Postoperative nausea and vomiting (PONV) remains a common problem associated with general anesthesia, with reported incidences ranging from 10% to >80% in certain high-risk populations.1,2 Although both unpleasant and emotionally distressing to patients, PONV can also add substantial morbidity to an otherwise uneventful procedure.1 Nausea and vomiting not only impede successful discharge after ambulatory surgery but they can also significantly delay recovery after same-day admission procedures,2 an effect that can have greater implications in an era of growing interest in enhanced recovery after surgery bundles. Significant research has gone into identifying primary risk factors associated with PONV in adults and in establishing a multimodal approach for the prevention of PONV, including appropriate pharmacologic and nonpharmacologic interventions.3,4
Midazolam, a short-acting benzodiazepine, has been used widely for premedicating patients because of its anxiolytic quality. It has also been used as a coinduction agent for general anesthesia because of its amnestic and anesthetic properties. Several studies have investigated the ability of midazolam to reduce the incidence of PONV.5,6 However, published consensus guidelines to date have only made allusions to IV midazolam’s potential for preventing PONV rather than to formally recommend IV midazolam.3,4 This may be due in part to a perceived lack of quality data, as well as to controversy associated with the retraction of several significant studies devoted to the topic.7,8 In this review, we conducted a meta-analysis of available randomized controlled trials to evaluate the ability of IV midazolam to prevent PONV when administered in either the pre- or intraoperative periods for general anesthesia in the adult population.
In this study, we followed the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. We searched MEDLINE, EMBASE, and CINAHL for all available studies from the year 1971 onward, with updates to October 2014. Inclusion criteria included (1) population: studies involving adult (age >18 years) human patients undergoing surgery under general anesthesia; (2) intervention: IV midazolam administered in either the preoperative or the intraoperative period; (3) predefined outcomes: incidence of postoperative nausea, vomiting, nausea and vomiting, or provision of rescue antiemetics within the first 24 hours; (4) design: randomized controlled trials published in English, full-text versions. No minimum sample size was required for inclusion.
Two authors screened the titles and abstracts of initial search results, extracted data, and independently assessed for risk of bias. Disagreements were resolved by group consensus. Demographic and clinical data, including PONV end points, were extracted from qualified studies and subsequently analyzed. Risk of bias was assessed using the Cochrane Collaboration tool, which considers the following domains: adequacy of sequence generation, allocation concealment, blinding of participants, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other potential sources of bias. A Jadad score was also calculated for each individual trial using previously described methodology.9 Individual analyses were performed both including and excluding high risk of bias (Cochrane score < 4 or Jadad scale < 3) studies, and any potential influence on outcome was reported in the results.
The primary end point was the incidence of PONV within 24 hours of the completion of surgery. Secondary end points included the incidence of rescue antiemetic within 24 hours of surgery. Other side effects, including dizziness, headache, excessive postanesthesia care unit (PACU) sedation, and overall PACU stay time, were also examined when data were available. Subgroup analysis was also performed to assess the pooled effects of IV midazolam on postoperative PONV end points for (1) trials excluding the use of thiopental as an induction agent; (2) trials using IV midazolam as a part of a combination of antiemetics; (3) trials specific to maintenance anesthetic; (4) trials specific to sex; (5) trials specific to surgery type; and (6) timing and dosage of administration of medication. For dichotomous data, risk ratio (RR) was used to describe the size of the treatment effect and, for continuous data, weighted mean difference was used. A random effects model was used. Funnel plots of the incidence of various end points were used to visually assess for publication bias. The level of significance for the primary outcomes was set at a level of 0.05. All statistical analyses were performed with Review Manager (RevMan) 5.3 (The Cochrane Collaboration 2014). Heterogeneity was measured and expressed as I 2, which describes the percentage of total variation across studies that is due to heterogeneity rather than chance. I 2 was calculated from basic results obtained from a typical meta-analysis as I 2 = 100% × (Q − df)/Q, where Q is the Cochrane heterogeneity statistic. A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity.
The initial search resulted in 733 studies (362 from MEDLINE and 371 from EMBASE) that met the inclusion criteria. After removing 202 duplicate studies, 531 potentially relevant articles were screened based on the abstract. After removing 473 abstracts that did not meet the inclusion criteria, the remaining 58 full-text articles were thoroughly reviewed. An additional 46 articles were excluded on the following basis: no data on outcomes of interest, midazolam not used as primary intervention, primarily regional anesthesia technique used, and study retraction. Twelve randomized controlled trials (n = 841) were included in the final analysis (Fig. 1) comparing control (no midazolam; n = 363) to IV midazolam (n = 478).
Table 1 summarizes characteristics of the studies, including total patients, sex, surgery type, induction agents, medication timing, maintenance anesthetic, and follow-up parameters.10–21 No additional intraoperative antiemetics were provided unless otherwise specified in one of the arms of the included trials. Six studies compared normal saline controls with midazolam experimental arms. Four studies investigated a drug in the control arm to a combination of that drug and midazolam in the experimental arm. Two studies included 4 arms comparing both a normal saline control versus midazolam and drug X versus drug X + midazolam. These were subsequently treated as 2 individual comparison groups in the analysis.
Figure 2 shows the effect of IV midazolam on PONV, nausea, and vomiting within in the first 24 hours after surgery. The meta-analysis of these trials indicated that there was a significant decrease in PONV (RR = 0.55; 95% confidence interval [CI], 0.43–0.70; P < 0.0001), nausea (RR = 0.62; 95% CI, 0.40–0.94; P = 0.02), and vomiting (RR = 0.61; 95% CI, 0.45–0.82; P = 0.001) among patients receiving midazolam compared with control patients. Based on an overall relative risk reduction of approximately 50% and a patient expected event rate of 50% to 60%, we calculate a number needed to treat between 3.6 and 4.0 patients to derive benefit from administration of IV midazolam.
IV midazolam was associated with a significant decrease in the requirement for rescue antiemetic (Fig. 3; RR = 0.49; 95% CI, 0.37–0.65; P < 0.0001) compared with controls. In addition, there was no significant difference between groups in the overall incidence of reported headache (RR = 0.85; 95% CI, 0.45–1.60; P = 0.62), dizziness (RR = 0.97; 95% CI, 0.56–1.67; P = 0.71), or length of PACU stay in minutes (mean difference = 0.74; 95% CI −1.38 to 2.86; P = 0.49). There was also no difference between groups in the incidence of significant sedation (RR = 1.91; 95% CI, 0.58–6.25; P = 0.29), an end point reported in 7 studies. Included studies exhibited no significant heterogeneity.
Exclusion of Thiopental Induction
Table 2 illustrates the pooled effect of IV midazolam on PONV excluding studies that use thiopental for the induction of anesthesia. Administration of midazolam is associated with significant reduction in PONV, nausea, vomiting, and provision of rescue antiemetics within 24 hours of surgery compared with controls.
When reviewing the use of IV midazolam as the sole antiemetic (compared with normal saline control) versus the use of IV midazolam as part of a combination of multimodal antiemetics (compared with a known antiemetic), midazolam is shown to significantly reduce the incidence of PONV, nausea, vomiting, and provision of rescue antiemetics within 24 hours of surgery compared with normal saline controls. Midazolam, when included as part of a combination with a known antiemetic, is shown to significantly reduce the incidence of PONV, nausea, vomiting, and provision of rescue antiemetics within 24 hours when compared with a single agent antiemetic alone.
Uniform Maintenance Anesthetic
A pooled analysis was performed for all cases involving the use of a combined nitrous oxide and inhaled fluorinated agent for the maintenance of anesthesia. IV midazolam was associated with a significant reduction in all PONV end points within 24 hours of surgery compared with control.
A subgroup analysis of studies performed only on female patients showed that IV midazolam was associated with a significantly lower incidence of 24-hour PONV. In addition, IV midazolam administration among female patients was associated with significantly reduced incidence of nausea, vomiting, and requirement for antiemetics within 24 hours compared with control.
Analysis of studies involving high-risk surgeries, including middle ear, thyroidectomy, laparoscopic, and gynecological surgeries, revealed that IV midazolam was associated with a significantly lower incidence of 24-hour PONV. Similar findings were noted for 24-hour nausea, vomiting, and antiemetic requirement. There was no significant heterogeneity in the included studies.
Timing and Dose of Drug Administration
Bolus dose administration of IV midazolam in the preoperative period (RR = 0.51; 95% CI, 0.34–0.77; P = 0.001; Pfor heterogeneity = 0.50, I 2 = 0%), at induction (RR = 0.60; 95% CI, 0.41–0.89; P = 0.01; P for heterogeneity = 0.55, I 2 = 0%), and at the end of surgery (RR = 0.51; 95% CI, 0.33–0.81; P = 0.004; P for heterogeneity = 0.15, I 2 = 48%) were all associated with significantly lower incidences of PONV within 24 hours of surgery. Both lower dose (<0.05 mg/kg) and higher dose (≥0.075 mg/kg) resulted in similar efficacy in reducing PONV within 24 hours (RR = 0.42; 95% CI, 0.19–0.92; P = 0.03; P for heterogeneity = 0.03; I 2 = 72% and RR = 0.54; 95% CI, 0.38–0.75; P = 0.0003; P for heterogeneity = 0.62; I 2 = 0%, respectively).
Based on the pooled results of this review, the preoperative and intraoperative administration of IV midazolam is associated with reduced PONV and rescue antiemetic administration in the initial 24 hours after surgery. We further sought to address several subgroups, including pooled analysis of trials involving thiopental induction, nitrous oxide maintenance anesthetic, and high-risk populations. IV midazolam was associated with significant reduction in PONV end points across all these included subgroups in the initial 24 hours.
Although the results of the primary analysis are encouraging, there is potential for confounding when pooling data from studies that use different induction agents and maintenance anesthetics, given their variable emetogenic potential.3,4 After excluding trials that use thiopental for the induction of anesthesia, IV midazolam is still shown to provide antiemetic efficacy. Furthermore, when accounting for only trials using nitrous oxide plus inhaled fluorinated agent for maintenance anesthesia, we note similar findings. Among studies that included only females and notable high-risk surgical types (e.g., head, neck, gynecological, and laparoscopic), IV midazolam remains effective. These results are encouraging, in that they suggest that a wide range of patients undergoing a variety of surgical case types and anesthetic plans would directly benefit from low-dose IV midazolam.
Just as important, these high-risk populations are more likely to be targeted for a comprehensive approach to prevent PONV. With that in mind, a subgroup analysis of studies that use IV midazolam as part of a combination therapy showed increased efficacy over single-agent therapy alone. As multiple consensus guidelines have suggested,3,4 the use of a multimodal approach to prevent PONV is key, and these data would suggest that it is reasonable to include IV midazolam as part of that approach.
Despite the potential benefits of midazolam, providers may continue to have reservations of using it because of the concern for central nervous system side effects such as excessive postoperative sedation or cognitive delay. According to our results, the incidence of headache, dizziness, and reported PACU recovery times were not affected by administration of IV midazolam. Furthermore, although at least 2 studies noted an increase in early postoperative sedation,21,22 the effect was short-lived and was not found to be statistically significant when the pooled data were evaluated. Although other studies have linked the use of midazolam premedication to either impaired performance on early cognitive testing in the recovery room10 or prolonged PACU stay times23 in isolation, a prior systematic review did not show an association between midazolam administration and delayed postoperative recovery.24 This is consistent with our findings as well.
One explanation for the low incidence of side effects is relatively low target drug dosing in virtually all included studies. Although further work is required to identify consistent dosing regimens, the majority of the included studies in this analysis used single bolus dosing, which ranged from either a 2-mg dose to 0.04 to 0.075 mg/kg (2.8–5.25 mg in a 70-kg patient) with good effect. Although we examined the pooled effects of lower and higher dose midazolam, we did not note an appreciable difference in PONV efficacy. It is therefore likely that PONV can be prevented at subhypnotic doses (<0.05 mg/kg) without potentiating many of the less desirable effects of central nervous system during the recovery period.
Given the short-acting sedating effects of midazolam, one might expect that the timing of midazolam administration at the conclusion of surgery would be optimal. Interestingly, our study showed similar 24-hour efficacy across at least 3 time points, including administration of the drug in the preoperative period. Our findings coincide with those of another study that suggested that the antiemetic effect of midazolam may outlast its sedation profile for a period of up to 24 hours.25 This may be due in part to the potential for midazolam to act on multiple receptor types and exert clinical effects through alternative mechanisms. The mechanism of action of midazolam in preventing PONV is as yet uncertain. Competing theories include inhibition of dopamine release in the chemoreceptor trigger zone, either through adenosine as an intermediary or via direct antagonism versus inhibition of γ-amino butyric acid.26,27 Others have supported the potential for IV midazolam to reduce postoperative opioid requirements, which may in turn lessen the nidus for nausea.28–30 Regardless, the clinical implication of this long-lasting effect should not be overlooked. It would therefore be reasonable to continue to use midazolam as premedication to maximize both anxiolytic and antiemetic benefits.
This review was limited to the preoperative and intraoperative use of IV midazolam associated with general anesthesia in adults. It remains unclear if oral or intramuscular preparations convey similar benefit. Furthermore, our review was not designed to assess monitored anesthesia care with sedation, regional/neuraxial anesthetics, or pediatric populations. Other studies have been devoted to these topics separately.31–33 We also are unable to comment on the efficacy of midazolam in the postoperative period, although other studies suggest further benefit postoperatively as well.25,26,34 In addition, we cannot determine the efficacy of IV midazolam on postdischarge PONV.35 Last, there are few studies that directly compare known antiemetics and midazolam on their ability to prevent PONV. At least 2 studies have shown similar incidences of PONV when low-dose midazolam was compared directly with ondansetron,5,6 but additional work would add considerable depth to this topic area.
The results of this study support the use of IV midazolam as part of a multimodal approach to the prevention of PONV in adults who receive general anesthesia. In the perioperative setting, providers may consider midazolam premedication in subhypnotic doses not only for provision of anxiolysis but also for the prevention of PONV.
Name: Michael C. Grant, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Michael C. Grant approved the final manuscript.
Name: Jimin Kim, BS.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Jimin Kim approved the final manuscript.
Name: Andrew J. Page, MD.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Andrew J. Page approved the final manuscript.
Name: Deborah Hobson, BSN.
Contribution: This author helped design the study and conduct the study.
Attestation: Deborah Hobson approved the final manuscript.
Name: Elizabeth Wick, MD.
Contribution: This author helped design the study and conduct the study.
Attestation: Elizabeth Wick approved the final manuscript.
Name: Christopher L. Wu, MD.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
Attestation: Christopher L. Wu approved the final manuscript.
This manuscript was handled by: Tong J. Gan, MD.
The authors thank Blair Anton, Associate Director for Informationist Services of the William H. Welch Medical Library, for literature search assistance and Dr. Seied Heidari and Dr. Mahmood Saghaei for assistance in primary full-text acquisition.
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