keywords: Annexin A2; Atopic Dermatitis; Children
Introduction
Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects 1-3 % of adults and 15-20 % of children worldwide. The incidence of AD has increased over the last decades worldwide [1-2]. The pathogenesis of AD has not been clearly understood. It has been accepted that complex interactions between environmental and genetic factors, such as epidermal barrier dysfunctions, cause chronic dermal inflammation [3]. Phospholipids are catalyzed by phospholipases A2 (PLA2) enzymes that are involved in many pathophysiological processes, such as inflammation and eicosanoid production. Also, the activity of phospholipase A2 was reported to be involved in inflammatory skin diseases such as atopic dermatitis and psoriasis [4]. Annexins (ANXs) are a family of calcium-dependent membrane-binding pro¬teins that perform several different functions, such as membrane trafficking, ion channel regulation, and anticoagulant activities, as well as an anti-inflammatory effect. Twelve ANXs have been identified in verte¬brates. They are mainly localized in the cytosolic milieu, they can also be found in the extracellular milieu which has anticoagulant and anti-inflammatory effects [5]. It has been demonstrated that some of ANXs (ANX-1, -2, and -5) have strong anti-inflammatory effects [6]. Also, it was demonstrated that some of ANXs (ANX-5 > ANX-2 > ANX-1) have inhibition of PLA2 activities in the dermo-epidermal area [7]. The aim of this study was to investigate serum ANXA2 levels in SPT-Pos, SPT-Neg, and control groups.
Material and Methods
This prospective study was performed in the Maternity and Children’s Hospital, Batman, Turkey. In this study, AD was diagnosed based on standard Hanifin and Rajka criteria [8]. A total of 72 children aged 3 months – 3 years were enrolled in the study. Fifty patients with AD were divided into either the SPT-Pos (25 subjects) or the SPT-Neg group (25 subjects). The control group comprised of 27 healthy children. Children with infectious diseases, such as upper or lower airway infections within the four weeks prior to the study, were excluded. At the presentation, the children underwent skin prick testing (SPT) on the upper back. The SPT kit (Allergopharma, Reinbek, Germany) tested 10 antigens including two aero-allergens (Dermatophagoides farinae, Dermatophagoides pteronyssinus, cow’s milk, egg white, egg yolk, soy, nut, peanut, wheat, and tuna), with positive and negative controls, histamine and serum physiologic, respectively. Reactions were considered to be positive if an induration >3 mm was observed, compared to the negative control. Total IgE levels were measured with a nephelometric method. Eosinophil counts were determined with Coulter counter leukocyte measurements. Serum ANXA2 levels were measured using ELISA kit (Wuhan USCN Business Company, SEB944HU, Hubei, China), according to the manufacturer’s instructions
Data were analyzed using SPSS version 22 software (IBM, USA). The Shapiro-Wilk test was carried out to determine the normality of data distribution and revealed abnormal data distributions for ANXA2 levels, total IgE, and eosinophil counts (P<0.05). Hence, median values and minimum-maximum ranges were determined and all groups were compared using the Kruskal-Wallis test. We also used a post-hoc Bonferroni modified Mann-Whitney U test for binary comparison. Correlation analysis was performed with Spearman’s correlation test. Results with p- values <0.05 were considered statistically significant.
This study was approved by the ethic comity of Batman District State Hospital in Batman, Turkey. Written informed consent was acquired from the parents of all participating children.
Results
Of 50 patients with AD, 25 (50 %) were SPT-Pos (aged 3-24 months with median age 8 months, 13 males, and 12 females), 25 were SPT-Neg (aged 3-24 months with median age 11 months, 11 males, and 14 fe¬males). Twenty-seven children were enrolled as a control group (aged 3-34 months with median age of 12 months, 14 males, and 13 females). The demographic characteristics of children participating in our study are shown in Table 1.
Serum median ANXA2 levels were significantly lower in the disease group than in the control group [0.53 (range 0.14 – 4.38) pg/mL vs 0.94 (range 0.40 – 8.74) pg/mL, respectively; p = 0.01]. Levels of ANXA2 were found to be lower in SPT-Pos patients than in SPT-Neg patients [0.45 (range 0.14 – 2.98) pg/mL vs 0.76 (range 0.31 – 4.38) pg/mL, respectively; p = 0.01]. In addition, ANAXA2 levels were found to be lower in SPT-Pos patients than in controls [0.45 (range 0.14 – 2.98) pg/mL vs 0.94 (range 0.40 – 8.74) pg/mL, respectively; p = 0.01]. Lastly, we compared ANXA2 levels between SPT-Neg patients and controls. No significant differences were found between two groups [0.76 (range 0.31 – 4.38) pg/mL vs 0.94 (range 0.40 – 8.74) pg/mL, respectively; p = 0.36] (Table 1 and Figure 1).
When median IgE levels were compared, there was a statistically significant increase in disease group (SPT-Pos patients + SPT-Neg patients) compared to control group [226.5 (range 50 – 1284) IU/mL vs 140 (range 3 – 450) IU/mL, respectively; p=0,002]. Median IgE levels were significantly higher in the SPT-Pos group compared to the control group. [ 210 (range 76 -1284) IU/mL vs 140 (range 3 – 450) IU/mL, respectively; p= 0.014]. Also, there was a statistically significant increase in the SPT-Neg group compared to the control group for median IgE levels [230 (range 50 – 710) IU/mL vs 140 (range 3 – 450) IU/mL, respectively; p = 0.006]. However, no difference was found between SPT-Pos patients and SPT-Neg patients in terms of IgE levels [210 (range 76 – 1284) IU/mL vs 230 (range 50 – 710) IU/mL, respectively; p = 0.985].
Median eosinophil counts were significantly higher in the disease group than in the controls [370 (range 50 -1640) /mL vs 180 (range 4 – 740) /mL, respectively; p = 0.001]. As expected, eosinophil count in the SPT-Pos group was higher than in the SPT-Neg group [420 (range 120 – 1640) vs 260 (range 50 – 710 /mL) /mL, respectively; p = 0.015]. Also, eosinophil counts were remarkably higher in the SPT-Pos group than in the control group [420 (range 120 – 1640) /mL vs 180 (range 4 – 740) /mL, respectively; p <0.001]. Conversely, no difference was found in eosinophil counts between the SPT-Neg group and the controls [260 (range 50 – 710) /mL vs 180 (range 4 – 740 /mL), respectively; p = 0.068].
In the disease group (SPT-Pos group + SPT-Neg group), no correlation was found between eosinophil counts and IgE levels (r=0,15, p=0,283), between IgE levels and ANXA2 levels (r= -0,070, p=0,630), and between eosinophil counts and AXA2 levels (r= -0,076, p=0,601).
Also, in SPT-Pos group and SPT-Neg group, no correlation was found among the parameters, between eosinophil counts and IgE levels (r=0,203, p=0,330 and r=0,168p=0,422), between IgE levels and ANXA2 levels (r= -0,047, p=0,825 and r= -0,157 p=0,454), and between eosinophil counts and ANXA2 levels (r= -0,045, p=0,830 and r=0,112 p=0,596), respectively.
Discussion
Atopic dermatitis, allergic rhinitis, and asthma are common allergic conditions with high morbidity. To our knowledge, no one has investigated a possible role of serum ANXA2 in the pathogenesis of AD in children. In our study, serum ANXA2 levels were significantly lower in AD patients than in controls, especially in the SPT-Pos group. Chronic inflammation is one of the most important characteristics of patients with AD. Like other family members of ANXs, ANXA2 is a pleiotropic protein and is involved in diverse cellular processes, such as cell motility, endocytosis, fibrinolysis, ion channel formation, and as well as cell anti-inflammatory effects [5,9]. In murine models, it was shown that the depletion of ANXA2 down-regulated the production of IL-10 which can cause pro-inflammatory responses. Namely, ANXA2 is required for the optimal production of IL-10 which is an important anti-inflammatory cytokine [9]. Also, ANXA2 reduces plasmin-stimulated IL-6 production and bacteria-induced pulmonary inflammation [9,10]. In a publication, an in vivo murine model was used to examine the potential role of ANXA2 in allergic airway inflammation. In this study, it was shown that ANXA2 gene deletion reduces allergen-induced airway inflammation [10]. In this study, serum ANXA2 levels were lower in AD patients than in controls, especially in the SPT-Pos group which suggests a potential role of ANXA2 in the pathogenesis of AD. To our knowledge, one publication has been reported the ANXA2 role in patients with AD in the medical literature. In that publication, in contrast to our findings, ANXA2 levels were higher in patients with AD than in the controls in the AD lesions [11]. These different findings indicate that future studies are needed on this interesting molecule (ANXA2) in allergic diseases.
In conclusion, the lower levels of ANXA2 may reflect poor responses to chronic inflammatory processes in patients with AD. As known, there is no curative therapy for chronic allergic inflammation in patients with AD. For this purpose, new therapeutic approaches are needed to treat allergic diseases. The ANXA2-associated pathways may be considered in the development of novel therapeutic approaches for the treatment of patients with AD.
Acknowledgment
All authors contributed to designing the study, collecting and analyzing the data, writing, and revising the manuscript.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: 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. Sehra S, Serezani APM, Ocaña JA, Travers JB, Kaplan MH. Mast Cells Regulate Epidermal Barrier Function and the Development of Allergic Skin Inflammation. J Invest Dermatol. 2016;136(7):1429-37.
2. Avena-Woods C. Overview of atopic dermatitis. Am J Manag Care. 2017;23(Suppl. 8):S115-23.
3. Gittler JK, Shemer A, Suárez-Fariñas M, Fuentes-Duculan J, Gulewicz KJ, Wang CQ, et al. Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol. 2012;130(6):1344-54.
4. Maury E, Julié S, Charvéron M, Gall Y, Chap H. Lipids and skin inflammation: role of phospholipases A2. Pathol Biol (Paris). 2003;51(5):248-52.
5. Lizarbe MA, Barrasa JI, Olmo N, Gavilanes F, Turnay J. Annexin-phospholipid interactions. Functionalimplications. Int J Mol Sci. 2013;14(2):2652-83.
6. Fang M, Huang JY, Wang J, Ling SC, Rudd JA, Hu ZY, et al. Anti-neuroinflammatory and neurotrophic effects of combined therapy with annexin II and Reg 2 on injured spinal cord. Neurosignals. 2011;19(1):16-43.
7. Bastian BC, Sellert C, Seekamp A, Römisch J, Pâques EP, Bröcker EB. Inhibition of humanskinphospholipase A2 by “lipocortins” is an indirect effect of substrate/lipocortin interaction.J Invest Dermatol. 1993;101:359-63.
8. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol Suppl (Stockh). 1980; 92: 44–7.
9. Zhang S, Yu M, Guo Q, Li R, Li G, Tan S, et al. Annexin A2 binds to endosomes and negatively regulates TLR4-triggered inflammatory responses via the TRAM-TRIF pathway. Sci Rep. 2015;5:15859. DOI: 10.1038/srep15859.
10. Schuliga M, Langenbach S, Xia YC, Qin C, Mok JS, Harris T, et al. Plasminogen stimulated inflammatory cytokine production by airway smooth muscle cells is regulated by annexin A2. Am J Respir Cell Mol Biol. 2013;49(5):751-8.
11. Yamane Y, Moriyama K, Yasuda C, Miyata S, Aihara M, Ikezawa Z, et al. New horny layer marker proteins for evaluating skin condition in atopic dermatitis. Int Arch Allergy Immunol. 2009;150(1):89-101.
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Himmet Haluk Akar, Yakup Çağ, Mehmet Yaşar Özkars, Mikdat Yıldız. Decreased annexin a2 (anxa2) levels in children with atopic dermatitis: A case-control study. Ann Clin Anal Med 2021;12(2):172-175
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The use of ultrasonography in traumatic muscle lesions: A practical first-line imaging tool
Hasanali Durmaz¹, Mehmet Ercüment Döğen², Ümit Yaşar Ayaz², Erdem Birgi¹
¹Department of Radiology,University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, ²Department of Radiology, Mersin City Training and Research Hospital, Mersin, Turkey
DOI: 10.4328/ACAM.20239 Received: 2020-06-08 Accepted: 2020-07-11 Published Online: 2020-07-19 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):176-180
Corresponding Author: Hasanali Durmaz, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Department of Radiology, Ankara, Turkey. E-mail: dr.hasan.ali.durmaz@hotmail.com GSM: +90 538 279 79 07 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3230-9240
Aim: In this study, we aimed to evaluate traumatic muscle lesions and trauma-related gross intramuscular hemorrhages using ultrasonography (US). Material and Methods: This retrospective study included 32 cases (23 males, 9 females) with a history of muscle trauma that underwent US. The mean age was 24.3 years. Static and dynamic US and color Doppler US were performed in axial and longitudinal planes. Patients were divided into two groups as penetrating and non-penetrating (blunt) muscle trauma. The absence of intramuscular hematoma/fluid and muscle fibers was accepted as the criteria of muscle rupture in both trauma types. Non-penetrating traumas were also divided into intrinsic and extrinsic. Intrinsic muscle injuries were graded as mild, moderate, and severe.Results: Among the cases, 78.1% (n=25/32) developed as a result of non-penetrating trauma and 21.9% (n=7/32) cases as a result of penetrating trauma. Approximately 2/3 (64%) of non-penetrating muscle traumas (n=25/32) were intrinsic and 1/3 (36%) were extrinsic. In all cases, including unilateral muscle lesions such as collection/mass appearances compatible with hemorrhage-hematoma of various sizes and ages were demonstrated in gluteus maximus (25%), quadriceps femoris (18.7%), sternocleidomastoid (18.7%), rectus abdominis (15.6%), hamstring (9.4%), biceps brachii (6.3%) and gastrocnemius (6.3%). No vascularization in hemorrhage-hematoma was detected with Doppler US in any patient. Discontinuity in traumatized muscle fibers was present in all cases. Intrinsic muscle injury was classified as mild-grade 1 (12.5%), moderate-grade 2 (75%), and severe-grade 3 (12.5%) under ultrasonography.Discussion: Ultrasonography is a practical and effective imaging method in the diagnosis of traumatic muscle lesions.
Keywords: Ultrasonography; Muscles; Injuries
Introduction
The majority of radiologically detectable muscle pathologies are of traumatic origin. Ultrasonography (US) is a practical radiology method which enables rapid diagnosis of muscle traumas causing anatomical changes (muscle rupture, etc.) or resulting in collection (hematoma, etc.), does not contain ionizing radiation, is relatively inexpensive and portable when required, has a high anatomical resolution and also offers the opportunity for dynamic examination [1−4]. Connell et al. [5] reported that US was as useful as magnetic resonance imaging (MRI) in revealing acute hamstring injuries. However, in order to estimate the limits of US, it should be noted that US cannot show microscopic lesions such as micro-ruptures, which can cause muscle pain, and it has technical limitations. In this study, we aimed to evaluate traumatic muscle lesions developing in various forms and gross intramuscular hematomas due to trauma at different ages by using US.
Material and Methods
Thirty-two (23 males, 9 females) of 41 cases who were admitted with a history of various forms of muscle trauma and underwent US imaging between the years of 2001-2002 and 2011-2018, were included in this retrospective study. The mean age of the included patients was 24.3 years (range, 20 days−72 years). Nine cases were excluded from the study due to incomplete clinical data. The cases underwent static and dynamic gray-scale US in the axial and longitudinal planes with 7.5−8.0 MHz linear and 3.5−3.7 MHz convex probes and color Doppler US (CDUS) to evaluate vascularization. US examinations were performed in comparison with the contralateral side without any pathology. The mean time from trauma to US examination was 5.8 days (range, 5 hours−100 days). The cases were divided into two main groups as penetrating and non-penetrating/blunt muscle trauma in terms of causes of occurrence. Intramuscular hematoma/fluid and discontinuous muscle fibers were accepted as the criteria for muscle rupture in both types of trauma [6]. Non-penetrating traumas were also divided into two subgroups as intrinsic (caused by indirect muscle contraction by itself without any external impact) and extrinsic (caused by an external blunt impact) according to the mechanism of occurrence [7]. Intrinsic muscle traumas (ruptures, injuries) were graded as mild, moderate and severe based on the US appearances of the muscle in the axial plane. While there should be signs of injury (increased echogenicity, cavities less than 10 mm) in less than 5% of the muscle in mild muscle injury (grade 1, first-degree injury, elongation injury), it was examined whether there were partial ruptures involving more than 5% of the muscle but not 100% in moderate muscle injury (grade 2, second-degree injury, partial rupture). The muscle was completely ruptured from the myotendinous junction in severe muscle injury (grade 3, third-degree injury, complete rupture) [6]. Due to trauma, 13 cases were additionally evaluated using direct radiography, 15 with computed tomography (CT), and 18 with elective MRI after US. There was a history of hemophilia A disease in one case, hemophilia B disease in one case, and antiaggregant drug use in three cases as predisposing factors. The study was conducted in accordance with the ethical standards and the principles of the WHO Helsinki Declaration, after obtaining informed consent from the patients or their relatives.
Results
The cases developed as a result of non-penetrating trauma accounted for 78.1% (n = 25/32), while 21.9% (n = 7/32) of the cases developed as a result of penetrating trauma. Among muscle injuries (n = 25/32) as a result of non-penetrating trauma, approximately 2/3 (n = 16/25, 64%) were of intrinsic (indirect) type, while approximately 1/3 (n = 9/25, 36%) were of extrinsic (direct) type. Collection/mass appearances, unilateral in all cases, compatible with hemorrhage-hematoma, in various sizes and ages, with the largest one measuring 30 x 7 x 5 cm and the smallest one measuring 3.0 x 1.5 x 1.3 cm, were observed in the gluteus maximus muscle (Figure 1) in 25% (n = 8/32), quadriceps femoris muscle (Figure 2) in 18.7% (n = 6/32), sternocleidomastoid muscle in 18.7% (n = 6/32), rectus abdominis muscle (Figure 3) in 15.6% (n = 5/32), hamstring muscle in 9.4% (n = 3/32), biceps brachii muscle in 6.3% (n = 2/32) and gastrocnemius muscle in 6.3% (n = 2/32) of the cases. CDUS revealed no vascularized hemorrhage-hematoma in any of the cases, but increased vascularization compatible with inflammation was observed in vital tissues adjacent to the hemorrhage-hematoma. Discontinuity was observed in traumatized muscle fibers in all cases (n = 32/32, 100%). Ultrasonographically, 12.5% (n = 2/16) of intrinsic muscle injuries were graded as mild (first-degree), 75% (n = 12/16) as moderate (second-degree), and 12.5% (n = 2 /16) as severe (third-degree).
Discussion
Traumatic muscle lesions can develop in various forms. Depending on the type of trauma, penetrating and non-penetrating muscle injuries may occur. As a result, muscle rupture and intramuscular hematoma may be observed, and myositis ossificans, myositis, abscess and complications such as compartment syndrome, rhabdomyolysis and muscle hernia may develop in the post-traumatic period [4]. In our study, the lesions occurred as a result of non-penetrating trauma in the majority of cases (78.1%), and US could successfully show the lesions in both types of trauma.
Non-penetrating muscle rupture can develop by compression (extrinsically by direct trauma) or by distraction (intrinsically by indirect trauma) [7]. Compression-related muscle ruptures are common in contact sports and traffic accidents. In these cases, the muscle is compressed and crushed against the underlying bone by external factors. Therefore, muscle rupture and hematoma develop [4]. Prominent muscle ruptures developed due to compression are observed as irregular, subtle and low-echo cavities on US. The echogenicity of hematoma is generally high in the acute period, and the collection echo begins to decrease after approximately 2−3 days, and its margins can be understood more clearly [4,7]. In our study, 36% of non-penetrating muscle injuries occurred extrinsically due to compressive trauma and both acute and chronic lesions could be effectively demonstrated on US in accordance with the literature. In follow-up US examinations, the lesion begins to be filled with echogenic tissue from the periphery during the recovery period. Scar tissue is hyperechogenic, and an acoustic shadow can be observed if myositis ossificans develops. Myositis ossificans develops in nearly 20% of severe compressive ruptures [8]. Since our study was retrospectively designed, and follow-up US examinations of our cases could not be performed, the developmental process of scar tissue could not be monitored.
Unlike compressive ruptures, intrinsic muscle ruptures due to indirect trauma by distraction occur as a result of sudden and strong contractions or passive extension caused by the muscle itself. These ruptures are most frequently observed in the lower extremities, especially in the muscles crossing the joint. The most affected muscles are the hamstring muscles, rectus femoris muscles and medial gastrocnemius muscles [9-11]. The ruptured muscle is filled with blood in the acute period. Although there is no available classification for compressive ruptures, 3 main groups have been identified in this type of intrinsic, distractive ruptures based on sonographic findings as follows: elongation injury (first-degree, mild), partial rupture (second-degree, moderate) and complete rupture (third-degree, severe) [6]. On US, the muscle may appear mildly hyperechogenic due to edema. Even small hyperechogenic areas may be observed due to extravasated blood [12]. US reveals discontinuity in the muscle fibers and a hypoechoic gap in the muscle mass in cases of partial and complete muscle ruptures among indirect muscle ruptures that lead to more serious clinical consequences, and this gap is filled with hematoma. The free ends of the ruptured muscle fragments can be observed in the fluid [4]. In our study, these findings were successfully demonstrated in partial and complete muscle ruptures. US findings could be demonstrated less prominently and in a smaller area of the affected muscle in two cases diagnosed with a mild (first-degree) muscle injury. US examination should be performed in different planes in order to evaluate the amount of muscle remaining intact. If more than 2/3 of the muscle is ruptured, it may be indicative of surgical repair. It is also necessary to obtain images in the transverse plane for the determination of this condition [8,12].
Hematoma formation is the most prominent feature of muscle rupture. The size of hematoma usually indicates the extent of the underlying damage. However, intramuscular hematoma may be disproportionately large with the damage in patients with hemophilia or those receiving anticoagulant therapy [8]. In our study, one case with hemophilia B developed an acute hematoma of giant size in the rectus abdominis muscle due to second-degree (partial) muscle rupture only after severe cough (Figure 4). In another case with oral anticoagulant use and the anamnesis of vigorous efforts, a fluid collection (chronic hematoma) of 6 x 2.5 cm was observed in the biceps brachii muscle due to second-degree (partial) muscle rupture (Figure 5). Patients receiving anticoagulants may have spontaneous hemorrhages. However, soft tissue sarcomas, especially malignant fibrous histiocytoma, may emerge with acute intratumoral hemorrhage. A biopsy may, therefore, be required for an elderly person with a thigh hematoma not resorbing in the normal period [8].
Foreign bodies such as metal, glass, and wood can enter the muscle in penetrating muscle trauma. Thus, direct radiographs should be obtained first, and then reverberation, comet-tail artifacts, or posterior acoustic shadows should be sought by US. Although foreign bodies are generally hyperechogenic, a hypoechoic halo can be observed around the foreign body due to granulomatous reaction in chronic cases [13,14]. In addition to US, direct radiographs were obtained for trauma regions in all of the penetrating traumas, and CT examination was performed in some of them in order to investigate the presence of any foreign body in the wound in our study. No foreign body was revealed on US, direct radiography and CT. Muscle traumas should also be investigated for possible vascular damage, thrombosis, arteriovenous fistula, and pseudoaneurysm by CDUS [12]. In our study, CDUS was performed in all cases, and vascular lesions could be excluded in this way.
At the infraumbilical level, below the arcuate line, the rectus abdominis muscle lacks a posterior sheath. Peritoneal irritation may develop, and an acute abdomen may occur in some rectus abdominis hematomas. Therefore, it is necessary to make a definitive diagnosis. Ultrasonography can be useful to make a practical diagnosis in such cases. Berna et al. [15] reported that 11 of 13 hematoma cases were diagnosed by US, and the correct diagnosis was achieved in all 13 cases by CT in a series of 13 cases with rectus sheath hematoma. Moreno Gallego et al. [16] stated that when abdominal rectus sheath hematoma was correctly diagnosed, unnecessary surgical procedures would be decreased in most cases, and US was useful in diagnosis, but CT provided more accurate results compared to US. Berna et al. [17] performed US and CT examinations in all cases, and they were able to make a definitive diagnoses of hematoma in 9 cases using US and all cases using CT, in a series of 12 cases with abdominal rectus sheath hematoma and receiving anticoagulant therapy. In our study, all rectus abdominis ruptures and associated hematomas (n = 5/32) were diagnosed by US, and the effectiveness of US was confirmed by CT performed to investigate the presence of additional pathologies in all cases.
Dynamic imaging of the affected muscle by contracting during US can provide functional information [18]. In our study, it was possible to show and identify lesions in all cases thanks to a good evaluation of clinical data and obtaining good anamneses as well as proper US examination with dynamic imaging (co-use of linear-convex probes when needed, comparative examination of the lesioned muscle with the contralateral intact muscle and examination in different planes).
The most important limitation of our retrospective study is the limited number of cases undergoing US imaging and muscle types examined. Sending such cases to MRI instead of US due to some factors, such as the fact that MRI technology allows to complete the examination in a shorter period of time, and the number of these devices increases day by day, is among the most obvious reasons for this limitation. Another reason is thought to be sending cases with general body trauma directly to CT instead of US. A much larger number of patients could have enabled us to evaluate hemorrhage and rupture in different muscle groups and at different ages by US. The fact that we could not perform long-term follow-ups of muscle lesions with serial examinations can be considered as another limitation.
Conclusion
In conclusion, in case of proper evaluation of clinical data and anamnesis, US is a non-invasive, real-time, effective imaging method, which enables rapid and practical diagnosis of traumatic muscle lesions and accompanying gross intramuscular hematomas and the detection of the size and extent of the lesions, which does not contain ionizing radiation, and which provides multiplanar and dynamic imaging.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Lee B, Stubbs E. Sartorius muscle tear presenting as acute meralgia paresthetica. Clin Imaging. 2018; 51:209–12.
2. Chang KV, Wu WT, Özçakar L. Ultrasound imaging and rehabilitation of muscle disorders Part 1. Traumatic injuries. Am J Phys Med Rehabil. 2019;98(12): 1133-41. DOI: 10.1097/PHM.0000000000001307.
3. Loizides A, Gruber H, Peer S, Plaikner M. Muscular injuries of athletes: importance of ultrasound. Radiologe 2017; 57(12):1019–28.
4. Lee JC, Mitchell AW, Healy JC. Imaging of muscle injury in the elite athlete. Br J Radiol. 2012; 85(1016):1173–85.
5. Connell DA, Schneider-Kolsky ME, Hoving JL, Malara F, Buchbinder R, Koulouris G, et al. Longitudinal study comparing sonographic and MRI assessments if healing hamstring injuries. AJR Am J Roentgenol. 2004; 183(4):975–84.
6. Peetrons P. Ultrasound of muscles. Eur Radiol. 2002; 12(1):35–43.
7. Draghi F, Zacchino M, Canepari M, Nucci P, Alessandrino F. Muscle injuries: ultrasound evaluation in the acute phase. J Ultrasound. 2013; 16(4):209–14.
8. Holsbeeck MT, Introcaso JH. Musculoskeletal ultrasound. 2nd ed. St.Louis: Mosby; 2001. p.29-66.
9. Junge A, Engebretsen L, Mountjoy ML, Alonso JM, Renström PA, Aubry MJ, et al. Sports injuries during the Summer Olympic Games 2008. Am J Sports Med. 2009; 37(11):2165–72.
10. Walden M, Hagglund M, Ekstrand J. UEFA Champions League Study: a prospective study of injuries in professional football during the 2001–2002 season. Br J Sports Med. 2005; 39(8):542–6.
11. De Smet AA, Best TM. MR imaging of the distribution and location of acute hamstring injuries in athletes. AJR Am J Roentgenol. 2000; 174(2):393–9.
12. Balconi G, Monetti G, De Pra L. Muscles. In: Solbiati L, Rizzatto G, editors. Ultrasound of superficial structures. 1st ed. Edinburgh: Churchill Livingstone; 1995.p. 321−7.
13. Kalita A, Lynser D, Handique A, Daniala C. Diagnostic and therapeutic role of ultrasound in soft tissue foreign bodies and associated complications: a pictorial essay. Chin J Acad Radiol. 2019; 1(1):49–53.
14. Hiremath R, Reddy H, Ibrahim J, Haritha CH, Shah RS. Soft tissue foreign body: utility of high resolution ultrasonography. J Clin Diagn Res. 2017; 11(7):14−6.
15. Berna JD, Garcia-Medina V, Guinao J, Garcia-Medina J. Rectus sheath hematoma:
diagnostic classification by CT. Abdom Imaging. 1996; 21:62−4.
16. Moreno Gallego AM, Aguayo JL, Flores B, Hernández Q, Ortiz S, González-Costea R, et al. Ultrasonography and computed tomography reduce unnecessary surgery in abdominal rectus sheath haematoma. Br J Surg. 1997; 84(9):1295−7.
17. Berna JD, Zuazu I, Madrigal M, Garcia-Medina V, Fernandez C, Guirado F. Conservative treatment of large rectus sheath hematoma in patients undergoing anticoagulant theraph. Abdom Imaging. 2000; 25(3):230−4.
18. Lin J, Fessell DP, Jacobson JA, Weadock WY, Hayes CW. An illustrated tutorial of musculoskeletal sonography: part 1, introduction and general principles. AJR. 2000; 175(3):637−45.
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Hasanali Durmaz, Mehmet Ercüment Döğen, Ümit Yaşar Ayaz, Erdem Birgi. The use of ultrasonography in traumatic muscle lesions: A practical first-line imaging tool. Ann Clin Anal Med 2021;12(2):176-180
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The effect of a home exercise program prescribed by physiotherapists for pain relief
Muhammed Arca 1, Elif Dilara Durmaz 1, Omer Satıcı 2, Ayse Ferdane Oguzoncul 3
1 Physical therapy and rehabilitation, Saglik Bilimleri University, Diyarbakir Gazi Yasargil Training and Research Hospital, Diyarbakır, 2 Department of Biostatistics, Dicle University, Medical Faculty, Diyarbakır, 3 Department of Public Health, Firat University, Medical Faculty, Elazig, Turkey
DOI: 10.4328/ACAM.20232 Received: 2020-06-04 Accepted: 2020-07-12 Published Online: 2020-07-19 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):167-171
Corresponding Author: Ayse Ferdane Oguzoncul, Department of Public Health, Firat University, Medical Faculty, Elazig, Turkey. E-mail: aferdane@gmail.com GSM: +90 5324839830 P: 0090424 2370000-4685 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9820-9720
Aim: The aim of this study was to evaluate the effect of the home exercise program on the pain of physiotherapy and rehabilitation outpatients.Material and Method: The study included 316 patients with low back, neck, shoulder, and knee pain aged 18-65 years. A personal information form was filled out to obtain demographic information about these patients. After exercise training given by the physiotherapists, the pain of the patients was evaluated by a visual analog scale (VAS). After 4 weeks, the patients were called by telephone and questioned whether they were doing the exercises and their pain severity.Results: Among patients, 54,4% (172) were female; 72,8% of the patients with a mean age of 39.85±13.77 years were married, 40,8% were primary school graduates and 37,3% were housewives. One hundred three patients applied (32,6%) with neck pain, 132 (41,8%) with low back pain, 29 (9,2%) with shoulder pain and 52 (16,5%) with knee pain. It was observed that 55.4% (175) of the patients who were prescribed training did not perform their exercises. Among patients who exercised, 69,6% did not use analgesics in this process. A statistically significant result was found when the before and after exercise VAS data of participants who did exercise and those who did not were compared (p=0.001).Discussion: In the study by Kılıç, more than half of the patients who exercised benefited from the exercises they performed and stated that the exercise de-creased problems such as pain, locking, fatigue, and limitation of movement due to disease. It was determined that the patients who completed the exercise program had less pain. Regular exercise programs will lead to positive outcomes.
Keywords: Pain; Low back; Neck; Exercise
Introduction
Musculoskeletal system diseases (MSD) are an important health problem that negatively affects the quality of life and constitutes a serious burden on health expenditures [1]. It is defined as an important public health problem because it is affected by socioeconomic, demographic, and psychosocial factors [2].
The incidence of musculoskeletal problems in the world is reported to be 9,1% in the low back region, 4,8% in the neck region, 3,6% in the knee region, and 8,1% in other regions [3]. According to 2016 data, the rate in Turkey is reported to be higher than the rate in the world. It was found that low back problems accounted for 27,1% and neck problemsmade up 18,1% [Türkiye Sağlık Araştırması (Turkey Health Survey), 2016]. Patients, families, and society try many ways to get rid of the pain. Pharmacological methods are often used to control pain in patients. Analgesic treatment in pain control is the most preferred treatment method because it can be applied easily and affects quickly. However, the unconscious and intense use of analgesics is detrimental to the individual and national economies and has a negative effect on some physiological functions [4].
Active exercise-based treatment approaches are known to be effective in pain relief and functional recovery [5]. Nowadays, dynamic programs that require the active participation of the patient, which are aimed at improving the body flexibility, muscle strength, and functional capacity to reduce pain are recommended. These programs are called home exercise programs and are provided to support appropriate patient groups [6]. The aim of this study was to evaluate the effectiveness of exercise training prescribed to patients with musculoskeletal problems who were sent to the physiotherapy rooms for physical therapy and rehabilitation in an outpatient clinic.
Material and Methods
This study was conducted as an uncontrolled experimental study. This study was carried out in accordance with the rules set out in the Declaration of Helsinki (23.06.2017) after obtaining approval and chief physician approval from Dicle University Clinical Research Ethics Committee (23.06.2017, 131). The study was carried out the Training and Research Hospital Physiotherapy and Rehabilitation Unit between July 1 and September 29, 2017.
Three hundred fifty musculoskeletal patients with neck, low back, shoulder and knee pain were informed about the study. Three hundred sixteen patients who accepted the study were enrolled in exercise training after signing informed consent form. Patients with pain in low back, neck, and knee, who had no problem of perception and response, between the ages of 18-65, who were referred to the physiotherapy clinic for exercise training were included in the study. People who did not want to participate voluntarily and who had cancer pain, neuropathic pain and diagnosed rheumatic disease were excluded from the study.
All patients who came to the physiotherapy room for 3 months were interviewed and the patients who accepted to participate in the study completed their personal information form for their demographic information and a 4-week exercise program was given. At the end of 4 weeks, the patients were called by telephone and questioned about their pain and whether they had exercised.
After exercise training, the visuel analog scale (VAS), which is the most commonly used method for evaluating the effects of the exercises on pain severity, was used. The VAS used to assess pain is a scale of 0-10. A value of 0 corresponds to no pain and a value of 10 corresponds to very severe pain. The patient gives a value indicating the severity of pain.
Exercise programs consist of stretching, mobility, strengthening, and flexibility exercises for low back, neck, shoulder, and knee. A maximum of 5 exercises was given to each patient. The exercises are described as 10 actions 3 times a day for the first 15 days and 20 actions for the next 15 days. A leaflet with pictures of all the exercises was given, and the patients were called by phone after 4 weeks and their evaluations were made.
Types of exercise
Neck Exercises: It consists of active normal joint movements performed with neck flexion, right/left rotation, extension, right/left lateral flexion, and shoulder circulation [7].
Waist Exercises: McKenzie Extension Exercises (trunk extension, flexion and lateral displacements) and combined exercises consisting of Williams Flexion Exercises (trunk flexion, posterior pelvic tilt, lumbar extensor stretching) have been used [8].
Shoulder Exercises: Codman Pendulum Exercises (shaking movements by loosening the arm with its own weight) and Wand Exercises (front, side, out, back and inward movements with the help of a lath between hands) [9].
Knee Exercises: It consists of active normal joint movements performed with hip and knee flexion, straight leg lifting, terminal extension and squatting exercises [10].
SPSS 21.0 packaged software was used on the computer for coding and statistical analysis of the data. The Chi-square and T-tests as significance test and minimum, maximum, mean, standard deviation, percentage values were used for the data analysis. Then we used the GLM / Multivariate method for further analysis. The significance level was accepted as p<0.05.
Results
Among patients, 45,6% were male (n=144), 72,8% were married, 40,8% were primary school graduates and 37,3% were housewives (Table 1). The mean age of the patients was 39.85±13.77 (min = 17, max = 65) years.
Primary body regions in pain were low back (n=132) 41,8%, neck (n=103) 32,6%, knee (n=52) 16,5% and shoulder (n=29) 9,2%; 25,6% (n=81) of the patients had pain starting 2-6 months ago; 77,8% of them did not receive physical therapy or did not exercise at all. It was determined that 69,6% of the participants did not use any analgesics in this process and 50,6% of the participants had continuous pain (Table 2).
It was found that 55,4% (n=175) of the patients did not perform the prescribed home exercise program. According to gender analysis of exercise, it was seen that there were statistically more men who train than women (Table 3, p<0.001). No significant relationship was found between exercise and age, marital status, education and occupation groups. Paticipants who did exercise constituted 42.6% of married ones and 50.9% of high school graduates.
A statistically significant result was found when the before and after exercise VAS data of participants who did exercise and those who did not were compared (Table 4, p=0.001).
Discussion
Pain negatively affects the lives of millions of people around the world and ranks first in the use of medical, financial, and social resources [11]. In this study, 316 patients with a mean age of 39,8 years applied for exercise therapy with pain in different body regions. In the study conducted by Iaroshevskyi et al. on 87 people with an average age of 39 years, the prevalence of pain in different body regions was found to be 40% [12]. In our study, 54,4% of the patients were women. This may be due to the greater incidence of musculoskeletal diseases in women due to gender-related biological factors, pain sensitivity, or psychological factors.
It has been reported that social support factors such as family existence and marital status provide better adaptation to pain [13]. Although 72,8% of the respondents were married, married participants were in the group with the lowest rate in the evaluation of the people who exercised.
Education, socio-economic status, and unemployment determine the duration and recurrence of MSD pain [14]. In the study carried out by Khosravi et al, it was found that those who are illiterate are 19.4% and those with high school or above are 64.8% [15]. In this study, when the relationship of the participants who did exercises with the education level was examined, it was found that non-literate people constituted the group with the lowest rate (34,3%) and high school graduates constituted the group with the highest rate (50,9%). As the level of education increased, the awareness of exercise increased.
Moya et al. reported that low back pain, which is one of the primary MSD, has a negative effect on many daily life activities, from standing to walking, weight-lifting, travel, social and working life, clothing, and sexual relations [16]. In this study, 60,5% of the exercisers were found to be civil servants as highest. The rates of retirees (18,2%), housewives (37,3%), and those who did not work were low. In the study by Kılıç et al., it was determined that the active workers (69,4%) were more likely to exercise than those who were not active (52.2%) [17]. These long-term problems turn into a chronic picture and create a burden on patients, employers, and the health system. This burden brings along economic losses [18].
In our physical therapy unit, the most frequently treated body regions were low back, neck, knee, and shoulder, respectively. This has been found to be compatible with the detection of the frequency and distribution of MSD pain in the community and to identify these four regions as the most common regions of pain [19]. According to the results of the study conducted by Quintana et al., the most pain areas defined by the participants were waist, knee and hand regions, respectively [20]. Similarly, a study in the UK showed that the most severe pain to withstand was in the low back (25%), neck (18%), knee (17%), and shoulder regions (17%) [21].
In this study, 22,2% of the participants had previously received physical therapy or did exercises for their disease.
The results showed that 30.4% of people with pain used medication for pain. In a study investigating the prevalence of pain, it was reported that 96.7% of the 91 patients with pain used pain medication and 67.8% used analgesics daily. The prevalence of analgesic use was found to be in the range of 27-44% among the pain relief methods in the elderly. These findings indicate that the use of medication is important for relieving pain [22].
It is important to maintain continuity of exercise therapy in the control of painful diseases related to the musculoskeletal system [23]. It was determined that 44.6% of the participants did their exercises regularly and 55.4% did not. In the study by Suyabatmaz et al., the rate of patients with exercise habits was found to be 10.8% [24]. The increasingly popular vision is to support individuals to become active participants in the management of their diseases and to create opportunities. It is stated that it is possible to be take the disease under control through patient education and exercise programs [25].
A statistically significant result was found when the before and after exercise VAS data of participants who did exercise and those who did not were comparedid. In the study by Kilic, more than half of the patients who exercised benefited from the exercises they performed and stated that the exercise decreased the problems such as pain, locking, fatigue, and limitation of movement due to disease [17]. Baczyk and colleagues found that planned home exercises had reduced complaints regarding increased pain, stiffness, falls, and so on [26].
It is suggested that the variables related to the communication and interaction of physiotherapists with their patients are important for determining compliance with home exercises. In the studies by Elnaggar et al., patients with mechanical low back pain applied an exercise program at home with their physiotherapist supervision for 2 weeks. After the program, all scores of the McGill Pain Questionnaire decreased [27].
Conclusion
It was found that the community did not show sufficient sensitivity to exercise regularly. The patients who had low back, neck, knee, and shoulder pain had decreased pain, stress, and concentrated more in daily life when they performed the exercises.
In today’s health policies, preventive health services are seen as the most baseline method and for this purpose, exercise is given priority. It will be useful to include a wider range of training practices on issues that increase the sensitivity of the society to exercise by using professional health personnel and mass media.
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. Briggs AM, Cross MJ, Hoy DG, Sanchez-Riera L, Blyth FM, Woolf AD, et al. Musculoskeletal health conditions represent a global threat to healthy aging: a report for the 2015 World Health Organization world report on ageing and health. Gerontologist. 2016;56(Suppl. 2):S243-55.
2. McGuigan FE, Patrik B, Kristina EÅ. Musculoskeletal health and frailty. Best PractRes Clin Rheumatol. 2017;31(2):145-59.
3. Lope HB, Alberto JCM. Musculoskeletal disorders. In: Detels R, Tan CC, editors. Oxford textbook of global public health. 6th ed. United Kingdom: Oxford University Press; 2015.p.1046-51.
4. Schug SA, Palmer GM, Scott DA, Halliwell R, Trinca J. Acute pain management: scientific evidence, 2015. MedJAust. 2016;204(8):315-17.
5. Hayden JA, Van Tulder MW, Malmivaara AV, Koes BW. Meta-analysis exercise therapy for nonspecific low-back pain. Ann Intern Med. 2005;142(9): 776-85.
6. Frih ZBS, Fendri Y, Jellad A, Baudoukhane S, Rejeb N. Efficacy and treatment compliance of a home-based rehabilitation program for chronic low-back pain. A Randomized, Controlled Study. Ann Phys RehabilMed. 2009;52(6):485-96.
7. Gross AR, Paquin JP, Dupont G, Blanchette S, Lalonde P, Cristie T, et al. Exercises for mechanical neck disorders: A Cochrane review update. Man Ther. 2016;24:25-45.
8. Moldovan M. Therapeutic Considerations and Recovery in Low Back Pain: Williams vs McKenzie. Timisoara Physical Education and Rehabilitation Journal. 2012;5.9:58.
9. Srivastava N, Joshi S. Comparison between the Effectiveness of Mobilization with Movement and End Range Mobilization along with Conventional Therapy for Management of Frozen Shoulder. Indian J Physiother OccupTher. 2017;11(4). DOI: 10.5958/0973-5674.2017.00141.1.
10. Carvalho NAdA, Bittar ST, Pinto FRDS, Ferreira M, Sitta RR. Manual for guided home exercises for osteoarthritis of the knee. Clinics. 2010;65(8):775-80.
11. Niv D, Kreeitler S. Pain and Quality of Life. Pain Practice. 2001; (2): 150 – 61.
12. Iaroshevskyi OA, Morozova OG, Logvinenko AV, Lypynska YV. Non-pharmacological treatment of chronic neck-shoulder myofascial pain in patients with forward head posture. Wiad Lek. 2019;72(1):84-8.
13. Simmonds MJ, Kumar S, Lechelt E. Psychosocial factors in disabling low back pain: causes or consequences? Disability and Rehabilitation.1994;18(4):161–8.
14. McBeth J, Jones K. Epidemiology of chronic musculoskeletal pain. Best Pract Res Clin Rheumatol. 2007;403-25.
15. Khosravi F, Amiri Z, Akhavan Masouleh N, Kashfi P, Panjizadeh F, Hajilo Z, et al. Shoulder pain prevalence and risk factors in middle-aged women: A cross-sectional study. J Bodyw Mov Ther. 2019;23(4):752-7.
16. Moya F, Grau M, Riesho N, Nunez M, Brancos MA, Valdes M. Chonic low back pain: multispecialty assessment of 100 patients. Aten Primaria. 2000;26:239-44.
17. Kiliç A, Doğan A, Doğan N. Osteoartritli Hastaların Evde Egzersiz Yapma ve Yarar Görme Durumları (Exercise at Home and Its Benefit of Patients with Osteoarthritis). Turkish Journal of Physical Medicine Rehabilitation. 2012;58:4.
18. Ferguson SA, Marras WS, Gupta P. Longitudinal quantitative measures of the natural course of low back pain recovery. Spine. 2000;25(15):1950–6.
19. Woo J, Leung J, Lau E. Prevalence and correlates of musculoskeletal pain in Chinese elderly and the impact on 4-year physical function and quality of life. Public Health. 2009;123(8):549-56.
20. Quintana R, Silvestre AMR, Goñi M, García V, Mathern N, Jorfen M, et al. Prevalence of musculoskeletal disorders and rheumatic diseases in the indigenous Qom population of Rosario, Argentina. Clin Rheumatol; 2016;35(Suppl. 1):S5-14.
21. Parsons S, Breen A, Foster NE, Letley L, Pincus T, Vogel S, et al. Prevalence and comparative troublesomeness by age of musculoskeletal pain in different body locations. Fam Pract. 2007;24(4):308-16.
22. Muula AS, Misiri HE Pain management among medical inpatients in Blantyre, Malawi. Int Arch Med. 2009;2(1):6.
23. Van Gool CH, Penninx BW, Kempen GI, Rejeski WJ, Miller GD, Eijk JTM, et al. Effects of exercise adherence on physical function among overweight older adults with knee osteoarthritis. Arthritis Rheum. 2005;53(1): 24–32.
24. Suyabatmaz Ö, Çağlar NS, Tütün Ş, Özgönenel L, Burnaz Ö, Aytekin E. Assessment of the Effect of Back School Therapy in Patients with Low Back Pain. İstanbul Med J. 2011; 12(1):5-10.
25. Jordan JI, Holden MA, Mason EEJ, Foster NE. Interventions to improve adherence to exercise for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev. 2010;(1). DOI: 10.1002/14651858.
26. Baczyk G, Samborski P, Pieścikowska J, Kmieciak M, Walkowiak I. Comparison functioning and quality of life of patients with osteoarthritis and rheumatoidarthritis. Advances in Medical Sciences. 2007;52(1):55-9.
27. Elnaggar IM, Nordin M, Sheikzadeh M, et al. Effects of spinal flexion and extension exercises on low back pain and spinal mobility in chronic mechanical low back pain patients. Spine. 1991;16(8):967–72.
Download attachments: 10.4328ACAM.20232.pdf
Muhammed Arca, Elif Dilara Durmaz, Omer Satıcı, Ayse Ferdane Oguzoncul. The effect of a home exercise program prescribed by physiotherapists for pain relief. Ann Clin Anal Med 2021;12(2):167-171
Citations in Google Scholar: Google Scholar
Retrospective analysis of smoking cessation campaign in aviation personnel
Erdinc Ercan 1, Pelin Ercan 2
1 Department of Aerospace Medicine, Health Science University, 2 Primary Health Care Center, Main Jet Base, Turkish Air Force, Eskisehir, Turkey
DOI: 10.4328/ACAM.20228 Received: 2020-05-28 Accepted: 2020-06-28 Published Online: 2020-07-09 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):157-161
Corresponding Author: Erdinc Ercan, Yunus Emre State Hospital, 2 Eylul Building, Hyperbaric Oxygen Therapy Clinic, Eskisehir, Turkey. E-mail: drerdincercan@gmail.com P: +90 541 367 7976 Corresponding Author ORCID ID: https://orcid.org/0000-0002-4478-7031
Aim: Because of many health hazards, we carry out training and treatment efforts to reduce the use of tobacco products by aviation personnel. In this retro-spective study, we aimed to evaluate our smoking cessation rates according to treatment modality, patients’ education level, and marital status via outpatient clinic records. Material and Methods: The records of the Smoking Cessation Policlinic between January 01, 2016 and April 30, 2018 were analyzed in this study. Patients’ demographics, smoking attitudes, cessation method, the Fagerström Test for Nicotine Dependence (FTND), anxiety and depression scales were evaluated. The Kolmogorov-Smirnov normality test, Independent Samples T-Test or the Mann-Whitney-U test were used in between-groups analyzes. The Chi-Squared test was used for testing relationship between categorical variables.Results: One hundred forty-two patients were included in this study and 3 of them were female. All females and 38.9% of males quit smoking. The overall cessation rate was 40.1%. The duration of smoking was higher, the first and last measured CO values were lower, and the follow-up periods were longer in the quitters’ group (p<0.05). The cigarettes smoked per day and FTND scores were higher in the non-quitters’ group (p>0.05). The cessation rate was slightly increased with education duration (p>0.05). Married patients’ cessation rate was higher than single or separated patients (p>0.05). The highest cessation rate was achieved in the Varenicline group (p<0.001).Discussion: The use of tobacco products in aviation personnel is similar to that of the normal population. We can suggest that cessation success can be af-fected by marital status, addiction level, education, and the treatment method.
Keywords: Smoking Cessation; Fagerström test; Nicotine addiction; Aviation personnel
Introduction
Many chemicals are released during the combustion of tobacco. These chemicals contain toxic and carcinogenic substances that can cause many diseases and cancers. The most well-known of these are tar and carbon monoxide. In addition, smoking is closely related to COPD and lung cancer [1]. Nicotine addiction is the leading cause of smoking. Because of many health hazards, we carry out training and treatment efforts to reduce the use of tobacco and tobacco products by aviation personnel. In 2015, the smoking cessation campaign was started, and lectures were given about the hazards of smoking. We gave consultancy to aviation personnel about smoking cessation therapies in this period. Smoking cessation outpatient clinic was established in January 2016. The patient’s health status, compliance with the treatment and the side effects of the smoking cessation drug were taken into consideration during the selection of smoking cessation methods in our outpatient clinic. In this retrospective study, we aimed to evaluate our smoking cessation rates according to treatment modality, patients’ education level, and marital status using outpatient clinic records.
Material and Methods
Each stage of the research was carried out based on the Helsinki Declaration, and the local Clinical Research Ethics Committee approved this study. Our study was planned as a retrospective study. The records of the patients who applied to the Smoking Cessation Policlinic between January 01, 2016 and April 30, 2018 were included and analyzed in this study. Demographic characteristics, smoking behavior and attitudes, cessation method, the Fagerström Test for Nicotine Dependence (FTND), anxiety and depression scales, and exhaled carbon monoxide (CO) levels were evaluated.
Patient smoking status at the beginning of the treatment, compliance with the treatment, and the cessation status were controlled with multiple implications of the “CO Exhalation Test” during the first visit and the follow-up period. Patients who had negative results of the CO Exhalation test especially in the last visit of the following period were accepted as “quitter”.
The study data were edited in Microsoft Excel and statistical analysis was executed in the SPSS program. The Kolmogorov-Smirnov normality test was done for all parameters. The Independent Samples T-Test or the Mann-Whitney-U test were used in between-groups analyzes. The Chi-Squared test was used for testing relationships between categorical variables. The Spearman Correlation test was used for ordinal variables.
Results
One hundred and ninety-one patients were admitted to our smoking cessation policlinic between January 01, 2016 and April 30, 2018. One hundred eighty-seven of them were males and 4 were females. The descriptive statistics of all applicants are presented in Table 1.
Forty-nine (48 male, 1 female) smokers did not attend the outpatient appointment after the counseling and were excluded from the study. One hundred forty-two patients were included in this study and 3 of them were female. All 3 female cases (100%) and 38.8% of males quit smoking after treatment. The overall cessation rate of smoking cessation policlinic was 40.1%. In our study, between-group analyzes could not be performed due to the small number of females receiving the treatment. A total of 139 male subjects were included in between-group analyzes in our study.
Cases were grouped according to smoking cessation status and normality analysis of these subgroups was evaluated using the Kolmogorov-Smirnov test. Only age and smoking duration variables were found to distribute normally in the subgroups formed according to smoking cessation status.
The mean age was similar between the groups and the difference was statistically insignificant. The duration of smoking was high (p = 0.028), the first and last measured CO values were low (p <0.001) in the quitters group. The number of cigarettes smoked per day and FTND scores were found to be higher in the non-quitters group (p>0.05). Patients were closely monitored and outpatient follow-up times were higher in the quitter’s group (p=0.008) (Table 2).
Control visit number of the quitters group (mean: 2.93±1.26; median: 3) was found to be higher than the non-quitters group (mean: 2.51±1.14; median: 2). A statistically significant weak correlation was found between the number of control visits and treatment success (r= 0.178, p=0.036).
It was found that the cessation rate was slightly increased with the increase of the education period (p>0.05) (Table 3).
The cessation rate of married patients was higher than single, or separated patients (p>0.05) (Figure 1).
Combine therapy was not used in our outpatient clinic and the highest smoking cessation rate was achieved in the Varenicline group (p<0.001). Smoking cessation rate of Varenicline group was higher than Psychosocial Support (85.0% versus 32.6%; odds ratio (OR):11.74; 95% CI, 2.94–46.81; p<0.001); higher than Nicotine Band (85.0% versus 33.3%; OR:11.33; 95% CI, 2.04–63.08; p<0.003); higher than Bupropion SR (85.0% versus 29.7%; OR:13.42; 95% CI, 3.52–51.23; p<0.001) (Figure 2). Comparison of Nicotine Band, Bupropion SR, and Psychosocial Support therapies showed that the difference in the cessation rates was not statistically significant (p>0.05).
Discussion
Smoking contributes to significant morbidity and mortality, including chronic obstructive pulmonary disease and lung cancers [1]. The global rate of tobacco smoking has declined substantially in recent years with an estimated 1.1 billion people consume tobacco products worldwide [2]. Training and treatment efforts were carried out globally to reduce the use of tobacco and tobacco products. While awareness of tobacco products’ harmful effects has increased, determinants associated with smoking status should be well analyzed.
Nagano T. et al. stated that for effective smoking cessation, making regular contact with healthcare workers is important. As a key to the continuation of smoking cessation, it is important to provide support for the prevention of re-smoking when relapse is likely to occur usually 3 months after the start of smoking cessation [3]. In our outpatient clinic, patients are closely monitored and, in every visit, non-invasive CO levels are measured and smoking status is documented in the patient records. In our study, the follow-up period was calculated via the outpatient clinic records, and the duration of the follow-up period might be different for each patient. Our follow time is similar to the published literature and outpatient follow-up times were higher in the quitter’s group (p=0.008). Control visit number of the quitters group was found to be higher than the non-quitters group and a statistically significant weak correlation was found between the number of control visits and cessation rate (r= 0.178, p=0.036).
Chang CP et al. found that the smoking cessation rate was 48.1% in the elderly population and declared no significant difference among the baseline characteristics between quitters and non-quitters except for the type of medication. There was no difference between the two groups in terms of age, gender, body weight, smoking duration, the daily consumption number of cigarettes, FTND score, and exhaled CO concentration [4]. In our study, it was found that the rate of smoking cessation polyclinic was 40.1% and the duration of smoking was higher (p <0.05) and the follow-up periods were longer (p <0.05) in the quitters group. In addition, the exhaled air CO test was performed on all patients at each control visit, and the mean value of the first and last CO tests results was lower in the quitters group than the non-quitters group (p=0.004, p<0.001). The number of cigarettes smoked per day and FTND scores were also found to be higher in the non-quitters group (p>0.05). In our study, the overall cessation rate was similar to the published literature. We can suggest that patients in the quitters group had a longer smoking history, were mentally more ready for the cessation and had a higher compliance with the treatment.
Peña P et al. report that years of education were associated with failure in therapy in the multivariate analysis and people with more than 12 years of education had significantly less risk of failure (OR 0.38, p = 0.014) [5]. We also found that the smoking cessation rate was slightly increased with the increase of the education period in our study (p>0.05).
Parekh TM et al. stated that marital status was significantly associated with reporting of former-smoker status; single (OR=0.66, 95% CI 0.51 to 0.87), divorced (OR=0.60, 95% CI 0.50 to 0.72) and widowed (OR=0.70, 95% CI 0.57 to 0.85) participants had lower odds of former-smoker status compared to those who were married [6]. Sagayadevan V. et al. report that only marital status was found to be a significant correlate of health reasons as a motivator to stop smoking and those who were ever married were less likely to report health reasons as a motivation to stop smoking than those who were never married (p=0.002) [7]. In our study, the cessation rate of married patients was higher than single or separated patients (p>0.05).
Gonzales et al. showed that 4-week continuous abstinence rate for Varenicline vs. placebo was 44.0% and 17.7% (OR, 3.85; P<.001); Varenicline vs. Bupropion SR 44.0% and 29.5% (OR, 1.93; P<.001), consecutively. They also state that Bupropion SR was significantly more efficacious than placebo (OR, 2.00; P<.001) [8]. Hurt RD. and colleagues showed that the prevalence of smoking-cessation rates at six weeks in the group taking 300 mg of Bupropion/day was significantly higher than that of a placebo group (44.2 % versus 19.0 %, p <0.01) [9]. Karadoğan D et al. report that patients smoking quit rate was 37.9% after the third month and Varenicline use was associated with higher treatment adherence (p<0.001) and only being in the treatment-adherent group was associated with cessation rate (OR=3.01, 95%CI: 1.88–4.81, p=0.001) [10]. In our study, the highest smoking cessation rate was achieved in the Varenicline group (p<0.001). Comparison of cessation rates of Nicotine Band, Bupropion SR, and Psychosocial Support therapies showed that the difference in the cessation rates was not statistically significant (p>0.05).
The use of tobacco products among aviation personnel is similar to that of the general population, and physicians who carry out aviation examinations and practice preventive medicine in the aviation field should be aware of the importance of this issue and have a good knowledge of how to treat tobacco dependence [11]. In addition, it was reported that smoking was the risk factor for cardiovascular diseases in a study conducted in commercial pilots [12]. In Giannakoulas G. et al.’s study, performance evaluations were conducted with the pilots via questionnaires, psychomotor test batteries, and computer-aided programs. These pilots were not allowed to smoke during flight for 12 hours; prolonged reaction times, irritability, and reasoning deterioration were detected in pilots, but these findings were not statistically significant [13]. We also believe that the prevalence of smoking in aviation personnel is similar with the general population and might threaten the aviation safety. Thus, we started a campaign in our workplace to reduce smoking, consisting of training, consultancy, and treatment. Our results showed that during the study period, our smoking cessation policlinic achievement rate was 40.1%.
Conclusion
Aviation personnel participate in medical checks regularly. They regularly attend healthy lifestyle classes including studying the harmful effects of tobacco products. They are highly motivated and believe in the cessation therapies and they are too cautious about their health.
Our result was fairly consistent with the published literature. However, the smoking cessation rate of Varenicline and Psychosocial Support is higher than in previous studies. We think that some characteristics of aviation personnel and working requirements might have contributed to these positive findings.
Published studies showed that smoking adversely affects the health and work performance of aviation personnel. Although the fight against cigarette addiction is very difficult and time-demanding, we believe that our efforts will protect and improve the health of aviation personnel.
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. Durham AL, Adcock IM. The relationship between COPD and lung cancer. Lung Cancer. 2015; 90(2): 121–7.
2. Riahi F, Rajkumar S, Yach D. Tobacco smoking and nicotine delivery alternatives: patterns of product use and perceptions in 13 countries. F1000Res. 2019; 8: 80.
3. Nagano T, Katsurada M, Yasuda Y, Kobayashi K, Nishimura Y. Current pharmacologic treatments for smoking cessation and new agents undergoing clinical trials. Ther Adv Respir Dis. 2019; 13. DOI: 10.1177/1753466619875925.
4. Chang CP, Huang WH, You CH, Hwang LC, Lu IJ, Chan HL. Factors correlated with smoking cessation success in older adults: a retrospective cohort study in Taiwan. Int J Environ Res Public Health. 2019; 16(18): 3462.
5. Peña P, Zagolin M, Acuña M, Navarrete S, Bustamante P, Canals A. Factors associated with success of a smoking cessation program. Rev Med Chil. 2016; 144(8): 965- 71.
6. Parekh TM, Wu C, McClure LA, Howard VJ, Cushman M, Malek AM, et al. Determinants of cigarette smoking status in a national cohort of black and white adult ever smokers in the USA: a cross-sectional analysis of the REGARDS study. BMJ Open. 2019; 9(5): e027175.
7. Sagayadevan V, Abdin E, Shahwan S, Satghare P, Devi F, Cetty L, et al. Motivations to quit smoking and challenges faced during cessation among individuals with first episode psychosis in Singapore. Early Interv Psychiatry. 2019; DOI: 10.1111/eip.12799.
8. Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing CB, et al. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs. Sustained-Release Bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA. 2006; 296: 47–55.
9. Hurt RD, Sachs DP, Glover ED, Offord KP, Johnston JA, Dale LC, et al. A comparison of Sustained-release Bupropion and placebo for smoking cessation. N Engl J Med. 1997; 337: 1195-202.
10. Karadoğan D, Önal Ö, Şahin DS, Kanbay Y, Alp S, Şahin Ü. Treatment adherence and short-term outcomes of smoking cessation outpatient clinic patients. Tob Induc Dis. 2018; 16: 38.
11. Grossman A, Landau D-A, Barenboim E, Goldstein L. Smoking Cessation Therapy and the Return of Aviators to Flying Duty. Aviat Space Environ Med. 2005; 76: 1064 –7.
12. Houston S, Mitchell S, Evans S. Application of a Cardiovascular Disease Risk Prediction Model Among Commercial Pilots. Aviat Space Environ Med. 2010; 81: 768 – 73.
13. Giannakoulas G, Katramados A, Melas N, Diamantopoulos I, Chimonas E. Acute Effects of Nicotine withdrawal Syndrome in Pilots During Flight. Aviat Space Environ Med. 2003; 74: 247–51.
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Etiology and prevalence of hyponatremia in geriatric patients with fragility hip fractures
Emine Emektar, Seda Dagar, Hüseyin Uzunosmanoğlu, Fatmanur Karaaslan, Şeref Kerem Çorbacıoğlu, Yunsur Çevik
Department of Emergency Medicine, Keçiören Training and Research Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.20229 Received: 2020-06-01 Accepted: 2020-07-01 Published Online: 2020-07-09 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):162-166
Corresponding Author: Emine Emektar, Department of Emergency Medicine, Keçiören Training and Research Hospital, Pınarbaşı, Sanatoryum Street No:25, 06280, Keçiören, Ankara, Turkey. E-mail: emineakinci@yahoo.com P: +90 5055562675 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6056-4401
Aim: In this study, we aimed to determine the prevalence and etiological factors of hyponatremia among geriatric patients, who presented to the emergency department (ED) with simple mechanical falls and were diagnosed with a hip fragility fracture, and to compare these patients’ clinical course with that of patients with a normal serum sodium level. Material and Method: This study is a retrospective study. Patients aged 65 years or older, admitted to the ED with hip fragility fracture, were enrolled in the study. The patients’ serum sodium level at admission was evaluated. Study data were analyzed with IBM SPSS 20.0 (Chicago, IL, USA) /statistical software. Results: This study enrolled 646 patients; 30.5 % of the patients were male and the median age was 85 (IQR 25-75, 78-89) years. Hyponatremia was present in 16.4% (n=106) of the patients. A comparison of the normonatremic and hyponatremic patients showed that the hyponatremic ones had a greater prevalence of osteoporosis, proton pump inhibitor (PPI), and diuretic use, a higher creatinine level, and a lower hematocrit level (p=0.002, p=0.042, p=0.008, p=0.023, p=0.001, respectively).Discussion: Hip fractures are emergency conditions associated with high mortality, which are especially common in the elderly. We showed a considerable prevalence of hyponatremia in geriatric hip fractures. We believe that mild chronic hyponatremia is one of the important risk factors for fragility hip fracture. The majority of hyponatremia cases are the result of comorbidities and polypharmacy.
Keywords: Fragility fracture; Hyponatremia; Geriatric
Introduction
Hip fractures are particularly common in the geriatric age group. They represent injuries with potentially increased morbidity and mortality rates due to certain factors related to the elderly population, such as limited physiological reserve, preoperative medical conditions, and a combination of trauma and major surgery [1, 2]. The mean survival of elderly people treated for hip fractures is shorter than that of the same age group without hip fractures [3].
A fragility fracture is a fracture resulting from a fall from standing height or less. These fractures, which most commonly occur in the hip, spine, or wrist, are an indication that the bones of the body have been weakened by underlying conditions [4, 5]. The risk factors for hip fragility fractures are advanced age, sex, race, weight loss, lack of exercise, nutritional disorders, metabolic disorders, smoking, and alcohol use. The majority of fractures of the femur neck are associated with osteoporosis-induced loss of bone mass [4]. Less commonly, other metabolic disorders such as osteomalacia and renal osteodystrophy, oncological diseases, and endocrinological disorders like diabetes mellitus (DM) and hyperthyroidism are also related to hip fractures. In addition to changes in bone mass, falls secondary to muscle strength and coordination problems, as well as inadequate absorption of fall energy play role in developing fall-associated fractures in the elderly [5]. Additionally, hyponatremia and hyponatremia-induced imbalance may be exemplified as metabolic disorders predisposing to falls [6, 7]. Plasma sodium concentration is the main determinant of plasma osmolality. Maintaining plasma sodium concentration and plasma osmolality at relatively constant levels is of paramount importance for maintaining cellular volume, especially in the brain. Alterations in sodium concentration may cause a series of abnormalities ranging from mild neurological signs (imbalance, vertigo, headache, confusion) to seizures, coma, and even death [6]. A review of the literature suggests that sodium disorders are common in the elderly; hyponatremia, in particular, may cause falls as a result of altered consciousness, such as confusion and delirium or balance problems [7-9].
In our study, we aimed to determine the prevalence and etiological factors of hyponatremia among geriatric patients presenting to the emergency department (ED) with simple mechanical falls who were diagnosed with a hip fragility fracture and to compare their clinical course with that of patients with a normal serum sodium level.
Material and Methods
Design and setting
Our retrospective study was conducted in a tertiary care ED with approximately 250,000 patient admissions per year. Prior to its implementation, our study’s protocol was approved by the local ethics committee (2012-KAEK-15/2023, 25/12/2019). As this is a retrospective study, the participants’ informed consent was not required.
Study population
This study involved patients admitted to the ED between 01.01.2014-01.11.2019, who were diagnosed with a hip fragility fracture, recorded with ICD codes of S72.00 (femur neck fracture), S72.10 (pertrochanteric fracture) and S72.20 (subtrochanteric fracture).
Fragility hip fracture was defined as any hip fracture that occurred in the absence of trauma or in the presence of a low-energy trauma resulting from a fall from a height equal to or less than 1 m. Patients with hip fractures caused by other mechanisms were excluded. Plasma sodium level that was less than 135 mmol/L was labeled as hyponatremia. The patients were categorized into mild hyponatremia (130-134 mmol/L), moderate hyponatremia (125-129 mmol/L), and severe hyponatremia (<125 mmol / L) groups, based on their serum sodium levels. The demographic information, comorbid disorders (systemic hypertension, diabetes mellitus, pulmonary disease, hypothyroidism, heart failure, ischemic heart disease, osteoporosis, dementia) medication use (selective Serotonin Reuptake Inhibitors (SSRI), Proton pump inhibitors (PPI), diuretics (thiazides and/or loop diuretics), vital signs, results of laboratory and imaging studies taken at admission, and 30-day mortality rate were recorded.
Patients with missing data were excluded.
Statistical Analysis
Study data were analyzed using IBM SPSS 20.0 (Chicago, IL, USA) statistical software. The normality of discrete and continuous variables was tested using the Kolmogorov-Smirnov test. Descriptive statistics included median and IQR25-75 (interquartile range) for discrete and continuous variables and number and (%) for categorical variables. Categorical variables were compared using the Chi-square test and continuous variables using the Mann-Whitney U test.
The results were considered statistically significant at a level of p<0.05.
Results
Initially, this study enrolled 744 patients. Ninety-eight patients with missing data were excluded, and the remaining 646 were included in the final analysis; 30.5 % of the patients were male and the median age was 85 (IQR 25-75, 78-89) years. The most common comorbidity was hypertension. PPI use was recorded in 57.1% of the patients. The median duration of hospital stay was 6 (IQR 25-75, 4-8) days; the 30-day mortality rate was 10.8% (n=70). The demographic data of the study population are presented in Table 1.
The blood tests performed at ED admission revealed hyponatremia in 16.4% (n=106) of the patients. A comparison of normonatremic and hyponatremic patients showed higher rates of osteoporosis, PPI and diuretic use; a higher creatinine level; and a lower hematocrit level in the hyponatremia group (p=0.002, p=0.042, p=0.008, p=0.023, p=0.001, respectively) (Table 2). There was no significant difference between the two groups with respect to other comorbidities, medications, type of fracture, laboratory results, Time from admission to surgery, duration of hospital stay, and mortality rate (for all parameters p>0.05) (Table 2).
Discussion
Hip fracture is an emergency condition that is especially common in the geriatric population, and it is associated with increased mortality and morbidity. In the present study, we examined the incidence of hyponatremia among geriatric patients with fragility hip fracture, and reached two important conclusions.
Firstly, we found that among geriatric patients, who developed hip fracture secondary to simple mechanical falls, the incidence of hyponatremia was 16.4%, and 13.2% of all hyponatremia cases were moderate/severe. The majority of patients who were found to have a reduced sodium level, thus had mild asymptomatic hyponatremia. Secondly, we observed that the prevalence of osteoporosis and PPI and diuretic use were higher among patients with hypernatremia, although we did not demonstrate any significant difference between other parameters. The majority of hyponatremia cases may have resulted from polypharmacy and is associated with inappropriate ADH syndrome.
A fragility fracture is an injury that influences morbidity and mortality rates in the elderly after simple trauma, and it occurs as a result of a number of factors, including hyponatremia [7]. Hyponatremia is one of the most commonly known electrolyte disorders in the elderly [9]. It is usually of mild severity (130-135 mmol/L) and has a chronic course (lasting for >48 hours) [10]. Although its prevalence differs between the older people living in the general population and those residing in nursing homes, it ranges between 7% and 18% [11].
Patients with asymptomatic hyponatremia are more likely to fall due to gait disorders and to develop fall-associated fractures [12]. Furthermore, hyponatremia per se may be responsible for fracture [13]. Hyponatremia stimulates osteoclast activation, thereby increasing the incidence of fragility fractures by contributing to low bone mineral density and osteoporosis [14].
In our study, osteoporosis was more common in the hyponatremia group. Osteoporosis is one of the most notable risk factors for osteoporosis fragility fractures. A study examining the relationship between hyponatremia and fractures in a cohort of elderly men enrolled by the Osteoporotic Fractures in Men Study (MrOS) demonstrated that hyponatremia was associated with approximately two-fold increase in the risk of hip and morphometric vertebra fracture [15]. Similarly, another cross-sectional study showed that a serum sodium level <132 mmol/L increases the risk of osteoporotic fractures (OR = 1.46;95% CI: 1.05 to 2.04) [16].
Elderly people are more prone to hyponatremia owing to comorbidities and polypharmacy-related factors [16, 17]. Moreover, chronic hyponatremia may be associated with weakness, cognitive failure, balance disorders, falls, infections, fractures, and frailty [9, 10, 17]. Thus, it is important to determine the causes of hyponatremia in the elderly. Hyponatremia in the elderly is frequently multifactorial, with drugs and inappropriate ADH syndrome being the most common causes [18, 19]. Inappropriate ADH syndrome is typically asymptomatic and idiopathic in the elderly [20]. Moreover, many drug groups such as thiazide diuretics, Renin-Angiotensin-Aldosterone system inhibitors, antidepressants, PPIs, and antipsychotics may cause inappropriate ADH syndrome and hyponatremia in this age group [19, 20]. Several studies have shown that loop diuretics are linked to osteoporosis and fracture risk [5, 16]. Diuretics eliminate sodium and calcium either indirectly via renal excretion or directly via bone resorption from hyponatremia [14, 21]. Our findings also support that diuretic (thiazide/loop diuretic) use was more common in patients with hyponatremia. Recently, there has been an increasing number of reports of polypharmacy-related hyponatremia in the geriatric population [17]. Hyponatremia induced by prescriptions combining thiazide diuretics and NSAIDs has recently been described as a “silent epidemic” [22]. There occurs an aging-related increase in the rate of using non-steroidal anti-inflammatory drugs, antiaggregants, and anticoagulants; gastrointestinal complaints also become more prevalent with aging. Therefore, PPIs are widely prescribed and used for long time periods, without considering their harm/benefit ratio in the elderly [23]. The prevalence of PPI use increases with advanced age, especially in our country. More than half of our patients were using PPI. Conflicting results have been reported in the literature regarding the relationship between the risk of hip fracture and PPI use [24]. In a large case-control study reported from the United Kingdom, a logistic regression analysis revealed that PPI use for more than 1 year increases the risk of hip fractures by a factor of 1.44 (95% CI 1.30–1.59) [24].
The relationship between hyponatremia and antidepressant use has been mentioned in many population-based studies. Such a relationship has been most commonly shown with SSRIs [25]. We did not find any difference in SSRI-use between the groups with low and normal sodium levels. This may be secondary to underlying comorbidities and polypharmacy.
Literature studies have shown that hyponatremia increases the duration of hospital stay and the time to surgery among geriatric patients with hip fractures [6]. However, we did not detect any difference between the two groups in this regard. This may have resulted from the fact that the majority of our hyponatremic patients had mild hyponatremia.
Limitations
Our study had some limitations. Firstly, our study was a single-center study and its results cannot be generalized to all centers. Secondly, its retrospective design may have influenced study findings owing to missing and inaccurate data. Other factors that potentially cause fragility may have not been properly addressed. Similarly, neither patients’ volume status nor gait and ataxic disorders, which may cause falls, were adequately studied.
Another limitation is the lack of repeated sodium level determinations during a hospital stay.
Conclusion
We demonstrated a considerably high prevalence of hyponatremia in geriatric hip fracture cases. We think that mild chronic hyponatremia is one of the most important risk factors for fragility hip fractures. We showed that the majority of hyponatremia cases are a result of polypharmacy and comorbidities. It needs to be kept in mind that medications and drug interactions may create problems with regard to hyponatremia and fragility fractures; therefore, we are of the opinion that unnecessary drug use should be avoided in this population. We also observed that even though sodium levels were low, hyponatremia did not alter the clinical course of the patients. This may have resulted from the fact that the majority of our patients had mild hyponatremia.
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. Streubel PN, Ricci WM, Wong A, Gardner MJ. Mortality after distal femur fractures in elderly patients. Clin Orthop Relat Res. 2011;469(4):1188-96.
2. Emektar E, Corbacioglu SK, Dagar S, Uzunosmanoglu H, Safak T, Cevik Y. Prognostic Value of the Neutrophil-Lymphocyte and Platelet-Hip fracture, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, one-year mortalityLymphocyte Ratios in Predicting One-Year Mortality in Patients with Hip Fractures and Aged Over 60 Years. Eurasian J Emerg Med. 2017; 16: 165-70.
3. Xu BY, Shi Yan, Low LL, Vasanwala FF, Low SG. Predictors of poor functional outcomes and mortality in patients with hip fracture: a systematic review. BMC Musculoskelet Disord. 2019; 20: 568.
4. Kauta N, Held M, Dlamini S, Kalula S, Ross I, Kalla G, et al. The management of fragility fractures of the hip: A quality assessment project. SAOJ. 2017;16(3):41-45.
5. Rocha AFB, Sá MVBO, Elihimas Junior UF. Hyponatremia in Elderly Patients With Fragility Fractures of the Proximal Femur: A Cross-Sectional Study. J Bras Nefrol. 2019;41(4):518-525.
6. Cassim B, Lipschitz S, Paruk F, Tipping B. Recommendations for the acute and long-term medical management of low trauma hip fractures. JEMDSA. 2013;18(1):21-32.
7. Cumming K, Hoyle GE, Hutchison JD, Soiza RL. Prevalence, Incidence and Etiology of Hyponatremia in Elderly Patients with Fragility Fractures. J Clin Med Res. 2015;7:45-51.
8. Hoorn EJ, Rivadeneira F, van Meurs JB, Ziere G, Stricker BH, Hofman A, et al. Mild hyponatremia as a risk factor for fractures: the Rotterdam Study. J Bone Miner Res. 2011;26(8):1822-8.
9. Cumming K, Hoyle GE, Hutchison JD, Soiza RL. Prevalence, incidence and etiology of hyponatremia in elderly patients with fragility fractures. PLoS One. 2014;9(2):e88272.
10. Soiza RL, Cumming K, Clarke JM, Wood KM, Myint PK. Hyponatremia: Special Considerations in Older Patients. J Clin Med. 2014;3(3):944-58.
11. Filippatos TD, Makri A, Elisaf MS, Liamis G. Hyponatremia in the elderly: challenges and solutions. Clin Interv Aging. 2017;12:1957-65.
12. Grundmann F. Electrolyte disturbances in geriatric patients with focus on hyponatremia. Z Gerontol Geriatr. 2016;49(6):477-82.
13. Ayus JC, Arieff. Chronic hyponatremic encephalopathy in postmenopausal women: association of therapies with morbidity and mortality. JAMA. 281(24):2299-304.
14. Barsony J, Sugimura Y, Verbalis JG. Osteoclast response to low extracellular sodium and the mechanism of hyponatremia-induced bone loss. J Biol Chem. 2011;286(12):10864 –75.
15. Jamal SA, Arampatzis S, Harrison SL, Bucur RC, Ensrud K, Orwoll ES, et al. Hyponatremia and fractures: Findings from the MrOS study. J Bone Miner Res. 2015;30(6):970-5.
16. Arampatzis S, Gaetcke LM, Funk GC, Schwarz C, Mohaupt M, Zimmermann H, et al. Diuretic-induced hyponatremia and osteoporotic fractures in patients admitted to the emergency department. Maturitas. 2013;75(1):81–6.
17. Soiza RL, Hoyle GE, Chua M. Electrolyte and salt disturbances in older people: causes, management and implications. Rev Clin Gerontol. 2008;18:143-58.
18. Hanotier P. Hyponatremia in the elderly: its role in frailty. Rev Med Brux. 2015;36:475-84.
19. Berl T. An elderly patient with chronic hyponatremia. Clin J Am Soc Nephrol. 2013;8:469-475.
20. Anpalahan M. Chronic idiopathic hyponatremia in older people due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) possibly related to aging. J Am Geriatr Soc. 2001;49(6):788-92.
21. Upala S, Sanguankeo A. Association Between Hyponatremia, Osteoporosis, and Fracture: A Systematic Review and Metaanalysis. J Clin Endocrinol Metab. 2016;101(4):1880-6.
22. Mann SJ. The silent epidemic of thiazide-induced hyponatremia. J Clin Hypertens. 2008;10(6):477–84.
23. Thompson W, Black C, Welch V, Farrell B, Bjerre LM, Tugwell P. Patient values and preferences surrounding proton pump inhibitor use: A scoping review. Patient. 2018;11(1):17-28.
24. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006; 296: 2947-53.
25. Mazhar F, Pozzi M, Gentili M, Scatigna M, Clementi E, Radice S, et al. Association of Hyponatraemia and Antidepressant Drugs: A Pharmacovigilance-Pharmacodynamic Assessment Through an Analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) Database. CNS Drugs. 2019;33:581-92.
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Emine Emektar, Seda Dagar, Hüseyin Uzunosmanoğlu, Fatmanur Karaaslan, Şeref Kerem Çorbacıoğlu, Yunsur Çevik. Etiology and prevalence of hyponatremia in geriatric patients with fragility hip fractures. Ann Clin Anal Med 2021;12(2):162-166
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The efficiency of deep learning for the diagnosis of psammomatous meningioma
Syed Usama Khalid Bukhari 1, Asmara Syed 3, Syed Khuzaima Arslan Bokhari 2, Syed Sajid Hussain Shah 3
1 Department of Computer Science, The University of Lahore, Islamabad, Pakistan, 2 Pediatric medicine, Doctors hospital, Lahore, Pakistan, 3 Faculty of Medicine, Northern Border University, Arar, Kingdom of Saudi Arabia
DOI: 10.4328/ACAM.20226 Received: 2020-05-27 Accepted: 2020-06-26 Published Online: 2020-07-05 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):153-156
Corresponding Author: Syed Usama Khalid Bukhari, Department of Computer Science, The University of Lahore, Islamabad, Pakistan. E-mail: usama.khalid@cs.uol.edu.pk P: +92 349 1050 449 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1581-8609
Aim: The study aims to assess the efficiency of deep machine learning (convolutional neural network architecture) for the diagnosis of psammomatous menin-gioma by evaluating the digital pathology images.Materials and Methods: A total of three hundred and twenty (320) digital images have been acquired from the anonymized hematoxylin and eosin-stained slides, which included 161 images of Psammomatous Meningioma and 159 images of normal intracranial tissue. The dataset was divided into a train set, 80% of the entire data, and 20% into the test data set. ResNet-18 architecture (state of the art deep learning computer vision algorithms) is used to diagnose these cases.Results: A total of 161 images of psammomatous meningioma and 159 images of normal tissue are used; 80% of the collected data was used for training, where 20% for testing purposes. Using deep learning, we achieved 98.79 F1-Score and 98.4% accuracy. Discussion: The advancement in the field of artificial intelligence has opened a lot of new channels and generated new opportunities to develop computer-aided diagnostic systems. The applications of machine learning have revealed promising results for the histopathological evaluation of neoplastic lesions. In the present study, the excellent diagnostic accuracy (98.4 %) has been achieved with the convolutional neural network architecture. There was an F1-score of 98.79 for the diagnosis of psammomatous meningioma in the present series. The studies conducted for the diagnosis of breast cancer metastasis, lung carcinoma, prostatic malignant tumors, and basal cell carcinoma also revealed excellent results. Convolutional neural network (CNN) architecture is emerging as a quite efficient deep machine learning tool for the analysis of the pathology images. This technology may be quite a valuable adjunct tool in diagnostic surgical pathology.
Keywords: Psammomatous meningioma; Histopathological diagnosis; Deep learning
Introduction
Among the primary intracranial neoplasms, meningiomas are the most frequent type of tumors [1-2]. Meningiomas are more common in females as compared to males [3]. However, the research data has revealed that the risk of death due to meningioma is lower in female patients than in male patients [4]. A rising trend in the incidence of meningioma has been observed over the past few years in many countries, which may be attributed to the increasing aged population and better availability of diagnostic and health facilities [5]. The risk factors of meningioma include ethnicity, history of allergy, gender, family history, genetic polymorphism, ionizing radiation, nutrition, and reproductive history. Some of these factors may also be a contributing factor in the increase in the incidence of these tumors [5]. The majority of meningiomas fall in the category of grade 1[6-7].
The histological variants of grade 1 meningioma are transitional, meningothelial, psammomatous, fibrous, microcystic, secretory, lymphoplasmacyte rich, angiomatous, and metaplastic [1]. The psammomatous meningioma is characterized by the presence of psammoma bodies, which are calcified masses. In certain tumors, the psammoma bodies are numerous, and the intervening meningothelial cells are less in quantity. The presence of characteristic calcified structure (psammoma bodies) makes the diagnosis of this subtype of meningioma relatively easy. Because of this characteristic visual pattern of this lesion, it would be essential to develop computer vision-based programs to diagnose such type of lesion to assist the health professionals in patient care.
The histopathological assessment of the biopsy specimen is vital for the conclusive diagnosis of tumors, which includes the fixation, processing, cutting, staining, and microscopic examination of the tissue sections. The histological assessment of tissue sections requires a lot of expertise in the field of histopathology. The increasing number of tumor biopsies with relatively less availability of consultant histopathologists requires assistance from artificial intelligence. The digitalization of pathology slides has made it easier to apply deep machine learning technology, particularly CNN, for the histopathological evaluation of digital images of various lesions.
The main aim of the present research project is to assess the efficiency of CNN for the diagnosis of psammomatous meningioma.
Material and Methods
This study has been conducted after getting ethical approval from the University of Lahore – Islamabad Campus. A total of three hundred and twenty (320) digital anonymized images have been acquired from the anonymized slides stained with hematoxylin and eosin stain, which included 161 images of Psammomatous Meningioma and 159 images of normal intracranial tissue. The dataset was divided into a train set, 80% of the entire data, and 20% into the test data set.
We have used ResNet-18 architectures. We used the transfer learning approach; the pre-trained ResNet18 on ImageNet data set [8] was used to avoid the limitation of the small dataset we manage to obtain. A total of 161 images of Meningioma and 159 images of normal tissue were used. These images have been reviewed and labeled by two histopathologists.
A random approach of FastAI API is used to load the data into train and test sets to avoid the chances of images of the same class been selected for a mini-batch input that can harm the performance of model validation. The entire dataset has been split into training and test sets. For training, 80% of the entire dataset was used, where for testing, 20% of the total dataset was used. For image, we used data augmentation for regulation.
Results
A total of three hundred and twenty (320) images were collected; one hundred and sixty-one images (161) of Meningioma and One hundred and fifty-nine (159) images of normal tissue. Two hundred and fifty-six (256) images were randomly chosen from both Meningioma and normal tissue images, 80% of the total data set and were employed for training data set. While sixty-four (64) images were randomly chosen from both Meningioma and normal tissue images, 20% of the data set was employed in the test data set. ResNet -18 architecture was used to classify the input image. Accuracy of 98.4 % and F1-score of 98.79 were obtained on the entire data set. ResNet implementation of FastAPI was used, on intel-i5 PC with RTX-2070 GPU.
Discussion
The accurate and rapid diagnosis of tumors plays a significant role in the management of patients suffering from neoplastic lesions. The conclusive diagnosis depends upon the critical and meticulously evaluation of biopsies from the tumors, which involves the critical step of microscopic examination. Based on characteristic microscopic features, the histopathologists make a critical decision regarding the diagnosis of these tumors. Any judgmental or interpretational error in the histopathology may reveal disastrous results in patient health care and may also result in litigations. The exhaustive and extensive work causes fatigability, which may be a significant cause of human errors. The rising trend in the prevalence of tumors is expected to contribute to the chance of errors to be more, which would be a significant challenge in the near future. The automation and computer-aided systems with the help of artificial intelligence algorithms may help reduce the burden of histopathological evaluation of biopsies as these may reduce the chance of human errors due to fatigability and may also improve the speed of decision-making process. In the present decade, deep learning technology has made it possible to make computer-aided systems that could assist in the histopathological assessment of biopsy specimens.
The availability of high-resolution image data of various pathological lesions, including malignancies, has made it possible to develop machine learning algorithms based on characteristics and distinguishing features and pattern of neoplastic lesions by extracting these features.
The progressive growth in the computational pathology with the advancement in artificial intelligence has paved the way for a more precise and better assessment of features present in the images for categorization, classification, and diagnosis. One of the critical subsets of artificial intelligence is deep machine learning. In deep learning technology, the convolutional neural network (CNN) architecture is commonly used to analyze digital images [9]. There are three main components of a convolutional neural network. It includes the input layer along with a large number of hidden layers, and the third component consists of the output layer [10].
The present study performed on the digital histopathological images for the diagnosis of psammomatous meningioma by applying convolutional neural network architecture revealed the diagnostic accuracy of 98.4 % and F1-score of 98.79. A closely similar diagnostic accuracy has been observed in the studies conducted for the diagnosis of breast cancer metastasis, lung carcinoma, prostatic malignant tumors, and basal cell carcinoma [11-13].
The deep machine learning technique is yielding promising results for the diagnosis of different types of cancers. The development of such tools will be a great help to the histopathologists in rendering better diagnostic services, which has got paramount importance in the healthcare system. The computational histopathology will reduce the chance of inter-observer discrepancies and improve diagnostic laboratories’ efficiency by decreasing the time of the biopsies for the final diagnosis. The application of computer vision-based programs for the diagnosis of malignancies will also reduce the chance of human errors due to fatigability. The diagnostic errors in pathology have an impact on patient care prognosis [14]. With the help of artificial intelligence, the mistakes can be reduced in the laboratory. In the near future, the application of machine learning (artificial intelligence) may be able to play a more influential role in health care and the capability to transform patient care [15].
Further research is recommended for the assessment of deep machine learning as a useful adjunct tool for the histopathological diagnosis of various types of neoplastic lesions.
Conclusion: The application of deep machine learning as a tool for the analysis of the pathology images has been emerging as an efficient technique. This technology may be quite a valuable adjunct tool in the diagnostic surgical pathology.
Acknowledgment
The authors are thankful to Syed Ali Imran, Farhan Mazher, and Syed Umar Armaghan for providing value able inputs and proofreading.
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. Buerki RA, Horbinski CM, Kruser T, Horowitz PM, James CD, Lukas RV. An overview of meningiomas. Future Oncol. 2018;14(21):2161-77. DOI: 10.2217/fon-2018-0006.
2. Almutrafi A, Bashawry Y, AlShakweer W, Al-Harbi M, Altwairgi A, Al-Dandan S. The Epidemiology of Primary Central Nervous System Tumors at the National Neurologic Institute in Saudi Arabia: A Ten-Year Single-Institution Study. J Cancer Epidemiol. 2020;2020:1429615. DOI:10.1155/2020/1429615.
3. Shah S, Rehman L, Ahmed N, Chaudhry MA. Surgical outcome of meningioma of brain tumours. Pakistan Journal of Medical and Health Sciences. 2015;9(3):1086-7.
4. Yang A I, Mensah-Brown K G, Rinehart C, Fathy R, Hitti FL, Brant J, et al. Inequalities in Meningioma Survival: Results from the National Cancer Database. Cureus. 2020: 12(3): e7304. DOI: 10.7759/cureus.7304.
5. Baldi I, Engelhardt J, Bonnet C, Bauchet L, Berteaud E, Gruber A, et al. Epidemiology of meningiomas. Neurochirurgie. 2018;64(1):5-14. DOI: 10.1016/j.neuchi.2014.05.006.
6. Assi HI, Hilal L, Abu-Gheida I, Berro J, Sukhon F, Skaf G, et al. Demographics and outcomes of meningioma patients treated at a tertiary care center in the Middle East. Clin Neurol Neurosurg. 2020;195:105846. DOI: 10.1016/j.clineuro.2020.105846.
7. Ostrom QT, Gittleman H, Xu J, Kromer C, Wolinnsky Y, Kruchko C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2009–2013. Neuro Oncol. 2016; 18(Suppl. 5); S1–75 . DOI: 10.1093/neuonc/now207.
8. Russakovsky O, Deng J, Su H, Krause J, Satheesh S, Ma S, et al. ImageNet Large Scale Visual Recognition Challenge. Int J Comput Vis. 2015; 115:211-52. DOI:10.1007/s11263-015-0816-y.
9. Chang HY, Jung CK, Woo JI, Lee S, Cho J, Kim SW, et al. Artificial Intelligence in Pathology. J Pathol Transl Med. 2019;53(1):1-12. DOI: 10.4132/jptm.2018.12.16.
10. Janowczyk A, Madabhushi A. Deep learning for digital pathology image analysis: A comprehensive tutorial with selected use cases. J Pathol Inform. 2016;7:29. DOI:10.4103/2153-3539.186902.
11. Ehteshami Bejnordi B, Veta M, Johannes van Diest P, van Ginneken B, Karssemeijer N, Litjens G, et al. Diagnostic assessment of deep learning algorithms for detection of lymph node metastases in women with breast cancer. JAMA. 2017;318(22):2199-2210. DOI: 10.1001/jama.2017.14585.
12. Campanella G, Hanna MG, Geneslaw L, Miraflor A, Silva VWK, Busam KJ, et al. Clinical-grade computational pathology using weakly supervised deep learning on whole slide images. Nat Med. 2019; 25: 1301–9. DOI: 10.1038/s41591-019-0508-1.
13. Coudray N, Ocampo PS, Sakellaropoulos T, Narula N, Snuderl M, Fenyo D, et al. Classification and mutation prediction from non-small cell lung cancer histopathology images using deep learning. Nat Med. 2018; 24: 1559–67. DOI: 10.1038/s41591-018-0177-5.
14. Santana MF, Ferreira LCL. Diagnostic errors in surgical pathology. J Bras Patol Med Lab. 2017;53 (2):124-9.
15. Rashidi HH, Tran NK, Betts EV, Howell LP, Green R. Artificial Intelligence and Machine Learning in Pathology: The Present Landscape of Supervised Methods. Acad Pathol. 2019;6. DOI: 10.1177/2374289519873088.
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Syed Usama Khalid Bukhari, Asmara Syed, Syed Khuzaima Arslan Bokhari, Syed Sajid Hussain Shah. The efficiency of deep learning for the diagnosis of psammomatous meningioma. Ann Clin Anal Med 2021;12(2):153-156
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Initial serum lactate levels of COVID-19 patients
Sadiye Yolcu 1, Kemal Sener 1, Nurettin Yılmaz 1, Mehmet Tunç 1, Ahmet Aktas 2, Nurettin O. Dogan 3
1 Department of Emergency Medicine, Adana City Research & Education Hospital, Adana, 2 Department of Internal Medicine, Cumhuriyet University Medical School, Sivas, 3 Department of Emergency Medicine, Kocaeli University Medical School, Kocaeli, Turkey
DOI: 10.4328/ACAM.20225 Received: 2020-05-28 Accepted: 2020-06-26 Published Online: 2020-07-04 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):150-152
Corresponding Author: Sadiye Yolcu, Department of Emergency Medicine, Adana City Research & Education Hospital, Adana, Turkey. E-mail: sadiyeyolcu@yahoo.com GSM: +90 5053596731 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3323-9213
Aim: In this study, we aimed to research whether the serum lactate of the COVID-19 patients presented to the initial emergency department can be used to make prognosis of the patients. Materials and Methods: A total of 39 COVID-19 patients were included in the study. Fourteen (35.8%) patients were over 65 years old (Group 1). Twenty-five patients (64.2%) were under 65 years old (Group 2). The diagnosis was made via the oro-nasopharyngeal swab PCR test. We noted the demographic data (age, gender, comorbidities), initial (emergency service presentation) complete blood count parameters including WBC, Plt/Lymp ratio, CRP, procalcitonin and serum lactate levels. We also noted the hospitalization unit (clinic/intensive care unit), hospitalization length, and the outcomes. Patients were divided into two groups according to 65 years and the groups’ laboratory results with the prognosis. Results: The mean age of the study group was 55 years. Fourteen (35.8%) patients were over 65 years old. Serum lactate levels did not significantly differ between groups. Hospital length of stay was significantly longer in patients over 65 years of age. Age and hospitalization length were positively correlated with age in all patients.Discussion: Serum lactate level measurement has recently become an important parameter especially for critically ill patients. It is beneficial for predicting the severity and prognosis in severe infections. Serum lactate levels in COVID-19 patients did not differ between age groups. Hospitalization length was longer in elderly patients.
Keywords: COVID-19; Lactate; Prognosis
Introduction
COVID-19 is a worldwide pandemic viral infection with a high prevalence and mortality rate [1]. Up to date, millions of people have been infected all over the world [2]. This rapid-spreading infection causes several systemic effects, such as pneumonia and myocarditis, on the other hand, most of the infected people may not have any symptom or a clinical finding [3,4]. The main symptoms and clinical findings include fever, cough, fatigue, loss of smell and taste dysfunction, and typical CT images of ground-glass [5,6].
Serum lactate is a well known valuable prognostic marker for different clinical situations, such as serious infections and sepsis [7-9]. Serum lactate level has a positive correlation with mortality in critically ill patients with severe infection [8-10]. Emergency clinicians use lactate for providing early goals of sepsis when the level is higher than 4.0 mmol/L [11,12]. It is an easy accessible, cheap and can be achieved from venous blood gase immediately.
The COVID-19 patients first present to the COVID area which is settled as a part of our emergency department. Emergency clinicians follow-up these patients till hospitalization in the inpatient clinic or intensive care unit. Because of a lack of data from the emergency departments, in this study, we aimed to research whether the serum lactate of the COVID-19 patients at the initial presentation to the emergency department can be used to make the prognosis of the patients. We also aimed to determine whether there is a difference between the patients under 65 years old and over 65 years old.
Material and Methods
After the ethics committee approval, in this retrospective study, we evaluated COVID-19 diagnosed and hospitalized patients between 15 March 2020 and 31 March 2020. Totally 39 COVID-19 patients were included. Fourteen (35.8%) patients were aged over 65 years (Group 1). Twenty- five patients (64.2%) were under 65 years old (Group 2). The diagnosis is made via the oro-nasopharyngeal swab PCR test. We noted the demographic data (age, gender, comorbidities), initial (emergency service presentation) complete blood count parameters including WBC, plt/lymp ratio, CRP, procalcitonin, and serum lactate levels. We also noted the hospitalization unit (clinic/intensive care unit), hospitalization length, and the outcome. Patients were divided into two groups according to 65 years and the groups’ laboratory results with the prognosis.
We included all COVID-19 diagnosed and hospitalized patients in this study. The exclusion criteria were patients under 18 years old, cardiopulmonary arrest in the ED, and the pregnants.
Statistical Analyses
Statistical comparisons were performed using the statistical software package SPSS 23.0 (SPSS Inc., Chicago, IL, USA). The Shapiro-Wilks test was used for normal distribution. For comparing parameters without normal distribution, the Mann-Whitney U test was used. The Chi-Square test was used for comparing the categorical variables. The Spearman’s test was used for correlation analyses. Definitive statistics were noted as “Mean ± standard deviation (SD)” and “ Median (interquartiles, IQR)”. The significance level was 0.05.
Results
We included 21 males, 18 females, totally 39 patients in our study. The mean age of the study group was 55 years. Fourteen (35.8%) patients were aged over 65 years. Serum lactate levels were not significantly different between groups. Hospitalization length was significantly longer in the patients aged over 65 years. The hospitalization unit and the outcomes did not differ between the groups (Table 1). Age and hospitalization length were positively correlated with age in all patients (Table 2).
Discussion
In this study, we included 39 COVID-19 PCR test positive patients. Hospitalization length was significantly longer in the patients aged over 65 years. Serum lactate levels, hospitalization unit, and the outcome did not differ between groups. Age and hospitalization length were positively correlated with age in all patients
Serum lactate level measurement is one of the most important tools for emergency clinicians. The physiologic processes of this marker are well defined and overproduction of this molecule and decreased elimination provide important data for critically ill patients, such as sepsis or other serious infections [13,14]. Anaerobic metabolism of the tissues results in high production of lactate and it is known that hyperlactatemia occurs in serious infections [15], and hyperlactatemia is associated with a higher mortality ratio in these patients [16]. As a result, when the initial serum lactate is high, additional clinical interventions should be provided to decrease tissue hypoxia. Oxygen support has not been shown clinically [17,18]. Cryptic shock is a term to define the normotensive septic patients with elevated serum lactate and it is related to high mortality. A high death ratio occurs when the serum lactate level is 4 mmol/L or higher [11].
This year, the COVID-19 pandemic has affected the whole world, and we do not have enough knowledge to manage these patients. Data on critically ill COVID-19 patients are especially important for all clinicians to save the lives of victims. The emergency management data on serum lactate levels are limited for these critically ill patients. According to a COVID-19 case series, hypotension occurred in 17 of 24 patients, which required fluid and vasopressor administration. Similarly, serum lactate levels are higher in critically ill COVID patients [13,18]. These data suggested us the lactate level can be a prognostic factor as it is commonly used in sepsis and septic shock.
Limitations
We included a small study group in this study because of the limited conditions and the required immediate data.
Conclusion
COVID-19 patients’ serum lactate levels did not differ between age groups. Hospitalization length was longer in elderly patients. Further comprehensive studies are required for the prediction of lactate levels, especially in critically ill COVID-19 patients, and also, serial lactate measurement might be more effective in the management.
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. Zhang X. Epidemiology of COVID-19. N Engl J Med. 2020;382(19):1896. DOI:10.1056/NEJMc2005157.
2. Huang X, Wei F, Hu L, Wen L, Chen K. Epidemiology and Clinical Characteristics of COVID-19. Arch Iran Med. 2020;23(4):268-71. DOI:10.34172/aim.2020.09.
3. Shi H, Han X, Jiang N. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. 2020;20(4):425-34. DOI: 10.1016/S1473-3099(20)30086-4.
4. 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; DOI: 10.1001/jamacardio.2020.1096.
5. Hu Z, Song C, Xu C. Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China. Sci China Life Sci. 2020;63(5):706-11. DOI: 10.1007/s11427-020-1661-4.
6. Xydakis MS, Dehgani-Mobaraki P, Holbrook EH. Smell and taste dysfunction in patients with COVID-19. Lancet Infect Dis. 2020;: DOI: 10.1016/S1473-3099(20)30293-0.
7. Puskarich MA, Jaillette E, Girault C, Brunin G, Zerimech F. Prognosis of emergency department patients with suspected infection and intermediate lactate levels: a systematic review. J Crit Care. 2016;20(Suppl.2):S94. DOI: 10.1186/s13054-016-1208-6.
8. Bakker J, Gris P, Coffernils M, Kahn RJ, Vincent J-L. Serial blood lactate levels can predict the development of multiple organ failure following septic shock. Am J Surg. 1996;171(2):221–6.
9. Jansen TC, van Bommel J, Bakker J. Blood lactate monitoring in critically ill patients: a systematic health technology assessment. Crit Care Med. 2009;37(10): 2827–39.
10. Mikkelsen M, Miltiades A, Gaieski D. Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock. Crit Care Med. 2009;37:1670–7.
11. Rivers E, Nguyen B, Havstad S. Early goal- directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368–677.
12. Wardi G, Brice J, Correia M, Liu D, Self M, Tainter C. Demystifying Lactate in the Emergency Department. Ann Emerg Med. 2020;75(2):287-98. DOI: 10.1016/j.annemergmed.2019.06.027.
13. Li X, Wang L, Yan S. Clinical Characteristics of 25 Death Cases With COVID-19: A Retrospective Review of Medical Records in a Single Medical Center, Wuhan, China. Int J Infect Dis. 2020; DOI: 10.1016/j.ijid.2020.03.053.
14. Wacharasint P, Nakada TA, Boyd JH, Russell JA, Walley KR. Normal-range blood lactate concentration in septic shock is prognostic and predictive. Shock. 2012;38(1):4-10.
15. Puskarich MA, Trzeciak S, Shapiro NI, Heffner AC, Kline JA, Jones AE. Outcomes of patients undergoing early sepsis resuscitation for cryptic shock compared with overt shock. Resuscitation. 2011;82(10):1289-93.
16. Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med. 1994;330(24):1717-22.
17. Marik PE, Sibbald WJ. Effect of stored-blood transfusion on oxygen delivery in patients with sepsis. JAMA. 1993;269(23):3024-9.
18. Bhatraju PK, Ghassemieh BJ, Nichols. COVID-19 in Critically Ill Patients in the Seattle Region – Case Series. Engl J Med. 2020;DOI: 10.1056/NEJMoa2004500.
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Sadiye Yolcu, Kemal Sener, Nurettin Yılmaz, Mehmet Tunç, Ahmet Aktas, Nurettin O Dogan. Initial serum lactate levels of COVID-19 patients. Ann Clin Anal Med 2021;12(2):150-152
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The relation between hyponatremia at presentation, severity of disease and length of stay in patients with bronchiolitis
Fatih Isleyen, Mehmet Tekin, Capan Konca
Department of Pediatrics, Adiyaman University, School of Medicine, Adiyaman, Turkey
DOI: 10.4328/ACAM.20211 Received: 2020-05-15 Accepted: 2020-06-15 Published Online: 2020-06-30 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):129-133
Corresponding Author: Mehmet Tekin, Adiyaman University, School of Medicine, Department of Pediatrics, Kahta Street, 02000 Adiyaman, Turkey. E-mail: drmehmettekin@hotmail.com GSM: +90 532 7699846 F: + 90 416 2252660 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1157-1314
Aim: In this study, we aimed to investigate the relationship between hyponatremia at presentation and severity of disease and length of stay in children admit-ted to hospital with acute bronchiolitis.Material and Methods: This cross-sectional study was performed at a tertiary care hospital between May 2017 and April 2018. One hundred seventy children aged 1-24 months admitted with a diagnosis of acute bronchiolitis were included in the study. Demographic and biochemical data were recorded together with data associated with clinical course and length of stay.Results: Hyponatremia was present in 62 (36.4%) of the 170 patients. Thirteen patients (20.9%) in the hyponatremic group were diagnosed with moderate bronchiolitis and 17 (27.5%) with severe bronchiolitis, while in the normonatremic group, 14 (12.9%) with moderate bronchiolitis and 9 (8.4%) with severe bronchiolitis (p<0.001). High-flow nasal cannula (FNC) requirement was present in 17 patients in the hyponatremic group and 17 in the normonatremic group (p=0.001). The risk of development of severe bronchiolitis increased 0.085-fold in patients with hyponatremia. The median length of hospitalization was 5 (2-21) days in the hyponatremic group and 4 (2-11) days in the normonatremic group (p=0.001). Hyponatremia increased length of stay approximately 4.7-fold. Discussion: The risk of developing severe bronchiolitis and non-invasive mechanical ventilation requirements was significantly higher in the hyponatremic group. The length of hospital stay was greater in cases of bronchiolitis with hyponatremia. We think that measuring sodium levels during hospitalization in cases of bronchiolitis will be useful in predicting the risk of development of severe bronchiolitis and extended length of stay.
Keywords: Bronchiolitis; Hyponatremia; Infant; Length of stay
Introduction
Acute bronchiolitis is one of the respiratory tract diseases frequently encountered in infancy. It is particularly common in children under 6 months and is the most frequent cause of hospitalization in children under 2 years [1, 2].
There is a few studies investigated the relationship between hyponatremia and length of hospital stay or poor outcomes in cases of bronchiolitis. The reported prevalence of hyponatremia in cases of severe bronchiolitis admitted to intensive care units is between 16% and 33% [3,4]. One study of cases of moderate-severe bronchiolitis aged less than 6 months presenting to the emergency department measured sodium levels using direct potentiometry and determined a prevalence of hyponatremia of 57% [5]. It has been proposed that hyponatremia may develop as a result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), hypotonic fluid use, or iatrogenic fluid loading [6]. Hyponatremia may be life-threatening since the passage of fluid into brain cells and alveoli is increased. It has also been suggested that in addition to the direct neurotoxic effects of viruses and upper respiratory tract obstruction, hyponatremia may also be responsible for neurological complications such as apnea, seizure and lethargy, seen in 1.2% of bronchiolitic patients admitted to the pediatric ward and in 39% of patients in the pediatric intensive care unit [7,8]. The mortality rate in bronchiolitis is generally less than 1%, although it may increase dramatically, to as high as 13%, in the presence of hyponatremia [4].
The purpose of this study was to investigate the relationship between severity of disease and length of hospitalization and hyponatremia at the time of presentation in children aged 1-24 months hospitalized with a diagnosis of bronchiolitis.
Material and Methods
This prospective cross-sectional study was performed at the Adıyaman University School of Medicine, Department of Pediatrics. The study was designed in accordance with the principles of the Helsinki Declaration, and was approved by the Adıyaman University Medical Faculty Clinical Research Ethical Committee (No. 2017/5-3, dated 20.06.2017). Informed consent forms were received from individuals responsible for the care of the patients enrolled.
Study population
One hundred seventy children aged 1-24 months hospitalized with a diagnosis of acute bronchiolitis between May 2017 and April 2018 were included in the study. Patients with accompanying pathologies such as gastroenteritis, pneumonia, bacteremia, meningitis, pyelonephritis, hypertriglyceridemia or hyperglycemia, with histories of chronic diseases, with a history of recent surgery, diuretic use or conditions capable of altering serum sodium levels, such as previously undiagnosed SIADH, and patients started on parenteral fluid support before being taken for tests were excluded.
Acute bronchiolitis has been defined as tachypnea, subcostal-intercostal retraction, prolonged expirium, and wheezing or rales/rhonchi at the physical examination in addition to respiratory system symptoms such as nasal discharge, cough, wheezing and respiration difficulty, together with a flattened diaphragm and hyperinflation at chest x-ray [9, 10]. Depending on clinical status, cases were divided into three groups, mild bronchiolitis (cases with mild retraction, a respiratory rate of 41-55 breaths per minute for <6 months, 31-45 for >6 months, and arterial saturation [SaO2] of 92-94% at room temperature), moderate bronchiolitis (cases with moderate retraction, a respiratory rate of 56-70 breaths per minute for <6 months, 46-60 for >6 months, and SaO2 90-91%), and severe bronchiolitis (cases with severe retractions, a respiratory rate of ≥71 for <6 months, ≥61 for >6 months, and SaO2 ≤89%) [11].
Hyponatremia was defined as a serum sodium concentration below 135 mEq/L. Hyponatremic cases were divided into three groups based on serum sodium value: mild (cases with serum sodium levels of 130-134 mEq/L), moderate (serum sodium levels of 125-129 mEq/L), and severe (serum sodium levels ≤124 mEq/L) [12].
Serum osmolality was calculated using the formula 2 x Na+2 + (Glucose/18) + (Urea/2.8). Cases meeting all diagnostic criteria of serum sodium ≤135 mEq/L, serum osmolality < 280 mOsm/kg, sodium in spot urine > 30 mEq/L, urine osmolality > 100 mOsm/kg, absence of hypovolemia and dehydration, normal thyroid and adrenal functions, and absence of advanced liver, kidney, and heart disease were regarded as SIADH [13].
Data acquisition
Blood specimens collected from all cases within 2 hours of admission before any fluid therapy were studied in the laboratory, and serum sodium levels were subsequently investigated once every 72 hour during hospitalization. Demographic data including age, sex, type of birth, birth week, history of neonatal intubation, type of nutrition, duration of symptoms, atopy, additional disease, family history of atopy, characteristics of the place of residence (rural or urban, presence of animals in the home, and dampness in the home), maternal smoking status during pregnancy, and smoking status within the home were recorded for patients admitted with a diagnosis of bronchiolitis. Data regarding clinical course were also recorded, including respiratory rate, heart rate, oxygen requirement, the severity of bronchiolitis, high-flow nasal cannulation (HFNC) requirement, intubation requirement, length of hospitalization, and fluid used. Laboratory results such as albumin, glucose, urea, creatinine, sodium, potassium, chloride, alanine aminotransferase (ALT), serum osmolality, and blood gas values (pH, carbon dioxide [pCO2] and bicarbonate [HCO3]), sodium in spot urine, and urine osmolality were also recorded.
Laboratory analysis
Venous blood specimens were collected from all patients during hospitalization. Biochemical parameters and sodium levels in spot urine were investigated with an Architect c8000 Processing Module (Abbott Laboratories, Japan) device. Blood gas was investigated using an ABL 700 Series (Radiometer Medical ApS, Denmark) device, and urine osmolality with a Beckman Coulter AU5811 (Diamond Diagnostics Inc., USA) device.
Statistical Analysis
Data were analyzed on SPSS (Statistical Package for Social Sciences Statistical Software) version 23.0 (SPSS, Inc., Chicago, USA) software. The chi-square test was employed in the analysis of categorical data. The Kolmogorov-Smirnov test was applied to determine whether continuous data were compatible with a normal distribution. Normally distributed data were expressed as mean ±standard deviation and were analyzed using the Independent Two Samples t-test. Non-normally distributed data were expressed as mean values (minimum-maximum) and were analyzed using the Mann-Whitney U test. P values <0.05 were regarded as statistically significant.
Linear multiple regression analysis (Backward LR model) was applied in order to identify independent predictor markers affecting length of hospitalization. Ordinal regression analysis was employed to determine independent markers capable of use in predicting the degree of severity of bronchiolitis.
Results
Sixty-two (36.4%) patients were hyponatremic and 108 (63.6%) were normonatremic. Mild hyponatremia was determined in 53 patients (85.4%) and moderate hyponatremia in nine (14.6%), while severe hyponatremia was not observed in any case. Boys represented 67.8% of hyponatremic cases and girls 32.2%.
No statistically significant difference was determined between the groups in terms of sex, age, duration of symptoms before presentation, type of birth, neonatal intubation, type of nutrition, recurrent wheezing, atopy, familial atopy, place of residence, presence of animals in the home, presence of damp in the home, smoking in the home, or maternal history of smoking during pregnancy (p>0.05).
Thirty-two (51.6%) patients in the hyponatremic group were diagnosed with mild, 13 (20.9%) with moderate, and 17 (27.5%) with severe bronchiolitis. In the normonatremic group, 85 (78.7%) patients were diagnosed with mild, 14 (12.9%) with moderate, and nine (8.4%) with severe bronchiolitis. The prevalence of moderate and severe bronchiolitis was significantly higher in the hyponatremic group than in the normonatremic group (p<0.001). Oxygen requirements were present in 31 (50%) of the hyponatremic group and 23 (21.2%) of the normonatremic group (p<0.001). Seventeen (27.4%) patients in the hyponatremic group and nine (0.08%) in the normonatremic group required HFNC (p=0.001). One patient in each group was intubated. No statistically significant difference was determined between the two groups in terms of intubation requirement (p=0.589). Median (minimum-maximum) length of hospitalization was 5 (2-21) days in the hyponatremic group and 4 (2-11) days in the normonatremic group (p=0.001). The length of hospitalization was significantly longer in the hyponatremic group (Table 1).
Mean serum osmolarity was 273.6±3.8 mOsm/L in the hyponatremic group and 284.5±4.3 mOsm/L in the normonatremic group (p<0.001). SIADH was determined in 33 patients in the hyponatremic group. No hyponatremia developed in any case that was normonatremic at baseline. No clinical findings of hyponatremia (nausea, vomiting, headache, lack of appetite, fatigue, lethargy, apathy, agitation, muscle cramps, and convulsion) were observed in any of our hyponatremic patients with bronchiolitis.
Ordinal logistic regression analysis was applied in order to identify independent predictors of the severity of bronchiolitis. The probability of developing severe bronchiolitis was 9.855 times higher in children who had never breastfed compared to those receiving mother’s milk + formula milk + additional food (p=0.040), 0.037 times higher in subject with atopy than in those without (p<0.001), and 0.085 times higher in subjects with hyponatremia than in those without (p<0.001) (Table 2).
Linear multiple regression (backward LR model) was applied in order to identify independent predictors of length of hospitalization in bronchiolitic cases. Female gender was observed to reduce length of hospitalization 0.4-fold (p=0.020), while a history of atopy increased the length of hospitalization approximately 4.7-fold (p=0.011) and hyponatremia also increased it approximately 4.7-fold (p<0.001) (Table 3).
Discussion
Acute bronchiolitis is responsible for 3-5% of emergency department presentations in infancy. No effectiveness has been proved for therapeutic methods other than hydration, nutrition, and oxygenation [10]. A gradual decrease in hospital presentations due to bronchiolitis has been reported, although numbers of cases requiring invasive or non-invasive mechanical ventilation have increased, and this has led to greater complication rates and costs [1]. It is therefore important to identify factors necessitating hospitalization in cases of bronchiolitis and that thus prolongs hospital stay or leads to the development of complications.
Hyponatremia has been reported to be capable of occurring in respiratory tract infections in addition to pathologies such as meningitis, encephalitis, head trauma, use of some drugs, and long-term hypotonic fluid use in hospitalized patients [14-16]. Hyponatremia has particularly been reported in association with SIADH in cases of pneumonia among respiratory tract problems [12]. Recent studies have investigated the relation between moderate-severe bronchiolitis and hyponatremia, and the development of neurological complications such as apnea and hyponatremia [3-6, 8]. This study examined the relation between hyponatremia and degree of bronchiolitis and length of hospitalization in cases of mild, moderate, and severe bronchiolitis.
Milani et al. [5] observed hyponatremia in 91 cases of moderate-severe bronchiolitis, with hyponatremia being mild in 74 cases (81.3%), moderate in 15 (16.4%), and severe in one (1.3%). Hyponatremia was present in 62 cases (36.4%) in our study, mild in 53 (85.4%) and moderate in nine (14.6%). No severe hyponatremia was determined in any of our patients.
Luu et al. [3] reported a mean age of 11.2 months in their hyponatremic group, but no significant difference in terms of age compared to the normonatremic group. Hasegawa et al. [4] reported that hyponatremia developed more frequently in patients with bronchiolitis aged 12-24 months. The mean age of the hyponatremic group in our study was 9.2 months, and we determined no statistically significant difference in terms of age compared with the normonatremic group.
Hasegawa et al. [4] compared the two groups in terms of the history of breastfeeding and reported that 19 patients (50%) in the hyponatremic group and 105 (54.4%) in the normonatremic group received mother’s milk, and that the difference between the groups was not statistically significant. In our study, 50 patients (80.6%) in the hyponatremic group and 90 (83.3%) in the normonatremic group had a history of breastfeeding. Our rate of breastfeeding was higher in both groups compared with those of other studies. However, the risk of development of severe bronchiolitis was 9.8-fold higher in patients who were not breastfed compared to those who received mother’s milk and mixed nutrition.
Shibli et al. [8] determined that neurological complication developed in one case of severe hyponatremia with a serum sodium level of 123 mmol/L among 84 cases of bronchiolitis with hyponatremia detected at presentation. They reported using hypotonic fluid containing 0.18% NaCl in that case. Shein et al. [6] also reported that the use of hypotonic fluid in patients with bronchiolitis led to hyponatremia, and that this resulted in poor outcomes. In our study, no neurological complications were observed in any case. We attribute this to the absence of any cases of severe hyponatremia (<125 mmol/L) in our study and to hypotonic fluid not being used during hospitalization.
Although several studies have investigated the relationship between the prevalence of SIADH and pneumonia, very few have examined the association between the prevalence of SIADH and acute bronchiolitis. One study from japan determined SIADH in 38.7% of cases of pneumonia, in 22.9% of cases of bronchitis and bronchiolitis, and in 13.3% of cases of pharyngitis and laryngitis [17]. Hasegawa et al. [18] reported hyponatremia in 73 out of 1191 patients admitted to the pediatric department, and that 10 of these were cases diagnosed with bronchiolitis. SIADH was determined in 33 (19.4%) of the bronchiolitis cases included in our study. However, considering that hyponatremia was not determined in 62 patients, we think that pathologies other than SIADH may be involved in the etiology of hyponatremia.
Anıl et al. [19] suggested that the presence of hyponatremia does not exacerbate the disease in cases of lower respiratory tract infection. However, it is difficult to standardize these data since that study evaluated not cases of bronchiolitis alone, but all diseases such as bronchiolitis, pneumonia, and bronchopneumonia under the heading of lower respiratory tract infections. Milani et al. [5] also reported no relation between hyponatremia and degree of severity of bronchiolitis. Hasegawa et al. [4] examined cases of moderate-severe bronchiolitis and reported a relation between hyponatremia and severity of bronchiolitis, greater mechanical ventilation requirements in hyponatremic cases, and that hyponatremia exacerbated the disease. Luu et al. [3] also reported no difference in terms of intubation requirements between hyponatremic and normonatremic cases, but that non-invasive ventilation requirements were higher in hyponatremic cases. While we observed no difference between our hyponatremic and normonatremic groups in terms of mechanical ventilation requirements, the frequency of development of severe bronchiolitis, and non-invasive ventilation requirements, such as HFNC, were significantly higher in the hyponatremic cases. In addition, ordinal regression analysis revealed a correlation between the development of severe bronchiolitis and hyponatremia, with hyponatremia increasing the risk of severe bronchiolitis 0.085-fold.
Don et al. [20] reported lengths of hospitalization of 5.35 days in hyponatremic cases and 5.50 days in non-hyponatremic cases in a patient group diagnosed with atypical pneumonia, and that hyponatremia did not affect the length of hospital stay in patients with pneumonia. In their study of children with pharyngitis, laryngitis, bronchiolitis, and pneumonia, Kaneko et al. [17] also reported that hyponatremia did not affect the length of hospitalization. However, Luu et al. [3], Hasegawa et al. [4] and Shein et al. [6] investigated the relationship between hyponatremia and severity of bronchiolitis and determined longer hospital stays in cases with hyponatremia compared to those without. We also determined longer hospitalization in bronchiolitis cases with hyponatremia compared to the normonatremic group. In addition to hyponatremia, male gender and history of atopy also prolonged length of hospital stay.
The limitations of our study may be listed as the relatively low patient number and the low number of patients with severe bronchiolitis.
In conclusion, the risk of development of severe bronchiolitis and of oxygen and non-invasive ventilation requirements was higher in the hyponatremic group compared to the normonatremic group. Hyponatremia was found to prolong hospitalization in cases of bronchiolitis.
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. Hasegawa K, Tsugawa Y, Brown DF, Mansbach JM, Camargo CA Jr. Trends in bronchiolitis hospitalizations in the United States, 2000–2009. Pediatrics. 2013;132(1):28–36.
2. Rivera-Sepulveda A, Garcia-Rivera EJ. Epidemiology of bronchiolitis: a description of emergency department visits and hospitalizations in Puerto Rico, 2010-2014. Trop Med Health. 2017;45:24.
3. Luu R, DeWitt PE, Reiter PD, Dobyns EL, Kaufman J. Hyponatremia in children with bronchiolitis admitted to the pediatric intensive care unit is associated with worse outcomes. J Pediatr. 2013;163(6):1652-6.
4. Hasegawa K, Stevenson MD, Mansbach JM, Schroeder AR, Sullivan AF, Espinola JA, et al. Association between hyponatremia and higher bronchiolitis severity among children in the ICU with bronchiolitis. Hosp Pediatr. 2015;5(7):385-9.
5. Milani GP, Rocchi A, Teatini T, Bianchetti MG, Amelio G, Mirra N, et al. Hyponatremia in infants with new onset moderate-severe bronchiolitis: A cross-sectional study. Respir Med. 2017;133:48-50.
6. Shein SL, Slain K, Martinez Schlurmann N, Speicher R, Rotta AT. Hyponatremia and hypotonic intravenous fluids are associated with unfavorable outcomes of bronchiolitis admissions. Hosp Pediatr. 2017;7(5):263-70.
7. Hanna S, Tibby SM, Durward A, Murdoch IA. Incidence of hyponatraemia and hyponatraemic seizures in severe respiratory syncytial virus bronchiolitis. Acta Paediatr. 2003;92(4):430–4.
8. Al Shibli A, Abukhater D, Al Kuwaiti N, Noureddin MB, Al Harbi M, Al Kaabi A, et al. Hyponatraemia and neurological complications in children admitted with bronchiolitis. Paediatr Int Child Health. 2016;36(3):175-80.
9. Coates BM, Camarda LE, Goodman DM. Wheezing, Bronchiolitis, and Bronchitis. In: Kliegman RM, Stanton BF, St Geme III JW, Schor NF, Behrman RE. Nelson Textbook of Pediatrics, 20th ed. Philadelphia: Saunders Elsevier; 2015.p.2044-8.
10. Kou M, Hwang V, Ramkellawan N. Bronchiolitis: From Practice Guideline to Clinical Practice. Emerg Med Clin North Am. 2018;36(2):275-86.
11. Golan-Tripto I, Goldbart A, Akel K, Dizitzer Y, Novack V, Tal A. Modified Tal Score: Validated score for prediction of bronchiolitis severity. Pediatr Pulmonol. 2018;53(6):796-801.
12. Lavagno C, Milani GP, Uestuener P, Simonetti GD, Casaulta C, Bianchetti MG, et al. Hyponatremia in children with acute respiratory infections: A reappraisal. Pediatr Pulmonol. 2017;52(7):962-67.
13. Reddy P, Mooradian AD. Diagnosis and management of hyponatremia in hospitalized patients. Int J Clin Pract. 2009;63:1494-508.
14. Rondon-Berrios H, Agaba EI, Tzamaloukas AH. Hyponatremia: pathophysiology, classification, manifestations and management. Int Urol Nephrol. 2014;46(11):2153-65.
15. Moritz ML, Ayus JC. Hospital-acquired hyponatremia–why are hypotonic parenteral fluids still being used? Nat Clin Pract Nephrol. 2007;3(7):374-82.
16. Gankam Kengne F, Decaux G. Hyponatremia and the Brain. Kidney Int Rep. 2017;3(1):24-35.
17. Kaneko K, Kaneko KI. Hyponatremia in children with respiratory tract infection. Pediatr Nephrol. 2009;24(8):1595-6. DOI: 10.1007/s00467-009-1139-4.
18. Hasegawa H, Okubo S, Ikezumi Y, Uchiyama K, Hirokawa T, Hirano H, et al. Hyponatremia due to an excess of arginine vasopressin is common in children with febrile disease. Pediatr Nephrol. 2009;24(3):507-11.
19. Anıl A, Anıl M, Köse E, Zengin N, Alparslan C, Bayram N, et al. Alt solunum yolu enfeksiyonlu çocuklarda serum sodyum düzeyi (Serum sodium level in children with lower respiratory tract infections). J Pediatr Inf. 2011;5:100-5.
20. Don M, Valerio G, Korppi M, Canciani M. Hyponatremia in pediatric communityacquired pneumonia. Pediatr Nephrol. 2008;23(12):2247-53.
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Fatih Isleyen, Mehmet Tekin, Capan Konca. The relation between hyponatremia at presentation, severity of disease and length of stay in patients with bronchiolitis. Ann Clin Anal Med 2021;12(2):129-133
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Comparison of primer and revisional laparoscopic mini-gastric bypass (MGB) for failed restrictive procedures: 2-year results at a tertiary center
Fahrettin Acar, Bayram Çolak, Mustafa Şahin
Department of Surgery, Faculty of Medicine,Selcuk University, Konya, Turkey
DOI: 10.4328/ACAM.20210 Received: 2020-05-14 Accepted: 2020-06-15 Published Online: 2020-06-30 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):124-128
Corresponding Author: Fahrettin Acar, Department of General Surgery, Selcuk University, Faculty of Medicine, Campus of Alaaddin Keykubat, 42075, Selcuklu, Konya, Turkey. E-mail: drfacar@hotmail.com GSM: +90 533 9638946 P: +90 332-241-5000 int-44709 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1797-1770
Aim: Revisional surgery is becoming a common and challenging practice in bariatric centers. The aim of this study was to evaluate laparoscopic mini-gastric bypass (MGB) as a revisional procedure for failed restrictive bariatric procedures.Material and Methods: One hundred sixty patients who underwent MGB between April 2012 and December 2017 were included in this retrospective study. Revisional MGB was defined as rMGB performed after failure of a first restrictive procedure. The main outcome measures were the success of therapeutic strategies, morbidity, body mass index (BMI), and percentage of excess BMI loss (%EBMIL) before and after revision.Results: Forty patients (25%) who had prior restrictive bariatric surgery (including 26 laparoscopic sleeve gastrectomies, 9 gastric plications, and 5 adjustable gastric bandings) underwent conversion to rMGB. Ninety patients (75%) underwent primary MGB (pMGB group). Both groups were comparable in age, gender, BMI, and preoperative co-morbidities. The pre-operative mean BMI of the rMGB group was 45.5 ± 7 kg/m2. No increase in morbidity was found between the 2 groups. Two patients with pMGB and one patient required conversion to RYGB after rMGB because of intractable biliary reflux. At 2 years, mean BMI was 30.5 kg/m2 and mean %EBMIL was 72% after rMGB; no significant differences were found compared with pMGB (BMI =29.5 kg/m2, %EBMIL =73%). Co-morbidities and remission rates were statically similar.Discussion: The results of our study show that rMGB is a safe and effective revisional procedure after failed restrictive bariatric surgery compared with pMGB.
Keywords: Bariatric surgery; Revision; Mini-Gastric bypass; Sleeve gastrectomy; Gastric plication
Introduction
Bariatric surgery currently represents the best treatment option for morbid obesity and its related diseases [1]. Over the past 25 years, laparoscopic adjustable gastric banding (LAGB) has been one of the most popular interventions until long-term studies reported a high rate of poor responders and band complications [2,3].Laparoscopic sleeve gastrectomy (LSG) has recently become the most frequently performed bariatric procedure worldwide due to its simplicity, versatility, and effectiveness [4]. However, there are conflicting data, regarding long-term outcomes of LSG, especially in comparison with laparoscopic Roux-en-Y gastric bypass (LRYGB), and reflux consequences after this procedure are still a matter of concern [5,6]. Laparoscopic gastric plication (LGP) is an evolving technique that gained popularity with the idea of reproducing a sleeve gastrectomy but without tissue transection [7]. With an increasing number of purely restrictive procedures, the significant issue of weight regain is becoming more prevalent and many studies have reported unreliable long-term results [8]. Different procedures have been proposed as revisional surgery for the increasing number of patients who had previously undergone a failed and/or bariatric restrictive procedure (LAGB, LGP or LSG).
Previously published studies have mainly reported outcomes of conversion from restrictive surgery to LRYGB or purely malabsorptive procedures such as bilio-pancreatic diversion with duodenal switch (BPD/DS) or single anastomosis duodenal switch [9-11]. Laparoscopic MGB as a primary and revisional surgery is growing in adoption around the world [12]. Laparoscopic MGB bypass links the effect of RYGB as a low-pressure system and a less dangerous malabsorptive procedure than BPD/DS [13]. Thus, it associates the positive effects of BPD/DS and RYGB with further excess weight loss (%EWL) and the treatment of GERD. The current literature confirms the safety and long-term effectiveness of MGB as a primary procedure as well as a revisional surgery for failed gastric restrictive procedures [14,15]. The aim of this study was to present the short-term result of converting failed LAGB, LGP and LSG to rMGB from our high-volume bariatric center.
Material and Methods
The local ethics committee of Selcuk University Hospital approved this study. All study participants were consented before retrospective data review and analysis. Data of the patients who underwent MGB in Selcuk University Hospital Department of Obesity and Metabolic Surgery between April 2012 and December 2017 were retrospectively reviewed. Patients who underwent revisional (rMGB) after failed restrictive obesity surgery were identified. Adjustable gastric band and gastric plication procedures are never performed in our clinic and these patients were referred to us at the tertiary unit. Primary and rMGB were performed by the same surgeon (FA) and followed the same standardized technique. The study was approved by the local Ethics Committee and the need for patients’ informed consent was waived due to the retrospective nature of the study. The type of revisional surgery was determined by patient preference unless there is an absolute contraindication. Preoperatively, all patients underwent a standard preoperative evaluation consisting of an abdominal ultrasound, an upper gastrointestinal endoscopy, and cardiac, pulmonary, and endocrinological evaluations. An upper GI contrast study was additionally performed in all revisional cases. A standard dietary protocol was followed for all patients. This protocol included a 1-month liquid diet and then a 1-month soft diet. A regular diet was allowed postoperatively at 2 months. No vitamin supplements or proton pump inhibitors (PPI) were prescribed during hospital discharge. Vitamin and mineral deficiencies were determined according to follow-up results. Patients were regularly followed up in the outpatient clinic under the guidance of an experienced dietician and a member of the surgical team. After the first follow-up visit on a postoperative day 7, follow-up visits were performed at 1, 3, 6, 12, and 24 months. Patients’ data including patients’ characteristics, comorbidities, preoperative BMI, percentage of excess BMI loss (%EBMIL), complications, and causes for revisional surgery were obtained from hospital charts and office records. Patient contact with a surgeon and dietitian was guaranteed through phones numbers or online.
Surgical Technique
Laparoscopic one-anastomosis gastric bypass as a revisional procedure was performed as described by Rutledge [16]. The technique used for rMGB is based on a 5-port approach. For patients with previous SG, the gastric sleeve is dissected free from firm adhesion between the staple line and surrounding tissues, starting from the distal staple line and proceeding to the angle of His. For patients with previous GP, the plicated part of the stomach was dissected free from surrounding tissues and the line of sutures was disrupted only where the first staples were placed. The first step of rMGB involved a calibrated (36 F tube) sleeve using a 60-mm Medtronic Tri-Staple® (Medtronic Inc., Dublin, Ireland) removing all the excessive and/or plicated gastric tissue along with plicature sutures.
For patients with previous AGB, the gastric band was freed from the surrounding capsule and adhesions and cut and extracted through the 15mm port. The internal fibrous tissue between the band and the stomach was removed as well to prevent stenosis of the tube at this level. The gastric greater curvature was then completely freed starting at 4 cm proximal to the pylorus using LigaSure (Covidien, Minneapolis, MN, USA) along with the direct release of lower sac adhesions and scarring to the left crus. A long, narrow gastric pouch was constructed starting from beyond the crow’s foot to just lateral to the angle of His over a 36-Fr orogastric tube using a 60-mm Medtronic Tri-Staple. The final stapling was carried out just lateral to the gastrooesophageal fat pad. A biliopancreatic limb of 200 cm was then measured from the ligament of Trietz using markings on the instruments as a guide. Gastrojejunostomy was then performed using a 45-mm Medtronic® (Medtronic Inc., Dublin, Ireland) linear stapler followed by continued absorbable barbed suture (V-Loc, Covidien, USA) closure of the stapler entry opening. There was no difference in the construction of gastrojejunostomy between the two groups. Also, we used a hanging suture between the gastric pouch and the afferent loop to minimize reflux and a retaining suture between the lower part of the pouch and the antrum to prevent it from twisting. A Closed suction drainage system was used along the resection margin.
Intraoperative methylene blue test was performed to exclude a leak. Increasing systolic blood pressure to 130 mmHg while decreasing the pneumoperitoneum pressure allowed the achievement of hemostasis at the staple line by cautery or oversuturing and abdominal drainage was left in place. Every patient who underwent a bariatric operation in our division had recorded video from the laparoscopic camera, that allows for time recording and video staff presentations, as well as a reference in case of medicolegal issues.
Statistical analyses
The statistical analyses were conducted by Statistical Package for Social Sciences software (SPSS v22, IBM Corp., Armonk, NY, US), and p value was considered significant when it was less than 0,05. The chi-square and Fisher’s exact tests were used for comparing the categorical data between independent groups. Independent-samples t-test was used to compare the continuous data, while Levene’s test was implemented to assess the equality of variance.
Results
Our retrospective review revealed that 160 patients underwent MGB surgery during the study period. Among these patients, 40 underwent revision (rMGB) after failed restrictive bariatric surgery (Table 1,2). The mean duration of surgery was 142±24 minutes in the rMGB group and 117±38 minutes in the pMGB group. No intraoperative and postoperative patient death was reported. In 1 patient (0.5%), major late morbidity was observed; this patient required conversion to an RYGB for intractable biliary reflux two years after rMGB. In the pMGB group, major early morbidity requiring surgery occurred in 4 patients (3.3%) (Table 3). One patient experienced late marginal ulcer perforation 4 years after MGB. This case was successfully treated by an emergency laparotomy. One patient who presented with bowel obstruction due to postoperative adhesions 3 years after pMGB was treated laparoscopically. Two patients who had intractable biliary reflux necessitated surgical treatment 3 and 4 years after pMGB. There was no significant difference between the two groups as per the early and late major morbidity rates. The mean BMI was30.5±4 kg/m2, and the mean EBMIL% was 72±11% two years after rMGB (Table 3). Two groups were similar in terms of BMI and EBMIL% by the end of the follow-up period.
Nutritional status and co-morbidities
After 2 years, no cases developed severe malnutrition after pMGB and rMGB. Mean albumin level was 38 ± 4 g/L in the overall series and no significant differences were found between the 2 groups. Significant decrease in the rates of hypertension, T2DM, hyperlipidemia and sleep apnea syndrome were observed at the end of the follow-up period compared with the preoperative period in each group. After 2 years, no significant differences were found in the remission rates of any obesity-related co-morbidities that occurred in the rMGB and pMGB groups (Table 3).
Discussion
Weight loss failure is still a significant issue after bariatric surgery [17]. Therefore, revision surgery is becoming a common practice in bariatric centers. Today, as many as 15% of bariatric surgery procedures are revision surgeries; this number will likely increase shortly. Revision procedures are challenging for surgeons due to altered anatomy and firm adhesions [18]. In line with this, revision surgeries are associated with increased rates of perioperative surgical complications. Most of these complications arise from the gastric pouch or gastric remnant. Although LSG is a simple and popular bariatric surgery procedure, long-term data suggest that weight loss failure is not uncommon after this surgery with a conversion rate of up to 35.8% at 10 years [18]. The LGP is an evolving bariatric procedure; however, it is also associated with a high surgical revision rate [19]. It was reported that reaching 57.7% of all LGP procedures necessitated revision surgery within 18 months. Anatomical and surgical factors increasing the risk of weight regain after LSG procedure include an initial large sleeve, incompletely resected fundus, and a large remnant antrum [19]. On the other hand, dilatation or prolapse of gastric plication is the main factor related to weight regain after LGP. Single anastomosis duodenal-ileal bypass is currently considered as an effective salvage method for failed sleeve gastrectomy procedure. However, this procedure has the risks of duodenal fistula formation and malnutrition [20]. Alternatively, it can be converted to a functional single-anastomosis gastric bypass for revision purposes.
Our study compared the 2-year outcomes of 40 morbidly obese patients who underwent revision MGB for a failed restrictive bariatric procedure with those of 120 patients who underwent primary MGB. Our main findings indicate that rMGB is an effective and safe procedure in the long term. They also showed no significant increase in morbidity with rMGB procedure during a 2-year postoperative follow-up. Also, our cohort’s major morbidity rate was in line with the rates reported in the literature for revision LRYGB performed secondary to a failed restrictive procedure [21–23]. As such, the 6.6% early major complication rate in our rMGB group appears to be acceptable.
Our analysis elucidated that the two groups were similar in terms of weight loss. Besides, the mean EBMIL% of 66% at two years in our rMGB group compares favorably with the post-rRYGB EBMIL% reported in the literature [21,22]. This finding supports the hypothesis that rMGB can provide weight loss successfully after a failed restrictive bariatric procedure.
The long-term efficacy of MGB expresses itself also by proper management of obesity-related co-morbidities, including T2DM [15,24]. In our study, remission rates from all co-morbidities were improved, and they were similar between two patient groups: Approximately 78% of the T2DM patients in the rMGB group experienced remission; this rate was 80% for the patients in the pMGB group. These promising results regarding weight loss and management of obesity-related co-morbidities are consistent with the outcomes reported for rLRYGB in the current literature [21,22]. Also, they encourage performing rMGBP for surgical treatment of morbid obesity after a failed restrictive bariatric procedure.
Our study has some weaknesses which should be considered while evaluating its findings. First, it is a retrospective study that could be affected by all inherent limitations stemming from its retrospective design. Second, our data did not include the results of the tests assessing esophageal pressures such as esophageal manometry and additional tests such as pH, upper gastrointestinal endoscopy, and upper gastrointestinal series. Since patient stress and anxiety can also affect the outcomes, the fact that we did not assess our patients’ stress and anxiety levels can be considered as another limitation of our study.
Conclusion
Laparoscopic revisional bariatric surgery is technically demanding but it is safe and effective when the causes of failure of the primary procedure were identified, addressed and corrected by an experienced laparoscopic team. Revisional procedures involving the addition of malabsorption result in a greater weight loss than gastric restriction alone. The results of our study show that rMGB after a failed restrictive procedure was well tolerated and effective compared with primary surgery in the mid-term. Further studies are required.
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. Sjöström L. Bariatric surgery and reduction in morbidity and mortality: experiences from the SOS study. Int J Obes. 2008;32(Suppl.7):S93–7.
2. Buchwald H, Williams SE. Bariatric surgery worldwide 2003. Obes Surg. 2004;14(9):1157–64.
3. O’Brien PE, MacDonald L, Anderson M, Brennan L, Brown WA. Long-term outcomes after bariatric surgery: fifteen-year follow-up of adjustable gastric banding and a systematic review of the bariatric surgical literature. Ann Surg. 2013;257(1):87–94.
4. Angrisani L, Santonicola A, Iovino P, Vitiello A, Higa K, Himpens J, et al. IFSO worldwide survey 2016: primary, endoluminal, and revisional procedures. Obes Surg. 2018;28(12):3783–94.
5. Juodeikis Z, Brimas G. Long-term results after sleeve gastrectomy: a systematic review. Surg Obes Relat Dis. 2017;13(4):693–9.
6. Genco A, Soricelli E, Casella G, Maselli R, Castagneto-Gissey L, Di Lorenzo N, et al. Gastroesophageal reflux disease and Barrett’s esophagus after laparoscopic sleeve gastrectomy: a possible, underestimated long-term complication. Surg Obes Relat Dis. 2017;13(4):568-74.
7. Chouillard E, Schoucair N, Alsabah S, Alkandari B, Montana L, Dejonghe B, et al. Laparoscopic gastric plication (LGP) as an alternative to laparoscopic sleeve gastrectomy (LSG) in patients with morbid obesity: a preliminary, short-term, case-control study. Obesity Surgery. 2016;26(6):1167–72.
8. Zerrweck C, Rodr´ıguez JG, Aramburo E, Vizcarra R, Rodríguez JL, Solórzano A, et al. Revisional surgery following laparoscopic gastric plication. Obesity Surgery. 2017;27(1):38–43.
9. Creange C, Jenkins M, Pergamo M, Fielding G, Ren-Fielding C, Schwack B. Gastric band conversion to Roux-en-Y gastric bypass shows greater weight loss than conversion to sleeve gastrectomy: 5- year outcomes. Surg Obes Relat Dis. 2018;14(10):1531–6.
10. Boru CE, Greco F, Giustacchini P, Raffaelli M, Silecchia G. Shortterm outcomes of sleeve gastrectomy conversion to R-Y gastric bypass: multi-center retrospective study. Langenbecks Arch Surg. 2018;403(4):473–9.
11. Moon RC, Fuentes AS, Teixeira AF, Jawad MA. Conversions after sleeve gastrectomy for weight regain to single and double anastomosis duodenal switch and gastric bypass at a single institution. Obes Surg. 2019;29(1):48–53.
12. De Luca M, Tie T, Ooi G, Higa K, Himpens J, Carbajo MA, et al. Mini gastric bypass-one anastomosis gastric bypass (MGB-OAGB)-IFSO position statement. Obes Surg. 2018;28(5):1188–206.
13. Disse E, Pasquer A, Espalieu P, Poncet G, Gouillat C, Robert M. Greater weight loss with the omega loop bypass compared to the Roux-en-Y gastric bypass: a comparative study. Obes Surg. 2014;24(6):841–6.
14. Musella M, Susa A, Manno E, De Luca M, Greco F, Raffaelli M, et al. Complications following the mini/one anastomosis gastric bypass (MGB/OAGB): a multiinstitutional survey on 2678 patients with a mid-term (5 years) follow-up. Obes Surg. 2017;27(11):2956–67.
15. Bruzzi M, Voron T, Zinzindohoue F, Berger A, Douard R, Chevallier JM. Revisional single anastomosis gastric bypass for a failed restrictive procedure: 5- year results. Surg Obes Relat Dis. 2016;12(2):240–5.
16. Rutledge R. The mini-gastric bypass: experience with the first 1274 cases. Obes Surg. 2001;11:276–80.
17. Stroh C, Weiner R, Wolff S, Manger T, Arbeitsgruppe Adipositaschirurgie, Kompetenznetz Adipositas. Revisional surgery and reoperations in obesity and metabolic surgery: data analysis of the German bariatric surgery registry 2005-2012. [Article in German]. Chirurg. 2015;86(4):346–54.
18. Noel P, Nedelcu M, Eddbali I, Manos T, Gagner M. What are the long-term results 8 years after sleeve gastrectomy? Surgery for Obesity and Related Diseases. 2017;13(7):1110–15.
19. Albanese A, Prevedello L, Verdi D, Nitti D, Vettor R, Foletto M. Laparoscopic gastric plication: an emerging bariatric procedure with high surgical revision rate. Bariatr Surg Pract Patient Care. 2015;10(3):93–8.
20. Vilallonga R, Balibrea JM, Curell A, Gonzalez O, Caubet E, Ciudin A, et al. Technical options for malabsorption issues after single anastomosis duodenoileal bypass with sleeve gastrectomy. Obes Surg. 2017;27(12):3344–48.
21. Elnahas A, Graybiel K, Farrokhyar F, Gmora S, Anvari M, Hong D. Revisional surgery after failed laparoscopic adjustable gastric banding: A systematic review. Surg Endosc. 2013;27(3):740–5.
22. Thereaux J, Corigliano N, Poitou C, Oppert JM, Czernichow S, Bouillot JL. Five-year weight loss in primary gastric by pass and revisional gastric bypass for failed adjustable gastric banding: Results of a Case-Matched Study. Surg Obes Relat Dis. 2015;11(1):19–25.
23. Mor A, Keenan E, Portenier D, Torquati A. Case-matched analysis comparing outcomes of revisional versus primary laparoscopic Roux-en-Y gastric bypass. Surg Endosc. 2013;27(2):548–52.
24. Lee WJ, Ser KH, Lee YC, Tsou JJ, Chen SC, Chen JC. Laparoscopic Roux-en-Y vs. mini-gastric bypass for the treatment of morbid obesity: a 10-year experience. Obes Surg. 2012;22(12):1827–34.
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Fahrettin Acar, Bayram Çolak, Mustafa Şahin. Comparison of primer and revisional laparoscopic mini-gastric bypass (MGB) for failed restrictive procedures: 2-year results at a tertiary center. Ann Clin Anal Med 2021;12(2):124-128
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Evaluation of protective effect of L-carnitine and N-acetylcysteine in mesenteric ischemia-reperfusion injury model in rats
Utku Murat Kalafat 1, Busra Bildik 1, Serkan Dogan 1, Rabia Birsen Tapkan 1, Melis Dorter 1, Ayse Fethiye Basa Kalafat 1, Bahaeddin Tapkan 2, Said Incir 3, Basar Cander 1
1 Department of Emergency Medicine, Kanuni Sultan Suleyman Training and Research Hospital, University of Health Science, 2 Department of General Surgery, İstanbul Training and Research Hospital, 3 Department of Biochemistry, Koc University, Medical Faculty, Istanbul, Turkey
DOI: 10.4328/ACAM.20212 Received: 2020-05-17 Accepted: 2020-06-27 Published Online: 2020-06-30 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):134-138
Corresponding Author: Busra Bildik, Atakent Mh. Turgut Ozal Cd. No:1 Altinsehir/Kucukcekmece, 34303, Istanbul, Turkey. E-mail: drbusrabeyoglu@gmail.com P: +90 532 605 47 36 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1546-4612
Aim: Ischemia-reperfusion injury is an important dilemma in surgical modalities. The mechanism of IR damage is related to oxidative stress mediators. L-carnitine and N-acetylcysteine are thought to have antioxidant activity. In our study, we aimed to evaluate the effects of short-term administration of these two drugs and to compare their effects on oxidative stress parameters in the experimental mesenteric ischemia-reperfusion model in rats. Materials and Methods: Twenty-four female Sprague-Dawley rats were allocated into 3 experimental groups. In Group 1 (CG) (n=8), rats underwent occlusion of the superior mesenteric artery for 30 minutes and were not given any medications. In Group 2 (NG) and Group 3 (LG), rats underwent occlusion as CG. Rats were given 150 mg/kg (IP) N-acetylcysteine and 300 mg/kg IP L-carnitine according to their groups 15 minutes before reperfusion. Rats were sacrificed with high dose anesthetic drugs after 60 minutes of reperfusion. Blood and liver tissue samples were obtained to investigate total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI). Results: By biochemical examination, all groups showed similar levels of TOS. There was no statistically significant difference between the level of TAS and OSI in all groups (p>0,05). There was no any statistically significant difference between the groups for TAS measurements (p=0.061; p>0.05); however, higher measurement values in the L-Carnitine group is considerable.Discussion: Although the use of drugs with proven antioxidant efficiency after ischemia may cause a histologically significant difference in IR injury, there was no significant efficiency in the reduction of superoxides in the circulation. Therefore, we believe that the use of NAC and L-carnitine as antioxidants after the development of ischemia does not help to prevent intestinal IR injury.
Keywords: Ischemia, L-carnitine, Mesenteric, N-acetylcysteine
Introduction
Mesenteric ischemia is a vascular emergency condition with a high potential for fatal progression [1]; therefore, early diagnosis and treatment are essential. Although diagnostic methods have recently improved, the diagnosis of this condition depends on clinical suspicion [2]. It is obvious that the primary objective after diagnosis is to prevent ischemia-dependent necrosis which may be achieved only with reperfusion.
Intestinal ischemia-reperfusion (IR) is one of the significant surgical dilemmas for patients with mesenteric ischemia [3]. Reperfusion damage appears in the intestinal area by the achievement of the blood supply into the occluded artery. Although the mechanism of damage generation has not yet been clarified, the generally accepted hypothesis is the important role of oxidative stress mediators [3]. Besides, an increase of the capillary permeability, accompanied by vasodilatation after intestinal reperfusion, causes leakage of fluid and erythrocytes into the intestinal lumen; this leads to capillary plugs. Such plugs cause a decrease in the blood supply of the tissue again, which is called the “No-reflow phenomenon” [4]. Due to oxidative stress mediators and “No-reflow phenomenon”, no blood supply into the tissue can be achieved, and the tissue cannot revert even if the occlusion is eliminated. Like the disease itself, reperfusion damage also appears with high mortality and morbidity.
Carnitine is an endogenous ester with well-defined metabolic effects in the literature which transports long-chain fatty acids into the mitochondria for beta-oxidation [5]. It is known that carnitine acts as a cleaner for free oxygen radicals, suppresses the oxidative stress, and reduce lipid peroxidation [6]. It was considered to play a protective role in metabolic diseases for a long period. Furthermore, it is known for many years that carnitine reduces ATP loss and prevents acidosis. It reduces the damage through anti-radical efficiency and acts as an energy source in reperfusion damage. Carnitine stabilizes the cytosolic membrane and prevents the release of cytotoxic enzyme. The protective effect of carnitine on endothelium is also well-known. Such effects play an important role in the reduction of the “No-reflow phenomenon” [3].
N-acetylcysteine (NAC) is a small molecule including a thiol group which has been popularly analyzed recent years [7]. NAC is known to be effective in the reduction of endothelial dysfunction, inflammation, and fibrosis [8]. The thiol group involved in the molecule gives the hydrogen ion to oxygen radicals easily, reduces the radicals into the water; and thereby mitigates the epithelial injury induced by H2O2. The aforementioned reaction is caused by the direct antioxidant effect of NAC whereas it creates an indirect antioxidant effect through glutathione [9].
The present study aimed to evaluate the protective effect of the aforementioned molecules, which were analyzed in different aspects in the literature, on a mesenteric ischemia-reperfusion model created experimentally on rats and to compare them with each other.
Material and Methods
Animals and Experimental Design
The present experimental study was performed after approval of the Ethical Committee of Animal Experiments within Mehmet Akif Ersoy Experimental Research and Development Training Center in Istanbul. All experimental and surgical procedures in animal experiments were performed at the Mehmet Akif Ersoy Experimental Research and Development Training Center in Istanbul. National guidelines and regulations for the care and use of animals have been followed.
In the present study, 24 8-month-old Sprague-Dawley female rats with bodyweight between 250 g and 350 g living under standard environment conditions (22°C, individual steel cage, 12-hour day and 12-hour night cycle, ad libitum feeding) were used. All rats were operated after a fasting period of 12 hours and they were allowed to drink water within those 12 hours before the procedure. The rats were randomly divided into 3 groups including 8 rats in each group as follows: Group 1 (Control group = CG); Group 2 (N-acetylcysteine Group = NG); Group 3 (L-carnitine Group = LG).
Surgical Procedures
The animals included in the experiment were sedated with intraperitoneal xylazine hydrochloride (5 mg/kg; Rompun® 2%, Bayer) and anesthetized with intraperitoneal ketamine hydrochloride (35 mg/kg; Ketalar®, Pfizer) before the surgical procedure. Spontaneous ventilation of the animals was enabled during the experiment period. The rats were taken onto the operating table on a warming pad (12 DVC voltage- 2,5 A-Kent Scientific Corporation) in an operating room environment at 14.8°C temperature and 42% humidity; a 3cm laparotomic incision was performed on the midline after dermal sterilization through Betadine® and the intestinal tissue deviated to the left. The superior mesenteric artery was dissected by a forceps and flow was measured through laser doppler (Periflux System 5000, Perimed) before mesenteric ischemia. The superior mesenteric artery was sutured to interrupt the flow-through 6-0 silk in a re-openable pattern after the measurement. Ischemia was confirmed through laser doppler again in all groups after the ischemia; and flow measurements were done (Figure 1). No drug or placebo was administrated to the control group during and after ischemia; 150 mg/kg intraperitoneal N-acetylcysteine was administered to Group 2 and 300 mg/kg L-carnitine was applied to Group 3 at 15th minute of ischemia. Intraperitoneal administration was used to supply a large number of drugs in the animal system.
The silk suture (6-0) was opened at 30th minute after ischemia and reperfusion were achieved. The achievement of flow was confirmed by laser Doppler. An intracardiac blood sample of 5 ml was obtained from each rat at the 90th minute of the study while the rats were still under anesthesia. All rats used in the study were sacrificed through a high dose of intraperitoneal ketamine hydrochloride (45 mg/kg; Ketalar®, Pfizer).
Biochemical Analysis
Blood samples were collected by cardiac puncture from the participants at the end of the 12-hour fasting period. Blood samples were collected into dry tubes and centrifuged at 3500 × g at 4 °C for 10 min. The serum was collected and stored at − 80 °C until further analysis.
Total Antioxidant Status (TAS) determination
The total antioxidant capacity of plasma was measured using an automated colorimetric measurement method developed by Erel [10]. Total Antioxidant Status (TAS) levels were measured spectrophotometrically by a commercial kit (Rel Assay, Gaziantep, Turkey). Antioxidants in the sample reduce dark blue-green colored ABTS radical to colorless form. The change of absorbance at 660 nm is related to the total antioxidant level of the sample. The assay is calibrated with a stable antioxidant standard solution which is traditionally called a Trolox Equivalent that is vitamin E analog. Total antioxidant activities of the samples were expressed in mmol Trolox Equiv/L.
Total Oxidant Status (TOS) determination
The total oxidant capacity of plasma was measured using an automated colorimetric measurement method developed by Erel [11]. Total Oxidant Status (TOS) levels were measured by a spectrophotometric method by a commercial kit (Rel Assay, Gaziantep, Turkey). Oxidants present in the sample oxidize the ferrous ion chelator complex to ferric ion. The oxidation reaction is prolonged by enhancer molecules, which are abundantly present in the reaction medium. The ferric ion makes a color complex with chromogen in an acidic medium. The color intensity, which can be measured spectrophotometrically, is related to the total amount of oxidant molecules present in the sample. The assay is calibrated with hydrogen peroxide and the results were expressed in terms of micromolar hydrogen peroxide equivalent per liter (µm H202Equiv/L).
The ratio of TOS to TAS was accepted as an oxidative stress index (OSI). For the calculation; the unit of TAS was converted to mmol/L, and the OSI value was calculated according to the following formula: OSI (arbitrary unit): TOS (µmH202Equiv/L) / TAS (mmolTroloxEquiv/L) [12].
Statistical Analyses
NCSS (NumberCruncher Statistical System) 2007 (Kaysville, Utah, USA) program was used for statistical analyses. Descriptive statistical methods (first quartile, third quartile, and median) were used to assess the study data. The conformity of quantitative data to normal distribution was tested by the Shapiro-Wilk test and graphical reviews. The Kruskal-Wallis test was used to compare three and more groups without normal distribution. The significance was assessed at p<0.05 level.
Results
The first quartile, third quartile, and median values of TAS in the blood were 2.282, 3.183, and 2.594, respectively whereas the first quartile, third quartile, and median values of TOS were 57.008, 97.598 and 77.593, respectively. The first quartile, third quartile, and median values of OSI were 1.855, 3.663, and 2.804, respectively (Table 1).
There was no statistically significant difference between the groups in terms of TAS, TOS, and OSI measurements (p>0.05) (Table 2).
For TAS analyzed in the liver tissue; the first quartile, third quartile, and median values were 0.386, 0.645, and 0.504. The first quartile, third quartile, and median values of TOS were 19.310, 31.172, and 23.952. The first quartile, third quartile, and median values of OSI were 4.376, 5.728, and 4.878.
There was no statistically significant difference between the groups in terms of TAS measurements (p=0.061; p>0.05); however, higher measurement values in the L-Carnitine group is considerable. (Table 3)
Discussion
IR damage is a common phenomenon in surgical pathologies [13]. The pathophysiological events caused by IR are likely to be observed more commonly in the intestinal, cardiac, and cerebral tissues [14]. Reperfusion in the ischemic tissues causes a series of events in the affected tissue. The lipids located on the membranes of the cell organelle, which plays an important role in this cascade, are vulnerable against injury by free radicals, and lipid peroxidation appears when such free radicals react with the lipids. Such reactions create many toxic derivatives, such as superoxide anion, hydrogen peroxide, peroxynitrite, and hydroxyl radicals which would disrupt the cellular function [15, 16].
One of the important mechanisms in the pathogenesis of IR damage is the inflammatory pathways [15]. Inflammatory cytokines and neutrophil infiltration were known to be effective in the injury. Due to the aforementioned mechanisms, treatment regimens should be designed to prevent tissue injury and irreversible damage that was defined before. Possible anti-inflammatory, anti-apoptotic and anti-oxidant agents that may be effective for treatment were analyzed in IR injury that appeared in different organs. The efficiency of some agents such as sodium nitroprusside, atorvastatin, MgSO4, mannitol, ethyl private was tested in different IR injuries [7, 13, 15, 17, 18]. We reviewed the efficiency and superiority of L-carnitine and N-acetylcysteine on the IR injury model created on the animal model.
It is well known that L-carnitine transports long-chain fatty acids for beta-oxidation and may scavenge free oxygen radicals and reduce lipid peroxidation [5]. Therefore, it has been subject to many metabolic studies. Virmani et al. examined the neuroprotective effects of L-carnitine and stated that L-carnitine enables mitochondrial transmission, regulates the activity of permeability transmission pores and associatively reduce the peroxynitrite level [19]. Although this is theoretically possible, we did not detect any statistically significant difference between the L-carnitine group and the control group in terms of TAS, TOS, and OSI values. This may be explained by the different characteristics of the analyzed tissues and the difference in energy metabolisms used in the tissues.
Hosgorler et al. examined tissue and blood samples after reperfusion for 3 hours following L-carnitine administration at 8th minute of ischemia for 10 minutes and detected that morphological injury is statistically less, whereas perfused microvessels and epithelial regeneration were statistically higher in the rats treated with L-carnitine [3]. Such difference may be explained by longer ischemia period and shorter reperfusion period in the present study when compared with the study conducted by Hosgorler et al. Because the damage that appeared in intestinal ischemia is known to be dependent on ischemia duration and intensity [3].
Kalimeris et al. did not detect any difference between oxidative indicators in the plasma in their experimental study where IR injury was created to compare NAC doses [20]. In the studies where the protective effect of the agents such as NAC and atorvastatin was significant, the aforementioned drugs were administrated to the animals before the creation of ischemia [15,20, 21]. Another study focusing on the protective effect of NAC and atorvastatin in IR damage created in the colon did not detect any significant difference in superoxide dismutase activity [22]. A previous study analyzing the IR injury on renal tissue did not detect any statistically significant difference in superoxide dismutase levels between non-treated IR group and NAC- and erdosteine-treated rats. There is a significant difference in renal tissue histology of the group treated with erdosteine which started to be administrated 2 days before the creation of ischemia [23]. Baumann et al. performed an experimental study with hepatic ischemia and reported that short-term use of NAC is not successful for the preservation of hepatic functions [24]. A review on IR injury in an experimental model stated positive efficiency on the markers associated with liver damage of NAC which was used before the formation of ischemia [25]. Lack of a significant difference in the levels of oxidative biomarker of NAC and L-carnitine, which we administer after the creation of ischemia, is consistent with some studies in the literature.
Limitations
We declare that our study has limitations. These limitations include the small number of animals per group, the potentially unknown effects of the presence of the anesthetic agents on the parameters measured, the absence of histopathological evaluation of intestines, and whether the agents intraperitoneally administered were actually absorbed by the bowel.
Conclusion
Although the use of the drugs with proven antioxidant efficiency after ischemia may cause a histologically significant difference in IR injury, no significant efficiency was shown in the reduction of superoxides in the circulation. Therefore, we believe that the use of NAC and L-carnitine as antioxidants after the development of ischemia is not useful to prevent intestinal IR injury in the emergency medicine departments.
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. Aköz A, Türkdoğan KA, Kahraman Çetin N, Kum S, Duman A, Türe M, et al. Predicting critical duration and reversibility of damage in acute mesenteric ischemia: An experimental study. Ulus Travma Acil Cerrahi Derg. 2018;24(6):507-13.
2. Ardic S, Gumrukcu A, Gonenc Cekic O, Erdem M, Reis Kose GD, Demir S, et al. The value of endoplasmic reticulum stress markers (GRP78 and CHOP) in the diagnosis of acute mesenteric ischemia. Am J Emerg Med. 2019; 37(4): 596-602.
3. Hosgorler FU, Atila K, Terzi C, Akhisaroglu ST, Oktay G, Kupelioglu A, et al. Carnitine protects the intestine against reperfusion injury in rats. J Surg Res. 2010; 159(1): 603-10.
4. Çağlayan F, Çağlayan O, Günel E, Çakmak M. Investigation of The Oxidant Stress on The Other Organs, After Intestinal Ischemia/Reperfusion. Turk J Biochem. 2000; 25(3): 104-8.
5. Yuan Y, Guo H, Zhang Y, Zhou D, Gan P, Liang DM, et al. Protective effects of L-carnitine on intestinal ischemia/reperfusion injury in a rat model. J Clin Med Res. 2011; 3(2): 78-84.
6. Augustyniak A, Skrzydlewska E. L-Carnitine in the lipid and protein protection against ethanol-induced oxidative stress. Alcohol. 2009; 43(3): 217–23.
7. Turkmen S, Mentese A, Karaguzel E, Karaca Y, Kucuk A, Uzun A, et al. A comparison of the effects of N-acetylcysteine and ethyl pyruvate on experimental testicular ischemia-reperfusion injury. Fertil Steril. 2012; 98(3): 626-31.
8. Dekhuijzen PNR. Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease. Eur Respir J. 2004; (49)23: 629–36.
9. Zafarullah M, Li WQ, Sylvester J, Ahmad M. Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci. 2003; 60(1): 6–20.
10. Erel O. A novel automated method to measure total antioxidant response against potent free radical reactions. Clin Biochem. 2004; 37(2): 112–19.
11. Erel O, Neselioglu S. A novel and automated assay for thiol/disulphide homeostasis. Clin Biochem. 2014; 47(18): 326-32.
12. Demirbag R, Gur M, Yilmaz R, Kunt AS, Erel O, Andac MH. Influence of oxidative stress on the development of collateral circulation in total coronary occlusions. Int J Cardiol. 2007; 116(1): 14–19.
13. Akin M, Kurukahvecioglu O, Gulbahar O, Isikgonul I, Taneri F, Tezel E, et al. Comparison of the effects of sodium nitroprusside and L-carnitine in experimental ischemia-reperfusion injury in rats. Transplant Proc. 2007; 39(10): 2997-3001.
14. Anadol AZ, Bayram O, Dursun A, Ercan S. Role of endogenous endothelin peptides in intestinal ischemia-reperfusion injury in rats. Prostaglandins Leukot Essent Fatty Acids. 1998; 59(4): 279-83.
15. Alexandropoulos D, Bazigos GV, Doulamis IP, Tzani A, Konstantopoulos P, Tragotsalou N, et al. Protective effects of N-acetylcystein and atorvastatin against renal and hepatic injury in a rat model of intestinal ischemia-reperfusion. Biomed Pharmacother. 2017; 89: 673-80.
16. Devasagayam TPA, Boloor KK, Ramsarma T. Methods for estimating lipid peroxidation: Analysis of merits and demerits (minireview). Indian J. Biochem. Biophys. 2003; 40(5): 300-8.
17. Kurt O, Yazici CM, Erboga M, Turan C, Bozdemir Y, Akbas A, et al. Mannitol has a protective effect on testicular torsion: An experimental rat model. J Pediatr Urol. 2016; 12(3):167.e1-8.
18. Turkmen S, Cekic Gonenc O, Karaca Y, Mentese A, Demir S, Beyhun E, et al. The effect of ethyl pyruvate and N-acetylcysteine on ischemia-reperfusion injury in an experimental model of ischemic stroke. Am J Emerg Med. 2016; 34(9):1804-7.
19. Virmani A, Gaetani F, Imam S, Binienda Z, Ali S. Possible mechanism for the neuroprotective effects of L-carnitine on methamphetamine-evoked neurotoxicity. Ann N Y Acad Sci. 2003; 993: 197-207; discussion 287-8.
20. Kalimeris K, Briassoulis P, Ntzouvani A, Nomikos T, Papaparaskeva K, Politi A, et al. N-acetylcysteine ameliorates liver injury in a rat model of intestinal ischemia reperfusion. J Surg Res. 2016; 206(2): 263-72.
21. Cusumano G, Romagnoli J, Liuzzo G, Ciavarella LP, Severino A, Copponi G, et al. N-Acetylcysteine and High-Dose Atorvastatin Reduce Oxidative Stress in an Ischemia-Reperfusion Model in the Rat Kidney. Transplant Proc. 2015; 47(9): 2757-62.
22. Yasar M, Erdi I, Kaya B. The preventive effects of atorvastatin and N-acetylcysteine in experimentally induced ischemia-reperfusion injury in rats. Bratisl Lek Listy. 2018; 119(3): 167-74.
23. Erdogan H, Fadillioglu E, Yagmurca M, Uçar M, Irmak MK. Protein oxidation and lipid peroxidation after renal ischemia-reperfusion injury: protective effects of erdosteine and N-acetylcysteine. Urol Res. 2006; 34(1): 41-6.
24. Baumann J, Ghosh S, Szakmany T, Jancso G, Ferencz A, Roth E, et al. Short-term effects of N-acetylcysteine and ischemic preconditioning in a canine model of hepatic ischemia-reperfusion injury. Eur Surg Res. 2008; 41(2): 226-30.
25. Jegatheeswaran S, Siriwardena AK. Experimental and clinical evidence for modification of hepatic ischaemia-reperfusion injury by N-acetylcysteine during major liver surgery. HPB (Oxford). 2011; 13(2): 71-8.
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Utku Murat Kalafat, Busra Bildik, Serkan Dogan, Rabia Birsen Tapkan, Melis Dorter, Ayse Fethiye Basa Kalafat, Bahaeddin Tapkan, Said Incir, Basar Cander. Evaluation of protective effect of L-carnitine and N-acetylcysteine in mesenteric ischemia-reperfusion injury model in rats. Ann Clin Anal Med 2021;12(2):134-138
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The Efficiency of Colistin, Minocycline, Tigecycline and Doxycycline against multidrug-resistant Acinetobacter strains
Selim Gorgun 1, Murat Guzel 2, Ozgur Gunal 3, S. Sırrı Kılıc 3
1 Department of Microbiology and Clinical Microbiology Laboratory, Training and Research Hospital, Health Sciences University, 2 Department of Emergency Medicine, Training and Research Hospital, Health Sciences University, 3 Department of Infectious Diseases and Clinical Microbiology, Training and Research Hospital, Health Sciences University Samsun, Turkey
DOI: 10.4328/ACAM.20207 Received: 2020-05-20 Accepted: 2020-06-20 Published Online: 2020-06-30 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):120-123
Corresponding Author: Selim Gorgun, Department of Microbiology and Clinical Microbiology Laboratory, Training and Research Hospital, Health Sciences University, Ilkadım, 55090, Samsun, Turkey. E-mail: selimgorgun55@gmail.com P: +90 5366168844 F: +90 3622778569 Corresponding Author ORCID ID: https://orcid.org/0000-0001-5841-591X
Aim: In recent years, it has been emphasized that antibiotics less used in the past may be an alternative for the treatment of infections caused by multidrug-resistance (MDR) Acinetobacter strains. In this study, we aimed to determine the effectiveness of colistin, tigecycline, minocycline, and doxycycline against MDR Acinetobacter strains. Material and Methods: The study was carried out in Samsun Training and Research Hospital in 2018. MDR Acinetobacter spp. obtained from 68 patients and reproduced in various clinical samples. Vitec 2 system (BioMerieux, France) was used for the identification of strains and susceptibility testing. The sensitivity of minocycline, tigecycline, and doxycycline was studied in Mueller Hinton agar by Kirby Bauer disc diffusion method. Colistin resistant strains were studied using tube dilution method and minimal inhibitory concentration (MIC) values were determined. Results: MDR Acinetobacter strains were mostly isolated from cultures from tracheal aspirate (32.4%) and wound samples (31.5%). The sensitivity of MDR Acinetobacter strains to colistin, tigecycline, doxycycline, and minocycline were 82.4%, 41.2%, 23.5%, 8.8%, respectively. Discussion: We consider that the sensitivity to colistin is high in MDR Acinetobacter spp. infections and that combination of antibiotics, which were used in the past but became less-used later, and other antibiotics can be used for the treatment.
Keywords: MDR Acinetobacter spp; Tigecycline; Colistin; Minocycline; Doxycycline
Introduction
In the last 50 years, multidrug-resistant (MDR) Acinetobacter strains seem to be an increasing cause of death for the patients receiving long-term treatment, intensive care unit patients, burns, and oncological patients. MDR Acinetobacter strains resisting more than three of the available antibiotics might cause different infections such as bloodstream infections, meningitis, ventilator-induced pneumonia, urinary tract infections, skin, and soft tissue infections, and lead to death. These infections can occur in a single patient, or they can easily be transmitted to other inpatients in the service and cause outbreaks. Another important problem is, as Acinetobacter species show intense and widespread resistance to many antibiotics, the treatment of the infections caused by these strains becomes difficult. Over the time, highly resistant species have emerged including XDR (Extreme-drug-resistance) [1,2]. As the infections caused by these factors are increasing, alternative antibiotics that can be used as limited treatment preferences are studied thoroughly. The studies conducted to find sensitive antibiotics became even more important due to the decrease in effective antibiotics, the lack of new antibiotics in treatments and limited antibiotic combinations [1]. Moreover, some antibiotics such as colistin, minocycline, and doxycycline, which have not been used for various reasons for a long time, have come to fore due to high costs and long research period required for finding alternative effective antibiotics for the treatment [2]. Colistin is a toxic drug that has been discontinued due to its side effects. Today, when the number of alternative antibiotics is rapidly depleted, it is planned to use colistin again in treatments after its side effects are reduced. It is emphasized that doxycycline and minocycline, the second-generation tetracyclines, have long serum half-lives, high lipid solubility, low resistance potential, and increased activity against certain pathogens, and like colistin they have been used for a very long time. According to some literature, it is stated that minocycline and doxycycline may be an alternative in the treatment of some infections caused by Acinetobacter spp. [2-4]. Tigecycline, a member of the tetracycline group, is a new alternative antibiotic in the treatment of some infections caused by resistant bacteria [1,2]. However, there are some limitations, such as the resistance developed against minocycline and doxycycline, side effects of colistin, and not being able to use tigecycline against all types of infections. The rapid increase in resistance against existing antibiotics at hand and the inability to launch new antibiotics pushed researchers to seek alternative treatments. In addition to different combinations of various antibiotics, the clinical use of antibiotics such as minocycline, doxycycline, and colistin, which have been out of use for a long time, has come to the forefront. Recently, the effectiveness of these antibiotics against infections caused by MDR Acinetobacter strains has been a matter of question, and researches have been carried out to find out the answer. In this study, we aimed to determine the effectiveness of colistin, minocycline, doxycycline, and tigecycline against MDR Acinetobacter strains.
Material and Methods
This study received approval of the local ethics committee number 2017/24:174. The study was carried out prospectively at Samsun Training and Research Hospital between January 2018 and December 2018. MDR Acinetobacter spp. strains reproduced in various clinical samples of 68 patients were included in the study.
Bacteria Identification and Evaluation of sensitivity tests
All samples were sown on 5% Sheep Blood agar, Eosin Methylene Blue agar and incubated at 37° C for 18-24 hours. Automatic bacteria identification system, Vitec 2 system (BioMerieux, France) was used for MDR bacteria identification and susceptibility testing. Minocycline and doxycycline susceptibility of Acinetobacter strains were studied by Kirby Bauer disc diffusion method in Mueller Hinton agar. Sensitive strains were determined by working with the tube dilution method with 0.5-16 MIC values. Sensitivity results were interpreted according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST). In our study, A.baumannii ATCC 19606 strain was used as a quality control strain.
Results
Forty-one (60.3%) of the patients included in the study were male and 27 (39.7%) were female. The average age of the study group was 66.2 years. MDR Acinetobacter strains were isolated from cultures collected from tracheal aspirate 35 (32.4%), wound 34 (31.5%), blood 13 (%12.0), sputum 13 (%12.0), urine 11 (%10.2) and catheter 2 (%1.9) samples.
Samples from which MDR Acinetobacter strains were isolated mostly belonged to patients hospitalized in critical units such as intensive care (69.1%), burn intensive care (8.8%) , and oncological intensive care. The detailed distribution of the samples by clinics is given in Table 1.
The susceptibility of MDR Acinetobacter strains to colistin tigecycline, doxycycline and minocycline were 82.4%, 41.2%, 23.5%, 8.8% respectively. The susceptibilities of the strains to other antibiotics are given in Table 2. MIC (minimal inhibitory concentration) values of colistin sensitive strains (82.4%) were determined to be between 0.5-2. (Table 3)
Discussion
With the increase of infections caused by MDR Acinetobacter strains, new alternative antibiotics are in great demand for treatment. In recent years, there has been a substantial limitation in terms of the introduction of new alternative antibiotics to clinical use. Although colistin, minocycline, and doxycycline were used in the past, they were abandoned but re-used against resistant bacteria. Tigecycline is a new broad-spectrum antibiotic with gram-positive and gram-negative activity [1]. However, tigecycline resistance was found in some MDR strains. This is caused by the ability of Acinetobacter strains to develop resistance easily [5]. In studies, these antibiotics, which have been interrupted over time and have been investigated as alternatives for resistant cases, have been the subject of research as it is suggested that they might be an option for the treatment of infections caused by MDR Acinetobacter strains [6]. In our study, we have examined whether these antibiotics can be an alternative against MDR Acinetobacter strains isolated from our hospital in order to contribute to this issue. In a study conducted by Wood et al. [3], they stated that seven out of eight cases caused by MDR Acinetobacter strain were successfully treated with minocycline and doxycycline. Griffith et al. [7] stated that in their study, seven of eight patients infected with diseases caused by MDR Acinetobacter strain were successfully treated with minocycline. Liang et al. [4] reported that 100% of meropenem resistant bacteria are sensitive to colistin and minocycline. Chen et al. [8] reported that combined treatments can be used against resistant Acinetobacter strains. In their study, Tan et al. [9] stated that 12 of the 13 MDR Acinetobacter strains responded to colistin and minocycline treatment. Falagas et al. reported that MDR Acinetobacter strains isolated from different clinical samples have a susceptibility rate between 71.9% and 87.5% against doxycycline, and minocycline in combination with other antibiotics, in their literature study [10]. In these studies, it is emphasized that the sensitivity has increased after the combination of doxycycline and minocycline antibiotics is included. In the studies carried out with doxycycline and minocycline against MDR Acinetobacter strains, various sensitivity rates have been reported in the range of 93.8% to 98.8% , and 72.3% to 84.5% [11-14]. In our study, the sensitivity of minocycline and doxycycline was found out to be 23.5% and 8.8%, respectively. This value was deemed low compared to the studies performed. There was a difference between the sensitivity of minocycline and doxycycline. Studies have shown that tigecycline and colistin are the most effective antibacterials in the treatment of infections caused by MDR Acinetobacter strains [2, 13-15]. Cakirlar et al. from Turkey [16] found the sensitivity of carbapenem-resistant Acinetobacter to colistin and tigecycline to be 100%. In recent studies, sensitivity rates to colistin and tigecycline have been reported as 100% [16-19]. In different studies, MDR Acinetobacter colistin sensitivity rates found to be ranging between 82.5% and 99.8% [13, 20-22], and tigecycline sensitivity rates are found to be in the range of 50.5% and 99.9% [20-24]. In our study, we found the sensitivity to colistin and tigecycline as 82.4% and 41.2%, respectively. These results were interpreted as low compared to the other studies conducted.
In a study, Acinetobacter strains were found to have high resistance to many antibiotics, while their sensitivity to colistin and minocycline was reported as 98.8% and 79.1%, respectively. Also in this study, minocycline was found to be more effective than doxycycline against Acinetobacter strains [16]. Similar results were also emphasized in the study by Siricilla et al. [20]. In our study, the number of doxycycline-sensitive strains was lower than the number of minocycline-sensitive strains. We interpreted this difference as a result of the fact that the routine use of doxycycline is more common than the use of minocycline. In studies carried out using the automated system Vitec 2, colistin sensitivity results have a reliability rate of over 90% [25].
However, EUCAST is suggested to give results with tube dilution MIC detection. In studies, automated systems that detect colistin resistance have been reported to be between 88% and 93%, compatible with microdilution and tube dilution results [25]. In our study, the strains that we found resistant with the automated system were detected with the tube dilution method with 100% accuracy between 0.5 and 2 MIC.
MDR Acinetobacter spp. strains are bacteria with high mortality, which are isolated from critical units over the time and which required us to move quickly at the time of isolation. Since our study covers a certain period of time, the shortage of strains obtained during this period was one of the limiting factors. However, we thought that the results were significant compared to the other studies conducted.
Conclusions
Colistin is the most important alternative in the treatment of infections caused by increasing MDR Acinetobacter species in critical units. In our study, in the light of the literature, we investigated whether antibiotics, which were in use in the past, but were interrupted later, can be used again as an alternative. However, we believe that combinations of these antibiotics with other antibiotics may create alternative treatments. Tigecycline, on the other hand, is a reliable antibiotic that can be used against diagnoses related to MDR Acinetobacter strains as an alternative to colistin, as it has fewer side effects.
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. Bishburg E, Bishburg K. Minocycline-an old drug for a new century: emphasis on methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii. Int J Antimicrob Agents. 2009;34(5):395-401. DOI: 10.1016/j.ijantimicag.2009.06.021.
2. Giamarellou H. Multidrug-resistant gram-negative bacteria: how to treat and for how long. J Int Antimicrob Agents. 2010;36(Suppl. 2):S550-4. DOI: 10.1016/j.ijantimicag.2010.11.014.
3. Wood GC, Hanes SD, Boucher BA, Croce MA, Fabian TC. Tetracyclines for treating multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia. Intensive Care Med. 2003;29(11):2072-6. DOI: 10.1007/s00134-003-1811-2.
4. Liang W, Liu X-F, Huang J, Zhu DM, Li J, Zhang J. Activities of colistin and minocycline-based combinations against extensive drug resistant Acinetobacter baumannii isolates from intensive care unit patients. BMC Infect Dis. 2011;11:109. DOI: 10.1186/1471-2334-11-109.
5. Reid GE, Grim SA, Aldeza CA, Janda WM, Clark NM. Rapid development of Acinetobacter baumannii resistance to tigecycline. Pharmacotherapy. 2007;27(8):1198–201. DOI: 10.1592/phco.27.8.1198.
6. Maragakis LL, Perl TM. Acinetobacter baumannii: epidemiology, antimicrobial resistance, and treatment options. Clin Infect Dis. 2008;46(8):1254-63. DOI: 10.1086/529198.
7. Griffith ME, Yun HC, Horvath LL, Murray CK. Minocycline therapy for traumatic wound infections caused by the multidrug-resistant Acinetobacter baumannii-Acinetobacter colcoaceticus complex. Infect Dis Clin Pract. 2008;16:16-9. DOI: 10.1097/ipc.0b013e318159d595.
8. Chen S, Hu F, Zhang X, Xu X, Liu Y, Zhu D, et al. Independent emergence of colistin-resistant enterobacteriaceae clinical isolates without colistin treatment. J Clin Microbiol. 2011;49:4022-3. DOI: 10.1128/JCM.01233-11.
9. Tan TY, Ng LS, Tan E, Huang G. In vitro effect of minocycline and colistin combinations on imipenem-resistant Acinetobacter baumannii clinical isolates. J Antimicrob Chemother. 2007;60(2):421-3. DOI:10.1093/jac/dkm178.
10. Falagas ME, Vardakas KZ, Kapaskelis A, Triarides NA, Roussos NS. Tetracyclines for multidrug-resistant Acinetobacter baumannii infections. Int J Antimicrob Agents. 2015;45(5):455-60. DOI: 10.1016/j.ijantimicag.2014.12.031.
11. Cesur S, Kinikli S, Cesur S, Yucel M, Hatipoglu CA, Dinc B. Determination of polymyxin B, minocycline, colistin and phosphomycin susceptibilities in Acinetobacter baumannii strains showing carbapenem resistant multidrug resistance phenotype. J Health Sci Med. 2019;2(2):49-53. DOI: 10.32322/jhsm.456990.
12. Castanheira M, Mendes RE, Jones RN. Update on Acinetobacter species: mechanisms of antimicrobial resistance and contemporary in vitro activity of minocycline and other treatment options. Clin Infect Dis. 2014;59(Suppl. 6):367-73. DOI: 10.1093/cid/ciu706.
13. Greig SL, Scott LJ. Intravenous minocycline: a review in Acinetobacter infections. Drugs. 2016;76(15):1467-76. DOI: 10.1007/s40265-016-0636-6.
14. Yang YS, Lee Y, Tseng KC, Huang WC, Chuang MF, Kuo SC, et al. In vivo and in vitro efficacy of minocycline-based combination therapy for minocycline-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2016;60(7):4047-54. DOI: 10.1128/AAC.02994-15.
15. Siricilla S, Mitachi K, Yang J, Eslamimehr S, Lemieux MR, Meibohm B, et al. A new combination of a pleuromutilin derivate and doxycycline for treatment of multidrug-resistant Acinetobacter baumannii. J Med Chem. 2017;60:2869-72. DOI: 10.1021/acs.jmedchem.6b01805.
16. Cakirlar FK, Ciftci IH, Gonullu N. OXA-type carbapenemases and susceptibility of colistin and tigecycline among carbapenem-resistant Acinetobacter baumannii isolates from patients with bacteremia in Turkey. Clin Lab. 2015;61(7):741-7. DOI: 10.7754/clin.lab.2014.141116.
17. Ece G, Samlioglu P, Atalay S, Kose S. Evaluation of the in vitro colistin susceptibility of Pseudomonas aeruginosa and Acinetobacter baumannii strains at a tertiary care centre in western Turkey. Infez Med. 2014;22(1):36-40.
18. Yilmaz FF, Tasli H, Gul-Yurtsever S, Buyuk A, Hosgor-Limoncu M. Tigecycline susceptibility in multidrug resistant Acinetobacter isolates from Turkey. Pol J Microbiol. 2013;62(3):295-8.
19. Pakoz NIE, Kaya E, Orhan Z, Kayıs A, Aral M. Comparison of tigecycline, colistin resistance with disc diffusion, e-test and automated system methods in the highly resistant Acinetobacter baumannii isolates isolated from different clinical samples. Turk Hij Den Biyol Derg. 2018;75(2):109-16.
20. Pournaras S, Koumaki V, Gennimata V, Kouskouni E, Tsakris A. In vitro activity of tigecycline against Acinetobacter baumannii: global epidemiology and resistance mechanisms. Adv Exp Med Biol. 2016;897:1-14. DOI: 10.1007/5584_2015_5001.
21. Van TD, Dinh QD, Vu PD, Nguyen TV, Pham CV, Dao TT, et al. Antibiotic susceptibility and molecular epidemiology of Acinetobacter calcoaceticus-baumannii complex strains isolated from a referral hospital in northern Vietnam. J Glob Antimicrob Resist. 2014;2(4):318-21. DOI: 10.1016/j.jgar.2014.05.003.
22. Chamoun K, Farah M, Araj G, Daoud Z, Moghnieh R, Salameh P, et al. Surveillance of antimicrobial resistance in Lebanese hospitals: retrospective nationwide compiled data. Int J Infect Dis. 2016;46:64-70. DOI: 10.1016/j.ijid.2016.03.010.
23. Zhang Z, Chen M, Yu Y, Pan S, Liu Y. Antimicrobial susceptibility among gram-positive and gram-negative blood-borne pathogens collected between 2012-2016 as part of the tigecycline evaluation and surveillance trial. Antimicrob Resist Infect Control. 2018; 13(7):152. DOI: 10.1186/s13756-018-0441-y.
24. Jiang M, Zhang Z, Zhao S. Epidemiological characteristics and drug resistance analysis of multidrug resistant Acinetobacter baumannii in a China hospital at a certain time. Pol J Microbiol. 2014;63(3):275-81.
25. Chew KL, La MV, Lin RTP, Teo JWP. Colistin and polymyxin b susceptibility testing for carbapenem-resistant and mcr-positive enterobacteriaceae: comparison of sensititre, microScan, vitek 2, and etest with broth microdilution. J Clin Microbiol. 2017;55(9):2609-16. DOI: 10.1128/JCM.00268-17.
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Selim Gorgun, Murat Guzel, Ozgur Gunal, S. Sırrı Kılıc. The Efficiency of Colistin, Minocycline, Tigecycline and Doxycycline against multidrug-resistant Acinetobacter strains. Ann Clin Anal Med 2021;12(2):120-123
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The efficiency of Polytendon Complex (PC) and St. John’s Wort oil (Hypericum perforatum) on healthy Achilles tendon in rats
Kutsi Tuncer 1, 2, Mehmet Demir 1, Eyüp Şenocak 3, Ali Sefa Mendil 4, Arzu Gezer 5, Basri Pür 1, Recep Öztürk 6
1 Department of Orthopaedic and Traumatology, Medical Faculty, Ataturk University, Erzurum, 2 Anesthesiology Clinical Research Office, Ataturk University, Erzurum, 3 Clinic of Orthopaedic and Traumatology, Regional Education Research Hospital, Erzurum, 4 Department of Pathology, Veterinary Medicine Faculty, Erciyes University, Kayseri, 5 Department of Histology, Vocational School of Health Services, Ataturk University, Erzurum, 6 Department of Orthopaedic and Traumatology, Dr Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.20213 Received: 2020-05-18 Accepted: 2020-06-12 Published Online: 2020-06-24 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):139-143
Corresponding Author: Recep Öztürk, Dr Abdurrahman Yurtaslan Ankara Oncology Training And Research Hospital, Demetevler Mahallesi, Vatan Cad., 06200 Yenimahalle/Ankara, Turkey. E-mail: ozturk_recep@windowslive.com GSM: +90 5054634794 F: +90 312 334 03 52 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6753-9321
Aim: This experimental animal study aimed to investigate the effects of Tendoflex® (a polytendon complex) and St. John’s wort oil (Hypericum perforatum) on healthy Achilles tendons in rats.Material and Method: Twenty Wistar albino rats weighing 250-350 g were randomly allocated into four groups. In Group A, Tendoflex® capsule per 2.5 kg/day was administered orally via gavage. In Group B, Hypericum perforatum 300mg/kg/day was given orally via gavage. In Group C, Tendoflex® and Hypericum perforatum were given orally via gavage at the doses mentioned above. In Group D, no intervention was done to the control group. After four weeks, all rats were sacrificed and biomechanical tests of the Achilles tendon and histological examinations were performed.Results: Histological results revealed a significant difference between the groups regarding Type-1 and Type-3 immunopositivity in the Achilles tendon tissues (p <0.05). Immune-positivity values were high in group B, moderate in group C, mild in group A and insignificant in group D. The highest top tendon strengths in the biomechanical tests were recorded in the Hypericum perforatum and mix groups at the fourth week (83.75±16.1N and 81.875±9.7 N, respectively) followed by the Tendoflex® group (66.875±7.5 N). On the other hand, the lowest tendon strengths were obtained in the control group (54.375±7.1N).Discussion: Tendoflex® and Hypericum perforatum increased the Achilles tendon tensile strength in rats. This result may be related to the fact that Type-1 and Type-3 collagen immunity was higher in all groups compared to the control group. Tendoflex® and Hypericum perforatum can be used to prevent tendon rupture or to avoid re-rupture in patients undergoing tendon repair.
Keywords: Achilles Tendon; Tendoflex; Hypericum perforatum; Prophylaxis
Introduction
Achilles tendon is the strongest and biggest tendon in the body. However, this tendon is commonly torn in middle-aged men who exercise. The incidence of tendon rupture is estimated to be 18/100 000 [1]. Medical aids for preventing the tear or reducing the risk of re-rupture, which is frequently encountered in patients with tendon repairs, can minimize labor loss, hospital stay, and hospitalization costs [2,3].
Many medicines and substances have been studied in the literature that investigates the tendon healing process and are thought to affect this process positively [4-10]. Studies are investigating the contribution of elements such as vitamin C and collagen contained in Tendoflex to tendon healing [4]. St. John’s wort (centaury oil, Hypericum perforatum) is obtained from a medical plant and is used today to treat many different diseases, such as ulcer, burn, diabetic wounds, infections, and cancer [11-13]. Considering the mechanism of action of H. perforatum, its effects such as shortening the inflammatory process, increasing the collagen level, and decreasing fibroblast migration, which is thought to positively affect the tendon healing process, have been shown in publications [14].
As far as we know, there is no study in the literature on how Tendoflex and hypericum perforatum will affect the load capacity of intact tendons. This study aimed to investigate the effects of Tendoflex and St. John’s wort on the pulling load capacity of tendons and its histopathological mechanisms of action.
Material and Methods
The experiment was initiated after obtaining approval from the Atatürk University Local Ethics Committee for Animal Experiments. This study was carried out per the principles of “Care and Use of the Laboratory Animals,” and animal rights were protected [15]. Twenty Wistar-Albinorats weighing 250-350 grams were randomly allocated into 4 groups of 5 rats. In Group A, 1 Tendoflex® (Mega-Farma, Turkey) capsule/2.5 kg/day was given orally via gavage. In Group B, Hypericum perforatum 300 mg/kg/day was given orally through gavage. In Group C, Tendoflex® and Hypericum perforatum were administered orally through gavage at the daily doses mentioned above. Group D was designated as the control group, and no intervention was given to this group. The study was conducted in accordance with the principles of the Declaration of Helsinki.
The active substance doses specified in the publications were administered in the intervention groups. Since Tendoflex® contains more than one active substance, the treatment given has been decided by looking at these active ingredients one by one [5,16-19]. In one study, bromelain was found beneficial at a dose of 30 mg/kg for tendon injury [5]. In another study, it was reported that L-arginine was used in rats at doses of 30-60 mg/kg [18]. In another study, methyl sulfonyl methane was used at a dose of 50 mg/kg [19]. In the light of all these studies, 1 capsule of Tendoflex® was weighed to correspond to a 2.5 kg rat weight. It was given daily with the help of gavage according to the weight of the animal. The Hypericum perforatum extract was applied orally via gavage at a dose of 300 mg/kg daily,as suggested in the literature [12-13].
Four weeks later, the rats were sacrificed, and tissue samples were examined histologically following biomechanical tests of the Achilles tendons.
Biomechanical investigations:
Achilles tendons of the animals sacrificed in the fourth week were measured regarding their durability in the mechanical test device (Figure 1). Load capacities measured by 0.1% accuracy of the load cell of the device were entered into the software, and force values (F) were obtained. The tests were terminated after force reduction and sample rupture. The highest force value obtained for each sample was used for data analysis.
Immunohistochemical studies:
Achilles tendon tissues were investigated after the necropsy of the rats in a 10% neutral formalin solution. Routine tissue follow-up was done by alcohol-xylol and transferred into paraffin blocks. Then, sections of 5 µm thickness were taken on poly-L-Lysine-coated slides, passed through xylol and alcohol series, washed with PBS, and kept for 10 minutes in 3% H2O2 inactivating endogenous peroxidase inactivation. To expose antigens in the tissues, treatment with antigen retrieval solution at 500 watts for 2×5 minutes was applied. The tissues which were washed with PBS were incubated for 20 minutes at room temperature with Type-1 Collagen (Abcam, Catalog No ab34710 1/200 dilution rate) and Type-3 Collagen (Abcam, Catalog No ab7778 1/200 dilution rate). Secondarily, “Large Volume Detection System: anti-Polyvalent, HRP” (Thermofischer, Catalog number: TP-125-HL) was applied as recommended by the manufacturer. DAB (3,3’-Diaminobenzidine) was used as a chromogen. The slides were covered with Entellan and examined under a light microscope after contrasting with Mayer’s Hematoxylin. As a result of the examination, grading in the Achilles tendon tissues were performed as no (-), mild (+), moderate (++), and strong (+++).
Statistical Analysis
All statistical analyzes were done using the IBM SPSS 20.0 statistical software (IBM Corp., Armonk, NY, USA). Descriptive statistics were expressed as mean±standard deviation, frequency, and percentage. Differences between the groups were determined by the nonparametric Kruskal-Wallis test, and pairwise comparisons were made by the Mann-Whitney U test. The significance threshold was taken as p<0.05.
Results
None of the rats were lost during the study. In the examinations during the sacrifice of the rats, no macroscopic defect was detected in the integrity of the tendons.
Immunohistochemical Staining
In Achilles tendon tissues, there was a significant difference between the groups concerning Type-1 and Type-3 immunity (Table 1, p <0.05). Immunostaining of Type-1 and Type-3 in the Achilles tendon tissues of the control group rats were not significantly determined (Figures1 and 2). It was determined that the Tendoflex group had a mild level of Type-1 and Type-3 immunity to the Achilles tendon tissues (Figures1 and 2). While animals in the Tendoflex + St. John’s Wort group had moderate Type-1 and Type-3 immune positivity, Type-1 and Type-3 immune positivity in the St. John’s Wort group was strong (Figure 2 and 3).
Biomechanical measurements
When the strength of Achilles’ tendons at 4 weeks were examined, the best results were obtained in the Hypericum perforatum (Group B) and mixed (Group C) groups. The highest pulling load capacity was in the H. perforatum group (83.75 ± 16.1N), followed closely by the mixed group (81.875 ± 9.7 N). The Tendoflex® (Group A) had the third rank in pulling load capacity (66.875 ± 7.5 N). The lowest tendon powers were seen in the Control Group(Group D) (54.375 ± 7.1N) (Table 2).
Discussion
The fact that Achilles tendon rupture is a common issue, and there are potentially severe complications after surgery, increases the interest in the prevention and treatment strategies [6]. In this study, the contribution of various active substances to the Achilles tendon endurance in healthy rats was investigated mechanically and histologically. If the Achilles tendon endurance can be increased, the risk of rupture will naturally decrease. The use of Hypericum perforatum in rats increases the stamina of Achilles’ tendons in the best way. It was also found that the use of Tendoflex increased tendon strengths to a lesser extent than Hypericum perforatum. When using these two substances, higher values were obtained in the tendon strengths than the group using only Tendoflex. As a result, better pulling load capacities were obtained in all groups compared to the non-intervention group. Histological examinations supported these tensile test results too. Type1 and Type 3 immunopositivity rates were in line with the load capacity test results.
Although Hypericum perforatum is used in a wide variety of diseases, studies show that it increases tensile strength in wounds and contributes to wound healing [20]. In vivo and in vitro studies have shown that the H. Perforatum shortens inflammation time, stops the migration of fibroblasts, and increases collagen accumulation during wound healing [21]. Tensile strength is an objective criterion of wound healing and is known as the clinical entity that best reflects this process. Kahyaoğlu et al. attributed to H. perforatum increasing the tensile strength of the wound, having antibacterial effects, increasing the migration of fibroblasts, and increasing collagen [12]. In this study, it was determined that H. perforatum increased the strength of the healthy Achilles tendons and did this by increasing the amount of Type 1 and Type 3 collagen in the tissue
One of the products containing Polytendon complex, which is recommended by health care professionals to accelerate healing and increase the collagen amount of the repair-tissue after Achilles tendon injuries, is a commercial product called Tendoflex®. Studies investigate the effects of vitamin C and collagen, one of the factors included in this product, on tendon healing. In their research, Ömeroğlu et al. investigated the effects of parenteral high dose vitamin C on tendon healing. It increased angiogenesis and type1 collagen synthesis in the early period [4]. In this study, the effect of Tendoflex®️ on the strong Achilles tendon of the rats was examined. This active substance increased the strength of the intact Achilles tendon by raising its collagen content.
Other studies in the literature examine the increase of tensile strength and healing of the Achilles tendon using various active substances. Majevski et al. applied an autologous serum to the Achilles’ tendons after repair and found that this application increased type 1 collagen and decreased type 3 collagen [7]. Liang J et al. showed a positive effect on tendon healing of hyaluronic acid/tenocyte locally after tendon repair in rat Achilles tendon rupture models [8]. Özer et al. showed that oral glucosamine chondroitin sulfate positively affected tendon healing in the rat Achilles tendon model [9]. Eren et al. showed a positive effect of low molecular weight heparin and rivonoxab administered subcutaneously in the rat Achilles model on tendon healing, but could not find any difference biomechanically and histologically [10]. In a study on rats, Kajikava et al. showed that collagen synthesis is higher in patients who received platelet-rich plasma [22]. A study by Tsai et al. showed that transforming growth factor-beta release was stimulated by pulse ultrasound in repaired tendon cells [23].
Some limitations of this study were the small number of subjects and the lack of clinical and functional results due to the experimental nature of the study.
Conclusion
The single and combined use of Tendoflex® and Hypericum perforatum increased the Achilles tendon stretching power in rats. This finding may be related to the fact that Type-1 and Type-3 immunopositivity was higher in all groups compared to the control group. These two factors can prevent tendon rupture in patients who are predicted to have tendon injuries. It can also be used to avoid re-rupture in patients whose tendons have been repaired surgically.
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- Daghino W, Enrietti E, Sprio AE, diPrun NB, Berta GN, Massè A. Subcutaneous Achilles tendon rupture: a comparison between open technique and mini-invasive tenorrhaphy with Achillon® suture system. Injury. 2016;47(11):2591-5.
2- Su AW, Bogunovic L, Johnson J, Klein S, Matava MJ, McCormick J, et al. Operative Versus Nonoperative Treatment of Acute Achilles Tendon Ruptures: A Pilot Economic Decision Analysis. Orthop J Sports Med. 2020;8(3). DOI: 10.1177/2325967120909918.
3- Zellers JA, Christensen M, Kjær IL, Rathleff MS, Silbernagel KG. Defining Components of Early Functional Rehabilitation for Acute Achilles Tendon Rupture: A Systematic Review. Orthop J Sports Med. 2019;7(11). DOI: 10.1177/2325967119884071.
4- Omeroğlu S, Peker T, Türközkan N, Omeroğlu H. High-dose vitamin C supplementation accelerates the Achilles tendon healing in healthy rats. Arch Orthop Trauma Surg. 2009;129(2):281-6. DOI: 10.1007/s00402-008-0603-0.
5- Aiyegbusi AI, Duru FI, Awelimobor D, Noronha CC, Okanlawon AO. The role of aqueous extract of pine apple fruit parts on the healing of acute crush tendon injury. Nig Q J Hosp Med. 2010;20(4):223-7.
6- Genç E, Beytemur O, Yuksel S, Eren Y, Çağlar A, Küçükyıldırım BO, et al. Investigation of the biomechanical and histopathological effects of autologous conditioned serum on healing of Achilles tendon. Acta Orthop Traumatol Turc. 2018;52(3):226-31. DOI:10.1016/j.aott.2018.01.005
7- Majewski M, Ochsner PE, Liu F, Flückiger R, Evans CH. Accelerated healing of the rat Achilles tendon in response to autologous conditioned serum. Am J Sports Med. 2009;37(11):2117-25.
8- Liang JI, Lin PC, Chen MY, Hsieh TH, Chen JJ, Yeh ML. The effect of tenocyte / hyaluronic acid therapy on the early recovery of healing Achilles tendon in rats. J Mater Sci Mater Med. 2014;25(1):217-27. DOI:10.1007/s10856-013-5036-9.
9- Ozer H, Taşkesen A, Kul O, Selek HY, Turanlı S, Köse K. Glukozamin kondroitin sülfatın onarılmış tenotomize sıçan Aşil tendonları üzerine etkisi (Effect of glucosamine chondroitine sulphate on repaired tenotomized rat Achilles tendons). Eklem Hastalik Cerrahisi/Joint Diseases Surgery. 2011;22(2):100-6.
10- Eren Y, Adanır O, Dinçel YM, Genç E, Arslan YZ, Çağlar A. Effects of low molecular weight heparin and rivaroxaban on rat Achilles tendon healing. Eklem Hastalik Cerrahisi/ Joint Diseases Surgery. 2018;29(1):13-19. doi:10.5606/ehc.2018.54577
11- Altıparmak M, Eskitaşçıoğlu T. Comparison of Systemic and Topical Hypericum Perforatum on Diabetic Surgical Wounds. J Invest Surg. 2018 ;31(1):29-37. DOI: 10.1080/08941939.2016.1272654.
12- Kahyaoğlu F, Demirci B. Hypericum’s 90th Anniversary in theLaboratory. Eur J Ther. 2018; 24: 192-7.DOI: 10.5152/EurJTher.2018.517
13- Lyles JT, Kim A, Nelson K, Bullard-Roberts AL, Hajdari A, Mustafa B, et al. The Chemical and Antibacterial Evaluation of St. John’s Wort Oil Macerates Used in Kosovar Traditional Medicine. Front Microbiol. 2017;8:1639. DOI: 10.3389/fmicb.2017.01639.
14- Güneş S, Tıhmınlıoğlu F. Hypericum perforatum incorporated chitosan films as potential bioactive wound dressing material. Int J Biol Macromol. 2017;102:933-43. DOI: 10.1016/j.ijbiomac.2017.04.080.
15- National Research Council. Guide for the Care and Use of Laboratory Animals. Washington, DC: The National Academies Press; 1996. DOI:10.17226/5140.
16- Valvassori SS, Borges C, Bavaresco DV, Varela RB, Resende WR, Peterle BR. Hypericum perforatum chronic treatment affects cognitive parameters and brain neurotrophic factor levels. Braz J Psychiatry. 2018;40(4):367-75. DOI: 10.1590/1516-4446-2017-2271.
17- Yang SY, Juang SH, Tsai SY, Chao PD, Hou YC. St. John’s wort significantly increased the systemic exposure and toxicity of methotrexate in rats. Toxicol Appl Pharmacol. 2012;263(1):39-43. DOI:10.1016/j.taap.2012.05.020.
18- Moraes NV, Bergamaschi MM, Bianchi MLP, Bragheto JB, Malfará WR, Queiroz RHC. L-arginine, a nitric oxide precursor, reduces dapsone-induced methemoglobinemia in rats. Braz J Pharm Sci. 2012;48(1): 87-94.
19- Horváth K, Noker PE, Somfai-Relle S, Glávits R, Financsek I, Schauss AG. Toxicity of methylsulfonylmethane in rats. Food Chem Toxicol. 2002;40(10):1459-62. DOI:10.1016/s0278-6915(02)00086-8.
20- Broughton G II, Janis JE, Attinger CE. The basic science of wound healing. Plast Reconstr Surg. 2006;117(Suppl. 7):S12–34.
21- Suntar IP, Akkol EK, Yilmazer D, Baykal T, Kirmizibekmez H, Alper M, et al. Investigations on the in vivo wound healing potential of Hypericum perforatum L. J Ethnopharmacol.2010;127(2):468–77.
22- Kajikawa Y, Morihara T, Sakamoto H, Matsuda K, Oshima Y, Yoshida A, et al. Platelet-rich plasma enhances the initial mobilization of circulation-derived cells for tendon healing. J Cell Physiol. 2008;215(3):837-45. DOI:10.1002/jcp.21368.
23- Tsai WC, Pang JH, Hsu CC, Chu NK, Lin MS, Hu CF. Ultrasound stimulation of types I and III collagen expression of tendon cell and upregulation of transforming growth factor beta. J Orthop Res. 2006;24(6):1310-16. DOI:10.1002/jor.20130.
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Kutsi Tuncer, Mehmet Demir, Eyüp Şenocak, Ali Sefa Mendil, Arzu Gezer, Basri Pür, Recep Öztürk. The efficiency of Polytendon Complex (PC) and St. John’s Wort oil (Hypericum perforatum) on healthy Achilles tendon in rats. Ann Clin Anal Med 2021;12(2):139-143
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Renal leiomyosarcoma: A rare entity
Arzu Erdem Taşdemir, İpek Özer, Hatice Karaman
Department of Pathology, Kayseri City Training and Research Hospital, Kayseri, Turkey
DOI: 10.4328/ACAM.20263 Received: 2020-06-30 Accepted: 2020-12-23 Published Online: 2021-01-05 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):212-215
Corresponding Author: Arzu Erdem Taşdemir, Department of Pathology, Kayseri City Training and Research Hospital, Kayseri, Turkey. E-mail: atasdemir786@gmail.com P: +90 5327423680 Corresponding Author ORCID ID: https://orcid.org/0000000251836663
Renal leiomyosarcoma is one of the rare tumors. It constitutes only 0.5% of all primary renal malignancies. It accounts for 50-60% of primary renal sarcomas. The majority of cases are adults, and their mean age is 58 years. Renal leiomyosarcomas originate from the renal capsule, pelvis renalis, calyces, and vascular smooth muscles. These tumors have a poor prognosis, and surgery is the main treatment modality. In this article, in the light of the literature, we aimed to pres-ent a case report of renal leiomyosarcoma 16x15x11cm in size in the right kidney of a 39-year-old female patient who presented with complaints of abdominal pain and hematuria. Although leiomyosarcomas are limited in the kidney, they are aggressive tumors with a poor prognosis.
Keywords: Leiomyosarcoma; Kidney; Aggressive tumors
Introduction
Sarcomas are rarely encountered tumors, and renal sarcomas observed in adults include leiomyosarcoma, osteosarcoma, angiosarcoma, rhabdomyosarcoma, synovial sarcoma, pleomorphic sarcoma, and fibrosarcoma.
Primary leiomyosarcomas are rare tumors observed in adults, and these tumors, which show smooth muscle differentiation, are the most common renal sarcomas. Primary sarcomas in the kidney constitute 0.8-2.7% of renal tumors in adults. Leiomyosarcomas are aggressive and highly malignant tumors, and they originate from the renal capsule, pelvis renalis, calyces, and vascular smooth muscles. Although they have an equal prevalence in males and females, in some publications in the literature, a higher prevalence is reported for females. Leiomyosarcoma is observed at a younger age than classic renal cell carcinoma. It does not have any specific clinical findings, and patients most commonly present with abdominal pain, hematuria, and weight loss. The differential diagnosis includes angiomyolipoma, sarcomatoid renal cell carcinoma, and malignant melanoma. The radiological findings are nonspecific, and the diagnosis is made by a postoperative pathological examination. Leiomyosarcomas are aggressive tumors, and their 5-year survival rate is around 29-36% [1].
Case Report
When a 39-year-old female patient was admitted to the urology clinic of our hospital with complaints of abdominal pain and hematuria, the physical examination revealed a firm, well-circumscribed mass on the right side. Renal color Doppler ultrasonography revealed a solid space-occupying lesion 134×72 mm in size, with discrete contours and heterogeneous echotexture, showing discrete arterial and venous vascularization on Doppler examination, and originating from the right kidney and showing an exophytic medial extension (hypernephroma?). Magnetic resonance (MR) examination of the upper abdominal revealed parapelvic T1A hypointense and T2A hyperintense heterogeneous mass lesion with cystic cavities, approximately 162×106 mm in diameter, showing an exophytic extension and applying lateral pressure to the vena cava in the right kidney. Right radical nephrectomy was applied to the patient. The patient, who did not develop complications, was discharged on the 4th postoperative day with stable vital signs and laboratory values. The nephrectomy material which was sent to the pathology laboratory was 16x12x11cm in size and 1890g in weight. In the cross-section of the kidney, a solid cystic tumoral formation 15x12x11cm in size was observed in a gray-beige colored, well-circumscribed area based on the renal capsule. Necrotic areas were observed in serial sections. When examining multiple sections of the mass, the tumor structure was observed at a distance of 0.2 cm, when closest to the renal capsule, not exceeding the capsule, with well-circumscribed focal necrosis. It was observed that the tumor was composed of pleomorphic, large eosinophilic cytoplasmic spindle cells with a bizarre-looking nucleus in places that form intercrossing bundles (Figure 1A-B). Six-seven mitotic figures were observed in the 10 large augmentation areas (LAA) in the tumor. Capsule and perirenal fat tissue invasion was not observed. No lymphovascular invasion was observed. In the immunohistochemical staining process that was performed for the differential diagnosis, there was positive staining in tumor cells with smooth muscle actin (SMA) (Figure 2A), vimentin, desmin (Figure B), while there was negative staining with epithelial membrane antigen (EMA), S100, CD117, CD34, myoglobin, and mouse anti-human melanoma antibody -45 (HMB45). The rate of proliferation was found to be 60% with Ki67.
The patient was diagnosed as renal leiomyosarcoma with histopathological findings and immunohistochemical staining results. There was no diagnosed sarcoma in another localization. When the tumor was graded by the French Federation of Cancer Centers Sarcoma Group (FNCLCC) (Table 1), tumor differentiation was reported as a score: 1 (sarcoma closely resembling normal adult mesenchymal tissue), tumor necrosis score: 1(<50%), mitotic score: 1 (0–9 mitoses per 10 HPF), histological grade: 3 (total score: 3).
Discussion
Renal leiomyosarcomas are very rare tumors. Primary sarcomas in the kidneys constitute 0.8-2.7% of renal tumors in adults. These are the most common renal sarcoma subtypes (50-60%). They are mostly encountered in adults in the 5th-6th decade. While males and females are equally affected, in some publications in the literature, a higher prevalence is reported for females [2]. Leiomyosarcomas are solitary lesions, and abdominal pain, hematuria, and palpable mass are the main symptoms. The tumor is often localized on the right side [4]. The tumor originates from the renal capsule, pelvis renalis, calyces, and vascular smooth muscles. The most common origin is the smooth muscles of the renal vein [3]. It was located in the right kidney of our female patient and probably originated from the renal capsule.
The first and most common symptoms are abdominal pain and hematuria, while others are palpable mass and weight loss. In our case, hematuria and abdominal pain were the first clinical complaints.
Radiological examinations such as ultrasonography, tomography and magnetic resonance cannot differentiate leiomyosarcoma from renal cell carcinoma. The diagnosis is made by postoperative pathological examination.
Renal leiomyosarcomas are solid, gray-beige colored, well-circumscribed, necrosis-containing masses with a diameter of 5 to 17 cm. Most tumors have cystic changes [1]. Our case was 16 cm in diameter, and cystic changes and necrotic areas were observed.
Microscopy revealed fascicular, plexiform, spindle cell bundles exhibiting a random growth pattern with nuclear pleomorphism, mitosis, necrosis, and mitotic figures. In the differential diagnosis, sarcomatoid renal cell carcinoma and angiomyolipoma are important. Leiomyosarcoma is stained with desmin, vimentin, and SMA. The majority of tumors are negative for cytokeratin, CD34, CD117, EMA, and S100, although (uncommonly) focal aberrant expression of these markers can occur. Melanocytic markers (HMB45, and Melan-A), Myo-D1, and myogenin are negative. This staining profile supported a smooth muscle origin and confirmed the diagnosis of leiomyosarcoma. The tumor proliferation rate was calculated as 60% with ki67 immunohistochemical staining performed.
Renal leiomyosarcoma can be distinguished from leiomyoma and angiomyolipoma, by the presence of cellular pleomorphism, increased mitosis, and necrosis [5]. Angiomyolipomas are triphasic tumors, may have degenerative changes, but no marked atypia, no mitotic activity, positive for melanocytic markers.
High-grade tumors are pleomorphic, necrotic, requiring immunohistochemical stains to distinguish them from other tumors such as sarcomatoid carcinoma pleomorphic sarcomas, sarcomatoid renal cell carcinoma. While leiomyosarcomas contain predominantly monomorphic cells, sarcomatoid renal cell carcinomas contain pleomorphic cells and lack the typical fascicles of smooth muscle cells seen in leiomyosarcoma [6].
Conclusion
Although leiomyosarcomas are limited in the kidney, they are aggressive tumors with a poor prognosis, with a 5-year survival rate of 29-36% [1]. The majority of patients are lost within 2 years. Local recurrence is common. Distant metastases are hematogenous, and they are mostly observed in the lungs and bones.
Postoperative chemotherapy and radiotherapy can be generally performed in cases which have undergone partial resection. To date, studies published in the literature have shown that local control of the disease is better in cases of sarcoma that have undergone radical resection, but there is no survival benefit for adjuvant treatment with chemotherapy and radiotherapy. The possibility of treatment with KIT tyrosine kinase inhibitors, such as sunitinib, has been reported in phase II. Radiotherapy and chemotherapy were not applied to our case.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Dominici A, Mondaini N, Nesi G, Travaglini F, Di Cello V, Rizzo M. Cystic leiomyosarcoma of kidney: An unusual clinical presentation. Urol Int. 2000;65(4):229-31.
2. Cocuzza M, Arap S, Lucon AM, Saldanha LB. Renal leiomyosarcoma treated with partial nephrectomy. Clinics (Sao Paulo). 2005;60(4):345-6.
3. Venkatesh K, Lamba SM, Niveditha SR, Krishnagiri C, Babu S. Primary leiomyosarcoma of the kidney. Patholog Res Int. 2010; 2010. DOI:10.4061/2010/652398
4. Beardo P, José Ledo M, Jose Luis RC. Renal leiomyosarcoma. Rare Tumors. 2013;5(3):42.
5. Reetu K, Mahesh C, Rajpal SP, Purnima A. Primary renal leiomyosarcoma arising from renal vein: A case report of rare entity with review of literature. Indian J Med Paediatr Oncol. 2019;40(5):139-40.
6. Danny D, Fatima SA. Atypical Presentation of Renal Leiomyosarcoma: A Case Report. Cureus. 2019;11(8):5433.
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Arzu Erdem Taşdemir, İpek Özer, Hatice Karaman. Renal leiomyosarcoma: A rare entity. Ann Clin Anal Med 2021;12(2):212-215
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A Treatment arising from tradition: A Report of indigo blue therapy for granulomatous mastitis
Selim Keçeoğlu
Department of General Surgery, Acibadem Mehmet Ali Aydinlar University Atakent Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.20355 Received: 2020-09-27 Accepted: 2020-10-29 Published Online: 2020-11-09 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):219-221
Corresponding Author: Selim Keçeoğlu, Department of General Surgery, Acibadem Mehmet Ali Aydinlar University Atakent Hospital, Istanbul, Turkey. E-mail: selimkeceoglu@hotmail.com P: +90 5307892685 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9985-3972
The indigo plant is used globally for its blue dye, and plant-based indigo dyeing has been traditionally practiced for centuries in a broad geographic area. In addition to this purpose, indigo is used medically in many African tribal areas for its anti-inflammatory and anti-microbial effects. This article presents a case of granulomatous mastitis that was treated by a tribal healer with indigo blue, which provided temporary relief of symptoms for one year until secondary bac-terial infection occurred. Some studies reported that indigo blue provides symptomatic relief related to its anti-oxidant, anti-microbial and anti-inflammatory mechanisms, which could be helpful in autoimmune diseases such as granulomatous mastitis. We strongly believe that this patient’s results warrant further investigation of indigo blue’s effect on granulomatous mastitis.
Keywords: Indigo blue; Granulomatous mastitis; Indigofera
Introduction
The indigo plant is used globally for its blue dye. The tropical plant, also known by the Latin name Indigofera, has 800 local species in tropical and subtropical regions. Within the indigo plant family, approximately a dozen distinct species are used for dyeing blue in various geographic regions. The plant can provide a broad spectrum of strong blue colour ranging from navy to pale blue. Plant-based indigo dyeing has been traditionally practiced for centuries in a wide geographic area including the Mediterranean Basin, Africa, the Far East, China, Malesia, India, Bangladesh, Indonesia, Java and its archipelago, South America and Peru [1]. Additionally, it is used medically in many African tribal areas for its anti-inflammatory and anti-microbial effects. This article presents a case of granulomatous mastitis that was treated with indigo blue by a tribal healer.
Case Report
A 21-year-old woman presented with a one-year history of a right breast mass at Nyala Turkish Hospital, Sudan. She had no family history of breast cancer. The patient had a two-year-old child who had been breastfed until the onset of the lesion, at which time the breastfeeding was discontinued. The patient had a history of a large lump on her breast for one year, which was treated by the village healer until the time of presentation with an unknown topical cream called zhar, which proved very helpful, greatly relieving the swelling and thickening of the breast for one year (Figure 1).
The woman had experienced no problem with the breast when she used the cream, but yellow drainage has formed in the past two months, which has become very painful in the past week, so she was admitted to hospital.
The woman was afebrile, and a physical examination discovered a hard, painful, mobile mass, 8 cm in diameter, affecting all quadrants of her right breast. There were nipple discharge and skin retraction. The overlying skin showed signs of inflammation as well as remarkable, very large infected skin fissures; palpable lymph nodes were present in the ipsilateral axilla. The lesion was covered with a vivid blue dye; later, we were told that it was a specific blue dye extracted and produced from the indigo plant.
The wound was cleaned, the abscess drained, a core needle biopsy performed, and wide-spectrum antimicrobial and anti-inflammatory agents were prescribed, both orally and topically. The findings from cultures of the purulent discharge of the skin showed staphylococcus aureus, but the aspiration fluid remained sterile.
Discussion
Dyes have been used throughout history in various aesthetic and, later, practical applications. They are primarily used as colouring agents to dye materials in the cotton and textile industries, but our understanding of the importance of these substances has evolved, leading to their increased use across industry and science alike [2]. Currently, dyes are widely used and play an important role in modern electronics, in the printing industry, where they are used in electrophotography (laser prints and photocopies), and in medical applications, where they may be used to cure diseases and treat ailments [2,3]. Probably the oldest and most famous dye is indigo, which has an intense dark blue colour. The name indigo derives from the Greek endikoni, meaning Indian. It can be traced back to ancient Asian civilizations, whence it spread west across Europe, particularly in ancient Greece and Rome [2,3]. Historically, indigo naturalis (IN) has been used in China for the treatment of various inflammatory diseases and dermatitis, including ulcerative colitis (UC) [4]. Its primary active ingredients are indigo, indirubin, tryptanthrin and qingdainone. The clinical disease activity indexes and endoscopic Matts grades have been demonstrated to signifi¬cantly decrease following oral administration of IN powder in patients with UC who are unresponsive to 5 aminosalicylic acid, prednisolone and infliximab treatment [5,6]. Furthermore, IN has a powerful scavenging effect on hydroxyl radicals, and its extract has been successfully used to treat clinical psoriasis [5,7] and to induce apoptosis and autophagy of acute lymphoblastic leukaemia cell lines [5,8]. Additionally, Cheng et al.’s [9] experimental study on patients with moderate psoriasis identified IL-17 as a key pathway that can be modulated by treatment with IN. That study exemplified a novel approach to understanding the mechanism of action of IN, which can be used to understand the therapeutic effect of other forms of IN. In light of these studies, we believe that the relief that the patient experienced when using indigo blue is related to its anti-oxidant, anti-microbial and anti-inflammatory mechanisms, all of which could be helpful in autoimmune diseases such as granulomatous mastitis. We strongly believe that this patient’s results warrant further investigation of the effect of indigo blue on granulomatous mastitis.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Ercivan GB. The historical adventure of blue dye indigo plant. Journal of International Social Research. 2018;11(60):547-53.
2. Stasiak N, Wirginia KK, Kazimierz G. Modern industrial and pharmacological applications of indigo dye and its derivatives: a review. Acta Pol Pharm. 2014;71(71):215-21.
3. Heaton CA. The Chemical Industry. Berlin: Springer-Verlag; 1994.
4. Fukuda T, Naganuma M, Kanai T. Current new challenges in the management of ulcerative colitis. Intestinal Research. 2019;17(1):36.
5. Wang Y, Liu L, Guo Y, Mao T, Shi R, Li J. Effects of indigo naturalis on colonic mucosal injuries and inflammation in rats with dextran sodium sulphate induced ulcerative colitis. Exp Ther Med. 2017;14(2):1327-36.
6. Suzuki H, Kaneko T, Mizokami Y, Narasaka T, Endo S, Matsui H, et al. Therapeutic efficacy of the Qing Dai in patients with intractable ulcerative colitis. World J Gastroenterol. 2019;19(17):2718 22.
7. Lin YK, See LC, Huang YH, Chang YC, Tsou TC, Lin TY, et al. Efficacy and safety of Indigo naturalis extract in oil (Lindioil) in treating nail psoriasis: a randomized, observer blind, vehicle controlled trial. Phytomedicine. 2014;21(7):1015 20.
8. Lee MY, Liu YW, Chen MH, Wu JY, Ho HY, Wang QF, et al. Indirubin 3’ monoxime promotes autophagic and apoptotic death in JM1 human acute lymphoblastic leukemia cells and K562 human chronic myelogenous leukemia cells. Oncol Rep. 2013;29:2072 8.
9. Cheng HM, Wu YC, Wang Q, Song M, Wu J, Chen D, et al. Clinical efficacy and IL-17 targeting mechanism of Indigo naturalis as a topical agent in moderate psoriasis. BMC Complement Altern Med. 2017;17(1):439.
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Selim Keçeoğlu. A Treatment arising from tradition: A Report of indigo blue the- rapy for granulomatous mastitis. Ann Clin Anal Med 2021;12(2):219-221
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Teratoma of the greater omentum: An extremely rare case report
Oğuzhan Özdemir 1, Turgut Anuk 2, Volkan Kızılgöz 1, Hasan Çantay 2
1 Department of Radiology, Kafkas University, Faculty of Medicine, 2 Department of General Surgery, Kafkas University, Faculty of Medicine, Kars, Turkey
DOI: 10.4328/ACAM.20350 Received: 2020-09-22 Accepted: 2020-10-22 Published Online: 2020-10-27 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):216-218
Corresponding Author: Volkan Kızılgöz, Kafkas University, Faculty of Medicine, Department of Radiology, Kars, Turkey. E-mail: volkankizilgoz@gmail.com P: +90 5057994013 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3450-711X
Although mature cystic teratomas or dermoid cysts are common ovarian tumors, the extragonadal site is extremely low. The most common extragonadal site to find these tumors is the greater omentum. Reports reveal that only 32 cases of teratoma of the greater omentum have been published to date. We report an extremely rare case of mature cystic teratoma of the omentum in a 51-year-old woman who presented with nonspecific lower abdominal pain. After imaging with contrast-enhanced abdominal CT, the patient underwent cystectomy for the omental teratoma.
Keywords: Teratoma; Dermoid; Omentum; Omental teratoma; Computed tomography
Introduction
Mature cystic teratomas, also known as dermoid cysts are the most common benign tumors of the ovary. On the other hand, extragonadal teratomas are reported to be extremely rare and they are typically found in the greater omentum [1]. To the best of our knowledge, 32 cases of teratoma of the greater omentum have been published to date. Mature cystic teratomas are encapsulated tumors with mature tissue or organ components. They are composed of well-differentiated derivatives from at least two of three germ cell layers (i.e. ectoderm, mesoderm and endoderm). It is known that these tumors arise from the germ cells originating in the mature gonads [1, 2]. Reports suggest that primary omental teratomas are seen more often in females than males with a ratio of 1/12 (male to female ratio), pointing to a relation with female reproductive system [2, 3, 4]. During early fetal life, germ cells migrate along the route of mesentery toward the genital ridge, and this may explain the extragonadal site (e.g. omentum) of teratomas [2]. Abdominal pain, gastrointestinal or genitourinary symptoms, lower extremity or genital edema are the general complaints related to omental teratoma [5]. Here we report the clinical, computed tomography (CT) and intra-operative findings of a rare case of mature cystic teratoma of greater omentum.
Case Report
A 51-year old woman with nonspecific lower abdominal pain for the past two days was admitted to the emergency department. Physical examination and laboratory findings were not remarkable. Ultrasound (US) scan showed unremarkable findings with totally normal ovaries. She was discharged with oral analgesics. The next day, the patient came over with ongoing pain and was referred to the department of general surgery for further investigation. Her physical examination was still unremarkable. The detailed gynecologic examination was also normal without any previous history of gynecologic disease or surgery. CT scan revealed a left-sided mass of 3.5×4.5 cm in the greater omentum indenting the small bowel loop (Figure 1). The mass contained fat, calcification, and cystic areas compatible with features of mature cystic teratoma. While the adnexal regions were normal and the mass had a far location from the left ovary, our primary diagnosis was extragonadal teratoma in the greater omentum.
Preoperative laboratory test results were normal. Preoperative tests for tumor markeralso did not reveal an increase in the level of cancer antigens. After a detailed clinical evaluation, the patient underwent open laparotomy. The mass was found to be embedded into the greater omentum (Figure 2). Cystectomy was performed and the postoperative course of the patient was uneventful. The adnexal regions were also evaluated during open laparoscopy, and the ovaries were found normal. The pathologic report revealed features consistent with benign cystic teratoma attached to the greater omentum, without any remnants of ovarian stroma.
Discussion
The causes of extragonadal teratomas are poorly understood, but several mechanisms have been proposed. There are three basic theories to explain the extragonadal mature cystic teratomas as follows: 1) primary teratomas originating from displaced germ cells, 2) implantation into the extragonadal site from autoamputation of ovarian teratoma, and 3) teratomas arising in a supernumerary ovary. The studies to date proposed that the omentum was the primary location of the extragonadal teratomas for 32 reported cases, thought to occur with a mechanism of autoamputation [6]. Furthermore, reports suggest that there is a lack of histologic evidence supporting the first and third theories [2, 6]. The literature review revealed an ipsilateral absent or atrophic ovary in the reported 30 cases, supporting the theory of autoamputation [7]. In 22 of those cases, the teratoma contained microscopic ovarian tissue, bringing this theory to the fore. In the reported four cases, omental teratoma and ovarian teratoma were coexisting [1, 7]. In another report, a right-sided extragonadal teratoma near the right ovary was shown [6]. Despite the lack of ovarian tissue in the histologic examination and normal right ovary, they suggested that this case matched the second theory aforementioned due to the close proximity of the right ovary. Autoamputation was thought to result from a primary ovarian teratoma, probably undergoing torsion. Ovarian torsion caused by mature cystic teratoma is quite common, and when complicated with necrosis of the torsed ovary, it can result in ovarian tissue along with cells from the teratoma reimplanting into the greater omentum as an extragonadal teratoma [7]. Reviewing the literature, it can be strongly hypothesized that ovarian atrophy might be the result of past ovary torsion. Because of its special role in the inflammation or infectious defense processes, the omentum might be the potential primary site of for reimplantation of the autoamputated ovarian teratoma [1, 6, 7].
However, it is not clear how to distinguish autoamputation from the other theories, and we think that other theories should also be considered, as shown in the present case. In our case, both of the ovaries were normal without any space-occupying lesion (Figure 3). This was also confirmed during laparotomy. Microscopy of the patologic specimen showed mature cystic teratoma without any ovarian tissue component. This fact might point to the first theory above mentioned. Besides, the lack of ovarian stroma in the present case might be a clue to exclude the possibility of parasitic ovarian tissue related to previous gynecologic surgeries or supernumerary ovary as described in the literature [8]. However, there is still a necessity for other studies with further evidences to reveal the exact mechanism of extragonadal teratomas.
Ultrasound is generally the initial imaging tool in the diagnosis of mature ovarian cystic teratomas. CT and magnetic resonance imaging (MRI) are the problem solving imaging tools to further evaluate the adnexal masses. Besides, MRI with its high soft tissue resolution has the advantage to characterize the primary ovarian masses, to depict the adnexal anatomy, and to help in the diagnosis of ovary torsion and its possible complications [9]. It is clear that MRI is also an efficient imaging method for diagnosing extragonadal teratomas as well as scanning the ovaries at the same time. However, it was not possible to obtain an MRI scan in our claustrophobic patient. CT could clearly show the features of mature cystic teratoma with normal adnexal regions in the present case.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Hegde P. Extragonadal omental teratoma: a case report. J Obstet Gynaecol Res. 2014; 40(2):618-21.
2. Ali AA, Sall I, El Kaoui H, Bouchentouf SM, El Hjjouji A, El Fahssi M, et al. Teratoma of the greater omentum. Can J Surg. 2009;52(3):E54-5.
3. Ushakov FB, Meirow D, Prus D, Lisbon E, Ben Shushan A, Rojansky N. Parasitic ovarian 138 dermoid tumor of the omentum-A review of the literature and report of two new cases. Euro J Obstet Gynecol Reprod Biol. 1998;81(1):77–82.
4. Chen SS, Chen CP, Chien SC, Hsu CY. Spontaneous rupture of omental teratoma mimicking 141 a ruptured ovarian teratoma Taiwan. J Obstet Gynecol. 2008; 47(2):229–32.
5. Wani BN, Rathod V, Banode P, Bhole A. An omental teratoma in a young girl. Clin Pract. 143 2011;19:284–6.
6. Rampinelli F, Donarini P, Visenzi C, Ficarelli S, Gambino A, Ciravolo G. The Rare Extragonadal Omental Teratoma: A Case Report. J Minim Invasive Gynecol. 2017;24(6):1046-8. DOI: 10.1016/j.jmig.2017.05.022.
7. Lee KH, Song MJ, Jung IC, Lee YS, Park EK.Autoamputation of an ovarian mature cystic teratoma: a case report and a review of the literature. World J Surg Oncol. 2016;14(1):217. DOI: 10.1186/s12957-016-0981-7.
8. Özcan HÇ, Uğur MG, Gündüz R, Bozdağ Z, Kutlar İ. Parasitic omental ovarian dermoid tumour mimicking an adnexal mass: A report of two very unusual cases. Turk J Obstet Gynecol. 2015;12(4):251-3. DOI:10.4274/tjod.87259
9. Özdemir O, Metin Y, Metin NO, Küpeli A. Contribution of diffusion-weighted imaging to conventional MRI for detection of haemorrhagic infarction in ovary torsion. BMC Med Imaging. 2017;17(1):56. DOI:10.1186/s12880-017-0232-6
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Oğuzhan Özdemir, Turgut Anuk, Volkan Kızılgöz, Hasan Çantay. Teratoma of the greater omentum: An extremely rare case report. Ann Clin Anal Med 2021;12(2):216-218
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Serial casting for equinus deformity in children with cerebral palsy: A systematic review
Mohammed M. El Sayeh 1, Samia A. Abdel Rahman 2, Ihab M. Abd El Kafy 2, Mahmoud S. El Fakharany 2
1 Physical therapist at El Santa General Hospital, Ministry of Health, 2 Department of Physical Therapy for Pediatrics, Faculty of Physical Therapy, Cairo University, Cairo, Egypt
DOI: 10.4328/ACAM.20264 Received: 2020-06-27 Accepted: 2020-09-04 Published Online: 2020-10-28 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):222-227
Corresponding Author: Mahmoud S. El Fakharany, Department of Physical Therapy for Pediatrics , Faculty of Physical Therapy, Cairo University, Cairo, Egypt. E-mail: Mahmoud.samier@pt.cu.edu.eg P: 01067904792 Corresponding Author ORCID ID: https://orcid.org/0000-0002-3943-4469
Aim: The primary cause of gait deformity in children with cerebral palsy (CP) is equinus foot. Children with equinus foot typically receive physiotherapy as part of their care, as serial casting. In this study, we aimed to systematically examine the impact of serial casting procedure in children with CP with equinus deformity.Material and Methods: Articles were identified from 2008 to 2019 by literature searches using Medline (MEDLINE), physiotherapy evidence base (PEDro), and Cochrane database. Randomized trials focused on CP children with equinus deformity were included. Data were extracted from the included studies and methodological quality of these data was evaluated using the PEDro scale. The modified Sackett scale was used to evaluate the level of evidence of each intervention.Results: Four trials with good quality methodology were identified with good quality methodology. It was examined whether studies regarding intervention techniques were heterogeneous or not. Findings were analyzed in qualitative terms.This review revealed moderate evidence in three articles about the effec-tiveness of serial casting application and the ineffectiveness in one article, in addition to traditional physiotherapy programs. Meta-analysis was applied for homogeneous studies and it showed that serial casting could be used as a method to improve deformity of the equinus.Discussion: The current systematic review analyzed four randomized controlled trials, applying strict inclusion selection criteria. The present evidence supports the use of serial casting for improving equinus deformity and modulates spasticity in children with CP and it is considered a moderate evidence of the efficacy of serial casting application.Although the findings of this review support the effectiveness of serial casing application in CP children with equinus deformity, additional randomized control trials with a larger sample size are still required to confirm the present evidence.
Keywords: Serial casting; Deformity of equinus; Cerebral palsy; Toxin of botulinum; Abnormality of gait; Scissoring
Introduction
Equinus foot is a disorder of the musculoskeletal system often seen in patients with cerebral palsy (CP) and can restrict activities such as walking function [1]. Equinus is the most frequent problem in ambulatory children with spastic CP, resulting in an unstable and inefficient gait pattern.Without careful early treatment, it may evolve into permanent foot deformities which may require multiple surgical procedures. A variety of conservative approaches are currently available for managing Equinus in children with CP, such as bracing, stretching exercises, electrical stimulation, and casting/serial casting [2].
Through physical therapy, such as stretching and muscle strengthening exercises, antispastic medications, BTX-A injection, ankle-foot orthoses, and serial casting, or surgery, such as tendon elongation of Achilles, Equinus foot can be handled.BTX-An injection and serial casting are among such treatments with limited side effects relative to drug therapy [3].
Serial casting is described as using a series of progressive casts to increase the length of the muscle using low load prolonged stress on contracted tissues [4]. Serial casting aims to improve a pattern of the equinus gait in children with spastic CP (SCP) [5].
Numerous clinical trials have shown that casting is a useful adjunct to Botulinum toxin A (BoNT-A) for enhancing results, using either serial or single casts. In reducing spastic hypertonia, the combination of BoNT-A and casting was superior to BoNT-A alone [6].This systematic review aimed at verifying the effect of the application of serial casting on equinus deformity for children with CP.
Material and Methods
Search strategy
This study was based on the recommendations of the Statement on Preferred Reporting Items for Systemic Reviews and Meta-Analysis (PRISMA) [7]. Eligibility criteria were defined as follows: (a) Participants: children with CP accompanied by equinus deformity aged from 2 to 17 years of both genders, (b) Interventions: the study group received serial casting after BoNT-A and traditional physiotherapy program, (c) Outcomes: Passive range of motion (PROM), spasticity degree, ankle kinematics during gait, gross motor function level and (d) Study design: Randomized controlled trials (RCTs). Anelectronic search was done from 2008 to 2019, in the Cochrane Central Register of Controlled Trials, PEDro and PubMed databases using the following keywords: “Serial casting” and/or “Equinus deformity” or “Cerebral palsy” or “Botulinum toxin” or “Scissoring” or “Gait abnormality”.The search was limited to RCTs only which published from 2008 to 2019. Studies were excluded according to the following criteria: (a) Non RCTs, (b) Participants aged over 17 years, (c) If no English translation is available and/or (d) Unpublished studies. Two authors independently evaluated each title and abstract identified in the search against the eligibility criteria. The full text was obtained for complete analysis.
Data extraction
One reviewer extracted data from the included articles, and a second reviewer cross-checked it. The data extraction form included authors and year of publication, the characteristics of the participant, measures of intervention, and outcomes [8].
Quality assessment
Two authors applied the PEDro scale [9] separately to determine the quality of the trials and the third author resolved any disagreements.
Data analysis
The following classification was used for the quantitative quality rating: PEDro score < 4 indicated poor quality; 4-5 indicated fair quality; 6-8 for good quality and 9-10 indicated excellent quality. The modified Sackett scale [10] was used for assessing the level of evidence as follows:
Level 1a (Strong) = Well-designed meta-analysis or 2 or more ‘high’ quality RCTs (PEDro Scale scores ≥ 6) that show similar findings.
Level 1b (Moderate)= One RCT of ‘high’ quality (PEDro Scale score ≥ 6).
Level 2a (Limited) = At least one ‘fair’ quality RCT (PEDro Scale score= 4-5).
Level 2b (Limited)= At least one well-designed non-experimental study: non-RCT; quasi-experimental studies; cohort studies with multiple baselines; single- subject series with multiple baselines.
Level 3 (Consensus)= Agreement by an expert panel, a group of professionals in the field or a number of pre-post design studies with similar results.
Level 4 (Conflicting)= Conflicting evidence of two or more equally designed studies.
Level 5 (No evidence)= No well-designed studies: “Poor” quality RCTs with PEDro scores ≤ 3; only case studies/case descriptions or cohort studies/single subject series with no multiple baselines.
Results
Search results
The search identified 54 trials until July 2019. After screening titles and abstracts and removing duplicates, four studies(Dai and Demiryürek, 2017 [11]; Dursun et al., 2017 [12]; Kelly et al., 2019 [13] and Abd El-Monemet al., 2019 [14]) were included in this review.Search results are presented according to the flow chart (Figure 1).
Characteristics of the included studies
All included studies are RCTs. The summary of the included studies is presented in Table 1. The clinical homogeneity between some of the included trials allowed the quantitative analysis of their data.
Qualitative analysis
Participants
The sample size ranged from 10 to 80. There were a total of 176 children participating across the four RCTs, diagnosed with CP, including both genders and aged from 2 to17 years.
Interventions
The study versus the control groups in four of the included RCTs received botulinum toxin type A in addition to traditional sessions of physiotherapy.
Outcome measures
In the reviewed studies, spasticity testing was performed using modified Ashworth scale (MAS) and modified Tardieu scale (MTS), passive range of motion (PROM) was assessed using (MTS), gross motor function level was assessed using GMFM-66 and gait abnormalities were assessed using observational gait scale (OGS).
Quality of the included studies and the level of evidence
The methodological quality of included four studies is presented in Table 2. The quality of the studies is good with a mean PEDro score (range 6 to 7). The four included studies had similar groups at baseline, analyzed the between-group difference. The four studies carried out an intention-to-treat analysis, none of the studies blinded participants.
Evidence of serial casting application interventions
The results of the 4 reviewed trials (Dai and Demiryürek,2017, Dursun et al., 2017, Kelly et al., 2019, and Abd El-Monemet al., 2019) [11-14] which investigated the effects of serial casting application for CP children with equinus deformity are summarized in Table 3.
Statistical analysis:
Only three articles (Dai and Demiryürek (2017), Dursun et al., (2017), Kelly et al., (2019)) [11-13] have homogeneity in all four components (participants, intervention, outcome (modulation of spasticity) and the outcome measures) so only one meta-analysis was performed and this meta-analysis favors the use of serial casting application for modulation of spasticity in children with spastic CP.
Description and Interpretation of Forest plot of RevMan:
The Forest plot is composed of (from left to right):
1. The names of the included studies.
2. The data of the study and control groups including the mean difference between pre- and post-intervention, SD of the paired difference, and number of cases in each group.
3. The weight of each study as a % of the total of the meta-analysis (100%).
4. The difference in means between the 2 groups + the 95%CI of the difference.
5. The publication year again.
6. On the right side, there is a figure showing the same above results. Each study is represented by a square (its size = study weight, and its center is opposite to the mean’s difference) on a straight line (representing the 95%CI of the mean’s difference). The final results of the meta-analysis are represented by the black diamond (its center is the mean’s difference across all studies and the tips are the 95%CI of the mean’s difference across all studies).
7. The line in the middle of the graph is opposite the 0 value and it is called the equator line which means no difference between the groups. If the lines of any study and/or the diamond touch it, this means that there is no statistical difference between the 2 groups.
8. The last 2 lines written in the plot are for the heterogeneity represented by I2 statistic as a % and a p-value. When the p- value is < 0.05, then heterogeneity is considerable across the studies and we should take the results cautiously. The 2nd line is the p-value of the overall results (that are represented by the diamond in the graph). This is represented by Z- value and p-value. When the p-value is < 0.05, this means that the overall result is statistically significant.
9. Forest plots were done using Review Manager (RevMan) [Computer program] Version 5.3. Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration, 2014.
Statistical methods:
We analyzed data from the included studies using Review Manager (RevMan – version 5.2, The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark), and Microsoft Excel 2010 (Microsoft Corp., Redmond, WA, USA). A formal meta-analysis was conducted for our outcome (difference in MAS between pre- and post-intervention). The pooled MAS values were expressed as the mean difference (MD) between study and control groups, with 95%CI. We explored and quantified between-study statistical heterogeneity using the I2 test. Since I2 was 0%, we used the fixed-effect model. We considered 2-sided statistical analysis testing setting the α-error level at 0.05 (Figure 2).
Discussion
The aim of the current review is to determine the efficacy of serial casting on the deformity of the equinus in children with CP. The analysis covers studies conducted between 2008 and 2019 searched via PubMed, PEDro, Cochrane library, and Google scholar databases in the Medline database that most likely contain a large number of papers published annually.
The current systematic review analyzed four randomized controlled trials, applying strict inclusion selection criteria. All trials satisfied at least six PEDro-scale criteria. Three studies, including Dai and Demiryürek (2017) [11], Dursun et al. (2017) [12] and Kelly et al. (2019) [13] underwent meta-analysis.
The scoring of each study of the three studies with the PEDro scale is seven after collecting data based on AACPDM sheet items.The higher the number of scores of factors measuring the study’s efficiency, the greater the study’s efficiency. The research design of the three studies is randomized controlled trials with evidence level two; children involved in the three studies were spastic CP with ages ranging from 2 to 17 years.
The age range in Dai et al.’s study (2017) [11] was 2-4 years, in Dursun et al.’s study, (2017) [12] was 3-17 years and in Kelly et al.’s study (2019) [13], was from 2-7 years.
In the study by Dai and Demiryürek (2017) [11], the intervention was a 3-week serial casting application once a week and consisted of a dual cast which consisted of a standard long leg plaster cast and a circular cast from below the knee to above the knee, while in the study byDursun et al. (2017) [12], the intervention was three consecutive serial casting applications for three weeks once a week and consisted of a dual cast which consisted of a standard short leg plaster cast and a circular cast from below the knee to above the knee, with a follow-up period of 12 weeks. Moreover, the intervention in the study by Kelly et al. (2019) [13] was six weeks once a week and consisted of a dual cast which consisted of a standard short leg plaster cast.
Dai and Demiryürek (2017) [11] compared the use of serial casting with botulinum toxin type A in children with CP and spastic Paraparesis with scissoring of lower limbs. Dursun et al. (2017) [12] compared the effectiveness of intermittent serial casting on equinus foot in children with CP and BoNT-A. Kelly et al. (2019) [13] compared the effect of serial casting in spastic hypertonia of the triceps surae muscle with CP and equinus foot and BoNT-A.
All three studies usedMAS to assess spasticity. Dai and Demiryürek (2017) [11] used GMFM to assess the motor function of their participants. Dursun et al. (2017) [12] used MTS to assess spasticity and OGS to assess improvement of gait. Kelly et al. (2019) [13] used MTS to assess spasticity, GMFM to assess the motor function of their participants, and PEDI for assessing social function. The present evidence supports the use of serial casting applications for improving equinus deformity in children with CP.
In the study by Dai and Demiryürek (2017) [11], GMFM and child health questionnaire scores (CHQS) were markedly elevated in both groups following Botulinum toxin type A treatment, MAS scores decreased for 12 weeks in the Botulinum toxin type A injection with serial casting group (p<0.05), however no marked reduction in MAS scores in the Botulinum toxin type A injection only group.
In the study by Dursun et al. (2017) [12], there was a significant improvement in MAS, PROM in both groups (p<0.001 for all parameters of each group). The mean MAS and PROM of the casting group were better than those of the control group at week 4 (p=0.006, p=0.013) and week 12 (p=0.015, p=0.013) with significant improvement in OGS in both groups (p<0.001 in both groups).
Regarding Kelly et al.’s study (2019) [13], there is a significant improvement of MTS of dorsiflexion with knee extension (p<0.001) and dorsiflexion with knee flexion (p<0.001), a significant improvement for GMFM-66 (p=0.002) and all PEDI domains except social function caregiver assistance (p=0.009- <0.001).
There was no significant difference in ankle ROM, the distribution of spasticity grades of calf muscle tone, and the total score of OGS (p=0.64, p=0.44, p=0.64) inAbd El-Monem et al. (2019) [14].
Conclusion:
Although results from this analysis support the efficacy of using serial casing application for children with CP associated with equinus deformity, there is still a need for additional RCTs with larger sample sizes to validate the evidence.
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. Bax M, Goldstein M, Rosenbaum P, Leviton A, Paneth N, Dan B, et al. Proposed definition and classification of cerebral palsy. Dev Med Child Neurol. 2005; 47(8):571–6.
2. Brouwer B, Davidson LK, Olney SJ. Serial casting in idiopathic toe-walkers and children with spastic cerebral palsy. J PediatrOrthop. 2000; 20(2):221–5.
3. Goldstein EM. Spasticity management: an overview. J Child Neurolv. 2001; 16(1):16–23.
4. Flett PJ, Stern LM, Waddy H, Connell M, Seeger JD, Gibson SK. Botulinum toxin A versus fixed cast stretching for dynamic calf tightness in cerebral palsy. J Paediatr Child Health.1999; 35(1):71–7.
5. McNee AE, Will E, Lin JP, Eve LC, Gough M, Morrissey MC, et al. The effect of serial casting on gait in children with cerebral palsy: preliminary results from a crossover trial. Gait Posture. 2007; 25(3):463–8.
6. Hayek S, Gershon A, Wientroub S, Yizhar Z. The effect of injections of botulinum toxin type A combined with casting on the equinus gait of children with cerebral palsy. J Bone Joint Surg Br. 2010; 92(8):1152–9.
7. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009; 151(4):264-9.
8. Elnahhas AM, Elshennawy S, Aly MG. Effects of backward gait training on balance, gross motor function, and gait in children with cerebral palsy: a systematic review. ClinRehabil. 2019; 33(1):3-12.
9. Maher CG, Sherrington C, Herbert RD, Moseley AM, Elkins M. Reliability of the PEDro scale for rating quality of randomized controlled trials. PhysTher. 2003; 83(8):713-21.
10. Sackett DL, Straus SE, Richardson WS, Rosenberg W, Brian Haynes R. Evidence-based medicine. How to practice and teach EBM, 2nd ed. Edinburgh: Churchill Livingstone; 2000. p. 1071-4.
11. Dai AI, Demiryürek AT. Serial casting as an adjunct to Botulinum Toxin Type A treatment in children with cerebral palsy and spastic Para paresis with scissoring of the lower extremities. J Child Neurol. 2017;32(7): 671-5.
12. Dursun N, Gokbel T, Akarsu M, Dursun E. Randomized Controlled Trial on Effectiveness of Intermittent Serial Casting on Spastic Equinus Foot in Children with Cerebral Palsy After Botulinum Toxin-A Treatment. Am J Phys Med Rehabil. 2017; 96(4):221-5.
13. Kelly B, MacKay-Lyons M, Berryman S, Hyndman J, Wood E. Casting protocols following BoNT-A injections to treat spastic hypertonia of the triceps surae in children with cerebral palsy and equinus gait: a randomized controlled trial. Phys Occup Ther Pediatr. 2019; 39(1):77-93.
14. Abd El-Monem YM, Salem EE, Elassal MI, Mahran MA. Effect of intermittent serial casting on equinus ankle deformity in children with cerebral palsy. Med J Cairo Univ. 2019;87:2169-74.
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Therapeutic approaches for COVID 19: Challenges and successes
Rim M. Harfouch 1, Samer Alshaikh 2, Mohammad Alshimaly 3, Amany Assaad 3, Jehan Ahmad 3, Haya Zoughaibi 2, Maher Hammadi 3, Yahya Elshimali 4
1 Faculty of pharmacy, Al Sham private university, Latakia, Syria, 2 Faculty of medicine, Tartous university, Tartous, Syria, 3 Faculty of pharmacy, Tartous university, Tartous, Syria, 4 Faculty of medicine, Charles Drew University for Medicine and Science/University of California Los Angeles (UCLA), USA
DOI: 10.4328/ACAM.20270 Received: 2020-07-02 Accepted: 2020-08-11 Published Online: 2020-08-16 Printed: 2021-02-01 Ann Clin Anal Med 2021;12(2):228-233
Corresponding Author: Rim Harfouch, Department of microbiology and biochemistry, Faculty of pharmacy, Al Sham private university, Latakia, Syria 00000 E-mail: r.h.foph@aspu.edu.sy P: 00963932292303 Corresponding Author ORCID ID: https://orcid.org/0000-0001-7002-8728
The novel coronavirus SARS-COV-2 or COVID-19 was first discovered in Wuhan, China in late December 2019 and soon became a global pandemic. The virus causes flu- like symptoms and is potentially lethal. The rapid spread of the virus leaves the world in total paralysis and has devastating effects on the health, economic, and social levels of most countries.No treatment has been approved yet and the world really needs a precise and urgent medication. Certainly, the developing of a new specific drug for COVID-19 would take a longer time than expected but it is hoped that this task will be completed sooner than later; therefore recent studies have prioritized testing previously FDA-approved drugs for other indications and whether they have significant effects on COVID-19 or not. In this study, we discuss recent applications, protocols, and the outcomes of these drugs as advised by healthcare institutions and providers, as well as to conduct a literature review.
Keywords: COVID-19; Available treatments; Practical approach
Introduction
The novel coronavirus SARS-COV-2 or COVID-19 was first found in Wuhan, China and is the cause of severe acute respiratory distress syndrome [1]. Afterwards, this virus spread rapidly and became a global pandemic. Although the fatality rate is low (reported to be 2.5% as of 12 February 2020) [2], the accelerating transmission makes it a threat to mankind, and finding a curative treatment is a top priority. While no such treatment has been confirmed, many drugs and combinations are being suggested and some have even shown positive clinical results. On January 23, 2020, the first clinical trial for COVID-19 was registered, the number of trials then ascended to reach 125 registered trials by February 18, 2020. The 125 trials utilized various mechanisms of action, 33.3% used anti-viral drugs, 33.3% used traditional Chinese medicine (TCM) and herbs, 14.7% used using anti-inflammatories or immunomodulators, 9.3% used therapies based on cells, 2.3% used antioxidant agents, and 7.0% used other methods [3]. This article is an attempt to summarize the current situation regarding suggested methods of treatment and highlight the progress made towards a trusted treatment.
The mechanism of viral infection and potential therapies:
There are two proteins involved in viral penetration of cells, Angiotensin-Converting Enzyme II (ACE2) and Trans-membrane protease, serine 2 (TMPRSS2).
Angiotensin-Converting Enzyme II (ACE2) receptors are found mainly in the tissue of the lung, but also to a lesser degree in the tissues of the heart, kidney, pancreas, endothelium, and intestine [4]. They protect from lung injury [5], and appear to be the main entry point of the novel coronavirus SARS-COV-2 [6].
The SARS-COV virus binds to ACE2 receptors using its spike (S) protein [7]. It was found that the S protein in SARS-COV-2 is highly similar and also uses ACE2 receptors as entry points. [8] When the S protein binds to Angiotensin II type 1 (AT1) receptors, it results in over-activation of the ACE-AngII-AT1 pathway which has shown to induce inflammatory responses and possibly fibrosis of the lungs or other organs [9].
The logical approach to the therapy is to combat this interaction, thus the S protein presents a prime target for potential vaccines [10]. An article published on 17 March 2020 suggested the use of Losartan (ACE2 antagonist) as a potential protective barrier against the lung damage generated by COVID-19 infection [9]. Another suggested therapeutic option is to provide a soluble form of ACE2 as a competitive interceptor [11]. In a recent study, such a protein was generated by combining the extracellular domain of human ACE2 with the FC region of human immunoglobulin IgG1. The resulting protein had a high affinity for the receptor-binding domain of the virus and potently neutralized SARS-COV-2 in vitro by inhibiting its S protein [12].
SARS-COV-2 also uses the cellular protease TMPRSS2 for cell entry [6] which provides another possible target for therapy. Camostat mesylate is a clinically proven protease inhibitor and a recent study tested its effects on SARS-COV-2, SARS-COV, and MERS-COV where it effectively inhibited the viral infection by inhibiting (TMPRSS2) [13].
The viral entry into the endosomes is also assisted by Cathepsin L, an enzyme involved in innate immunity [14,15]. Cathepsin L has a vital role in viral infections [16]. The virus uses Cathepsin L to remove its S protein from the cell, enabling it to release RNA into the host [15]. Tiecoplanin is a glycopeptide antibiotic and an accustomed treatment for various bacterial infections. It acts on the previous interaction by inhibiting Cathepsin L preventing RNA release and thus the replication of the virus. Teicoplanin was found to inhibit the infection with novel coronavirus COVID-19 and was tested with IC50 = 1.66µM, where it prevented 2019-nCoV-Spike-pseudoviruses from entering the cytoplasm in in-vitro studies [17].
Chloroquine and its derivatives, a promising approach to treatment:
The fact of the S protein affinity to the ACE2 receptors also led to the examination of Chloroquine (CQ), which is an aminoquinoline and is the drug of choice for prophylaxis and treatment of malaria and connective tissue autoimmune diseases unresponsive to other agents [18]. CQ can be used to treat patients infected with the novel coronavirus SARS-COV-2 because it inhibits the glycosylation of ACE2 receptors, and also has alkaline properties which elevate the pH of acidic intracellular organelles, such as endosomes/ lysosomes, essential for membrane viral fusion [19]. However, while CQ itself showed antiviral effects on COVID-19, high dose intake for excessive periods of time induced several side effects [20]. Therefore, Hydroxychloroquine (HCQ) was suggested instead of CQ due to its similar effects as it is safer and causes fewer side effects [20, 21]. It also can be given at a better dosage, as CQ can only be given at a 500 mg dosage, whereas HCQ has a maximum tolerable dosage of 1200 mg, which is as effective as a 750 mg dosage of CQ [21,22].
HCQ proved to be more potent than CQ in vitro [23] and, more notably, a trial in France was published on 20 March 2020 yielding exceptional clinical results by using HCQ in combination with Azithromycin, although this method has a potential risk of severe QT prolongation that should be considered [24]. In China, Chloroquine Phosphate has also been tested on more than 100 patients where it promoted a virus-negative conversion and inhibited the aggravation of pneumonia, which improved lung findings, thus shortening the disease course. Furthermore, no severe adverse effects were noted [25].
On March 29, 2020, the US Food and Drugs Administration (FDA) has granted the emergency use authorization (EUA) for these drugs in the treatment of COVID-19 for a limited number of hospitalized cases, and to better evaluate the effectiveness of these drugs, high-quality randomized clinical trials are required. On the other hand, there are concerns about dangerous heart-related adverse events such as QT interval prolongation, ventricular tachycardia, and ventricular fibrillation in COVID-19 patients treated with hydroxychloroquine and chloroquine alone or in combination with azithromycin according to the American Association of Poison Control Centers National Poison Data System.
Remdesivir:
Remdesivir is an analog of adenosine. Its mechanism of action is to integrate with the chains of nascent viral RNA, causing premature termination of them. Wang et al. reported that the mechanism of action of remdesivir depends on blocking SARS-CoV-2 infection at low concentrations with a high selectivity index [26].
Although remdesivir (GS-5734) still needs clinical studies to prove its efficiency against COVID-19 but according to its broad-spectrum properties, it is expected to inhibit COVID-19 as it was a potential antiviral drug to treat other CoVs infections [27].
On the 5th of February, 2020, clinical studies on remdesivir in China were started using randomized placebo-controlled, double-blind, multicenter clinical trial. The group of patients included in this study received a primary dose of 200 mg of remdesivir IV then they received a subsequent dose of 100 mg IV for 9 sequential days, while another group of patients received routine treatment with the same dose of placebo [28]. It was used to successfully treat the first American case of SARS-COV-2 [29].
Other antivirals, such as lopinavir/ritonavir, have shown good clinical results against COVID-19 [30].
The number of trials reached 125 registered trials by February 18, 2020, and 33.3% of these trials utilized anti-viral drugs. A combination of remdesivir and chloroquine proved efficiency in inhibiting the recently emerged SARS-CoV-2 in vitro [31].
Several recent trials showed that remdesivir was not associated with clear clinical improvement and the SARS-COV2 presence in the bloodstream was not reduced. Further studies are required to confirm the feasibility and efficacy of using remdesivir for the treatment of COVID-19 patients.
Vitamin C:
Vitamin C is not synthesizable by humans, so it is gained from dietary sources. It is a primary antioxidant and enzymatic cofactor in physiological reactions, which is involved in collagen synthesis, production of hormones, and supports the immune system [32].
When used in an appropriate dose, Vitamin C acts as a powerful antiviral. It can be used alone or combined with other drugs. For many people, frequent oral intake of vitamin C to reach the daily limit of bowel tolerance provides good antiviral effects. Intravenous vitamin C is usually given in critical cases, and the sicker a person is, the more ascorbic acid he would tolerate orally without causing diarrhea. It could be combined with oral multivitamins which is an effective way to prevent coronavirus [33].
Vitamin C in high dosage is considered as rescue therapy in emergency cases [34]. But on the other hand, high doses of vitamin C may have side effects like osmotic death of immune cells, which might create a local inflammation in the alveolar medium; therefore, IV glucocorticoid is combined with vitamin C treatment to reduce the possible inflammatory complications caused by high doses.
Many studies showed that vitamin C might be preventive for the infection of the lower respiratory tract in certain conditions. As COVID-19 may infect the lower respiratory tract, a moderate dose of vitamin C might help in preventing COVID-19 [35].
Lidocaine:
The human-to-human viral spread is mostly caused by coughing, which is one of the common features of COVID-19 infections. Premedication with opioids like fentanyl is usually followed by coughing, therefore, a single IV dose of Lidocaine is given to patients to prevent such features.
Patients with COVID-19 should be administered injections of lidocaine before and after any procedure that requires intubation or/and extubation to prevent coughing [36]
Small Molecules Agents:
One of the strategies currently under study to treat SARS-COV-2 is the combination of small molecules that have anti-inflammatory properties and antiviral drugs. Some of the suggested such drugs are Baricitinib, Fedratinib, and Ruxolitinib, which are strong and selective Janus Kinase (JAK) inhibitors, making them powerful and effective against the consequences of the elevated levels of cytokines (including interferon-γ) typically observed with COVID-19 patients·[37]. These drugs inhibit clathrin-mediated endocytosis which in turn inhibits the viral cellular infection. They also inhibit members of the numb associated kinase (NAK) family including the Adaptor-associated protein kinase (AAK1) and the cyclin G-associated kinase (GAK) which has shown to reduce the viral infection in vitro [39, 40]. Among these drugs, Baricitinib is preferable because it has a particularly high affinity to AAK1[37]. Baricitinib has anti-inflammatory properties and can ameliorate the associated chronic inflammation in interferonopathies [41].
Its side effects and dosage are acceptable (given orally once daily), making it a good choice for treating COVID-19 patients. In addition, this medication has a little affinity to plasma proteins and a poor interaction with cytochrome enzymes making it safe when taken with other drugs, such as directed antivirals (lopinavir or ritonavir and remdesivir) which are currently being used against COVID-19 [38]. The combination of baricitinib and directed antivirals can reduce the viral infection and the inflammatory response [42].
Ivermectin:
Ivermectin is an FDA-approved anti-parasitic [43] with a safe clinical profile [44] which has shown antiviral capacities against a wide spectrum of RNA viruses [45].
Ivermectin was tested against SARS-CoV-2 in vitro where it effectively inhibited the virus, possibly by inhibiting IMPa/b1-mediated nuclear import of viral proteins. Caly et al. found a 93% reduction in viral RNA in the supernatant (the released virions) and a 99.8% reduction in cell-associated viral RNA (unreleased and unpackaged virions) after 24 hours of ivermectin treatment of SARS-CoV-2 infected cells [46]. Clinical evidence and further trials are necessary to confirm Ivermectin as a therapy for COVID-19.
Tocilizumab:
Tocilizumab is a monoclonal antibody against interleukin 6 (IL6) which is used primarily in rheumatoid arthritis. It may confer clinical benefit in COVID19 patients who present with high levels of IL6 [47].
In some critical patients, COVID19 may trigger a cytokine storm that is associated with high levels of plasma interleukin (IL)-6 as well. Tocilizumab binds to sIL-6R and inhibits the interaction between IL-6 and sIL-6R, thus it prevents the inflammatory response and the respiratory distress [48, 49].
A clinical test was conducted in the First Affiliated Hospital of the University of Science and Technology of China successfully. Twenty patients underwent treatment, and after the first day, the body temperature returned to normal in all of them and the symptoms were greatly relieved. Of the 20 patients, 19 were eventually discharged [50]. The number of patients was too small to draw a conclusion, but these results are promising.
In a clinical study for a series of patients with COVID-19 pneumonia, tocilizumab was administered subcutaneously for the first time, and it revealed good clinical and radiological outcomes [51].
On the other hand, tocilizumab revealed favourable clinical course and a positive impact on survival when used early during Covid-19 pneumonia with severe respiratory syndrome [52].
Ritonavir/Lopinavir, Darunavir, and Danoprevir:
The proteases of the hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) have shown a highly similar function to those of SARS-COV-2 [53], therefore protease inhibitors may have therapeutic effects on the novel coronavirus.
Ritonavir and lopinavir, a combination of drugs used to combat HIV [54], are antivirals that bind to the protease-like domain CEP-C30 on SARS-COV and SARS-COV-2 [55]. They inhibited SARS-COV in in-vitro and clinical studies [56], but further studies are required to confirm their effects on SARS-COV-2.
Similarly, darunavir binds to the PLVP protease of the virus, [55] and a study from China demonstrated its inhibitory effect on SARS-COV-2 in vitro [57].
The replication of SARS-COV-2 relies on a chymotrypsin-like protease (3CL pro) to form the RNA replicase-transcriptase complex [58]. The HCV drug danoprevir inhibits this protease, and was tested in conjunction with ritonavir on 11 patients. All of them were discharged with significantly improved symptoms and normal body temperatures within 12 days [59].
Corticosteroids:
Studies show that the use of corticosteroids might accelerate recovery from COVID-19. However, there are no controlled clinical trials that show whether the use of corticosteroids can reduce COVID-19-related death or not [47].
Miscellaneous drugs:
Nitric Oxide has a viricidal effect and was used against SARS-COV in 2004. A randomized clinical trial using nitric oxide on SARS-COV-2 is currently underway and results are to be published soon [60].
Other drugs under investigation include leronlimab which is a humanized monoclonal antibody for the Chemokine Receptor CCR5 and improves immune system response against cytokine release storm that may occur due to COVID-19 [61].
Other drugs such as umifenovir, galidesivir, camrelizumab, rintatolimod and brilacidin are suggested to be tested in clinical trials for COVID-19 treatment [62, 63].
Convalescent plasma possibilities against COVID-19:
Treating patients using plasma from patients who have completely recovered from the virus is a potential option. Using convalescent plasma as therapy for viral infections is not a newfound concept. In fact, it has been used against SARS-COV and recommended by WHO to treat the Ebola virus during the outbreak in 2014 [64].
The efficiency of convalescent plasma in treating viral infections could be explained by its ability to suppress viraema [65]. Multiple articles have discussed and suggested the use of convalescent plasma against SARS-COV-2 [66, 67], and a study on 20 January 2020 was conducted on 5 patients using convalescent plasma and methylprednisolone to treat SARS-COV-2. It showed to reduce the temperature and relieve most symptoms and 3 of the 5 patients were discharged from hospital after 12 days.
However, these results are controversial due to the limited number of patients and the use of methylprednisolone, which may have been the cause of recovery [68].
Further studies are required to test the viability of convalescent plasma as a treatment for COVID-19, so its use on critically ill patients was approved by FDA in March 2020 [69].
Conclusion:
Researches on COVID-19 treatments and preventive measures are rapidly progressing, and it is difficult to keep up with all presumptive treatments. In fact, most of the above-mentioned drugs have not been fully tested and further clinical studies are needed for the final approval. Therefore, due to the urgency of the situation, these drugs were advanced to be used in COVID-19 patients, depending on the encouraging and positive results obtained from different nations and on case to case basis.
On the other hand, researchers mostly tested drugs that had been already used against SARS-COV due to its similarities with SARS-COV-2, along with the other medications that were previously approved for various infections. Nevertheless, developing new drugs, clinical trials, and producing vaccines became a world health goal to be achieved and mandate us deeply to intense, understand and utilize our knowledge about SARS-COV-2 and its clinical manifestations. No vaccine is currently available and the development of one is an urgent matter. In fact, since, COVID-19 evolves continually and there are multiple strains and types of it, the promise to have an effective vaccine in the early stage is a big challenge and may not occur.
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. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395(10223): 497-506.
2. Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int J Antimicrob Agents. 2020;55(3):105924. DOI:10.1016/j.ijantimicag. 2020.105924.
3. Zhang T, He Y, Xu W, Ma A, Yang Y, Xu KF. Clinical trials for the treatment of Coronavirus disease 2019 (COVID-19): A rapid response to urgent need. Sci China Life Sci. 2020;63(5):774-6. DOI:10.1007/s11427-020-1660-2.
4. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631-7. DOI:10.1002/path.1570.
5. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11(8):875-879. DOI:10.1038/nm1267.
6. Hoffmann M, Kleine-Weber H, Krüger N, Mueller M A, Drosten C, Pöhlmann S. The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells. BioRxiv. 2020; DOI: 10.1101/2020.01.31.929042.
7. Li F, Li W, Farzan M, Harrison SC. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science.2005; 309(5742): 1864-8.
8. Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci. 2020;63(3):457-60. DOI:10.1007/s11427-020-1637-5.
9. Zeinalian M, Salari-Jazi A, Jannesari A, Khanahmad H. A potential protective role of losartan against coronavirus-induced lung damage. Infect Control Hosp Epidemiol. 2020;41(6):752-3. DOI:10.1017/ice.2020.80.
10. Alam I, Kamau A K, Kulmanov M, Arold ST, Pain AT, Gojobori T, et al. Functional pangenome analysis suggests inhibition of the protein E as a readily available therapy for COVID-2019. BioRxiv. 2020; DOI:10.1101/2020.02.17.952895.
11. Batlle D, Wysocki J, Satchell K. Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy? Clinical Science. 2020; 134(5): 543-5. DOI:10.1042/CS20200163.
12. Lei C, Fu W, Qian K, Li T, Zhang S, Ding M, et al. Potent neutralization of 2019 novel coronavirus by recombinant ACE2-Ig. BioRxiv.2020; DOI: 10.1101/2020.02.01.929976.
13. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271-80. DOI:10.1016/j.cell.2020.02.052.
14. Chen J, Zhang L, Yang N, Cao M, Tian M, Fu Q, et al. Characterization of the immune roles of cathepsin L in turbot (Scophthalmus maximus L.) mucosal immunity. Fish Shellfish Immunol. 2020; 97: 322-35. DOI: 10.1016/j.fsi.2019.12.005.
15. Zhang J, Ma X, Yu F, Liu J, Zou F, Pan T, et al. Teicoplanin potently blocks the cell entry of 2019-nCoV. BioRxiv. 2020; DOI: 10.1101/2020.02.05.935387.
16. Yang N, Shen HM. Targeting the Endocytic Pathway and Autophagy Process as a Novel Therapeutic Strategy in COVID-19. Int J Biol Sci. 2020;16(10):1724-31. DOI:10.7150/ijbs.45498.
17. Baron SA, Devaux C, Colson P, Raoult D, Rolain JM. Teicoplanin: an alternative drug for the treatment of COVID-19? Int J Antimicrob Agents. 2020; 55; DOI: 10.1016/j.ijantimicag.2020.105944.
18. Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020;55(5):105938. DOI:10.1016/j.ijantimicag.2020.105938.
19. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69. DOI:10.1186/1743-422X-2-69.
20. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020;16(3):155-66. DOI:10.1038/s41584-020-0372-x.
21. Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J Antimicrob Chemother. 2020;75(7):1667-70. DOI:10.1093/jac/dkaa114.
22. Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents. 2020; 55(4):105932. DOI: 10.1016/j.ijantimicag.2020.105932.
23. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Clin Infect Dis. 2020; 71(15):732-9. DOI:10.1093/cid/ciaa237.
24. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020;56(1):105949. DOI:10.1016/j.ijantimicag.2020.105949.
25. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14(1):72-3. DOI:10.5582/bst.2020.01047.
26. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-71. DOI:10.1038/s41422-020-0282-0.
27. Yethindra V. Role of GS-5734 (Remdesivir) in Inhibiting SARS-CoV and MERS-CoV: The Expected Role of GS-5734 (Remdesivir) in COVID-19 (2019-NCoV) – VYTR Hypothesis. Int J Res Pharm Sci. 2020; 11: 1-6. DOI: 10.26452/ijrps.v11iSPL1.1973
28. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther. 2020;14(1):58-60. doi:10.5582/ddt.2020.01012.
29. Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020. DOI:10.1056/NEJMoa2001191.
30. Lim J, Jeon S, Shin HY, Kim MJ, Seong YM, Lee WJ, et al. Case of the Index Patient Who Caused Tertiary Transmission of COVID-19 Infection in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Infected Pneumonia Monitored by Quantitative RT-PCR. J Korean Med Sci. 2020;35(6):e79. DOI:10.3346/jkms.2020.35.e79.
31. Guo YR, Cao QD, Hong ZS, Tan Y-Y, Chen S-D, Jin H-J, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status. Mil Med Res. 2020;7(1):11. DOI:10.1186/s40779-020-00240-0.
32. Boretti A, Banik BK. Intravenous Vitamin C for reduction of cytokines storm in Acute Respiratory Distress Syndrome. PharmaNutrition. 2020;12:100190. DOI:10.1016/j.phanu.2020.100190.
33. Simonson W. Vitamin C and coronavirus. Geriatr Nurs. 2020;41(3):331-2. DOI:10.1016/j.gerinurse.2020.05.002.
34. Matthay MA, Aldrich JM, Gotts JE. Treatment for severe acute respiratory distress syndrome from COVID-19. Lancet Respir Med. 2020;8(5):433-4. DOI:10.1016/S2213-2600(20)30127-2.
35. Wang L, Wang Y, Ye D, Liu Q. Review of the 2019 novel coronavirus (SARS-CoV-2) based on current evidence. Int J Antimicrob Agents. 2020;55(6):105948. DOI:10.1016/j.ijantimicag.2020.105948.
36. Aminnejad R, Salimi A, Saeidi M. Lidocaine during intubation and extubation in patients with coronavirus disease (COVID-19). Can J Anaesth. 2020;67(6):759. DOI:10.1007/s12630-020-01627-2.
37. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395 (10223):497–506. DOI:10.1016S0140–6736(20)30183–5.
38. Stebbing J, Phelan A, Griffin I, Tucker C, Oechsle O, Smith D, et al. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis. 2020;20(4):400-2. DOI:10.1016/S1473-3099(20)30132-8.
39. Bekerman E, Neveu G, Shulla A, Brannan J, Pu S-Y, Wang S, et al. Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects. J Clin Invest. 2017;127(4):1338-52. DOI:10.1172/JCI89857.
40. Pu SY, Xiao F, Schor S, Bekerman E, Zanini F, Barouch-Bentov R, et al. Feasibility and biological rationale of repurposing sunitinib and erlotinib for dengue treatment. Antiviral Res. 2018;155:67-75. DOI:10.1016/j.antiviral.2018.05.001.
41. Sanchez GAM, Reinhardt A, Ramsey S, Wittkowski H, Hashkes PJ, Berkun Y, et al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest. 2018;128(7):3041-52. DOI:10.1172/JCI98814.
42. Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, et al. Coronavirus susceptibility to the antiviral remdesivir (gs-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio. 2018;9(2): e00221–18. DOI:10.1128/mBio.00221-18.
43. González Canga A, Sahagún Prieto AM, Diez Liébana MJ, Fernández Martínez N, Sierra Vega M, García Vieitez JJ. The pharmacokinetics and interactions of ivermectin in humans–a mini-review. AAPS J. 2008;10(1):42-6. DOI:10.1208/s12248-007-9000-9.
44. Buonfrate D, Salas-Coronas J, Muñoz J, Trevino Maruri B, Rodari P, Castelli F, et al. Multiple-dose versus single-dose ivermectin for Strongyloides stercoralis infection (Strong Treat 1 to 4): a multicentre, open-label, phase 3, randomised controlled superiority trial. Lancet Infect Dis. 2019;19(11):1181-90. DOI:10.1016/S1473-3099(19)30289-0.
45. Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012;443(3):851-6. DOI:10.1042/BJ20120150.
46. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787. DOI:10.1016/j.antiviral.2020.104787.
47. Saghazadeh A, Rezaei N. Towards treatment planning of COVID-19: Rationale and hypothesis for the use of multiple immunosuppressive agents: Anti-antibodies, immunoglobulins, and corticosteroids. Int Immunopharmacol. 2020;84:106560. DOI:10.1016/j.intimp.2020.106560.
48. Liu T, Zhang J, Yang Y, Ma H, Li Z, Zhang J, et al. The role of interleukin-6 in monitoring severe case of coronavirus disease 2019. EMBO Mol Med. 2020;12(7):e12421. DOI:10.15252/emmm.202012421.
49. Davies R, Choy E. Clinical experience of IL-6 blockade in rheumatic diseases – implications on IL-6 biology and disease pathogenesis. Semin Immunol. 2014;26(1):97-104. DOI:10.1016/j.smim.2013.12.002.
50. Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117(20):10970-5. DOI:10.1073/pnas.2005615117.
51. Mazzitelli M, Arrighi E, Serapide F, Chiara Pelle M, Tassone B, Lionello R, et al. Use of subcutaneous tocilizumab in patients with COVID-19 pneumonia. J Med Virol. 2020; DOI:10.1002/jmv.26016.
52. Capra R, De Rossi N, Mattioli F, Romanelli G, Scarpazza C, Pia Sormani M, et al. Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia. Eur J Intern Med. 2020; DOI:10.1016/j.ejim.2020.05.009.
53. Yao TT, Qian JD, Zhu WY, Wang Y, Wang G-Q. A Systematic Review of Lopinavir Therapy for SARS Coronavirus and MERS Coronavirus-A Possible Reference for Coronavirus Disease-19 Treatment Option. J Med Virol. 2020. DOI: 10.1002/jmv.25729.
54. Su B, Wang Y, Zhou R, Jiang T, Zhang H, Li Z, et al. Efficacy and Tolerability of Lopinavir/Ritonavir- and Efavirenz-Based Initial Antiretroviral Therapy in HIV-1-Infected Patients in a Tertiary Care Hospital in Beijing, China. Front Pharmacol. 2019;10:1472. DOI:10.3389/fphar.2019.01472.
55. Lin S, Shen R, He J, Li X, Guo X. Molecular Modeling Evaluation of the Binding Effect of Ritonavir, Lopinavir and Darunavir to Severe Acute Respiratory Syndrome Coronavirus 2 Proteases. bioRxiv.2020; DOI: 10.1101/2020.01.31.929695.
56. Chu CM, Cheng VC, Hung IF, Wong M M L, Chan K H, Chan K S, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252-6. DOI:10.1136/thorax.2003.012658.
57. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther. 2020;14(1):58-60. DOI:10.5582/ddt.2020.01012.
58. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by the novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS. J Virol. 2020; 94(7):e00127-20. doi: 10.1128/JVI.00127-20.
59. Chen H, Zhang Z, Wang L, Huang Z, Gong F, Li X, et al. First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naive and Experienced COVID-19 Patients. medRxiv. 2020; DOI: 10.1101/2020.03.22.20034041.
60. Lei C, Su B, Dong H, Fakhr BS, Grassi LG, Di Fenza R, et al. Protocol for a randomized controlled trial testing inhaled nitric oxide therapy in spontaneously breathing patients with COVID-19. Preprint. medRxiv. 2020; DOI:10.1101/2020.03.10.20033522.
61. Miao M, De Clercq E, Li G. Clinical significance of chemokine receptor antagonists. Expert Opin Drug Metab Toxicol. 2020;16(19:11–30. DOI: 10.1080/17425255.2020.1711884.
62. McCreary EK, Pogue JM. Coronavirus Disease 2019 Treatment: A Review of Early and Emerging Options. Open Forum Infect Dis. 2020;7(4). DOI:10.1093/ofid/ofaa105.
63. Sorbera LA, Graul A I, Dulsat C. Taking aim at a fast-moving target: targets to watch for SARS-CoV-2 and COVID-19. Drugs of the Future. 2020; 45(4): 1-6. DOI: 10.1358/dof.2020.45.4.3150676.
64. Cheng Y, Wong R, Soo YO, Wong WS, Lee CK, Ng M H L, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005; 24(1): 44–6. DOI 10.1007/s10096-004-1271-9.
65. Chen L, Xiong J, Bao L, Shi Y. Convalescent plasma as a potential therapy for COVID-19. Lancet Infect Dis. 2020;20(4):398-400. DOI:10.1016/S1473-3099(20)30141-9.
66. Casadevall A, Pirofski LA. The convalescent sera option for containing COVID-19. J Clin Invest. 2020;130(4):1545-8. DOI:10.1172/JCI138003.
67. Shanmugaraj B, Siriwattananon K, Wangkanont K, Phoolcharoen W. Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19). Asian Pac J Allergy Immunol. 2020;38(1):10-18. DOI:10.12932/AP-200220-0773.
68. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020;323(16):1582-9. DOI:10.1001/jama.2020.4783.
69. Tanne JH. Covid-19: FDA approves use of convalescent plasma to treat critically ill patients. BMJ. 2020; DOI:10.1136/bmj.m1256.
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