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Original Research: Critical Care |

Single-Dose Etomidate Does Not Increase Mortality in Patients With SepsisEtomidate on Mortality in Patients With Sepsis: A Systematic Review and Meta-analysis of Randomized Controlled Trials and Observational Studies FREE TO VIEW

Wan-Jie Gu, MSc; Fei Wang, MD; Lu Tang, MD; Jing-Chen Liu, MD
Author and Funding Information

From the Department of Anaesthesiology (Mr Gu and Dr Liu), First Affiliated Hospital of Guangxi Medical University, Nanning; and Department of Anaesthesiology (Drs Wang and Tang), General Hospital of Jinan Military Command, Jinan, China.

CORRESPONDENCE TO: Jing-Chen Liu, MD, Department of Anaesthesiology, First Affiliated Hospital of Guangxi Medical University, 22 Shuangyong Rd, Nanning 530021, China; e-mail: jingchenliu1964@sina.cn


FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(2):335-346. doi:10.1378/chest.14-1012
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BACKGROUND:  The effect of single-dose etomidate on mortality in patients with sepsis remains controversial. We systematically reviewed the literature to investigate whether a single dose of etomidate for rapid sequence intubation increased mortality in patients with sepsis.

METHODS:  PubMed, Embase, and CENTRAL (Cochrane Central Register of Controlled Trials) were searched for randomized controlled trials (RCTs) and observational studies regarding the effect of single-dose etomidate on mortality in adults with sepsis. The primary outcome was all-cause mortality. The Mantel-Haenszel method with random-effects modeling was used to calculate pooled relative risks (RRs) and 95% CIs.

RESULTS:  Eighteen studies (two RCTs and 16 observational studies) in 5,552 patients were included. Pooled analysis suggested that single-dose etomidate was not associated with increased mortality in patients with sepsis in both the RCTs (RR, 1.20; 95% CI, 0.84-1.72; P = .31; I2 = 0%) and the observational studies (RR, 1.05; 95% CI, 0.97-1.13; P = .23; I2 = 25%). When only adjusted RRs were pooled in five observational studies, RR for mortality was 1.05 (95% CI, 0.79-1.39; P = .748; I2 = 71.3%). These findings also were consistent across all subgroup analyses for observational studies. Single-dose etomidate increased the risk of adrenal insufficiency in patients with sepsis (eight studies; RR, 1.42; 95% CI, 1.22-1.64; P < .00001).

CONCLUSIONS:  Current evidence indicates that single-dose etomidate does not increase mortality in patients with sepsis. However, this finding largely relies on data from observational studies and is potentially subject to selection bias; hence, high-quality and adequately powered RCTs are warranted.

Figures in this Article

In patients with sepsis, endotracheal intubation is a common and important procedure to secure the airway and guarantee sufficient ventilation. However, it can lead to life-threatening complications because of the vulnerable hemodynamic status of patients with sepsis.1 To avoid such complications, rapid sequence intubation with administration of an induction agent frequently is required. Etomidate often is used as an induction drug for rapid sequence intubation because it allows for a rapid, smooth, and hemodynamically stable procedure.2 However, etomidate inhibits adrenal mitochondrial 11-β-hydroxylase activity and can cause reversible adrenal insufficiency,3,4 which may restrict its use in patients with sepsis who are prone to relative adrenal insufficiency.5

Although there is no controversy about etomidate causing adrenal insufficiency, the effect of etomidate on mortality in sepsis remains an issue.6 So far, studies reporting the effect of etomidate on mortality in sepsis have conveyed conflicting results. Furthermore, due to small sample sizes, these studies were not adequately powered to detect the effect of etomidate on mortality in patients with sepsis. Thus, to provide the latest and most convincing evidence, we systematically reviewed the current available literature to investigate whether single-dose etomidate increases mortality in patients with sepsis. The secondary objective was to evaluate the effect of single-dose etomidate on adrenal insufficiency, length of hospital and ICU stay, and duration of mechanical ventilation (MV).

Literature Search and Selection Criteria

This systematic review and meta-analysis was conducted and reported in adherence to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).7 PubMed, Embase, and CENTRAL (Cochrane Central Register of Controlled Trials) were searched for records reporting the effect of single-dose etomidate on mortality in patients with sepsis. The search strategy is shown in Table 1. No language restriction was imposed. The last search was run on July 16, 2014. Two independent investigators carried out the initial search, deleted duplicate records, screened the titles and abstracts for relevance, and identified each as excluded or requiring further assessment. We reviewed the full-text articles designated for inclusion and manually checked the references of the retrieved articles and previous reviews to identify additional eligible studies.

Table Graphic Jump Location
TABLE 1 ]  Search Strategy

Studies meeting the following criteria were included: (1) population: adult patients with sepsis, severe sepsis, or septic shock; (2) intervention: single-dose etomidate; (3) comparison: other sedatives or no agent; (4) outcome: mortality (either hospital or 28-day); and (5) design: randomized controlled trials (RCTs) and observational studies (prospective or retrospective cohort studies). Agreement regarding study inclusion was assessed using the Cohen κ statistic.8

Data Extraction and Quality Assessment

Data extraction was performed by L. T. and confirmed independently by F. W. The following information was extracted from each study: first author, year of publication, country, study design, patient characteristics, number of patients enrolled, intervention, and outcome data (mortality, adrenal insufficiency, length of hospital stay, length of ICU stay, and duration of MV). When the same patients were reported in several publications, we retained only the largest study to avoid duplication of information. Extracted data were entered into a standardized Excel (Microsoft Corporation) file. Discrepancies were resolved by discussion between the two investigators. The primary outcome was all-cause mortality. Secondary outcomes were adrenal insufficiency, length of hospital and ICU stay, and duration of MV. The Cochrane risk of bias tool was adopted to assess the risk of bias for each RCT.9 Observational studies were evaluated using the Newcastle-Ottawa Scale.10

Statistical Analysis

Data were analyzed separately for RCTs and observational studies. Differences were expressed as relative risk (RR) with 95% CI. Heterogeneity across studies was tested with the I2 statistic, which is a quantitative measure of inconsistency across studies. Studies with an I2 statistic of 25% to 50% were considered to have low heterogeneity, those with an I2 statistic of 50% to 75% were considered to have moderate heterogeneity, and those with an I2 statistic of > 75% were considered to have high heterogeneity. I2 > 50% indicates significant heterogeneity.11 The Mantel-Haenszel method with random-effects modeling was used to calculate pooled RRs and 95% CIs.

Post hoc analysis of RCTs was considered equivalent to observational studies. In addition, subgroup analyses for observational studies were conducted according to study design (post hoc analysis of RCTs vs cohort studies), population (sepsis vs severe sepsis or septic shock), setting (single center vs multicenter), mortality end point (28-day vs hospital), sample size (≥ 500 vs < 500), and region (North America vs Europe vs Asia). The subgroup analyses were performed only for mortality due to small numbers of studies for other outcomes. We also investigated the influence of a single study on the overall pooled estimate by omitting one study in each turn for observational studies.

Publication bias was assessed by visually inspecting a funnel plot in which the log RRs were plotted against their SEs. The presence of publication bias was also evaluated by using the Begg and Egger tests.12,13P < .05 was considered statistically significant, except where otherwise specified. All statistical analyses were performed using Stata 12.0 (StataCorp LP) and RevMan 5.2 (Nordic Cochrane Centre).

Study Identification and Selection

A total of 424 records were identified from the initial database search. Ninety-eight records were excluded for duplicates, and 306 records were excluded for various reasons based on the titles and abstracts (reviews, letters, animal studies, or irrelevant to the analysis). The remaining 20 full-text articles were assessed for eligibility, and two were excluded because they focused on children.14,15 Finally, 18 studies were included in the meta-analysis.1633 The selection process is shown in Figure 1. The Cohen κ statistic for agreement on study inclusion was 0.91.

Figure Jump LinkFigure 1 –  Selection process for the studies included in the meta-analysis.Grahic Jump Location
Study Characteristics

The main characteristics of the included studies are shown in Table 2, and the outcome data of each included study are shown in Table 3. These studies were published between 2002 and 2014. The sample size ranged from 62 to 2,014 (total, 5,552; etomidate group, 2,801; other sedative group, 2,751). Of the included studies, two were RCTs,16,17 three were post hoc analyses of RCTs,1820 and 13 were cohort studies2133 (10 retrospective studies,21,22,24,25,27,28,3033 three prospective studies23,26,29). Among the 18 studies, 10 were conducted in North America,17,21,2528,3033 six in Europe,16,18,19,22,23,29 and two in Asia.20,24 Seven studies were multicenter studies.16,18,19,28,3032 All studies were published in English. Etomidate was compared with midazolam in two studies17,24 and with ketamine in one study,16 and the other studies did not specify the comparative sedatives.1823,2533 The subject population varied across studies as follows: Six included patients with sepsis,16,17,25,26,30,32 nine included patients with septic shock,1823,29,31,33 and three included patients with severe sepsis and septic shock.24,27,28 Five studies provided adjusted RRs for mortality, accounting for confounders.19,27,2931

Table Graphic Jump Location
TABLE 2 ]  Characteristics of Included Studies

Data are presented as median (interquartile range) or mean ± SD unless otherwise indicated. APACHE = Acute Physiology and Chronic Health Evaluation; NR = not reported; RCT = randomized controlled trial; SAPS = Simplified Acute Physiology Score; SOFA = Sequential Organ Failure Assessment.

a 

Median (range).

b 

Only mean available.

Table Graphic Jump Location
TABLE 3 ]  Outcome Data of Included Studies

Data are presented as proportion, median (interquartile range), or mean ± SD unless otherwise indicated. P values are from publication. AI = adrenal insufficiency; NS = not significant. See Table 2 legend for expansion of other abbreviations.

a 

95% CI.

b 

Only mean available.

Quality Assessment

Risk of bias assessment of the included studies is presented in Tables 4 and 5. Both RCTs16,17 generated an adequately randomized sequence, were conducted in a blinded fashion, reported the numbers and reasons for withdrawal or dropout, and were free of other bias. The allocation sequence concealment was not reported in the study by Tekwani et al.17 Based on the Newcastle-Ottawa Scale to assess the risk of bias of the cohort studies, 10 studies1923,2527,29,32 were rated as a total score of > 5 and five studies24,28,30,31,33 as a score of ≤ 5, indicating a high risk of bias.

Table Graphic Jump Location
TABLE 4 ]  Risk of Bias Assessment of the Randomized Controlled Trials

Risk of bias was assessed using the Cochrane risk of bias tool.

Table Graphic Jump Location
TABLE 5 ]  Risk of Bias Assessment of the Observational Studies

Risk of bias was assessed using the Newcastle-Ottawa Scale. A higher overall score corresponds to a lower risk of bias; a score of ≤ 5 (out of 9) indicates a high risk of bias.

Primary Outcome: All-Cause Mortality
Randomized Controlled Trials:

When only data collected from RCTs16,17 were pooled (Fig 2), no statistically significant higher mortality was associated with single-dose etomidate administration in patients with sepsis (RR, 1.20; 95% CI, 0.84-1.72; P = .31). There was no evidence of heterogeneity (I2 = 0%).

Figure Jump LinkFigure 2 –  Effect of single-dose etomidate on mortality in patients with sepsis. df = degrees of freedom; M-H = Mantel-Haenszel.Grahic Jump Location
Observational Studies:

Within observational studies1833 (Fig 2), single-dose etomidate was not associated with increased mortality in patients with sepsis (RR, 1.05; 95% CI, 0.97-1.13; P = .23). There was evidence of low heterogeneity (I2 = 25%). Further exclusion of any single study did not materially alter the overall combined RR, with a range from 1.02 (95% CI, 0.96-1.08) to 1.06 (95% CI, 0.97-1.16).

When only adjusted RRs were pooled in five observational studies,19,27,2931 RR for mortality was 1.05 (95% CI, 0.79-1.39; P = .748; I2 = 71.3%). The results also were consistent across all subgroup analyses for observational studies, as shown in Table 6.

Table Graphic Jump Location
TABLE 6 ]  Subgroup Analyses for Mortality in Observational Studies

RR = relative risk. See Table 2 legend for expansion of other abbreviation.

Secondary Outcomes

Eight of the included studies provided data for adrenal insufficiency.16,18,19,21,23,24,27,31 Single-dose etomidate increased the risk of adrenal insufficiency in patients with sepsis (RR, 1.42; 95% CI, 1.22-1.64; P < .00001) (Fig 3). Table 3 outlines data of length of hospital stay, length of ICU stay, and duration of MV. Original publications suggested that single-dose etomidate had no effects on these outcomes. Due to limited available data, pooled analyses for these outcomes were not conducted.

Figure Jump LinkFigure 3 –  Effect of single-dose etomidate on adrenal insufficiency in patients with sepsis. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
Publication Bias

For the meta-analysis of single-dose etomidate on all-cause mortality, there was no evidence of significant publication bias by inspection of the funnel plot and formal statistical tests (Egger test, P = .917; Begg test, P = .363) (Fig 4).

Figure Jump LinkFigure 4 –  Funnel plot for mortality in patients with sepsis. RCT = randomized controlled trial; RR = relative risk.Grahic Jump Location
Main Finding

The present systematic review and meta-analysis identified two RCTs and 16 observational studies investigating the effect of single-dose etomidate for rapid sequence intubation on mortality in patients with sepsis. The analysis showed that single-dose etomidate did not increase mortality in patients with sepsis, both in RCTs and in observational studies. Moreover, these findings were consistent across adjusted analyses, in the influence analysis, and across all subgroup analyses for observational studies.

Comparison With Previous Studies

Differences between the current meta-analysis and previous meta-analyses should be noted. A meta-analysis by Chan et al34 included one prospective cohort study26 and four “RCTs”16,17,19,20 in 865 patients and concluded that single-dose etomidate was associated with an increased mortality in patients with sepsis. Of note, two included studies19,20 were not RCTs but rather post hoc analyses of RCTs. It may be improper to directly consider these two studies as RCTs. In another meta-analysis focusing on critically ill patients, Albert et al35 also concluded that single-dose etomidate was associated with an increased mortality in patients with sepsis. The result was based on a subgroup analysis of seven studies and an improper fixed-effects model of Mantel-Haenszel due to significant heterogeneity (I2 = 75%). If adopting an appropriate random-effects model, no significant association is detected between single-dose etomidate and mortality in patients with sepsis (RR, 1.12; 95% CI, 0.91-1.38; P = .29). Overall, both previous meta-analyses had obvious flaws that might threaten the authenticity of their findings. After the two meta-analyses, several studies investigating single-dose etomidate in patients with sepsis were published. The present updated meta-analysis included 18 studies in 5,552 patients, and the data were from RCTs, post hoc analyses of RCTs, and prospective and retrospective cohort studies. In contrast with the previous meta-analyses, the present one suggests that single-dose etomidate is not associated with an increased mortality in patients with sepsis. Moreover, adjusted analyses, influence analysis, and all subgroup analyses for observational studies did not materially alter the pooled result, which added robustness to the main findings.

It is well-known that etomidate suppresses adrenal steroidogenesis for at least 24 to 48 h through the inhibition of 11-β-hydroxylase, even after a single dose.3 In a retrospective study of 152 patients with septic shock, the incidence of an inadequate response to corticotropin in patients receiving etomidate was significantly higher than in those who had not received etomidate (76% vs 51%, P < .01).21 Consistent with the meta-analysis by Chan et al,34 the present one also suggests that single-dose etomidate for intubation was associated with a higher risk of adrenal insufficiency in patients with sepsis. It would be logical for clinicians to assume that concurrent administration of corticosteroids could counterbalance this effect. However, supplementing hydrocortisone to compensate for the adrenal-suppressive effects of single-dose etomidate on outcomes did not seem to work, as shown in a subanalysis of the Corticosteroid Therapy of Septic Shock (CORTICUS) study wherein concurrent hydrocortisone administration did not change the mortality of patients with septic shock (45% vs 40%).19 An RCT was conducted to specifically address this question for critically ill patients.36 After single-dose etomidate for endotracheal intubation, patients were randomized to receive a 42-h continuous infusion of hydrocortisone 200 mg/d or saline, and no significant difference in 28-day mortality was detected.

A prospective study by Molenaar et al37 demonstrated that single-dose etomidate may attenuate stimulated more than basal cortisol synthesis and only partly contribute to adrenal dysfunction in the stressed patient with sepsis. Concurrent administration of opioids and benzodiazepines in these patients could induce adrenal insufficiency because of reduced secretion of adrenocorticotropic hormone.38 Considering that adrenal insufficiency might be a predictor of mortality in patients with sepsis,39 it was reasonable to infer that hydrocortisone therapy might improve survival of these patients. However, the latest meta-analysis of RCTs demonstrated that low-dose hydrocortisone therapy did not reduce 28-day mortality in patients with septic shock, although it attenuated septic shock at 7 and 28 days.40 Consequently, corticosteroids should be reserved for refractory shock independent of etomidate use in patients with sepsis. In this context, the efficacy of corticosteroids may be related to enhancing the hemodynamic response to norepinephrine rather than to mitigating etomidate-related 11-β-hydroxylase inhibition.

Several potential limitations should be taken into consideration when interpreting the present results. First, among the 18 included studies, only two were small RCTs, whereas the other 16 were observational studies. Observational studies are highly subject to selection bias and confounding by indication. Of the observational studies included in the present meta-analysis,1833 10 reported no significant difference in the baseline characteristics between the etomidate and control groups,18,2026,28,33 one used propensity-matched analysis to compare the etomidate and control groups,32 and the remaining five provided adjusted RRs to account for confounders.19,27,2931 Second, although no significant heterogeneity was found for the primary outcome, population characteristics, severity of illness, and type of comparative sedatives varied across the included studies. To examine the influence of these clinical factors on the overall pooled estimate and to verify the robustness of the findings, subgroup analyses were conducted and the results found consistent, which added robustness. Third, we were unable to assess the impact of single-dose etomidate on other clinically meaningful end points, such as length of hospital stay, length of ICU stay, and duration of MV, due to sparse and inconsistent reporting across studies.

In conclusion, the present systematic review and meta-analysis suggests that single-dose etomidate is not associated increased mortality in patients with sepsis. Etomidate may remain an acceptable option for rapid sequence intubation in patients with sepsis; however, the finding largely relies on data from observational studies, is potentially subject to selection bias, and should be interpreted cautiously. Hence, high-quality and adequately powered RCTs are warranted.

Author contributions: J.-C. L. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. W.-J. G. contributed to the study concept and design, data acquisition and interpretation, and drafting and final approval of the manuscript; F. W. and L. T. contributed to the data acquisition, data analysis and interpretation, and revision and final approval of the manuscript; and J.-C. L. contributed to the study concept and design, data analysis and interpretation, drafting and revision of the manuscript, and final approval of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

MV

mechanical ventilation

RCT

randomized controlled trial

RR

relative risk

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Figures

Figure Jump LinkFigure 1 –  Selection process for the studies included in the meta-analysis.Grahic Jump Location
Figure Jump LinkFigure 2 –  Effect of single-dose etomidate on mortality in patients with sepsis. df = degrees of freedom; M-H = Mantel-Haenszel.Grahic Jump Location
Figure Jump LinkFigure 3 –  Effect of single-dose etomidate on adrenal insufficiency in patients with sepsis. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4 –  Funnel plot for mortality in patients with sepsis. RCT = randomized controlled trial; RR = relative risk.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Search Strategy
Table Graphic Jump Location
TABLE 2 ]  Characteristics of Included Studies

Data are presented as median (interquartile range) or mean ± SD unless otherwise indicated. APACHE = Acute Physiology and Chronic Health Evaluation; NR = not reported; RCT = randomized controlled trial; SAPS = Simplified Acute Physiology Score; SOFA = Sequential Organ Failure Assessment.

a 

Median (range).

b 

Only mean available.

Table Graphic Jump Location
TABLE 3 ]  Outcome Data of Included Studies

Data are presented as proportion, median (interquartile range), or mean ± SD unless otherwise indicated. P values are from publication. AI = adrenal insufficiency; NS = not significant. See Table 2 legend for expansion of other abbreviations.

a 

95% CI.

b 

Only mean available.

Table Graphic Jump Location
TABLE 4 ]  Risk of Bias Assessment of the Randomized Controlled Trials

Risk of bias was assessed using the Cochrane risk of bias tool.

Table Graphic Jump Location
TABLE 5 ]  Risk of Bias Assessment of the Observational Studies

Risk of bias was assessed using the Newcastle-Ottawa Scale. A higher overall score corresponds to a lower risk of bias; a score of ≤ 5 (out of 9) indicates a high risk of bias.

Table Graphic Jump Location
TABLE 6 ]  Subgroup Analyses for Mortality in Observational Studies

RR = relative risk. See Table 2 legend for expansion of other abbreviation.

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