Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial

doi:10.1016/S0140-6736(09)60949-1

The Lancet

Volume 374, Issue 9686, 25–31 July 2009, Pages 293-300

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https://doi.org/10.1016/S0140-6736(09)60949-1 Get rights and content

Summary

Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Funding

French Ministry of Health.

Introduction

Critically ill patients often require emergency orotracheal intubation for airway control. Rapid sequence intubation with administration of a sedative and a paralytic agent is common. Etomidate is the sedative-hypnotic drug that is most often used in rapid sequence intubation, but its use has been challenged because it can cause a reversible adrenal insufficiency by dose-dependent inhibition of 11β-hydroxylase.1, 2

Several studies have suggested an association between the use of etomidate and the occurrence of adrenal insufficiency and increased morbidity in critically ill or injured patients, particularly in those with sepsis.3, 4, 5, 6, 7, 8 Because adrenal insufficiency when a patient is critically ill can increase the risk of death, several investigators have advised against the use of etomidate, even as a single bolus.⁹ However, no causal link has been established between its use and an increase in morbidity and mortality.

Etomidate's haemodynamic tolerance, even in patients with shock, and the excellent intubation conditions provided have to be weighed against potential adverse effects, including adrenal insufficiency.¹⁰ A possible alternative to etomidate is ketamine, which is not known to inhibit the adrenal axis. The aim of this randomised controlled study was to compare early and 28-day morbidity after a single dose of etomidate or ketamine used for emergency endotracheal intubation of critically ill patients.

Section snippets

Study setting and patients

This prospective, randomised, controlled, single-blind (caregiver) trial was undertaken from April 25, 2007, to Feb 27, 2008, by 12 emergency medical services or emergency departments and 65 intensive care units in France. The emergency medical services are ambulance base stations equipped with one or more mobile intensive care units, consisting of an ambulance driver, a nurse, and a senior emergency physician as the minimum team.¹¹

Patients who were 18 years or older and who needed sedation for

Results

Figure 1 shows the trial profile. Of the 689 patients assessed for eligibility, 655 were consecutively and randomly assigned to treatment and 650 were analysed (ITT population; figure 1). All allocated treatments were delivered to the randomised patients. The mITT analysis was undertaken in 469 patients (n=234 in etomidate group and n=235 in ketamine group). The number of patients who died before reaching hospital or who were discharged alive before 3 days from the intensive care unit was

Discussion

Our study shows that one etomidate bolus is not associated with a significant increase in morbidity or mortality compared with ketamine in patients admitted to the intensive care unit. The maximum SOFA score did not differ significantly between the two drugs in the subgroup of patients having sepsis or trauma. However, for the subgroup of septic patients (n=76), the small number of patients might account for the absence of significant difference. The mortality rate at day 28 in this subgroup

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Inside the black box: Random effects meta-analysis with zero heterogeneity
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The Effect of Ketamine Versus Etomidate for Rapid Sequence Intubation on Maximum Sequential Organ Failure Assessment Score: A Randomized Clinical Trial
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The use of induction agents for rapid sequence intubation (RSI) has been associated with hypotension in critically ill patients. Choice of induction agent may be important and the most commonly used agents are etomidate and ketamine.
This study aimed to compare the effects of a single dose of ketamine vs. etomidate for RSI on maximum Sequential Organ Failure Assessment (SOFA) score and incidence of hypotension.
This single-center, randomized, parallel-group trial compared the use of ketamine and etomidate for RSI in critically ill adult patients in the emergency department. The study was performed under Exception from Informed Consent. The primary outcome was the maximum SOFA score within 3 days of hospitalization.
A total of 143 patients were enrolled in the trial, 70 in the ketamine group and 73 in the etomidate group. Maximum median SOFA score for the ketamine group was 6.5 (interquartile range [IQR] 5–9) vs. 7 (IQR 5–9) for etomidate with no significant difference (–0.2; 95% CI –1.4 to 1.1; p = 0.79). The incidence of post-intubation hypotension was 28% in the ketamine group vs. 26% in the etomidate group (difference 2%; 95% CI –13% to 17%). There were no significant differences in intensive care unit outcomes. Thirty-day mortality rate for the ketamine group was 11% (8 deaths) and for the etomidate group was 21% (15 deaths), which was not statistically different.
There were no significant differences in maximum SOFA score or post-intubation hypotension between critically ill adults receiving ketamine vs. etomidate for RSI.
Ketamine during resuscitation – Is it as hemodynamically perfect as we think?
2023, American Journal of Emergency Medicine
Ketamine administration in patients experiencing or at risk for hypotension is common based upon the presumption of this agent's favorable hemodynamic profile. The Compensatory Reserve Measurement (CRM) is a novel algorithm that accurately tracks systemic adequacy for delivery of oxygen (DO2) to the tissues. We present a case series of trauma patients receiving ketamine with CRM measurements to offer insight into the DO2 during resuscitation.
We captured vital signs along with analog arterial waveform data from trauma patients meeting major activation criteria using a prospective study design. Study team members tracked interventions and vital signs including systolic blood pressure (SBP), mean arterial pressure (MAP), and heart rate (HR) throughout their emergency department stay.
Our study included 8 patients who received ketamine for intubation or analgesia (20-300 mg) and had adequate data for analysis. Most were male (88%) with a median age of 28. The most common mechanisms of injury were motor vehicle collisions (MVCs) (38%) and gunshot wounds (38%). After ketamine administration SBP, MAP, and HR all increased while the CRM exhibited minimal change.
SBP, MAP, and HR generally appeared to increase while the CRM remained unchanged. Our findings suggest that while standard vital sign measurements appear to increase, ketamine may not improve delivery of oxygen to the tissues. This warrants further study to better understand the effects of ketamine on hemodynamics.
Etomidate as an induction agent for endotracheal intubation in critically ill patients: A meta-analysis of randomized trials
2023, Journal of Critical Care
We performed a meta-analysis of randomized controlled trials to evaluate if etomidate impacted mortality in critically ill adults when compared with other induction agents.
We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials which compared etomidate with any other induction agent in critically ill adult patients undergoing endotracheal intubation. The primary outcome was mortality at the main timepoint defined by the study. We conducted a fixed-effects meta-analysis for the risk ratio. Using that risk ratio and 95% confidence interval, we then estimated the probability of any harm (RR > 1) and the number needed to harm ≤100 (RR ≥ 1.05).
We included 11 randomized trials comprising 2704 patients. We found that etomidate increased mortality (319/1359 [23%] vs. 267/1345 [20%]; risk ratio (RR) = 1.16; 95% confidence interval (CI), 1.01–1.33; P = 0.03; I² = 0%; number needed to harm = 31). The probabilities of any increase and a 1% increase (NNH ≤100) in mortality were 98.1% and 92.1%, respectively.
This meta-analysis found a high probability that etomidate increases mortality when used as an induction agent in critically ill patients with a number needed to harm of 31.
Pharmacotherapy optimization for rapid sequence intubation in the emergency department
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Rapid-sequence intubation (RSI) is the process of administering a sedative and neuromuscular blocking agent (NMBA) in rapid succession to facilitate endotracheal intubation. It is the most common and preferred method for intubation of patients presenting to the emergency department (ED). The selection and use of medications to facilitate RSI is critical for success. The purpose of this review is to describe pharmacotherapies used during the RSI process, discuss current clinical controversies in RSI medication selection, and review pharmacotherapy considerations for alternative intubation methods.
There are several steps to the intubation process requiring medication considerations, including pretreatment, induction, paralysis, and post-intubation sedation and analgesia. Pretreatment medications include atropine, lidocaine, and fentanyl; but use of these agents in clinical practice has fallen out of favor as there is limited evidence for their use outside of select clinical scenarios. There are several options for induction agents, though etomidate and ketamine are the most used due to their more favorable hemodynamic profiles. Currently there is retrospective evidence that etomidate may produce less hypotension than ketamine in patients presenting with shock or sepsis. Succinylcholine and rocuronium are the preferred neuromuscular blocking agents, and the literature suggests minimal differences between succinylcholine and high dose rocuronium in first-pass success rates. Selection between the two is based on patient specific factors, half-life and adverse effect profiles. Finally, medication-assisted preoxygenation and awake intubation are less common methods for intubation in the ED but require different considerations for medication use.
The optimal selection, dosing, and administration of RSI medications is complicated, and further research is needed in several areas. Additional prospective studies are needed to determine optimal induction agent selection and dosing in patients presenting with shock or sepsis. Controversy exists over optimal medication administration order (paralytic first vs induction first) and medication dosing in obese patients, but there is insufficient evidence to significantly alter current practices regarding medication dosing and administration. Further research examining awareness with paralysis during RSI is needed before definitive and widespread practice changes to medication use during RSI can be made.
Con: The Best Induction Agent for the Physiologically Difficult Airway Is Ketamine-Propofol Admixture (“Ketofol”)
2023, Journal of Cardiothoracic and Vascular Anesthesia

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ArticlesEtomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study setting and patients

Results

Discussion

Lancet

Resuscitation

Ann Thorac Surg

Pharmacol Biochem Behav

Ann Emerg Med

Etomidate suppresses adrenocortical function by inhibition of 11 beta-hydroxylation

J Clin Endocrinol Metab

Risk factors of relative adrenocortical deficiency in intensive care patients needing mechanical ventilation

Intensive Care Med

A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin

JAMA

Relative adrenal insufficiency as a predictor of disease severity, mortality, and beneficial effects of corticosteroid treatment in septic shock

Crit Care Med

Adrenal function in sepsis: the retrospective Corticus cohort study

Crit Care Med

One single dose of etomidate negatively influences adrenocortical performance for at least 24 h in children with meningococcal sepsis

Intensive Care Med

Adrenal suppression following a single dose of etomidate for rapid sequence induction: a prospective randomized study

J Trauma

ICU physicians should abandon the use of etomidate!

Intensive Care Med

Intubating conditions and hemodynamic effects of etomidate for rapid sequence intubation in the emergency department: an observational cohort study

Acad Emerg Med

The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine

Intensive Care Med

Articles
Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial