Review question
Does a single dose of etomidate increase mortality or complications in people who are critically ill and undergoing emergency endotracheal intubation?
Background
People who are critically ill often need help breathing. One way to do this is called endotracheal intubation. This involves placing a tube into the windpipe (trachea) and having a ventilator (breathing machine) help the patient breathe.
People are often given sedative agents during endotracheal intubation to make them unaware of the procedure. Many sedative agents cause a potentially harmful drop in blood pressure.
Etomidate is commonly used to sedate patients before endotracheal intubation because it has minimal effects on blood pressure. However, when someone is given etomidate their adrenal glands do not function as well. This may be harmful to them.
Study characteristics
We looked at the evidence up to February 2013 and found 1666 studies. We included eight studies in our review and seven studies (involving 772 patients) in our meta-analysis. The studies involved people who were in an unstable condition and critically ill. They were given one dose of etomidate or another sedative agent for endotracheal intubation. We reran the search in August 2014. We will deal with any studies of interest when we update the review.
Results
No strong evidence exists to suggest that etomidate, when compared to other bolus dose induction agents, increases mortality in critically ill patients. We must be careful in interpreting this finding because only large studies would be able to show a difference in mortality. So far, no such study has been completed.
Etomidate does seem to impair adrenal gland functioning. Functioning is impaired most between four and six hours after etomidate is given.
Sequential Organ Failure Assessment (SOFA) scores are used to find out how badly someone’s organs are failing. Using etomidate results in worse SOFA scores but this difference is small and not clinically meaningful.
The effects of impaired adrenal gland functioning and higher SOFA scores on people’s health is unknown. Using etomidate does not seem to increase the length of time someone is in hospital (including an intensive care unit), the length of time a person is connected to a mechanical ventilator (a machine to assist with breathing), or the use of vasopressors (medicines to increase blood pressure).
Quality of the evidence
Most of the evidence was moderate quality. This is mainly because some small studies we looked at did not check up on people adequately after they were intubated.
Most people that were involved in one study were intubated because they were in a coma. These people comprise 42% of those involved in the studies we looked at. People in a coma are unlike other critically ill people because they may not benefit to the same extent from having stable blood pressure during endotracheal intubation, which etomidate provides, nor are they at high risk from impaired adrenal gland function compared to other critically ill patients, for example those with severe infection.
Although we have not found conclusive evidence that etomidate increases mortality or healthcare resource utilization in critically ill patients, it does seem to increase the risk of adrenal gland dysfunction and multi-organ system dysfunction by a small amount. The clinical significance of this finding is unknown. This evidence is judged to be of moderate quality, owing mainly to significant attrition bias in some of the smaller studies, and new research may influence the outcomes of our review. The applicability of these data may be limited by the fact that 42% of the patients in our review were intubated for "being comatose", a population less likely to benefit from the haemodynamic stability inherent in etomidate use, and less at risk from its potential negative downstream effects of adrenal suppression.
The use of etomidate for emergency airway interventions in critically ill patients is very common. In one large registry trial, etomidate was the most commonly used agent for this indication. Etomidate is known to suppress adrenal gland function, but it remains unclear whether or not this adrenal gland dysfunction affects mortality.
The primary objective was to assess, in populations of critically ill patients, whether a single induction dose of etomidate for emergency airway intervention affects mortality.
The secondary objectives were to address, in populations of critically ill patients, whether a single induction dose of etomidate for emergency airway intervention affects adrenal gland function, organ dysfunction, or health services utilization (as measured by intensive care unit (ICU) length of stay (LOS), duration of mechanical ventilation, or vasopressor requirements).
We repeated analyses within subgroups defined by the aetiologies of critical illness, timing of adrenal gland function measurement, and the type of comparator drug used.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; CINAHL; EMBASE; LILACS; International Pharmaceutical Abstracts; Web of Science; the Database of Abstracts of Reviews of Effects (DARE); and ISI BIOSIS Citation indexSM on 8 February 2013. We reran the searches in August 2014. We will deal with any studies of interest when we update the review.
We also searched the Scopus database of dissertations and conference proceedings and the US Food and Drug Administration Database. We handsearched major emergency medicine, critical care, and anaesthesiology journals.
We handsearched the conference proceedings of major emergency medicine, anaesthesia, and critical care conferences from 1990 to current, and performed a grey literature search of the following: Current Controlled Trials; National Health Service – The National Research Register; ClinicalTrials.gov; NEAR website.
We included randomized controlled trials in patients undergoing emergency endotracheal intubation for critical illness, including but not limited to trauma, stroke, myocardial infarction, arrhythmia, septic shock, hypovolaemic or haemorrhagic shock, and undifferentiated shock states. We included single (bolus) dose etomidate for emergency airway intervention compared to any other rapid-acting intravenous bolus single-dose induction agent.
Refinement of our initial search results by title review, and then by abstract review was carried out by three review authors. Full-text review of potential studies was based on their adherence to our inclusion and exclusion criteria. This was decided by three independent review authors. We reported the decisions regarding inclusion and exclusion in accordance with the PRISMA statement.
Electronic database searching yielded 1635 potential titles, and our grey literature search yielded an additional 31 potential titles. Duplicate titles were filtered leaving 1395 titles which underwent review of their titles and abstracts by three review authors. Sixty seven titles were judged to be relevant to our review, however only eight met our inclusion criteria and seven were included in our analysis.
We included eight studies in the review and seven in the meta-analysis. Of those seven studies, only two were judged to be at low risk of bias. Overall, no strong evidence exists that etomidate increases mortality in critically ill patients when compared to other bolus dose induction agents (odds ratio (OR) 1.17; 95% confidence interval (CI) 0.86 to 1.60, 6 studies, 772 participants, moderate quality evidence). Due to a large number of participants lost to follow-up, we performed a post hoc sensitivity analysis. This gave a similar result (OR 1.15; 95% CI 0.86 to 1.53). There was evidence that the use of etomidate in critically ill patients was associated with a positive adrenocorticotropic hormone (ACTH) stimulation test, and this difference was more pronounced at between 4 to 6 hours (OR 19.98; 95% CI 3.95 to 101.11) than after 12 hours (OR 2.37; 95% CI 1.61 to 3.47) post-dosing. Etomidate's use in critically ill patients was associated with a small increase in SOFA score, indicating a higher risk of multisystem organ failure (mean difference (MD) 0.70; 95% CI 0.01 to 1.39, 2 studies, 591 participants, high quality evidence), but this difference was not clinically meaningful. Etomidate use did not have an effect on ICU LOS (MD 1.70 days; 95% CI -2.00 to 5.40, 4 studies, 621 participants, moderate quality evidence), hospital LOS (MD 2.41 days; 95% CI -7.08 to 11.91, 3 studies, 152 participants, moderate quality evidence), duration of mechanical ventilation (MD 2.14 days; 95% CI -1.67 to 5.95, 3 studies, 621 participants, moderate quality evidence), or duration of vasopressor use (MD 1.00 day; 95% CI -0.53 to 2.53, 1 study, 469 participants).