Effect of Prophylactic Ondansetron on the Incidence of Spinal Anesthesia-Induced Shivering and Hypotension in Elective Cesarean Sections:Double-Blind, Placebo-Controlled, Randomized Clinical Trial

Background: Spinal anesthesia is the preferred method of anesthesia for caesarean section; 17 however, it is associated with dangerous adverse effects on both mother and fetus, this 18 includes: spinal anesthesia induced shivering and hypotension. Previous studies suggest 19 serotonin may have a role in hypotension, bradycardia, and shivering occurrence 20 perioeratively. In this prospective double-blind randomized control trial study, we evaluated 21 the efficacy of the ondansetron, a serotonin receptor antagonist, on the incidence of spinal 22 anesthesia-induced shivering, hypotension, nausea, vomiting and other possible 23 complications in elective caesarean sections. This study conducted in Palestine, West Bank, 24 Nablus city in the caesarean section operation rooms, and post-anesthesia care unit at Rafidia 25 governmental hospital. Eighty full-term elective caesarean section parturient (Age 18-50 26 years) with ASA 1 or 2 classification were recruited and randomly allocated into two groups: prophylactic ondansetron treatment group and placebo 0.9% saline control group. The primary outcomes were the incidence of spinal anesthesia-induced shivering and 29 hypotension, while secondary outcomes were perioperative bradycardia, nausea, vomiting, 30 headache, pain, pruritus, dizziness and respiratory depression and parturient satisfaction. 31 Results: Incidence of intraoperative hypotension and dizziness in the ondansetron group was 32 significantly lower than which occurred in the control group (22.5% vs. 62.5% respectively; 33 P < 0.001), the incidences and intensity of intraoperative shivering in the ondansetron group 34 was lower than the control group (12.5 % vs. 32.5 % respectively; P = 0.032), Intraoperative 35 nausea intensity in the ondansetron group was lower than control group (P = 0.049). 36 Postoperatively, the incidence of postoperative dizziness in the ondansetron group was lower 37 than the control group (5% vs. 37.5 % respectively; P = 0.001), the incidence and intensity of 38 postoperative shivering in the ondansetron group was lower than the control group (12.5% vs. 39 37.5 % respectively; P = 0.01). Incidence and intensity of postoperative nausea in the 40 ondansetron group was lower than the control group (17.5% vs. 40 % respectively; P = 41 0.026), the incidence of postoperative vomiting in the ondansetron group was lower than the 42 control group (25.5% vs. 2.5 % respectively; P = 0.014). 43 Conclusion : Prophylactic 4 mg IV ondansetron can significantly attenuate the incidences of spinal anesthesia-induced shivering and hypotension, dizziness, nausea, and vomiting occurrence and increase parturient satisfaction scale for parturient who undergo caesarean 46 section.


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Spinal anesthesia is often used in cesarean section delivery due to its rapid onset, 50 definite motor and sensory blockade, and low risk of local anesthetic systemic toxicity. 51 Furthermore, it offers diverse benefits for both mothers and their developing infant's 52 outcomes, i.e., better oxygenation and acid-base balance, despite of that, it is not free of risks 3 (Ghani et al., 2015). Spinal-anesthesia-induced shivering and hypotension frequently occur 54 perioperatively, with an incidence of 80% and 60%, respectively (Habib, 2012; Tie et al., 55 2014). These complications have harmful effects on the fetus and the delivering mother, 56 including reduced utero placental perfusion, impaired fetal perfusion and gas exchange, fetal 57 acidemia, serious maternal complications, e.g., reduced cardiac output and diminished 58 cerebral perfusion (Limongi & Lins, 2011), altered level of consciousness, nausea, and 59 vomiting (Lee, George, & Habib, 2017). 60 Hypotension can lead to nausea, vomiting, altered consciousness, an increased risk of 61 aspiration, and reduced uterine-fetal blood flow. The mechanisms that cause hypotension 62 during spinal anesthesia are sympatholysis, where systemic vascular resistance is induced 63 (Langesaeter et al., 2008), as well as the activation of Bezold-Jarisch reflex which leads to 64 vasodilatation, bradycardia, and hypotension (Warltier et al., 2003). Several receptors are 65 involved in these changes, including the 5-HT3 receptor. In human studies, 5-HT3 receptor Dwersteg, 1987). Furthermore, it leads to hypercarbia, hypoxemia, lactic acidosis, and 72 worsening pain sensation (Begum et al., 2008). In addition to that, shivering prolongs 73 hospital stay, may lead to surgical wound infection, decreases immunity, causes 74 coagulopathy, and increases the incidence of cardiac morbidity (Kim et al., 2014;Reynolds 75 et al., 2008). All of this burdens health care facilities and put the patient's overall health 76 status at risk. 77 It is worth to mention that, until now there is no consensus regarding the efficacy of 78 ondansetron on the reduction of spinal anesthesia-induced shivering and hypotension. 79 This study primarily carried out to evaluate the efficacy of prophylactic 4mg intravenous 80 ondansetron on the reduction of spinal anesthesia-induced shivering and hypotension in an 81 obstetric population that undergoes elective cesarean section. 82 83 Spinal anesthesia is often complicated by postoperative hypotension and shivering. 84

Problem statement
Hypotension affects approximately 50% of the obstetric population (Klöhr et al., 2010). A 85 drop in arterial blood pressure can lead to nausea and vomiting, altered consciousness, an 86 increased risk of aspiration, and reduced uterine-fetal blood flow. The mechanisms that cause 87 hypotension during spinal anesthesia include sympatholysis, which induces a decrease in 88 systemic vascular resistance (Langesaeter et al., 2008), as well as the Bezold-Jarisch reflex. 89 The latter phenomenon leads to vasodilation, bradycardia, and hypotension (Warltier et al., 90 2003). Several receptors are involved in these changes, including the 5-HT3 receptor. 91 Antagonists for this receptor can block the Bezold-Jarisch reflex in animal models (Yamano 92 et al., 1995). In human studies, 5-HT3 receptor antagonists have been evaluated for their 93 efficacy to prevent spinal-anesthesia-related hypotension, but the results are inconsistent 94 Preoperative shivering amplifies the metabolic heat yield up to 6-fold above the baseline 96 metabolic rate (Giesbrecht et al., 1994); it is clinically associated with different frequencies 97 of tonic or clonic skeletal muscular hyperactivity (Javaherforoosh et al., 2009).This 98 augmented muscular activity increases oxygen consumption approximately 200-500% (Bay, 99 al., 2008). This excited muscular activity compromises myocardial function and worsens 102 morbidity rates, especially when the patient has preexisting diminished myocardial oxygen 103 flow, e.g. arteriosclerosis (Alfonsi, 2001;Ciofolo et al., 1989). These conditions will affect 104 uteroplacental blood flow. Some of used drugs for treating post-anesthesia shivering are 105 meperidine, tramadol, and clonidine, but all of these have adverse effects, including sedative 106 effects, nausea, vomiting, bradycardia, and hypotension. Postoperative shivering prolongs 107 hospital stays, may lead to surgical wound infection, decreases immunity, causes 108 coagulopathy, and increases the incidence of cardiac morbidity (Kim et al., 2014;Reynolds et 109 al., 2008). These morbidities burden health care facilities and put the patient's overall health 110 status at risk. 111 112 This study was conducted to achieve the following objectives:   Spinal-anesthesia-induced shivering and hypotension have significant negative consequences 122 on the mother and infant during cesarean section. These factors can increase the length of a 6 hospital stay and cause financial and other burdens to health services. Conducting this study 124 will help to whether ondansetron can reduce these complications. Moreover, earlier studies 125 suggest that avoiding shivering will provide valuable benefits in patients and promote a 126 superior prognosis (Kurz et al., 1996). Notably, this study is the first of its kind in Palestine. 127

Study objectives
The results should provide benefits to our patients and their relatives by decreasing their 128 preventable suffering and to our hospitals by decreasing patients' hospitalization and, 129 consequently, the economic burden on these health care facilities. 130

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Study design 132 133 The study was conducted as a prospective, cohort, randomized, double-blinded, placebo-134 controlled trial (RCT). This design was adopted due the strength of the hierarchy of scientific 135 evidence, namely, reduced bias and more accurate results. 136 The sample size was calculated using the tools at https://clincalc.com/stats/samplesize.aspx, 177 an evidence-based clinical decision support tools and calculators for medical professionals. 178

Clinical Trial Registration
The following assumptions were used to calculate the sample size: 179  The accepted alpha is 5% and beta is 20%. 180  The median incidence of spinal-anesthesia-induced shivering in a review of 21 studies is 181 55%. It is expected to go down to 22.5% with ondansetron treatment. A sample size of 34 182 subjects in each group would be required to detect this difference. 183  The incidence of spinal hypotension during caesarean delivery is 77%, which would be 184 expected to decrease to 45% with ondansetron treatment. A sample size of 35 subjects in 185 each group would be required to detect this difference. 186 The participants who met the inclusion criteria and according to randomization list formatted 192 by www.randomization.com, the participants were randomized into two groups: The 193 treatment group received intravenous ondansetron (4 mg diluted in 10 ml 0. Data Analysis 267 268 The data were analysed with SPSS version 22

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Ninety women were assessed for eligibility; 10 did not meet the inclusion criteria, were 317 contraindicated for spinal anesthesia, and converted to general anesthesia. The remaining 80 318 women were enrolled and randomized into the treatment or control group, Consort diagram 319 (Fig. 1). There were no differences in demographic data between the groups, p value was > 320 0.05 (Table 2).

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To our knowledge, this study is the first performed in Palestine to assess the effects of the 453 5HT3 antagonist ondansetron on the incidence of hypotension and shivering after 454 administration of spinal anesthesia. Ninety women were assessed for eligibility, but 10 were 455 excluded and switched to general anesthesia because spinal anesthesia was contraindicated. 456 The remaining 80 women were enrolled in the study and randomly allocated into two groups: 457 intravenous 4 mg ondansetron or intravenous 0.9% saline; each treatment was administered 458 prior to spinal anesthesia induction (Fig. 1). There were no demographic differences between 459 the groups (P > 0.05; Table 2). Numerous hemodynamic parameters and other observations 460 were recorded every 3 min during the intraoperative period and every 5 min in the PACU. 461

4-The Effect of Ondansetron on Pruritus 559
The present study showed no significant differences regarding the incidence of intraoperative 560 and postoperative pruritus. These findings are consistent with Terkawi et al. (2016). In this 561 study, 86 subjects underwent elective cesarean section, they were randomly allocated, they 562 were anesthetized using a mixture of 15 mg of 0.75% bupivacaine, 20 mcg of fentanyl, and 563 100 mcg of preservative-free morphine. The occurrence of pruritus was not statistically 564 different between the ondansetron (63%) and placebo (56%) groups (P = 0.59). Moreover, 565 the study results are in line with Ortiz-Gomez et al. (2014). This RCT with 128 participants-566 randomly divided into placebo or intravenous ondansetron (2, 4, or 8 mg)-revealed no 567 statistical differences among the groups regarding pruritus incidence (P =0.77). Our study is 568 inconsistent with the results of Yeh et al. (2000), in which 60 participants were randomly 569 divided into 0.9% saline, diphenhydramine, and ondansetron groups. The ondansetron group 570 showed a significantly lower pruritus incidence (25%) compared to the other groups. They 571 concluded that prophylactic ondansetron can statistically reduce the incidence of pruritus 572 (Yeh et al., 2000). 573 574 575

5-The Effect of Ondansetron on Pain and Headache 576
There were no significant differences between the groups regarding the incidence of 577 intraoperative and postoperative pain and headache. The results are consistent with Yeh et al. 578 (2000), where 60 participants were randomly divided into 0.9% saline, diphenhydramine, and 579 ondansetron groups. The postoperative pain score and headache among all study groups did 580 not statistically differ in that study. 581 582

Recommendations 583
In clinical practice, it is recommended to administer 4 mg ondansetron intravenously prior to 584 spinal anesthesia induction for women who will undergo a cesarean section. This 585 administration should attenuate the incidence of spinal anesthesia-induced shivering and 586 hypotension. Furthermore, ondansetron is a category A drug and is thus safe to use during 587 pregnancy. It also has well-known antiemetic and anti-nausea effects. Larger sample sizes are 588 required to detect the exact effectiveness of ondansetron on the attenuation of spinal 589 anesthesia-induced shivering and hypotension in women who undergo a cesarean section.