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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

The effect of a bolus dose of etomidate on cortisol levels, mortality, and health services utilization: a systematic review

CM Hohl, CH Kelly-Smith, TC Yeung, DD Sweet, MM Doyle-Waters, and M Schulzer.

Review published: 2010.

Link to full article: [Journal publisher]

CRD summary

This generally well-conducted review concluded that the evidence suggested etomidate suppressed adrenal function transiently without demonstrating a significant effect on mortality during rapid-sequence intubation of critically-ill patients; however, studies were not adequately powered to detect an effect on mortality. Evidence appeared to support the authors’ conclusions, but the limited quality and variability of the included studies may undermine their reliability.

Authors' objectives

To compare the effect of a bolus dose of etomidate on cortisol levels, mortality and health service utilisation with other induction agents during rapid sequence intubation.

Searching

Ten databases including MEDLINE, EMBASE, CINAHL, LILACS and the Cochrane Library were searched to June 2008. Search terms were reported; no language filters were used in these searches. Twelve named journals and relevant conference proceedings were handsearched from 1997 to 2008. Sources of grey literature were searched, including the clinical trial registries Websites Current Controlled Trials, National Health Service-The National Research Register, ClinicalTrials.gov. Google, websites of manufacturers of intravenous induction agents and relevant professional societies were also searched. Unreported data was requested from authors of all ongoing trials. Experts in the field were contacted. Reference lists of all relevant retrieved articles were screened.

Study selection

Studies were eligible if they compared the effect of a bolus dose of etomidate with another currently-used rapidly-acting intravenous induction agent for rapid sequence induction of adults (aged over 16 years). Studies had to assess either the primary outcome (mean difference in serum cortisol) or a secondary outcome (odds of death or mean differences in the number of days in intensive care unit, on ventilator support, or in hospital). Studies were excluded if they evaluated etomidate infusions or included only patients receiving exogenous steroids. Studies were only included if they were written in English, French or German.

All of the included studies used etomidate in doses of 0.2 to 0.4mg/kg; most used 0.3mg/kg. Comparator interventions were standard intubating doses of thiopental, methohexitol, propofol, ketamine and benzodiazepines (including small doses of midazolam) with and without narcotics. Most studies were of patients undergoing elective general anaesthesia; others were in critically-ill patients. Where reported, patients were American Society of Anesthesiologists (ASA) grades 1to 4. Most studies were set in operating theatres; others were set in emergency departments, intensive care units or out of hospital.

Two reviewers independently selected studies and resolved disagreements through discussion.

Assessment of study quality

Two authors independently scored the quality of randomised controlled trials (RCTs) using the 5-point Jadad scale; RCTs scoring 1 to 3 were classified as low-quality and RCTs scoring 4 or 5 were classified as high-quality. The quality of non-randomised studies was assessed by rating the potential for selection, performance, attrition and detection bias. Disagreements were resolved by consensus.

Data extraction

Mean differences with 95% confidence intervals (CIs) were calculated for continuous data; odds ratios (ORs) with 95% confidence intervals were calculated for dichotomous data. Where required, authors of primary studies were contacted for missing data.

Two reviewers independently extracted data from English language studies. Disagreements were resolved by consensus. One reviewer extracted data from studies written in French and German.

Methods of synthesis

Data were pooled using a random-effects model where four or more studies of the same design and comparable populations measured the same outcome measure. Interventions were compared at various time intervals; changes from baseline at successive points were combined statistically. Pooled odds ratios and pooled mean differences (MDs) were calculated with 95% confidence intervals. Statistical heterogeneity was assessed using the Cochran Q test.

Sensitivity analysis was conducted by separately analysing studies with etomidate dose lower than usual (<0.3mg/kg) and greater than usual (>0.35 mg/kg).

Results of the review

The review included 18 RCTs (n=951 patients), one non-randomised prospective study (n=106 patients) and one retrospective study (n=159 patients). Jadad scores for RCTs ranged from 1 to 5; 14 RCTs scored 1 or 2 points, two scored 3 points and two scored 4 or 5 points. Two non-RCTs were at moderate to high risk of selection, performance and attrition bias, but at low risk for detection bias.

Cortisol levels (16 RCTs): Fourteen RCTs reported depressed cortisol levels post-induction with etomidate. Nine RCTs could be pooled.

For patients who were undergoing elective surgery and were graded ASA grade 1 or 2 (nine RCTs, n=201 patients), etomidate was associated with a significantly lower cortisol level than comparator groups at one hour (MD 6.1μg/dL, 95% CI 2.4 to 9.9), two hours (MD 13.3μg/dL, 95% CI 7.7 to 18.9), three hours (MD 12.6μg/dL, 95% CI 6.6 to 18.4) and four hours (MD 16.4μg/dL, 95% CI 9.7 to 23.1) after induction. There was no significant difference at five hours. Significant statistical heterogeneity was found (p<0.1) for all analyses. Grouping the trials by etomidate dose (lower and higher than standard doses) reduced the heterogeneity but did not significantly change results.

Three RCTs in elective patents that were not suitable for pooling showed consistent findings for cortisol in ASA I and III patients at or above baseline at seven and 12 hours post-induction.

It was not possible to pool data from four studies of critically-ill patients since studies assessed outcomes at different times. The largest RCT (n=655 patients with cortisol levels reported for 232) reported that etomidate was associated with significantly reduced cortisol levels compared with ketamine after a median of seven hours post-induction (16.0 versus 25.0μg/dL, p<0.001). Findings were similar in one of the three smaller RCTs at four to six hours; the other two RCTs reported no significant difference at 24 hours.

Mortality (six RCTs, one prospective observational study and one retrospective study): There was no significant difference in mortality between etomidate and comparator agents (five RCTs of 741 critically-ill patients).

Other outcomes: One of four RCTs reported that etomidate was associated with a longer period of ventilation, intensive care unit stay and hospital stay than comparator groups. One of three RCTs reported a longer hospital stay in the etomidate group.

Other results were also reported.

Authors' conclusions

Available evidence suggested that etomidate suppressed adrenal function transiently without demonstrating a significant effect on mortality. However, no studies to date have been adequately powered to detect a difference in mortality or hospital, ventilator or intensive care unit length of stay.

CRD commentary

The review question was clearly stated and inclusion criteria were appropriately defined. The search was extensive and included attempts to minimise publication bias. There were some language restrictions which raised the potential for language bias. Each stage of the process for English language papers was undertaken in duplicate, but the process for foreign language papers was not clear, so reviewer error and bias may have been introduced.

Study quality was assessed but only composite Jadad scores were reported, which made it difficult to adequately judge the quality of the evidence; most RCTs appeared to be of limited quality. It was appropriate to only pool clinically homogeneous studies, but there was still evidence of statistical heterogeneity for cortisol levels. A potential cause of heterogeneity was explored. Some limitations of the review were discussed. The review was generally well conducted.

Evidence appeared to support the authors’ conclusions, but the limited quality of the included studies and heterogeneity may undermine the reliability of the evidence.

Implications of the review for practice and research

Practice: The authors stated that a significant effect of etomidate on mortality could not be excluded. Data on prolonged adrenal suppression (from 12 to 48 hours post-induction) in critically-ill patients were limited, so a more prolonged effect cannot be ruled out in this population.

Research: The authors stated that there is a need for further research into the effect of etomidate on mortality.

Funding

Vancouver Coastal Health Research Institute.

Bibliographic details

Hohl CM, Kelly-Smith CH, Yeung TC, Sweet DD, Doyle-Waters MM, Schulzer M. The effect of a bolus dose of etomidate on cortisol levels, mortality, and health services utilization: a systematic review. Annals of Emergency Medicine 2010; 56(2): 105-113.e5. [PubMed: 20346542]

Indexing Status

Subject indexing assigned by NLM

MeSH

Anesthesia, Intravenous /methods /mortality; Anesthetics, Intravenous /pharmacology; Etomidate /administration & dosage /adverse effects /pharmacology; Hospital Mortality; Humans; Hydrocortisone /blood; Length of Stay /statistics & numerical data; Outcome Assessment (Health Care) /statistics & numerical data; Respiration, Artificial /statistics & numerical data

AccessionNumber

12010005871

Database entry date

21/09/2011

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 20346542

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