P Jabre, X. Combes, F. Lapostolle, et al. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients : a multicentre randomised controlled trial. Lancet 2009;374:293.
Critically ill patients often require emergency intubation. The use of etomidate as the sedative agent in this context has been challenged because it might cause a reversible adrenal insufficiency, potentially associated with increased in-hospital morbidity. We compared early and 28-day morbidity after a single dose of etomidate or ketamine used for emergency endotracheal intubation of critically ill patients.
In this randomised, controlled, single-blind trial, 655 patients who needed sedation for emergency intubation were prospectively enrolled from 12 emergency medical services or emergency departments and 65 intensive care units in France. Patients were randomly assigned by a computerised random-number generator list to receive 0·3 mg/kg of etomidate (n=328) or 2 mg/kg of ketamine (n=327) for intubation. Only the emergency physician enrolling patients was aware of group assignment. The primary endpoint was the maximum score of the sequential organ failure assessment during the first 3 days in the intensive care unit. We excluded from the analysis patients who died before reaching the hospital or those discharged from the intensive care unit before 3 days (modified intention to treat). This trial is registered with ClinicalTrials.gov, number NCT00440102.
234 patients were analysed in the etomidate group and 235 in the ketamine group. The mean maximum SOFA score between the two groups did not differ significantly (10·3 [SD 3·7] for etomidate vs 9·6 [3·9] for ketamine; mean difference 0·7 [95% CI 0·0–1·4], p=0·056). Intubation conditions did not differ significantly between the two groups (median intubation difficulty score 1 [IQR 0–3] in both groups; p=0·70). The percentage of patients with adrenal insufficiency was significantly higher in the etomidate group than in the ketamine group (OR 6·7, 3·5–12·7). We recorded no serious adverse events with either study drug.
Our results show that ketamine is a safe and valuable alternative to etomidate for endotracheal intubation in critically ill patients, and should be considered in those with sepsis.
Emergency endotracheal intubation is one of the most delicate moments in the care of the critically ill. Time is of the essence, and the margin for error is small, while the potential consequences of error are large. Many factors may complicate attempts to control the airway, including agitation, airway edema, bleeding, in addition to hemodynamic, respiratory or metabolic embarrassment. Many agents commonly used to induce anesthesia in other situations (opioids, benzodiazepines) may worsen the patient’s condition. Rapid sequence intubation (RSI) describes the administration of an agent to induce anesthesia almost simultaneously with the administration of neuromuscular blockade; RSI has been reported to improve the success rate of emergency intubation to 98% [Reynolds & Heffner, Chest 2005;127:1397.] Etomidate is an imidazole derivative that rapidly induces unconsciousness without causing hypotension. Because of these properties, it has been used frequently for RSI of critically ill patients, especially those with hemodynamic compromise. Observations made over 25 years ago showed a strong association between continuous IV etomidate use and increased mortality [Ledingham & Watt, Lancet 1983;321:1270.] This association is attributed to etomidate’s effects on adrenocortical function. Etomidate inhibits 11-beta-hydroxylase, which plays a key role in the final steps of cortisol synthesis; etomidate thus causes adrenocortical insufficiency in a dose-dependent fashion [de Jong et al., J Clin Endocrinol Metab 1984;59:1143.] In several retrospective studies, a single dose of etomidate has also been associated with worse outcomes. In a retrospective analysis of patients enrolled in the CORTICUS trial, 28-day mortality was higher among patients who received etomidate [Sprung et al., N Engl J Med 2008;358:111.] Some experts have recommended against using even a single dose of etomidate [Annane, Int Care Med 2005;31:325.]
Jabre and colleagues performed a prospective, multi-center, randomized, single-blind trial to compare etomidate to ketamine for use at the time of RSI. Adult (18-years-old or more) patients who required emergency intubation by ambulance or emergency department personnel were randomized to receive either intravenous etomidate (0.3 mg/kg) or ketamine (2 mg/kg) in addition to succinylcholine. Exclusion criteria included cardiac arrest, contraindications to succinylcholine or one of the study drugs, and known pregnancy. Patients who died prior to hospitalization or who were discharged from intensive care within 3 days were also excluded. 655 patients were randomized out of 689 who were screened for eligibility; 328 received etomidate and 327 received ketamine. A total of 469 subjects were followed for 28 days and included in the final analysis (234 in the etomidate group, 235 in the ketamine group.) Reasons for exclusion after randomization included missing data (4), withdrawal of consent (1), death before reaching the hospital (27), and discharge from the ICU within 3 days (154). Excluded subjects were evenly distributed between the two groups. The demographic and clinical composition of each group was similar, including indications for intubation, vital signs, and Simplified Acute Physiology Score (SAPS) II.
The outcomes in each group were also similar. The primary endpoint (maximum sequential organ failure assessment (SOFA) score) and secondary endpoints (including change in SOFA score, 28-day mortality, ICU-free days, and organ-support-free days) were similar in both groups. One notable difference was the incidence of adrenal insufficiency. The investigators defined adrenal insufficiency as a random serum cortisol level below 276 nmol/L (10 mcg/dL) or an increase of less than 250 nmol/L (9 mcg/dL) 30 or 60 minutes after the administration of synthetic adrenocorticotropic hormone (ACTH). The dose and timing of synthetic ACTH administration were not specified. 86% of the subjects who received etomidate met criteria for adrenal insufficiency, compared with 48% of those who received ketamine. Mean cortisol levels, both before and after the administration of ACTH were also lower in the group receiving etomidate.
Adrenal insufficiency is a controversial area of critical care medicine. Randomized trials of cortisol supplementation for critical illness were published over 40 years ago [Cooperative Study Group, JAMA 1963;183:462]; decades later, a clear answer about the benefit that cortisol supplementation might provide remains elusive. One significant problem remains the way in which serum cortisol is measured. Most clinical centers utilize immunoassays to measure total serum cortisol. These assays, however, may be unreliable in the critically ill [Arafah, J Clin Endocrinol Metab 2006;91:3725, Bornstein, N Engl J Med 2009;360:2328.] Another issue is whether measuring total serum cortisol is the most appropriate test. Most circulating cortisol is bound to cortisol-binding globulin and other plasma proteins; however, free cortisol is believed to exert biological effect. The amount of free serum cortisol rises in critically ill individuals [Hamrahian et al., N Eng J Med 2004;350:1629] although the total serum cortisol may appear low. Furthermore, studies have cast doubt on the reliability of the ACTH-stimulation test. Two studies suggest that many patients will have an ACTH-stimulation test result that classifies them as having adrenal insufficiency on one day but not on another [Bouachour et al., Ann Int Med 1995;123:962, Loisa et al., Anesth Analg 2005;101:1792.] Venkatesh and co-workers found that spontaneous hour-to-hour changes in critically ill patients’ total serum cortisol level frequently exceeds 250 nmol/L without ACTH stimulation [Venkatesh et al., Anaesth Intensive Care 2005;33:201.] Thus, it is difficult to know what to make of the findings presented in Jabre’s study. Patients who received etomidate had lower total serum cortisol levels and a smaller response to ACTH stimulation, and a higher proportion of the group who received etomidate met the study’s criteria for adrenal insufficiency. The use of catecholamines was similar in both the etomidate and the ketamine group, however, suggesting that shock was not more prevalent in the etomidate group. Kaplan-Meier curves describing duration of vasopressor therapy were also similar. The incidence of hyponatremia or hyperkalemia, common findings in adrenal insufficiency, were not presented. Thus, it seems that the adrenal insufficiency identified by the investigators did not have a large clinical impact.
The investigators conclude that ketamine and etomidate are equally safe for RSI in critically ill patients. They recognize that a single etomidate dose is not associated with increased morbidity or mortality, notwithstanding their findings on adrenocortical function. They caution, however, that the small number of patients with sepsis (18% of the etomidate group and 15% of the ketamine group) does not permit them to draw firm conclusions about the safety of etomidate for patients with sepsis. This is especially important because patients with sepsis may be at highest risk for developing adrenal dysfunction during critical illness.
In summary, this is a rigorously designed clinical trial whose findings are likely easily extrapolated to most critically ill patients. Both ketamine and etomidate appear to be safe for RSI in a broad population of the critically ill. Though etomidate seems to cause biochemical evidence of adrenal insufficiency, the tests on which this diagnosis is based appear to be unreliable in the ICU. Furthermore, clinical outcomes, including the incidence and duration of shock, as well as SOFA scores, appear to be similar in patients who received either drug. For the time being, clinicians should feel relatively safe choosing either of these agents for RSI.