SUBMITTED 15 DEC 2022 1 REVISION REQ. 2 JAN 23; REVISION RECD. 20 JAN 23 2 ACCEPTED 5 FEB 23 3 ONLINE-FIRST: FEBRUARY 2023 4 DOI: https://doi.org/10.18295/squmj.1.2023.009 5 6 Efficacy of Granisetron versus Sufentanil on Reducing Myoclonic 7 Movements Following Etomidate 8 A double-blind, randomized clinical trial 9 Mohammad Alipour,1 Naeem Abdi,2 *Parisa Zaj,1 Leila Mashhadi1 10 11 1Department of Anesthesiology, Faculty of Medicine, Mashhad University of Medical 12 Sciences, Mashhad, Iran; 2Student Research Committee, School of Nursing and Midwifery, 13 Shiraz University of Medical Sciences, Shiraz, Iran. 14 *Corresponding Author’s e-mail: parisazaj66@yahoo.com 15 16 Abstract 17 Objective: Etomidate-induced myoclonus occurs in up to 85% of patients under general 18 anesthesia. This type of myoclonus can induce significant clinical and economic problems in 19 patients with special conditions. Hence, to reduce the intensity of myoclonus movements, the 20 present study was conducted to compare the effectiveness of granisetron and sufentanil on 21 reducing the intensity of etomidate-induced myoclonic movements. Methods: This double-22 blind randomized clinical trial study consisted of 96 adult patients. Using block 23 randomization, subjects were divided into three groups of 32: the group receiving granisetron 24 40 μg / kg (group G), the group receiving sufentanil 0.2 μg / kg (group S), and the control 25 group who did not receive the pretreatment (group C). Patients received these medications as 26 pretreatments 120 seconds before induction with etomidate. After injection of etomidate with 27 a dose of 0.3 mg/kg, the incidence of myoclonus was evaluated. After evaluating the 28 myoclonus, the full dose of narcotics (fentanyl 1 μg / kg) and muscle relaxants (atracurium 29 0.5 mg/kg) were administered to patients, and a suitable airway was established for them. 30 Results: The findings indicated that granisetron reduced the intensity and incidence of 31 myoclonic movements more than sufentanil. In addition, myoclonic movements were 32 observed at a significantly higher intensity in the control group (P=0.001). Conclusion: The 33 results obtained from the current study indicate that granisetron and sufentanil as 34 pretreatments are effective for reducing myoclonus in patients. 35 Keywords: Granisetron; Sufentanil; Etomidate; Myoclonus; Movement. 36 37 Advances in Knowledge: 38  Clinical Function: Considering the effectiveness of granisetron in controlling and 39 reducing myoclonic movements during general anesthesia, it can be effective in 40 improving the quality of anesthesia when using in the hospital. 41  Education: The results of this research can provide a new insight into the use of 42 granisetron in controlling and reducing myoclonic movements during general 43 anesthesia for professors, students, and educational planners. 44  Research: The results of this research can set the ground for further quantitative 45 studies on the drug granisetron and comparing its effectiveness with other drugs in 46 controlling and reducing myoclonic movements during general anesthesia. 47 Application to Patient Care: 48  Regarding the use of granisetron and sufentanil in controlling and reducing myoclonic 49 movements during general anesthesia, it can be effective in improving the quality of 50 anesthesia in case of using in the hospital. 51 52 Introduction 53 Etomidate is an intravenous general anesthetic agent, whose clinical effects are developed 54 through enhancing the GABA inhibitory system by altering chloride conduction.1 Due to its 55 rapid induction of anesthesia with minimal changes in cardiovascular function, it is one of the 56 most widely used intravenous anesthetics in patients with limited cardiorespiratory 57 function.1,2 It is derived from imidazole and may cause pain as well as myoclonus in patients 58 during and after injection.3 Etomidate injection pain is minimized by applying fat emulsions 59 in etomidate compounds, but myoclonus caused by etomidate is still a clinical challenge. 4 60 Myoclonus refers to sudden, brief twitching or jerking as well as shock-like involuntary 61 movements of a muscle or group of muscles5,6. Myoclonus caused by etomidate occurs in up 62 to 85% of patients under anesthesia.5 It begins in a limited part of the body and spreads to 63 muscles in other areas. Myoclonus can cause many significant problems in more severe 64 cases, such as ventilation disturbance.5,6 Electrophysiological studies are useful in evaluating 65 myoclonus, not only for confirming the clinical diagnosis but also for understanding the 66 underlying physiological mechanisms. Since the majority of myoclonic jerks are believed to 67 be caused by hyperexcitability of a group of neurons in certain cerebral structures, the 68 relationship of myoclonic jerks with EEG activity is of primary importance in the study of 69 myoclonus.7,8 70 71 Different drugs (fentanyl,9 remifentanil,10 midazolam,11 etc.) have been used as pretreatment 72 for myoclonus caused by etomidate, each with exclusive side effects, while the best option 73 for clinical treatment of etomidate-induced myoclonus has not yet been determined.12 74 Fentanyl is a single synthetic opiate used for analgesia. Today, fentanyl is widely used for 75 anesthesia and pain relief. Among the side effects of this drug are itching and impaired 76 breathing.5,9 As an opioid analgesic, sufentanil is an analog of fentanyl and is used to induce 77 as well as maintain anesthesia plus postoperative analgesia. In practice, it seems that the 78 hemodynamic stability of sufentanil anesthesia during surgery is better than that of other 79 opioids or inhaled anesthesia13,14. The side effects of sufentanil include hypotension and 80 impaired respiration.14,15The effect of sufentanil pretreatment on myoclonus caused by 81 etomidate has been studied by many researchers who have published different results. 82 According to a study in 2003, the incidence of etomidate-induced myoclonus in patients 83 receiving sufentanil as a pretreatment was zero.15 In another study in 2016, the incidence of 84 etomidate-induced myoclonus with sufentanil pretreatment was reported to be 28%. 16 85 86 Granisetron is one of the serotonin receptor antagonists that is used as an anti-nausea and 87 vomiting drug in the operation room, chemotherapy, etc.,17 This drug has minor side effects 88 and may cause headaches, confusion in people who are allergic to the drug, and 89 constipation.17 The effect of granisetron on etomidate-induced myoclonus has not been 90 studied yet. However, the efficacy of granisetron was investigated as a pretreatment on 91 propofol-induced myoclonus in a study by Alipour M (2013). It showed that the incidence of 92 propofol-induced myoclonus with granisetron was only 5.5% and most of the patients 93 (94.5%) experienced myoclonic movements with grade 0 (without myoclonus)18. Since 94 myoclonus induced by etomidate injection in certain patients can have significant side 95 effects, this study was conducted for the first time to determine the effectiveness of 96 granisetron on intensity of myoclonus induced by intravenous administration of etomidate 97 and to compare with sufentanil. 98 99 Materials and Methods 100 This double-blind clinical trial study was performed on selected patients referring to 101 educational hospitals affiliated with Mashhad University of Medical Sciences in 2021. After 102 obtaining the ethics approval from the Medical Ethics Committee of Mashhad University of 103 Medical Sciences (code: IR.MUMS.MEDICAL.REC.1399.509) and registration at the 104 Iranian Clinical Trial Center (#IRCT20210221050436N1), sampling and data collection 105 began. In this study, 96 patients were selected via convenience sampling and randomly based 106 on a table of random numbers created by a computer. Then, based on random blocks and in 107 parallel, they were divided into two intervention groups (granisetron and sufentanil groups) 108 plus a control group with 32 subjects each. 109 110 Inclusion criteria were patients undergoing general anesthesia with (1) American Society of 111 Anesthesiologists Classification (ASA) I, II, (2) and age between 15-60 years. Exclusion 112 criteria included (1) adrenal dysfunction, (2) history of allergy to opioid analgesics and 113 hypnotics drugs, (3) mental disorders, (4) neuromuscular diseases, (5) seizure, (6) electrolyte 114 imbalanced, (7) history of addiction, (8) long QT syndrome, as well as severe cardiovascular 115 diseases, (9) high Intracranial pressure (ICP) and Intraocular pressure(IOP), and (10) 116 increased intra-abdominal pressure. Written consent was obtained from all subjects, and they 117 were assured that all their information would remain confidential. Also, at any time, and even 118 after giving consent, they could withdraw from the study voluntarily (Figure1). 119 120 Patients underwent isotonic IV fluid therapy at 5ml/ kg for 10 minutes before induction. 121 Further, standard monitoring, including pulse oximetry, electrocardiogram, non-invasive 122 blood pressure, and capnography, was performed on them. Patients were randomly (block 123 randomization) assigned into three groups of granisetron (group G 40 μg / kg), sufentanil 124 (group S 0.2 μg / kg), and control group (group C). First, the studied drugs with a volume of 125 5 ml were administered within 30 seconds. Then, after 120 seconds, etomidate was injected at 126 a dose of 0.3 mg/kg for 30 seconds. The incidence and intensity of myoclonus was evaluated 127 by a person who was not aware of the group allocations (anesthesia resident) 2 minutes after 128 administration of etomidate. The drugs were injected by an anesthetist who was unaware of 129 the type of drugs. 130 131 In this double-blind study, the intensity of myoclonus was measured with a score between 0 132 and 3, where 0 represents no myoclonus, 1 indicates mild as small movements of a part of the 133 body such as finger or wrist, 2 denotes moderate as gentle movements of two different 134 muscle groups such as face and legs, and 3 indicates severe as severe clonic movements in 135 two or more muscle groups or rapid limb adduction. Thereafter, the three groups were 136 compared with each other.16,19 After evaluating the myoclonus, the patient was prescribed a 137 full dose of a narcotic drug (fentanyl 1 microgram/kg), muscle relaxant (atracurium 0.5 138 mg/kg), and a suitable airway was established for the patient. No pretreatment was injected 139 before etomidate administration in the control group. Sixty seconds before and after injection 140 of each drug under study (sufentanil and granisetron), heart rate, systolic and diastolic blood 141 pressure, and arterial oxygen pressure were measured and recorded. According to the 142 patient's vital signs, fentanyl was injected as needed in all three groups. Given that fentanyl 143 was administered after completion of the study, it did not affect the study process. All of the 144 administered drugs had been produced by Abu Reihan Company in Iran. 145 146 All patients were visited by an anesthesiologist for 24 hours after surgery, and their clinical 147 condition was assessed. Confounding variables were controlled according to the control 148 group and random assignment of samples. Using the formula of comparing a qualitative trait 149 in two communities and taking into account the findings of the study of Alipour et al,16 who 150 reported the incidence of grade 0 myoclonus in sufentanil recipients as 72% and the clinical 151 estimate of this index as 35% in granisetron recipients, taking into account the 5% alpha error 152 and 80% power, the sample size in each group was equal to 29 people, which increased to 32 153 in each group after calculating a dropout of 10%. 154 155 In this study, descriptive statistical tests, and chi-square as a non-parametric test for 156 qualitative demographic variables and incidence of myoclonus was used. Also, analysis of 157 variance (ANOVA) was performed to compare the mean of quantitative variables between 158 groups using SPSS19 software. 159 160 Results 161 In this study, from a total of 96 patients, the mean and standard deviation of the age variable 162 in the three groups of sufentanil (S), granisetron (G), and control (C) were 39.25±1.53, 163 39.25±12.03, and 38.63±10.61, respectively; according to the ANOVA test, no significant 164 difference was observed among the three groups in terms of age variables (P = 0.96). The 165 results of this study revealed that the three groups were not significantly different in terms of 166 demographic characteristics such as gender, anesthesia class (ASA), underlying diseases 167 (hypothyroidism and hyperthyroidism, hypertension, diabetes, and ischemia) based on the 168 chi-square test. Also, other important demographic characteristics were height, weight, and 169 BMI (Body Mass Index); according to the ANOVA test, the mean and standard deviation of 170 these variables did not differ significantly between the three groups (Table 1). In this study, 171 patients' hemodynamic status was monitored and recorded based on the variables of systolic 172 and diastolic blood pressure, heart rate, and arterial oxygen pressure 60 seconds before and 173 after injection of the studied drugs. The study results based on ANOVA statistical test 174 indicated that there was no significant difference between the three groups (Table 2). 175 According to the main objective of the present study, one of the most important variables was 176 the intensity of etomidate-induced myoclonic movements. Patients in the granisetron group 177 showed less intensity of myoclonic movements relative to the sufentanil and control groups 178 based on chi-square test. However, in the control group, these movements were measured and 179 recorded with more intensity and created a statistically significant difference from the other 180 two groups (Tables 3). 181 182 Discussion 183 The major advantage of etomidate is its stable cardiovascular profile which aids in 184 counteracting the sympathetic stress response during laryngoscopy and intubation.20 Despite 185 all benefits of this drug, myoclonus is still a significant side effect.16,21 The main mechanism 186 of myoclonus caused by etomidate is unknown. However, one hypothetical mechanism for 187 etomidate-induced myoclonus is that high concentrations of etomidate suppress cortical 188 activity earlier than subcortical function. For this reason, the extent and severity of 189 myoclonus can be reduced through pretreatments that inhibit the excitatory activity of the 190 subcortical region.16,19-21 The use of various drugs as pretreatment agents to reduce 191 myoclonus induced by etomidate injection has been investigated, such as dexmedetomidine,20 192 opioids,21 benzodiazepines,21 lidocaine,22 magnesium sulfate,20 muscle relaxants, 23,24 193 gabapentin.25 However, the drugs offered should be limited to specific and exact cases. It is 194 important to choose an optimal agent as a pretreatment in relation to the type and duration of 195 surgery as well as the patient's condition. Accordingly, this double-blind study was 196 performed to evaluate the effect of granisetron and sufentanil on reducing the intensity of 197 myoclonic movements following etomidate injection as a pretreatment in comparison with 198 the control group. 199 200 One of the differences between this study compared to similar works was investigating the 201 effectiveness of granisetron that had not been studied before. The efficacy of granisetron was 202 investigated as a pretreatment in a study by Alipour M (2013), showing that the incidence of 203 propofol-induced myoclonus with granisetron was only 5.5% and most of the patients 204 (94.5%) experienced myoclonic movements with grade 0 (without myoclonus)18. Since the 205 results of the present study are in line with the previous study, and a significant reduction has 206 been observed in the intensity and incidence of myoclonus movements, although the 207 functional mechanism of granisetron in reducing myoclonus movements is not clear yet, it 208 can be introduced as a new and valuable pretreatment. The sufentanil group also experienced 209 less intensity and incidence of myoclonic movements compared to the control group, and the 210 results of this study confirm its effectiveness. Numerous studies have shown that narcotics 211 effectively reduce the intensity of myoclonus movements, though they may come at the cost 212 of respiratory depression, apnea, nausea, and vomiting.26,27 Nyman Y et al. (2011) 213 demonstrated that pretreatment with 100 micrograms of fentanyl reduced the incidence of 214 myoclonus by up to 8%. 28 Also, in a study by Stockham RJ et al., higher doses of fentanyl 215 (500 μg) significantly reduced myoclonic movements. However, the incidence of apnea 216 increased during induction.29A study by Kelsaka E et al. (2006) demonstrated that 217 remifentanil injection (1μg/kg) 2 minutes before the etomidate injection reduced myoclonic 218 movements by up to 7% without any clinical changes.30 In many studies, it has been 219 demonstrated that sufentanil (0.3 μg/kg) is an effective pretreatment in reducing the intensity 220 of myoclonic movements induced by etomidate injection.15 In the study by Alipour et al. 221 (2016), the effectiveness of sufentanil (0.2 μg/kg) in reducing the intensity and duration of 222 myoclonic movements was also confirmed, which was consistent with the present study. 16 A 223 study by Feng et al (2022) clarified that etomidate increased the mean behavioral scores and 224 glutamate levels in the CSF plus neocortex during anesthesia. More importantly, they 225 demonstrated a strong correlation between the myoclonus and neocortical glutamate 226 accumulation. In this study, they concluded etomidate-induced myoclonus is associated with 227 neocortical glutamate accumulation. Suppression of the astrogliosis in neocortex and 228 promoting extracellular glutamate uptake by regulating glutamate transporters (EAATs) in 229 the motor cortex may be the therapeutic target for preventing etomidate-induced 230 myoclonus.31 Accordingly, it can be postulated that the action of granisetron in reducing 231 myoclonic movements is the above mechanism, though it needs more investigations 232 especially in terms of pharmaceutical, cellular, and molecular properties. In general, different 233 outcomes may depend on several factors and may be partly due to the dose as well as timing 234 of pretreatment agents along with the different conditions of patients. The findings of the 235 present study regarding reduction if the intensity of myoclonic movements due to the 236 pretreatment sufentanil are in line with the results of other studies. However, the pretreatment 237 effect of granisetron significantly reduced myoclonus induced by etomidate injection 238 compared to placebo, making it even superior to sufentanil. 239 240 In past studies, it has been stated that myoclonus can cause important clinical complications, 241 but whether these complications cause permanent damages or not has not been proven and is 242 debatable. 243 244 One of the most important limitations in this study was the lack of previous studies on the use 245 and effectiveness of granisetron as a pretreatment in reducing myoclonic movements. This 246 made the mechanism of action of granisetron for reducing myoclonic movements unclear. 247 Thus, it is recommended to conduct larger studies with more samples and different doses of 248 granisetron. Another limitation was that, although authors refer to it as a blinded study, 249 blinding was a nonformal "observer blinded" approach. 250 251 Conclusion 252 Overall, the study results suggest that granisetron is similar to sufentanil and even more 253 effective in reducing the intensity of myoclonic movements following etomidate's injection 254 and can be an important step in the development of further studies in this field. It is 255 recommended that further studies be performed to compare granisetron with other 256 pretreatment agents in the future. 257 258 Authors’ Contribution 259 MA, NA, PZ, LM conceptualised and designed the research. PZ, MA and LM were 260 responsible for sampling and intervention. NA was responsible for statistical analysis. PZ, 261 MA drafted the manuscript. NA and LM reviewed and edited the manuscript. All authors 262 approved the final version of the manuscript. 263 264 Acknowledgments 265 We would like to thank all the patients and their families who made this research possible, 266 and we also thank the Vice Chancellor for Research of Mashhad University of Medical 267 Sciences for their good cooperation. 268 269 Conflict of Interest 270 The authors declare no conflicts of interest . 271 272 Funding 273 No funding was received for this study. 274 275 References 276 1. Tobias JD. Etomidate in pediatric anesthesiology: Where are we now? Saudi J 277 Anaesth. 2015;9(4):451-6. 278 2. Shilpashri AM, Gayathri G, Palakshappa KR. Etomidate is Rapid Acting and has 279 Good Cardiovascular and Respiratory Stability than Thiopentone Sodium. Indian 280 Journal of Public Health Research & Development. 2015 Jul 1;6(3). 281 3. Bertram G. Katzung, Marieke Kruidering-Hall, Anthony J. Trevor. Katzung & 282 Trevor’s Pharmacology Examination& Board Review. 12th, editor. 592 p. 283 4. Doenicke A, Roizen MF, Nebauer AE, Kugler A, Hoernecke R, Beger-Hintzen H. A 284 comparison of two formulations for etomidate, 2-hydroxypropyl-beta-cyclodextrin 285 (HPCD) and propylene glycol. Anesth Analg. 1994;79(5):933-9. 286 5. Isitemiz I, Uzman S, Toptaş M, Vahapoglu A, Gül YG, Inal FY, et al. Prevention of 287 etomidate-induced myoclonus: which is superior: Fentanyl, midazolam, or a 288 combination? A Retrospective comparative study. Med Sci Monit. 2014;20:262-7. 289 6. Eberhardt O, Topka H. Myoclonic Disorders. Brain Sciences. 2017;7(8):103. 290 7. Halliday AM. The electrophysiological study of myoclonus in man. Brain 291 1967;90:241–284 292 8. Shibasaki H, Hallett M. Electrophysiological studies of myoclonus. Muscle & Nerve: 293 Official Journal of the American Association of Electrodiagnostic Medicine. 2005 294 Feb;31(2):157-74. 295 9. Prakash S, Mullick P, Virmani P, Talwar V, Singh R. Effect of pre-treatment with a 296 combination of fentanyl and midazolam for prevention of etomidate-induced 297 myoclonus. Turkish Journal of Anaesthesiology and Reanimation. 2021 Feb;49(1):11. 298 10. Lang B, Zhang L, Li F, Lin Y, Zhang W, Yang C. Comparison of the efficacy and 299 safety of remifentanil versus different pharmacological approaches on prevention of 300 etomidate-induced myoclonus: a meta-analysis of randomized controlled trials. Drug 301 Design, Development and Therapy. 2019;13:1593. 302 11. Zhou C, Zhu Y, Liu Z, Ruan L. Effect of pretreatment with midazolam on etomidate-303 induced myoclonus: A meta-analysis. J Int Med Res. 2017;45(2):399-406. 304 12. Taher‐Baneh N, Ghadamie N, Sarshivi F, Sahraie R, Nasseri K. Comparação de 305 fentanil e dexmedetomidina como adjuvante à bupivacaína para raquianestesia 306 unilateral em cirurgia de membros inferiores: estudo randômico. Brazilian Journal of 307 Anesthesiology. 2019;69(4):369-76. 308 13. Monk JP, Beresford R, Ward A. Sufentanil. Drugs. 1988;36(3):286-313. 309 14. Lv Y, He H, Xie J, Jin W, Shou C, Pan Y, et al. Effects of transcutaneous acupoint 310 electrical stimulation combined with low-dose sufentanil pretreatment on the 311 incidence and severity of etomidate-induced myoclonus: A randomized controlled 312 trial. Medicine (Baltimore). 2018;97(23):e10969-e. 313 15. Hueter L, Schwarzkopf K, Simon M, Bredle D, Fritz H. Pretreatment with sufentanil 314 reduces myoclonus after etomidate. Acta Anaesthesiologica Scandinavica. 315 2003;47(4):482-4. 316 16. Alipour M, Tabari M, Azad AM. Comparative study evaluating efficacy of sufentanil 317 versus midazolam in preventing myoclonic movements following etomidate. J 318 Anaesthesiol Clin Pharmacol. 2016;32(1):29-32. 319 17. Spartinou A, Nyktari V, Papaioannou A. Granisetron: a review of pharmacokinetics 320 and clinical experience in chemotherapy induced-nausea and vomiting. Expert 321 opinion on drug metabolism & toxicology. 2017 Dec 2;13(12):1289-97. 322 18. Alipour M, Tabari M, Alipour M. Comparison use of paracetamol, magnesium 323 sulfate, ondansetron, granisetron and lidocain on propofol injection pain in elective 324 surgeries, a thesis presented for the degree specialty of anesthesiology. mashhad 325 university of medical sciences, iran; 2013, 57-58. 326 19. Doenicke AW, Roizen MF, Kugler J, Kroll H, Foss J, Ostwald P. Reducing 327 myoclonus after etomidate. The Journal of the American Society of Anesthesiologists. 328 1999 Jan 1;90(1):113-9. 329 20. Ghodki PS, Shetye NN. Pretreatment with dexmedetomidine and magnesium sulphate 330 in prevention of etomidate induced myoclonus–A double blinded randomised 331 controlled trial. Indian Journal of Anaesthesia. 2021 May;65(5):404. 332 21. Sedighinejad, A., et al., comparison of the effects of low-dose midazolam, magnesium 333 sulfate, remifentanil and low-dose etomidate on prevention of etomidate-induced 334 myoclonus in orthopedic surgeries. Anesthesiology and pain medicine, 2016. 6(2). 335 22. Gultop, F., et al., Lidocaine pretreatment reduces the frequency and severity of 336 myoclonus induced by etomidate. Journal of anesthesia, 2010. 24(2): p. 300-302. 337 23. Choi, J.M., et al., pretreatment of rocuronium reduces the frequency and severity of 338 etomidate-induced myoclonus. Journal of clinical anesthesia, 2008. 20(8): p. 601-604. 339 24. Nooraei, N., A. Solhpour, and S.A. Mohajerani, Priming with atracurium efficiently 340 suppresses etomidate-induced myoclonus. Acta Anaesthesiologica Taiwanica, 2013. 341 51(4): p. 145-148. 342 25. Yılmaz Çakirgöz, M., et al., Efeito do pré-tratamento com gabapentina sobre a 343 mioclonia após etomidato: um estudo randômico, duplo-cego e controlado por 344 placebo. Revista Brasileira de Anestesiologia, 2016. 66: p. 356-362. 345 26. He, L., et al., Butorphanol pretreatment prevents myoclonus induced by etomidate: a 346 randomised, double-blind, controlled clinical trial. Swiss medical weekly, 2014. 347 144(4142). 348 27. Ko, B.J., et al., comparison of effects of fentanyl and remifentanil on hemodynamic 349 response to endotracheal intubation and myoclonus in elderly patients with etomidate 350 induction. Korean journal of anesthesiology, 2013. 64(1): p. 12. 351 28. Nyman, Y., et al., Effect of a small priming dose on myoclonic movements after 352 intravenous anaesthesia induction with Etomidate-Lipuro in children. British journal 353 of anaesthesia, 2011. 107(2): p. 225-228. 354 29. Stockham, R., et al., Fentanyl pretreatment modifies anaesthetic induction with 355 etomidate. Anaesthesia and intensive care, 1988. 16(2): p. 171-176. 356 30. Kelsaka, E., et al., Remifentanil pretreatment reduces myoclonus after etomidate. 357 Journal of clinical anesthesia, 2006. 18(2): p. 83-86. 358 31. Feng Y, Liu J, Zhang WS. Etomidate-induced myoclonus correlates with the 359 dysfunction of astrocytes and glutamate transporters in the neocortex of Sprague-360 Dawley rats. European Review for Medical and Pharmacological Sciences. 2022 Sep 361 1;26(17):6221-35. 362 363 364 365 366 367 Enrollment 368 369 370 371 372 373 374 Allocation 375 376 377 378 379 380 381 Analysis 382 383 384 385 Figure1: The consort flow diagram 386 387 Assessed for eligibility (n=105) Excluded (n=9) Not meeting inclusion criteria (n=8) Refused to participate (n=1) Randomized (n=96) Allocated to Granisetron Group (n=32) Allocated to Control Group (n=32) Analyzed (n=32) Excluded from analysis (n=0) Analyzed (n=32) Excluded from analysis (n=0) Allocated to Sufentanil Group (n=32) Analyzed (n=32) Excluded from analysis (n=0) Table1. Underlying diseases and demographic variables in the experimental and control 388 groups 389 Variables Group value P value Granisetron Sufentanil Control Gender Male 15 46.9 12 37.5 15 46.9 3.28 0.19 Female 17 53.1 20 62.5 17 53.1 ASA class ASAI 21 65/50 26 81/3 22 68/8 2.16 0.33 ASAII 11 34/50 6 18/2 10 31/2 HTN Yes 3 9.4 5 15.6 5 15.6 0.70 0.71 No 29 90.6 27 84.4 27 84.4 Hypothyroidism Yes 1 3.1 5 15.6 2 6.2 3.54 0.17 No 31 96.9 27 84.4 30 93.8 Hyperthyroidism Yes 1 3.1 0 00 0 00 2.02 0.36 No 31 96.9 32 100 32 100 Diabetes Yes 4 12.5 7 21.9 4 12.5 1.42 0.42 No 28 87.5 25 78.1 28 87.5 IHD Yes 1 3.1 2 6.2 3 9.4 1.06 0.58 No 31 96.9 30 93.8 29 90.6 Height(cm) ----- 172.50 4.62 171.62 5.67 172.69 5.16 5.87 0.82 Weight(kg) ------ 73.68 3.84 72.50 4.13 72.40 3.89 6.45 0.89 BMI ------ 24.49 1.51 24.41 2.46 24.52 2.25 0.89 0.92 Height, weight and BMI expressed as mean ± Standard deviation. Other variables expressed 390 as frequency and percent. 391 392 Table 2: Comparison of hemodynamic variables of patients in three groups 60 seconds 393 before and after injection of studied drugs. 394 variables Group value P value Granisetron Sufentanil Control Mean SD Mean SD Mean SD 0.81 0.44 Systolic I 135.00 20.85 133.84 23.18 128.25 23.86 Diastolic I 92.81 16.22 90.13 17.18 87.78 14.16 0.80 0.45 Systolic II 133.75 20.81 125.41 16.54 124.50 22.61 6.63 0.48 Diastolic II 91.94 15.84 81.77 13.56 85.88 13.63 3.97 0.22 HR I 88.4 19.9 89.25 13.98 90.21 13.42 12.11 0.18 HR II 86.19 13.96 87.63 11.02 88.66 11.62 11.31 0.20 SPO2I 99.84 0.51 99.53 0.80 99.72 0.52 0.79 0.14 SPO2II 99.91 0.29 99.98 0.12 99.94 0.25 0.94 0.20 In the table above, hemodynamic variables recorded and measured 60 seconds before 395 injection are marked with Roman numeral I, and variables recorded 60 seconds after injection 396 of the studied drugs are marked with Roman numeral II. 397 398 Table 3: The intencity and incidence of myoclonus in the experimental and control groups 399 after injection of etomidate. 400 Variables Group P value Granisetron Sufentanil Control Frequent Percent Frequent Percent Frequent Percent 0.001 0= without myoclonus 30 93.75 25 78.12 3 9.37 1= mild as small movements of a part of the body such as finger or wrist 2 6.25 5 15.62 20 62.50 2= moderate as gentle movements of 2 different muscle groups such as face and legs 0 0 2 6.26 7 21.88 3= severe as severe clonic movements in 2 or more muscle groups or rapid limb adduction 0 0 0 0 2 6.25 401