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Prevention of Spinal Anesthesia-Induced Hypotension During Cesarean Delivery by 5-Hydroxytryptamine-3 Receptor Antagonists: A Systematic Review and Meta-analysis and Meta-regression

Heesen, Michael MD, PhD; Klimek, Markus MD, PhD, DEAA, EDIC; Hoeks, Sanne E. MD, PhD; Rossaint, Rolf MD, PhD

doi: 10.1213/ANE.0000000000001511
Obstetric Anesthesiology: Meta-Analysis
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BACKGROUND: Hypotension remains a frequent complication of spinal anesthesia, increasing the risk of nausea and vomiting, altered mental status, and aspiration. The aim of this systematic review and meta-analysis was to determine whether 5-hydroxytryptamine3 (5-HT3) receptor antagonists, administered before the initiation of spinal anesthesia, mitigate hypotension.

METHODS: After a systematic literature search in various databases, randomized placebo-controlled double-blind trials studying the preventive effect of 5-HT3 receptor antagonists were included. A random-effects model was applied, risk ratio (RR, binary variables) or weighted mean difference (continuous variables) with 95% confidence intervals (CIs) were calculated. The primary outcome was the incidence of hypotension.

RESULTS: Seventeen trials (8 obstetric, 9 non-obstetric) reporting on 1604 patients were identified. Ondansetron in doses from 2 to 12 mg was studied in 12 trials. Prophylactic 5-HT3 administration significantly reduced the risk of hypotension in the combined analysis of 17 trials, RR 0.54 (95% CI 0.36–0.81, I2 = 79%). In obstetric trials, the RR was 0.52, 95% CI 0.30–0.88, I2 = 87% (number needed to treat 4). In non-obstetric studies, the 95% CIs were wide and included a clinically relevant reduction in the risk of hypotension (RR 0.50, 95% CI 0.22–1.16; I2 = 66%). Contour-enhanced funnel plots confirmed publication bias. Meta-regression showed a significant ondansetron dose response in non-obstetric patients (β = −0.355, P = .04). In the combined and in the obstetric-only analysis, the risk of bradycardia was significantly reduced as was the use of phenylephrine equivalents.

CONCLUSIONS: 5-HT3 antagonists are effective in reducing the incidence of hypotension and bradycardia; the effects are moderate and are only significant in the subgroup of patients undergoing cesarean delivery. The effects in the non-obstetric population are not significant.

Supplemental Digital Content is available in the text.

From the *Department of Anesthesia, Kantonsspital Baden, Baden, Switzerland; Department of Anesthesia, Erasmus University Medical Center, The Netherlands; and Department of Anesthesia, University Hospital RWTH Aachen, Aachen, Germany.

Accepted for publication June 19, 2016.

Funding: Departmental.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Michael Heesen, MD, PhD, Department of Anesthesia, Kantonsspital Baden, Im Ertl, 5400 Baden, Switzerland. Address e-mail to michael.heesen@ksb.ch.

Spinal anesthesia is often complicated by hypotension, affecting approximately one-third of the non-obstetric1,2 and 50% of the obstetric population.3 A fall in arterial blood pressure can lead to nausea and vomiting, altered consciousness, and increases the risk of aspiration. Among the mechanisms causing hypotension during spinal anesthesia is sympatholysis inducing a decrease in systemic vascular resistance,4 as well as the Bezold-Jarisch reflex. The latter becomes activated by decreased venous return to the right heart, triggering receptors in the cardiac wall, leading to vasodilation, bradycardia, and hypotension.5 Among the receptors involved are chemoreceptors responding to 5-hydroxytryptamine3 (5-HT3, serotonin). 5-HT3 receptor antagonists were found to block the Bezold-Jarisch reflex in animal models.6 Subsequently, 5-HT3 receptor antagonists were evaluated in human studies for their potential to prevent spinal anesthesia-induced hypotension. The results of these trials were not consistent.7,8 We, therefore, set out to identify the available literature and submitted the retrieved data to a meta-analysis to estimate the effect of 5-HT3 receptor antagonists on the frequency of hypotension in patients undergoing spinal anesthesia.

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METHODS

Our study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.9 The databases PubMed, Embase, CINAHL, LILACS, CENTRAL, Clinicaltrials.gov, and ISI WOS were searched without filters and without language restrictions for studies published from inception to January 20th, 2016. The following search strategy was applied: (ondansetron OR granisetron OR tropisetron) OR (serotonin antagonist) OR ((“serotonin”[MeSH Terms] OR serotonin[Text Word]) AND antagonist[All Fields]) OR (“Serotonin 5-HT3 Receptor Antagonists”[Mesh])) AND ((“Anesthesia, Spinal”[Mesh]) OR (combined spinal-epidural anesthesia) OR ((analgesia OR anesthesia) AND ((spinal OR intrathecal OR subarachnoid)))). The bibliographies of retrieved articles were also screened to identify additional studies. Authors were contacted when original data were missing. Two investigators (M.H., M.K.) independently evaluated each study for methodological quality based on guidance developed by the Cochrane collaboration to determine the risks of selection bias (random sequence generation, allocation concealment), performance bias (blinding of study subjects and personnel), and detection bias (blinding of assessor).10 To be included a trial had to be randomized, study subjects and outcome assessors had to be blinded for treatment allocation, and at least 6 of the 12 domains that we assessed had to be scored “yes.” According to our study protocol, a third author resolved any discrepancies (R.R.). Studies were eligible that explored the effect of IV 5-HT3 receptor antagonists compared with placebo for prophylaxis of hypotension in patients undergoing spinal anesthesia for any type of surgery including cesarean delivery. Exclusion criteria were as follows: patient age <18 years, lack of a placebo group, studies using a fixed combination of a 5-HT3 receptor antagonist with another drug, administration of the 5-HT3 receptor antagonist for treatment and/or administration of the 5-HT3 receptor antagonist during surgery.

The primary outcome variable of our study was the incidence of hypotension, with the definition of hypotension used by the authors of the individual trials. Bradycardia, vasopressor use, maternal side effects, and neonatal outcome were secondary outcome variables. If 2 or more 5-HT3 receptor antagonist doses were studied, we initially combined the data for meta-analysis. In case of continuous variables, we applied the formulae from the Cochrane Handbook.10

We performed additional subgroup analyses of different doses of ondansetron, of cesarean delivery studies and non-obstetric surgery trials separately, and of ondansetron-only studies (all ondansetron doses combined, excluding other 5-HT3 receptor antagonists).

Some of the trials retrieved by our search assessed the effect of 5-HT3 receptor antagonists on nausea and vomiting. Since meta-analyses on these outcome variables have been published previously,11,12 we did not evaluate nausea and vomiting in the current study.

We used the Review Manager (RevMan, version 5.1) Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008 for meta-analysis. A random-effects model was applied since we expected clinical and methodological heterogeneity across studies. The risk ratio (RR) and 95% confidence interval (95% CI) were calculated for binary variables; for continuous parameters, weighted mean difference and 95% CIs were computed. The I2 statistic served to assess heterogeneity, describing the percentage of variation across trials that is caused by heterogeneity rather than the play of chance.13P values < .05 were considered statistically significant. For statistically significant outcomes, the number needed to treat (NNT) was calculated (http://clincalc.com/Stats/NNT.aspx). Contour-enhanced funnel plots were used to assess publication bias if there were more than 10 studies. In case of funnel plot asymmetry, the trim-and-fill method was used by imputing “missing” studies to increase funnel plot symmetry. To assess a dose-response effect, a random-effects meta-regression was done with the ondansetron dose as moderator. Meta-regression, bubble plots, and contour-enhanced funnel plots (with trim-and-fill method) were performed with R version 3.1.3 with the “meta” package (version 4.2-0) and “metafor” package (version 1.9-7).

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RESULTS

Table 1

Table 1

Table 2

Table 2

Table 3

Table 3

Figure 1

Figure 1

Our literature search identified 369 trials (Figure 1); 17 trials reporting on 1604 patients were included in the meta-analysis.7,8,14–28 Nine studies were performed in a non-obstetric population14–19,21,22,28 and 8 studies included parturients undergoing cesarean delivery.7,8,20,23–26,28 The methodological quality of the included studies is shown in Tables 1 and 2; Table 3 shows details of the studies. The study by Rashad and Farmawy29 was excluded because it was not double-blinded.

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Prevention of Hypotension: All Studies Combined

When combining obstetric and non-obstetric trials, prophylactic administration of a 5-HT3 antagonist significantly reduced the risk for hypotension, RR 0.54, 95% CI 0.36–0.81, I2 = 79% (Figure 2). The NNT was 6.3. In the obstetric studies, RR was 0.52, 95% CI 0.30–0.88, I2 = 87% (NNT = 4); in non-obstetric trials, the RR was 0.56, 95% CI 0.28–1.12, I2 = 59%.

Figure 2

Figure 2

Ondansetron was the most frequently used drug. RR of hypotension for the 12 obstetric and non-obstetric trials studying ondansetron 2–12 mg was 0.67, 95% CI 0.48–0.92, I2 = 65% (Supplemental Digital Content 1, http://links.lww.com/AA/B471). The NNT was 9.6.

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Prevention of Hypotension: Obstetric Studies

Of the 8 obstetric trials, 7 studied ondansetron7,8,20,23–25,28 and 1 study used granisetron.26 The doses of ondansetron used in these trials varied from 2 to 12 mg. When analyzing the 7 ondansetron studies,7,8,20,23–25,28 the RR was 0.70, 95% CI 0.49–0.99, I2 = 71%. In addition, we performed an analysis with the obstetric studies that used higher doses of ondansetron (>4 mg),8,23,25,27 The RR was 0.77, 95% CI 0.41–1.41, I2 = 86%.

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Prevention of Hypotension: Non-obstetric Studies

Of the non-obstetric trials, 7 trials14,15,17,19,21,22,28 studied ondansetron in doses ranging from 4 to 12 mg. One study used granisetron17 and another trial18 studied ramosetron. Subgroup analysis of the non-obstetric trials using ondansetron,14,15,17,19,21,22,28 did not find a statistically significant effect of 5-HT3 antagonists on the incidence of hypotension: RR 0.50, 95% CI 0.22–1.16, P = .10, I2 = 66%; however, the CI was wide and did not exclude a clinically significant reduction in the risk of hypotension. We performed a meta-analysis excluding the 2 studies14,19 using low-dose ondansetron (4 mg). Analysis of the trials of high-dose ondansetron15,17,21,22,28 only (6–12 mg) revealed a significant reduction in the risk of hypotension, RR 0.23, 95% CI 0.06–0.86, I2 = 70%.

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Sensitivity Analysis

We performed sensitivity analyses including only those studies that had hypotension as the primary outcome variable. In a combined analysis of obstetric and non-obstetric studies,7,8,17,20,21,23–28 the RR was 0.47, 95% CI 0.28–0.77, P = .003, I2 = 86%. Analysis of obstetric studies alone7,8,20,23–27 gave a RR 0.52, 95% CI 0.30–0.88, P = .01, I2 = 87%. Analysis of non-obstetric trials17,21,28 gave a RR 0.16, 95% CI 0.01–2.17, I2 = 84%.

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Bradycardia

Figure 3

Figure 3

Analysis of all studies combined, only the obstetric studies found that the incidence of bradycardia was significantly lower in the 5-HT3 antagonist group (Figure 3). In these studies, only ondansetron was used. Subgroup analysis of the 3 non-obstetric studies15,21,22 showed no significant difference, but the CI was wide.

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Need for Vasopressors

Five studies15,17,22,27,28 reported on the number of patients needing treatment with a vasopressor; all 5 studies used ephedrine. The use of 5-HT3 antagonist did not reduce the number of subjects who required ephedrine (RR 0.6, 95% CI 0.35–1.04; P = .07, I2 19%) (Supplemental Digital Content 2, http://links.lww.com/AA/B472). The total dose of vasopressor was analyzed in 5 trials7,20,23,24,26 of parturients undergoing cesarean delivery. One study used ephedrine7 and 420,23,24,26 used phenylephrine. We computed the phenylephrine equivalents based on the assumption that 5 mg ephedrine are equivalent to 62 µg phenylephrine.30 5-HT3 antagonists significantly reduced the amount of vasopressor needed for the treatment of hypotension (weighted mean difference −48 µg, 95% CI −86 to −10, I2 = 77%) (Supplemental Digital Content 3, http://links.lww.com/AA/B473). We performed a sensitivity analysis without the study by Sahoo et al,20 because the phenylephrine dose was an order of magnitude lower than in the other trials. The weighted mean difference was −64 µg, 95% CI −99 to −30, P = .0003, I2 = 36%.

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Investigation of Publication Bias

Figure 4

Figure 4

Funnel plots of the analyses of the incidence of hypotension combining obstetric and non-obstetric studies, the subset of those trials that only used ondansetron, the obstetric and the non-obstetric trials were asymmetric and suggestive of bias (data not shown). Contour-enhanced funnel plots with trim-and-fill method were done for obstetric and non-obstetric trials combined (Figure 4) and for the subgroup of obstetric and non-obstetric trials that used ondansetron (Supplemental Digital Content 4, http://links.lww.com/AA/B474). The plots confirmed publication bias.

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Meta-regression for Ondansetron Dosing

Meta-regression analysis found no dose-response relationship of ondansetron in both the combined analysis and in the obstetric trials alone (Supplemental Digital Content 5, http://links.lww.com/AA/B475). There was a significant dose-response relationship for prevention of hypotension in the non-obstetric trials, β = −0.355, P = .04. There was no evidence of a dose-responsive relationship for bradycardia (Supplemental Digital Content 6, http://links.lww.com/AA/B476).

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Other Side Effects

Other side effects included tachycardia, dysrhythmia, headache, drowsiness, discomfort, rigor, and skin flushing. No significant difference between the 5-HT3 antagonist and the placebo group was observed (data not shown).

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DISCUSSION

Our study found that prophylactic administration of 5-HT3 receptor antagonists significantly reduced the incidence of spinal anesthesia–induced hypotension. Most studies used ondansetron, and limiting the analysis to only these studies did not change the results. A similar decrease in risk of hypotension was observed when limiting the analysis to only obstetric trials, but was not observed for non-obstetric trials. However, the 95% CIs for RR in non-obstetric studies were wide, suggesting that the data were inadequate to draw any definitive conclusions. 5-HT3 antagonist use did not lower the number of patients who required vasopressor for the treatment of hypotension; however, the dose of vasopressor was significantly lower in 5-HT3 antagonist–treated patients. The incidence of bradycardia was also significantly reduced by the use of a 5-HT3 antagonist. Maternal side effects were unaffected by 5-HT3 antagonists.

No dose responsiveness of ondansetron was observed for the prevention of hypotension in the combined analysis of obstetric and non-obstetric trials or in obstetric trials alone. However, a statistically significant dose-response relationship was observed for the prevention of hypotension in the non-obstetric population. A possible explanation for these findings is that the overall analysis included trials using low doses (eg, 4 mg) as well as high doses of ondansetron. Indeed, an analysis without these low-dose non-obstetric studies revealed a significantly reduced incidence of hypotension.

Numerous studies have dealt with strategies to reduce the incidence of spinal-related hypotension in parturients. Preload with crystalloids has been found to be ineffective. Volume load with crystalloids starting immediately after spinal injection (coload) has been suggested as well as colloid preload and coload.31,32 Among vasopressors, the pure α-adrenergic receptor agonist phenylephrine has become the first-line treatment,33 because of a more favorable effect on neonatal pH compared with ephedrine.34 Proactive administration of phenylephrine is currently advocated31 because it is more effective than an administration only after blood pressure has fallen.35 After continuous infusion of 25–50 µg/min phenylephrine, hypotension was still noted in 15%–30% of the patients.36

Bradycardia is a known side-effect of phenylephrine, affecting approximately 10% of the women receiving this vasopressor.34,37 In a trial of continuous phenylephrine infusion, as many as 32% of the patients experienced bradycardia with infusion rates of 75 and 100 µg/min.36 Heart rate was suggested as a surrogate parameter for cardiac output by Dyer et al38 as well as Langesaeter et al.4 It is cardiac output that reflects more accurately uteroplacental perfusion than maternal blood pressure,39 and the well-being of the fetus, unable to store oxygen, finally depends on maternal cardiac output.40 Often one phenylephrine bolus or the chosen infusion rate of phenylephrine is not sufficient to reverse low blood pressure. It would be of interest to study the use of 5-HT3 antagonists in this situation. Recently, Ngan Kee et al41 compared phenylephrine with the nonspecific adrenergic agonist, norepinephrine, highlighting the ongoing search for alternatives to the negative chronotropic effects of phenylephrine. Indeed, norepinephrine use was associated with less bradycardia and consequently higher cardiac output, with no difference in blood pressure between the 2 treatment arms.41

The Bezold-Jarisch reflex has been proposed to explain perioperative hypotension associated with bradycardia.42 A rationale for the use of 5-HT3 antagonists to prevent Bezold-Jarisch reflex is based on chemoreceptors sensitive to 5-HT3; 5-HT3 agonists activate the reflex.5 Animal studies have demonstrated the effectiveness of 5-HT3 antagonists in blocking Bezold-Jarisch reflex.6

The effects of 5-HT3 antagonists in obstetric patients were moderate, as reflected by NNTs of 5.3 and 7.6 for the prevention of hypotension and bradycardia, respectively. Interestingly, George et al12 estimated that the NNT for prevention of nausea and vomiting in obstetric patients under spinal anesthesia are 8.6 and 11, respectively. Bonnet and colleagues11 found a NNT of 6 for the combined outcome postoperative nausea and vomiting.

We acknowledge several limitations of our study: First, heterogeneity in all our analyses was high with the exception of bradycardia. Funnel plots were indicative of publication bias. Differences in the spinal anesthesia technique, the fluid management, and the vasopressor used are other factors contributing to heterogeneity. Second, the definitions of hypotension varied across the studies included in our meta-analysis. The definition of hypotension affects the incidence3 and this makes it difficult to compare results. Third, definition of bradycardia was also different or was not even defined in some of the included studies. Fourth, there is a paucity of neonatal outcome data. Moreover, the data were obtained from healthy parturients with uncomplicated term pregnancies undergoing elective cesarean delivery. Our results, therefore, cannot be extrapolated to emergency delivery and compromised fetuses.

While our manuscript was under review, a similar meta-analysis43 was published. Gao et al43 included 10 studies (6 obstetric, 4 non-obstetric) reporting on 863 patients receiving prophylactic ondansetron. However, there are several major differences between the report by Gao et al43 and our study. The meta-analysis by Gao et al43 did not include 5 studies14,16,18,19,25 that we included. A study29 that had methodological flaws (no patient blinding) was included by Gao et al43 but excluded by us. Our meta-analysis included sophisticated tools to evaluate publication bias and a meta-regression to study dose-responsiveness. However, our results largely confirm those of Gao et al.43

The heterogeneity was high in many analyses and funnel plots were performed in the study by Gao et al43 and in our study. However, funnel plot asymmetry can be caused by reasons other than publication bias. We, therefore, added contour-enhanced funnel plots that are more specific for the evaluation of publication bias. We also performed a sensitivity analysis of trials that hypotension had as a primary outcome.

Taken together, our results suggest that 5-HT3 antagonists have an effect in preventing hypotension and bradycardia when analyzing obstetric trials alone or when combining obstetric and non-obstetric surgery trials. Ondansetron was the most frequently used substance in the trials; it remains unclear whether the effects seen in our study are specific for this drug only or for all 5-HT3 antagonists. Only when trials of 4 mg ondansetron were excluded from the analysis was significant effect observed. In the trials entered in our meta-analysis, 5-HT3 antagonists were studied prophylactically. We suggest that these drugs should be studied for the treatment of hypotension.

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DISCLOSURES

Name: Michael Heesen, MD, PhD.

Contribution: This author was responsible for study design, literature search, data extraction, quality analysis of the retrieved trials, meta-analysis, interpretation of results, writing of the manuscript.

Name: Markus Klimek, MD, PhD, DEAA, EDIC.

Contribution: This author was responsible for literature search, data extraction, writing of the manuscript.

Name: Sanne E. Hoeks, MD, PhD.

Contribution: This author was responsible for meta-analysis (Contour-enhanced funnel plots), interpretation of results, writing of manuscript (revised version).

Name: Rolf Rossaint, MD, PhD.

Contribution: This author was responsible for study design, interpretation of results, writing of the manuscript.

This manuscript was handled by: Cynthia A. Wong, MD.

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