Ondansetron Does Not Attenuate Hemodynamic ...

ORIGINAL ARTICLE

Ondansetron Does Not Attenuate Hemodynamic Changes in Patients Undergoing Elective Cesarean Delivery Using Subarachnoid Anesthesia A Double-Blind, Placebo-Controlled, Randomized Trial Abdullah S. Terkawi, MD,* Mohamed Tiouririne, MD,* Sachin H. Mehta, MD,* Jordan M. Hackworth, MD,* Siny Tsang, MA,† and Marcel E. Durieux, MD, PhD* Introduction: Hypotension is the most common complication after subarachnoid anesthesia for cesarean delivery. Several therapeutic and preventive measures are used to attenuate this side effect. Serotonin receptor– blocking drugs have been suggested as one such approach. We sought to determine whether prophylactically administered intravenous ondansetron could attenuate hypotension in patients undergoing elective cesarean delivery performed under subarachnoid anesthesia. Methods: Eighty-six patients undergoing elective cesarean delivery were recruited and randomly allocated to receive either 8 mg intravenous ondansetron (group O; n = 44) or placebo (group P; n = 42) in a prospective double-blind design. Systolic blood pressure (SBP), mean arterial pressure (MAP), diastolic blood pressure (DBP), and heart rate (HR) were measured at baseline and at 3-minute intervals from the time of initiation of subarachnoid anesthesia until delivery. Ondansetron effect on hemodynamics (SBP, DBP, MAP, and HR) was quantified and analyzed using a linear mixed effect model. Results: We did not find differences in SBP (P = 0.78), MAP (P = 0.89), DBP (P = 0.82), or HR (P = 0.18) between the 2 groups during the study period. Phenylephrine requirements to treat hypotension were 350 μg (175–700 μg) in group O and 450 μg (300–700 μg) in group P (P = 0.30). The incidence of pruritus was 63% (n = 28 of 44) in group O and 56% (n = 23 of 42) in group P (difference, 0.08 [95% confidence interval, −0.23 to 0.41], P = 0.59). No difference in the incidence of nausea and vomiting or sensory level was found. Conclusions: Ondansetron premedication does not attenuate hemodynamic changes after subarachnoid anesthesia nor does it reduce the amount of vasopressor use, pruritus, or nausea and vomiting. (Reg Anesth Pain Med 2015;40: 344–348)

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ypotension is the most common complication after subarachnoid anesthesia for cesarean delivery.1 Initially, hypotension is caused by a decrease in systemic vascular resistance secondary to blockade of sympathetic fibers.2 The Bezold-Jarisch reflex (BJR) has been proposed as an additional explanation for hypotension in patients undergoing subarachnoid anesthesia.3 This reflex is mediated by serotonin receptors (5-HT3 subtype) located on the vagus nerve and within the wall of the cardiac ventricles. They are activated by serotonin released in response to systemic hypotension4 and cause an increase in efferent vagal signaling.5 Serotonin induces arterial and venous constriction during hypovolemic states in both humans and animals through an From the Department of *Anesthesiology, University of Virginia, Charlottesville, VA; and †Department of Epidemiology, Columbia University, New York, NY. Accepted for publication April 24, 2015. Address correspondence to: Mohamed Tiouririne, MD, Department of Anesthesiology, University of Virginia Health System, PO Box 800710, Charlottesville, VA 22908-0710 (e‐mail: [email protected]). Copyright © 2015 by American Society of Regional Anesthesia and Pain Medicine ISSN: 1098-7339 DOI: 10.1097/AAP.0000000000000274

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interaction with α-adrenergic receptors and serotoninergic receptors (5HT2A subtypes).6–8 Conversely, binding of serotonin to the 5HT3 receptor subtype activates the BJR, leading to bradycardia and hypotension.5,9 Ondansetron, a 5HT3 antagonist, has been suggested to attenuate hypotension after subarachnoid anesthesia in both nonobstetric3,10 and obstetric patients.11–13 However, results of these studies are limited by a small sample size and are in some aspects contradictory: Sahoo et al11 and Wang et al12 reported that ondansetron (4 mg) mitigated hypotension in patients undergoing elective cesarean delivery; Ortiz et al,13 studying ondansetron 2, 4, or 8 mg, did not find a beneficial effect. To clarify the utility of ondansetron in preventing hypotension, we sought to determine whether prophylactically administered intravenous ondansetron could attenuate hemodynamic changes in patients undergoing elective cesarean section performed using subarachnoid anesthesia. Specifically, we studied the period between subarachnoid administration of local anesthetic and delivery of the baby, so that the findings would not be confounded by effects of uterotonic drugs, blood loss during placenta extraction, and vagal responses to uterine externalization.

METHODS Enrollment After institutional review board approval (IRB-HSR 14583), patients who presented for elective cesarean delivery at our institution between September 2010 and December 2012 were approached to participate in a double-blind, randomized, controlled trial (NCT-01414777) comparing the effects of ondansetron with those of placebo on hypotension and bradycardia after subarachnoid anesthesia. Exclusion criteria were diabetes, chronic hypertension, gestational hypertension, preeclampsia, cardiac disease, patients with a long QT syndrome, and known contraindications to neuraxial anesthesia.

Randomization After patients signed the consent form to participate in the study, our research nurse called the pharmacist. The pharmacist was unblinded and prepared the syringes for all our study patients. Patients were randomized to 2 groups using Research Randomizer (www.researchrandomizer.org). All research team members were blinded. After randomization, age, weight, height, body mass index (BMI), and gestational age were recorded.

Study Protocol An intravenous cannula was inserted, and all patients received aspiration prophylaxis (oral sodium citrate 30 mL, intravenous famotidine 20 mg, and metoclopramide 10 mg). All patients received 500 mL of hetastarch (Voluven) within 20 to 30 minutes of transfer to the operating room. Multiple Electrolytes Injection

Regional Anesthesia and Pain Medicine • Volume 40, Number 4, July-August 2015

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Ondansetron and Hemodynamic Changes

(Plasmalyte) was then used as maintenance fluid throughout the intraoperative period. On arrival to the operating room, ASA standard monitors were attached and initial vital signs (blood pressure, HR, and SpO2) were obtained. An oscillometric blood pressure measurement device was used. While in the sitting position, study drug was administered for a period of 5 minutes. Group O, the ondansetron group, received 8 mg intravenous ondansetron diluted in 10 mL of saline 5 minutes before administration of the subarachnoid anesthetic, whereas group P, the placebo group, received 10 mL of saline. Lumbar puncture was then performed using sterile technique, with a 24-gauge pencil-point needle at L4-L5 or L3-L4 level. A mixture of 15 mg of 0.75% bupivacaine, 20 μg of fentanyl, and 100 μg of preservative-free morphine was administered after confirmation of free flow of cerebrospinal fluid. Patients were then placed in the recumbent position with 15 degrees left uterine displacement. Sensory level of anesthesia was assessed using cold sensitivity to ice at 5 minutes, 10 minutes, and at the end of surgery. Bromage score was used for motor assessment, and the results are presented as follows: 3 = unable to move feet or knees, 2 = able to move feet only, 1 = able to move knees only, and 0 = full flexion of knees and feet.

extent of sensory block; estimated blood loss; total amount of fluid administered; and Apgar scores at 5 minutes were recorded and analyzed. The incidence of pruritus was calculated as the number of times the patient complained of pruritus after subarachnoid anesthesia until the time of discharge from the postanesthesia care unit.

Outcome Measurements

where yij is the outcome variable, βn are the fixed-effect coefficients, xnij are the fixed-effect predictors for observation j in patient i, bin are the random-effect coefficients (assumed to be multivariate normally distributed), znij are the random-effect predictors, and εij is the error for observation j in patient i. The model fitted for SBP, MAP, DBP, and HR is:

The overall differences in SBP, MAP, DBP, and HR between the treatment group and control group from the time of initiation of subarachnoid anesthesia until delivery was considered our primary outcome. Hypotension was defined as SBP less than 90 mmHg. We also considered SBP less than 90 mmHg as a threshold for treatment of hypotension; this was standardized to boluses of 100 μg of phenylephrine given incrementally until SBP was more than 90 mmHg. Heart rate less than 60 beats/min was treated with intravenous atropine 0.4 mg or 0.2 mg glycopyrrolate. The amounts of phenylephrine, atropine, and glycopyrrolate administered; the incidence of pruritus, nausea, and vomiting; the

Statistical Analysis The effect of the treatment (ondansetron) on hemodynamic variables was assessed using linear mixed-effects models (LMMs). Data from 2 minutes after the administration of subarachnoid anesthetic and every 3 minutes up to time of delivery were included in the models. Linear mixed-effects models were used because of the repeated nature of the hemodynamic data (ie, SBP, MAP, DBP, and HR), and LMMs are robust for data that are not normally distributed and with missing values.14 The groups (ondansetron and placebo) and the linear and quadratic association with time (from 2 minutes after initiation of subarachnoid anesthesia up to delivery) were modeled as fixed effects, and patients were modeled as random effects. The LMM takes the form of: yij ¼ β 0 þ β 1 x1ij þ β 2 x2ij⋅⋅⋅β n xnij þ bi1 z1ij þ bi2 z2ij⋅⋅⋅bin znij þ εij

yij ¼ β 0 þ β 1 x1ij þ β 2 x2ij þ β 3 x3ij þ bio þ εij where yij is the outcome variable (ie, SBP, MAP, DBP, HR), x1ij, x2ij, and x3ij are the linear time, quadratic time, and Group (Ondansetron/Placebo) fixed effects for observation j in patient

FIGURE 1. Consort flow diagram. Protocol violation: phenylephrine dose given was more or less than the standardized dose of 100 μg per bolus. © 2015 American Society of Regional Anesthesia and Pain Medicine

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Terkawi et al

TABLE 1. Demographic, Intraoperative, and Neonatal Data Characteristic

Group O (Ondansetron), n = 44

Age* BMI* ASA I† ASA II† Time to delivery, min* Time from study drug administration to subarachnoid local anesthetic administration, min*‡ Time from subarachnoid local anesthetic administration to incision, min* Time from subarachnoid local anesthetic administration to delivery, min* Intraoperative fluids, mL* APGAR score at 5 min§ APGAR score at 10 min§ Estimated blood loss, mL§

P

Group P (Placebo), n = 42

30 ± 5.43 32 ± 5.58 8 (18%) 36 (82%) 19 ± 8.91 8.20 ± 4.80

28 ± 5.41 34 ± 7.90 5 (12%) 37 (88%) 20 ± 7.40 9.12 ± 4.95

0.18 0.21 0.69 0.94 0.24 0.31

16.12 ± 3.46

16.76 ± 3.01

0.38

35.46 ± 10.58

37.49 ± 8.41

0.34

2190 ± 663 8 (8, 9) 9 (9, 9) 750 (600, 850)

2297 ± 667 8 (8, 9) 9 (9, 9) 700 (500, 1000)

0.43 0.60║ 0.81║ 0.89║

*Presented as mean ± SD. †Presented as number and percent. ‡The drug was administered 5 minutes before subarachnoid anesthesia was attempted. §Presented as median and IQR (ie, first quartile, third quartile). ║Using Mann-Whitney U test, as these are not normally distributed data. BMI indicates body mass index; ASA, American Society of Anesthesiologists physical status score.

i, bi0 is the random intercept for patient i, and εij is the error for observation j in patient i. Shapiro-Wilk test, histograms, and Q-Q plots were used to assess normality assumption of the outcome variables. Mean and SD were used for descriptive analysis of normally distributed variables, whereas median and 25th and 75th interquartile range (IQR) were used for non-normally distributed variables. We analyzed by intention to treat. Secondary outcomes were compared using either the 2-sample t test for variables that are normally distributed or Mann-Whitney U test for variables that were not. Categorical data were compared using χ2 test. A value of P = 0.05 was considered statistically significant. SPSS 21 software (SPSS, Chicago, Illinois) was used for analysis, whereas the LMMs and the graphs were prepared using the R programming language (R Foundation for Statistical Computing, Vienna, Austria).

RESULTS We recruited 86 patients for this study. A CONSORT trial flow diagram is presented in Figure 1. The 2 groups were well randomized; there was no statistically significant difference in demographics or in clinical characteristics or confounders (Table 1). Bromage scores in both groups were not different, and there was no difference in the sensory levels throughout the procedure (Table 2).

Primary Outcomes Blood pressure and HR differences between the 2 groups from the time of initiation of subarachnoid anesthesia up to the time of delivery were quantified and analyzed using an LMM, and no differences were observed between the 2 groups, although SBP, DBP, and HR changed across time (Table 3; Fig. 2). Results showed a quadratic relation between time and SBP, DBP, and HR, meaning that these parameters decreased initially and increased as more time passed. From the model, we quantified the effect of ondansetron to

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be 0.55 ± 1.99 mmHg on SBP, 0.19 ± 1.48 on MAP, and 0.03 ± 1.28 for DBP. This clearly indicates, at 95% CI, the effect of ondansetron on average SBP, MAP, and DBP is less than 5 mmHg on each direction, therefore, supporting our conclusion of no difference. Heart rate models in which time was also modeled as the random effect resulted in a better fit than if time was not included as the random effect. This suggests that individuals’ HR differed at time 0 (baseline) as well as across time. The overall incidence of bradycardia (HR < 60 beats/min) was 15% (n = 6/41) in each group (OR, 1; 95% CI, 0.24–4.08; P = 1).

Secondary Outcomes The median and IQR of phenylephrine consumption up to delivery time was 350 (175–700) μg in group O and 450 (300–700) μg in group P. The mean glycopyrrolate consumption was 25 ± 80 μg in group O and 16 ± 55 μg in group P (P = 0.53). The overall incidence of pruritus was 63% (n = 28/44) in TABLE 2. Characteristics of Sensory and Motor Block Between the 2 Groups Group O Group P (Ondansetron) (Placebo) Sensory level at 5 min* Sensory level at 10 min* Sensory level at end of surgery* Bromage scale at 5 min† Bromage scale at 10 min† Bromage Scale at end of surgery†

T5 (T4, T7) T3 (T2, T4) T3 (T2, T4) 2 ± 0.64 2.6 ± 0.48 3 ± 0.33

T5 (T3, T6) T3 (T2, T4) T3 (T2, T4) 2 ± 0.75 2.9 ± 1.26 2.7 ± 0.71

P 0.31 0.27 0.56 0.74 0.20 0.64

*Data presented as median and IQR (first quartile, third quartile), calculated using Mann-Whitney U test. †Motor block data presented as mean ± SD.

© 2015 American Society of Regional Anesthesia and Pain Medicine



TABLE 3. Effect of Ondansetron Versus Placebo on Hemodynamics Across Time; Linear Mixed Effects Models Variable

Estimate

Systolic blood pressure Intercept 112.94 Time −0.67 0.01 Time2 Groups 0.55 Mean arterial pressure Intercept 74.30 Time 0.10 −0.001 Time2 Groups 0.19 Diastolic blood pressure Intercept 69.8 Time −1.23 0.02 Time2 Groups −0.03 Heart rate Intercept 84.35 Time −0.83 0.01 Time2 Groups 3.01

SE

t

P

3.20 0.09 0.002 1.99

−7.90 6.59 0.28