REVIEW ARTICLE

Ketamine Versus Etomidate for Rapid

Sequence Intubation: A Systematic Review and
Meta-Analysis of Randomized Trials
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Alisha Greer, MD1,2

OBJECTIVES: To compare the safety and efficacy of ketamine and etomidate as Mark Hewitt, MD, MSc1,2
induction agents to facilitate emergent endotracheal intubation.
Parsa T. Khazaneh, MD2
DATA SOURCES: We searched MEDLINE, Embase, Cochrane Clinical Trials Begum Ergan, MD3
Register, and ClinicalTrials.gov from inception to April 3, 2024.
Lisa Burry, PharmD, PhD4,5
STUDY SELECTION: We included randomized controlled trials (RCTs) that Matthew W. Semler, MD, MSc6
compared ketamine to etomidate to facilitate emergent endotracheal intubation
Bram Rochwerg, MD, MSc2,7
in adults.
Sameer Sharif , MD, MSc1,2,7
DATA EXTRACTION: Reviewers screened abstracts, full texts, and extracted data
independently and in duplicate. We pooled data using a random-effects model,
assessed risk of bias using the modified Cochrane tool and certainty of evidence
using the Grading Recommendations Assessment, Development, and Evaluation
approach. We pre-registered the protocol on PROSPERO (CRD42023472450).
DATA SYNTHESIS: We included seven RCTs (n = 2384 patients). Based on
pooled analysis, compared with etomidate, ketamine probably increases hemo-
dynamic instability in the peri-intubation period (relative risk [RR], 1.29; 95% CI,
1.07–1.57; moderate certainty) but probably decreases the need for initiation of
continuous infusion vasopressors (RR, 0.75; 95% CI, 0.57–1.00; moderate cer-
tainty) and results in less adrenal suppression (RR, 0.54; 95% CI, 0.45–0.66;
moderate certainty). Ketamine probably has no effect on successful intubation
on the first attempt (RR, 1.01; 95% CI, 0.97–1.05; moderate certainty) or organ
dysfunction measured as the maximum Sequential Organ Failure Assessment
(SOFA) score during the first 3 days in ICU (mean difference, 0.55 SOFA points
lower; 95% CI, 1.12 lower to 0.03 higher; moderate certainty) and may have no
effect on mortality (RR, 1.00; 95% CI, 0.83–1.21; low certainty) when compared
with etomidate.
CONCLUSIONS: Compared with etomidate, ketamine probably results in more
hemodynamic instability during the peri-intubation period and appears to have no
effect on successful intubation on the first attempt or mortality. However, ketamine
results in decreased need for the initiation of vasopressor use and decreases ad-
renal suppression compared with etomidate.
KEYWORDS: adrenal insufficiency; critical care; emergency; etomidate;
intubation; ketamine; rapid sequence intubation

E
mergency airway management most often requires use of an induction
agent to facilitate endotracheal intubation. Commonly used agents in-
clude propofol, ketamine, and etomidate. The choice of induction agent
is important as each have unique side effect profiles including differences in Copyright © 2024 by the Society of
Critical Care Medicine and Wolters
hemodynamic instability. This is an important consideration as post-intubation
Kluwer Health, Inc. All Rights
hypotension is associated with increased in-hospital mortality and length of Reserved.
stay (LOS) (1).
DOI: 10.1097/CCM.0000000000006515

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 Greer et al

Whether this post-induction hypotension has an im-

pact on survival is not known (12). There is limited and
KEY POINTS conflicting data comparing single-dose ketamine and
etomidate for sedation to facilitate endotracheal intu-
Question: What is the comparative safety and ef- bation in critically ill patients (13–16). This systematic
ficacy of ketamine as compared with etomidate to review and meta-analysis aims to compare single-dose
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facilitate emergent endotracheal intubation of crit-

etomidate vs. single-dose ketamine as induction agents
ically ill adults?
to facilitate endotracheal intubation.
wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 12/09/2024

Findings: Compared with etomidate, ketamine

probably increases hemodynamic instability in the
peri-intubation period (relative risk [RR], 1.29; 95% METHODS
CI, 1.07–1.57; moderate certainty) but probably We registered the protocol for this systematic review
decreases the need for the initiation of continuous on the PROSPERO (CRD42023472450). We used
infusion vasopressors (RR, 0.75; 95% CI, 0.57–
the Preferred Reporting Items for Systematic reviews
1.00; moderate certainty) and results in less ad-
renal suppression (RR, 0.54; 95% CI, 0.45–0.66; and Meta-Analysis (PRISMA) statement to guide
moderate certainty). the design and reporting of this review (Appendix
6, Supplement Table 6, http://links.lww.com/CCM/
Meaning: In adults undergoing emergent endo-
H620) (17).
tracheal intubation, compared with etomidate,
ketamine probably results in more hemodynamic
instability during the peri-intubation period, but it Data Sources and Strategy
decreases initiation of continuous infusion vaso-
pressors and adrenal suppression. We searched MEDLINE, Embase, Cochrane Clinical
Trials Register, and ClinicalTrials.gov in conjunction
with an expert Librarian for eligible articles published
Etomidate, which works on gamma-aminobutyric from inception to April 3, 2024. We also searched
acid receptors, is an attractive induction agent given for unpublished studies using the World Health
its relatively limited impact on hemodynamics (1). Organization International Clinical Trials Registry and
However, its use in critically ill patients, especially the ClinicalTrials.gov database (Appendices 3 and 4,
those with sepsis, and when used in a continuous in- http://links.lww.com/CCM/H620). We included the fol-
fusion, has been associated with adrenal insufficiency lowing key search terms: “randomized,” “clinical trial,”
and increased mortality (2). The mechanism of ad- “etomidate,” “ketamine,” “intubation,” “airway manage-
renal insufficiency is thought to be due to inhibition ment,” and “induction” (Appendices 1–3, http://links.
of 11-beta-hydroxylase, which is required for cor- lww.com/CCM/H620). We used the Medical Subject
tisol synthesis (3). Despite this, etomidate remains Headings database for identification of synonyms. We
the most commonly administered induction agent for examined the reference list of full-text articles for ad-
emergency tracheal intubation in many settings (4, ditional relevant studies. A methodological filter was
5) given its limited side effect profile compared with applied to limit the retrieval to reports of randomized
other agents (6). There has been conflicting data as to controlled trials (RCTs) and human population. We ran
whether a single dose of etomidate, as opposed to a the MEDLINE and Embase strategies simultaneously as
continuous infusion, leads to clinically important ad- a multifile search in Ovid and the results de-duplicated
renal insufficiency or impacts patient outcomes (7–9). using the Ovid de-duplication tool.
A meta-analysis comparing etomidate to nonetomi-
date induction agents showed an increased risk of ad-
Study Selection
renal suppression as well as increased risk of mortality
in patients with sepsis (10). We included all RCTs that examined adult patients (≥
Ketamine, a N-methyl-D-aspartate receptor antag- 18 yr old) compared ketamine and etomidate as in-
onist that has additional sympathomimetic proper- duction agents to facilitate emergent endotracheal in-
ties, has a similarly attractive safety profile but its use tubation. We excluded case reports, case series, and
can sometimes be associated with hypotension (11). observational studies. We excluded studies examining

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 Review Article

elective intubations. We included studies that reported and have contextualized results using GRADE narra-
on any of the following outcomes: peri-intubation he- tive statements (high certainty = no qualifiers, mod-
modynamic instability (as defined by individual study erate certainty = “probably,” low certainty = “may,” and
authors), vasopressor requirements, vasopressor du- very low certainty = an uncertain effect) (25). For im-
ration of use, organ dysfunction (as measured using precision assessments, we used the null as threshold
Sequential Organ Failure Assessment [SOFA] score), for all dichotomous outcomes. For LOS, we used 1 day
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incidence of adrenal insufficiency (as defined by in- as the threshold, and for SOFA score, we used 1 point
dividual study authors), first-pass success rate of in- as this has been shown to correlate with mortality (26).
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tubation, mortality (at longest reported follow-up),

and ICU LOS. Screening of titles and abstracts was Subgroup Analyses
performed by two reviewers independently and in du-
plicate. Citations deemed relevant by either screener We performed pre-planned subgroup analyses exam-
at titles and abstract stage were advanced to full-text ining high vs. low RoB studies, patients with sepsis vs.
review. Full texts were subsequently reviewed for eligi- patients without sepsis, trauma vs. nontrauma patients,
bility, with disagreements resolved by consensus, and patients in shock vs. not in shock, pre-hospital vs. in-
third party adjudication if required. We captured rea- hospital patients, and patients receiving vs. not receiving
sons for exclusion at the full-text screening stage. neuromuscular blockade for intubation. We hypoth-
esized that there would be evidence of improved out-
comes with ketamine compared with etomidate in the
Data Extraction and Risk of Bias Assessment
following: 1) high RoB studies; 2) patients with sepsis;
Reviewers extracted data independently and in dupli- 3) patients in shock; 4) pre-hospital patients; and 5)
cate using Covidence and pre-piloted data abstraction patients who also received neuromuscular blockade.
forms (18). We assessed risk of bias independently and For subgroup findings that were statistically signif-
in duplicate using modified version of the Cochrane icant, we used the Instrument to assess the Credibility
risk-of-bias (RoB) 2.0 tool for randomized trials for of Effect Modification Analyses (ICEMAN) tool to
which each domain is rated as “low,” “probably low,” judge subgroup credibility (27). The ICEMAN tool was
“probably high,” or “high” (19). We rated the overall employed by two authors independently and in dupli-
RoB for an individual study as the highest risk attrib- cate to judge subgroup credibility, with disagreements
uted to any domain (19). resolved by third party adjudication.

Data Synthesis and Analysis RESULTS

We pooled outcome data using RevMan, Version 5 Of 166 citations, we excluded 36 duplicates and another
(Copenhagen, Denmark: The Nordic Cochrane Center, 109 citations after title and abstraction screening. We
The Cochrane Collaboration 2014) software (20). We assessed 21 full texts (Appendix 4, Supplement Fig.
used the DerSimonian and Laird random-effects mod- 1, http://links.lww.com/CCM/H620) and included
els and determined study weights using the inverse seven RCTs (n = 2384 patients). We initially included
variance method (21). We reported the results as rela- one other RCT (28) but subsequently excluded it as
tive risk (RR) with 95% CIs for dichotomous outcomes a substudy of a trial already included in our analysis.
and as mean difference (MD) or standardized MD for Baseline characteristics of included trials are sum-
continuous outcomes with 95% CIs. marized in Appendix 6 (Supplement Table 1, http://
links.lww.com/CCM/H620) and the complete GRADE
Assessment of Certainty of Evidence summary of findings is in Appendix 6 (Supplement
Table 2, http://links.lww.com/CCM/H620).
We used the Grading of Recommendations, Assessment,
Development, and Evaluation (GRADE) approach to
Description of Included Studies
assess the certainty of evidence for each outcome (22–
24). We used the Guideline Development Tool (www. Of the seven RCTs, one was multicenter (n = 469) (8)
gradepro.org) to build the Summary of Findings table and six were single center (n = 1995) (9, 16, 29–32).

Critical Care Medicine www.ccmjournal.org     3

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 Greer et al

The studies were completed in Turkey (29), France (8), during or immediately after intubation (9); 3) use of a
The Netherlands (30), the United States (9, 16, 31), and vasopressor medication within 24 hours after intuba-
Thailand (32). Two studies were judged to be at high tion (32); and 4) the use of vasopressors during intu-
risk of bias (30, 31) while five were judged to be at low bation (29).
risk of bias (8, 9, 16, 29, 32) (Appendix 6, Supplement
Table 3, http://links.lww.com/CCM/H620). Efficacy Outcomes
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The dosing of etomidate among included studies

Compared with etomidate, ketamine probably
was between 0.2 and 0.3 mg/kg with four of seven (8,
results in more peri-intubation hemodynamic insta-
wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 12/09/2024

16, 29, 31) using 0.3 mg/kg and the others (9, 30, 32)
bility (RR, 1.29; 95% CI, 1.07–1.57; risk difference
using a range of 0.2–0.3 mg/kg. A wider range of dos-
[RD], 4.1% more; 95% CI, 1.0–8.1% more; mod-
ing was used for ketamine (0.5–2 mg/kg). However,
erate certainty) (Table 1 and Fig. 1), but probably
four of seven studies (8, 16, 29, 31) used 2 mg/kg of
decreased the need for the initiation of continuous
ketamine with the others using 0.5 mg/kg (30), 1.2 mg/
infusion vasopressors (RR, 0.75; 95% CI, 0.57–1.00;
kg (9), and a range of 1–2 mg/kg (32). Most of the in-
RD, 14.0% fewer; 95% CI, 0–24.0% fewer; moderate
cluded studies used neuromuscular blockade in addi-
certainty) (Table 1 and Fig. 2). Ketamine may lead
tion to induction agents to facilitate intubation (8, 9,
to more vasopressor-free days at 28 days compared
16, 30, 32). Two studies used succinylcholine in doses
with etomidate (MD, 2.3 d more; 95% CI, 0.76 d
ranging from 1 to 1.5 mg/kg (8, 32). One study used
more to 3.84 d more; low certainty) (Table 1; and
rocuronium without any dosing specified (30). The
Appendix 5, Supplement Fig. 2, http://links.lww.
other studies had the provider use their own discretion
com/CCM/H620). For those that required vasopres-
regarding neuromuscular blockade (9, 16). Two studies
sors, ketamine has no effect on vasopressor dura-
did not report whether neuromuscular blockade was
tion compared with etomidate (MD, 0.07 d more;
used (29, 31). Medication dosing and use of paralytic
95% CI, 0.14 d fewer to 0.27 d more; high certainty)
are outlined for each study in Appendix 6 (Supplement
(Table 1; and Appendix 5, Supplement Fig. 3, http://
Table 1, http://links.lww.com/CCM/H620).
links.lww.com/CCM/H620).
The definitions of all the recorded outcomes are
Compared with etomidate, ketamine probably has
provided in the Appendix 6 (Supplement Tables 4
no effect on successful intubation on the first attempt
and 5, http://links.lww.com/CCM/H620). Specifically,
(RR, 1.01; 95% CI, 0.97–1.05; RD, 0.9% more; 95% CI,
peri-intubation hemodynamic instability was defined
2.7% fewer to 4.5% more; moderate certainty) (Table 1;
in the six studies that reported this outcome as: 1) va-
and Appendix 5, Supplement Fig. 4, http://links.lww.
sopressor use in the peri-intubation period (29); 2)
com/CCM/H620), an uncertain effect on ICU LOS
cardiac arrest during intubation (8); 3) hypotension
(MD, 1.43 d fewer; 95% CI, 6.59 d fewer to 3.74 d
(systolic blood pressure [SBP] below 90 mm Hg) in
more; very low certainty) (Table 1; and Appendix 5,
the emergency department after intubation (16); 4)
Supplement Fig. 5, http://links.lww.com/CCM/H620)
new post-induction SBP below 65 mm Hg and/or im-
and probably has no effect on ICU-free days at 28
mediate need for vasopressor bolus or dose escalation
days (MD, 0.51 d more; 95% CI, 1.56 d more to 0.53
and/or cardiac arrest or death within 1 hour of intuba-
d fewer; moderate certainty) (Table 1; and Appendix
tion (9); 5) 20% decrease in SBP post-induction; and 6)
5, Supplement Fig. 6, http://links.lww.com/CCM/
SBP less than 90 mm Hg or mean arterial blood pres-
H620).
sure less than 65 mm Hg post-intubation (32). Of these
six studies, four reported on the initiation of contin-
Safety Outcomes
uous infusion vasopressors as well. Three of these stud-
ies (n = 2305 patients) specifically defined the need for Ketamine may have no effect on mortality (RR, 1.00;
the initiation of continuous vasopressors as follows: 1) 95% CI, 0.83–1.21; RD, 0%; 95% CI, 4.7% fewer to
requiring continuous infusion vasopressors (8); 2) any 5.8% more; low certainty) (Table 1 and Fig. 3), prob-
receipt of continuous vasopressor or inotrope infusion ably decreases adrenal suppression (RR, 0.54; 95%
at any point on days 1–4 but did not include isolated CI, 0.45–0.66; RD, 9.3% fewer; 95% CI, 11.1% fewer
bolus doses of vasopressors or inotropes administered to 6.9% fewer; moderate certainty) (Table 1 and Fig.

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TABLE 1.
Abbreviated Grading Recommendations Assessment, Development, and Evaluation Summary of Findings
№ of Patients Effect

№ of Relative

Critical Care Medicine

Studies Ketamine Etomidate (95% CI) Absolute (95% CI) Certainty Narrative Summary
Peri-intubation hemodynamic instability
 6 191/1044 (18.3%) 148/1039 (14.2%) RR, 1.29 41 more per 1000 (from ⨁⨁⨁◯ Ketamine probably results in more peri-intuba-
(1.07–1.57) 10 more to 81 more) Moderatea tion hemodynamic instability compared with
etomidate
Initiation of continuous infusion vasopressors
 4 358/770 (46.5%) 431/772 (55.8%) RR, 0.75 140 fewer per 1000 (from ⨁⨁⨁◯ Ketamine probably decreases the need for initi-
(0.57–1.00) 240 fewer to 0 fewer) Moderateb ation of continuous vasopressors compared
with etomidate
Vasopressor use duration
 2 535 557 — MD, 0.07 d higher (0.14 ⨁⨁⨁⨁ Ketamine has no effect on vasopressor use
lower to 0.27 higher) High duration compared with etomidate
Vasopressor-free days at 28 d
 2 305 307 — MD, 2.3 d lower (0.76 ⨁⨁◯◯ Ketamine may have more vasopressor-free
lower to 3.84 lower) Lowc days at 28 d compared with etomidate
First-pass success
 3 431/475 (90.7%) 434/481 (90.2%) RR, 1.01 9 more per 1000 (from ⨁⨁⨁◯ Ketamine probably has no effect on first-pass
(0.97–1.05) 27 fewer to 45 more) Moderated success compared with etomidate
Mortality
 7 308/1184 (26.0%) 329/1200 (27.4%) RR, 1.00 0 fewer per 1000 (from ⨁⨁◯◯ Ketamine may have no effect on mortality com-
(0.83–1.21) 47 fewer to 58 more) Lowd pared with etomidate
Adrenal suppression
 3 67/641 (10.5%) 130/642 (20.2%) RR, 0.54 93 fewer per 1000 (from ⨁⨁⨁◯ Ketamine probably decreases adrenal
(0.45–0.66) 111 fewer to 69 fewer) Moderatee suppression compared with etomidate
MD = mean difference, RR = risk ratio.
a
All the included studies used varying definitions of peri-intubation hemodynamic instability.
b
An I2 of 79% and nonoverlapping CIs decreases our certainty in this outcome.
c
Limited sample size with only one study contributing to the pooled results lowers our certainty in this outcome.
d

www.ccmjournal.org
CIs that do not exclude benefit or harm reduces our certainty in this outcome. Given the wider CIs for the RR for mortality, imprecision was lowered two levels for this outcome.
e
The included studies used various definitions of adrenal suppression; this lowers our certainty in this outcome.

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    5
Review Article
 Greer et al
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Figure 1. Forest plot comparing ketamine and etomidate for the outcome of peri-intubation hemodynamic instability. df = degrees of
freedom, M-H = Mantel-Haenszel.

without sepsis, there

was no credible sub-
group effect found for
the outcome of mor-
tality (p for interac-
tion = 0.49) (Appendix
5, Supplement Fig. 12,
Figure 2. Forest plot comparing ketamine and etomidate for the outcome of initiation of continuous http://links.lww.com/
vasopressors. df = degrees of freedom, M-H = Mantel-Haenszel. CCM/H620). Due to
lack of data from in-
4) and probably has no effect on organ dysfunction cluded studies, we were unable to perform all the pre-
compared with etomidate (MD, 0.55 SOFA points specified subgroup analyses.
lower; 95% CI, 1.12 points lower to 0.03 points
higher; moderate certainty) (Table 1; and Appendix DISCUSSION
5, Supplement Fig. 7, http://links.lww.com/CCM/
H620). Of note, adrenal insufficiency was defined This systematic review and meta-analysis found that,
variably in the four studies that reported this out- compared with etomidate, ketamine probably results
come (Appendix 6, Supplement Table 5, http://links. in more peri-intubation hemodynamic instability, but
lww.com/CCM/H620) and included the measure- after this peri-intubation period, ketamine probably
ment of serum cortisol levels, performing an adre- decreases the need for the initiation of continuous
nocorticotropic hormone (ACTH) stimulation test, infusion vasopressors. Furthermore, compared with
and clinically diagnosing it. etomidate, ketamine may have no effect on mortality
based on low certainty evidence, and probably has no
Subgroup Analyses effect on first-pass success, organ dysfunction, and
ICU-free days at 28 days. Furthermore, our subgroup
We found no evidence of credible subgroup effects analysis found no effect on mortality when comparing
in any of the pre-planned analyses (Appendix 5, ketamine and etomidate in patients with and without
Supplement Figs. 8–21, http://links.lww.com/CCM/ sepsis, although this was based on low certainty evi-
H620). We found evidence of a statistically significant dence. Importantly, ketamine probably decreases ad-
subgroup effect comparing high vs. low RoB stud- renal suppression when compared with etomidate
ies for the outcome of ICU LOS; this subgroup was although the importance of this outcome in isolation
judged to be of low credibility, but to be conservative, is uncertain particularly as most of the weight of this
we lowered certainty in findings for this outcome outcome was from a single study (8).
due to risk of bias (Appendix 5, Supplement Fig. 11, The increased peri-intubation hemodynamic in-
http://links.lww.com/CCM/H620). Specifically with stability with ketamine appears to be transient as ke-
respect to sepsis, when comparing patients with and tamine had no effect on the duration of vasopressor

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 Review Article
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Figure 3. Forest plot comparing ketamine and etomidate for the outcome of mortality. df = degrees of freedom, M-H = Mantel-Haenszel.

of adrenal insufficiency
among included stud-
ies such as serum cor-
tisol levels below 276
nmol/L, inadequate
response to ACTH
Figure 4. Forest plot comparing ketamine and etomidate for the outcome of adrenal suppression. df =
stimulation test (< 250
degrees of freedom, M-H = Mantel-Haenszel. nmol/L rise), clinical
diagnosis of adrenal
use throughout the ICU stay. Of note, the definition insufficiency or need for IV corticosteroids, and con-
of peri-intubation hemodynamic instability varied sistent with these older septic shock studies, our anal-
between studies and included peri-intubation vaso- ysis found an increased risk of adrenal suppression
pressor use, SBP below 90 mm Hg, mean arterial pres- with the use of etomidate (Appendix 5, Supplement
sure below 65 mm Hg, 20% decrease in SBP, and cardiac Table 5, http://links.lww.com/CCM/H620). It is im-
arrest during intubation (Appendix 6, Supplement portant to note, however, that despite the sympatho-
Table 4, http://links.lww.com/CCM/H620). Despite mimetic properties of ketamine, it was associated
this period of hemodynamic instability, ketamine with peri-intubation hypotension (4). Based on our
had no effect on mortality and resulted in a decreased analysis, this effect appears to be transient. It is likely
need for the initiation of vasopressors. The outcome that patients in a catecholamine deplete state may be
of initiation of vasopressors was based on four stud- more susceptible to this effect (33). This is particu-
ies whereby the vast majority of the patients required larly troublesome as many critically ill patients fall in
catecholamines either within 24 hours of intubation this category.
or between days 1 and 4 of intubation. Our finding Despite increasing peri-intubation hemodynamic
of decreased need for the initiation of vasopressors instability, ketamine did not result in increased mor-
is based on moderate certainty evidence given the tality or organ dysfunction compared with etomidate
upper end of the CI hits the threshold of 1.00 result- when used as single dose to facilitate intubation. Given
ing in the lowering our certainty in this finding for there are many ICU-based factors that affect these out-
imprecision. Due to lack of data, we were unable to comes such as critical care related complications, noso-
gather the specifics of dose changes of vasopressors; comial infections, and other life support interventions,
however, there was no difference in duration of va- it is less likely that a single dose of intubation med-
sopressor use between ketamine and etomidate. One ication would impact mortality or organ dysfunction
explanation for this finding is that compared with ke- in addition to the other factors associated with critical
tamine, etomidate may increase adrenal suppression, illness (34). Successful intubation on first attempt was
a concern that has been previously demonstrated in not affected by choice of induction agent. This out-
patients with septic shock and led to a black box warn- come has been shown to correlate with operator expe-
ing for this drug (2, 7, 13). Despite varied definitions rience, patient features of difficult airway, use of video

Critical Care Medicine www.ccmjournal.org     7

Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
 Greer et al

laryngoscopy, and use of neuromuscular blockade and reporting in accordance with PRISMA guideline,
(35–37). Only three of seven studies reported first-pass comprehensive search, and GRADE assessment of
success as an outcome and none of them commented certainty of evidence. We also included two recently
on these other contributing factors. Importantly, five published RCTs examining ketamine vs. etomidate
studies protocolized co-administration of neuromus- to facilitate intubation, which were not included in
cular blockade as part of intubation, which is known previous meta-analyses (9, 32, 44). Furthermore, the
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to improve first-pass success (37). Unfortunately, due previously published meta-analyses (44) included
to a lack of data, we were unable to assess for subgroup observational data, whereas this study only included
wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 12/09/2024

effect based on this factor. RCTs, increasing the certainty of evidence of our find-
A recently published Bayesian meta-analysis found ings and in keeping with direction from the Cochrane
that the probability that induction with ketamine collaborative.
reduced mortality was 83.2% (376/1475 [25%] vs. This study also has limitations. First, many outcomes
411/1503 [27%]); however, the pooled risk ratio was were limited by imprecision leading to low or very low
0.93 and with imprecise 95% credible intervals of 0.79– certainty of evidence. Second, there was heterogeneity
1.08, leading to results with uncertain applicability in how outcomes were reported (i.e., varying defini-
(38). In comparison to these findings, we did not find tions of adrenal suppression and peri-intubation he-
a difference in mortality when comparing ketamine modynamic instability) between studies although this
and etomidate, albeit based on low certainty evidence. rarely contributed to important statistical heteroge-
One of the reasons for this difference may be due the neity. Third, neuromuscular blockade was not used
aforementioned meta-analysis pooling both RCTs uniformly across studies. Fourth, we were unable to
and observational studies (39) despite the recommen- complete many of the pre-planned subgroup analyses
dation by the Cochrane collaborative to avoid pool- due to lack of reported data.
ing randomized and nonrandomized data together
(40). Another reason for the different results may be CONCLUSIONS
due to the other meta-analysis including a RCT that Compared with etomidate, ketamine probably results
compared a ketamine/propofol admixture, whereas in more hemodynamic instability during the peri-
we only examined the use of ketamine vs. etomidate intubation period and has no impact on successful
(41). Finally, another reason for our discrepant results intubation on the first attempt or mortality. However,
may be that the authors of the previously published ketamine results in decreased need for the initiation
meta-analysis used a Bayesian framework that consid- of continuous infusion vasopressors and decreases ad-
ers “priors” to generate posterior probabilities of effect, renal suppression compared with etomidate.
whereas we used a frequentist statistical approach (42).
Based on our analysis, one possible interpreta- ACKNOWLEDGMENTS
tion is that ketamine may be a better induction agent
for patients who are more hemodynamically stable, We thank Karin Dearness, Director of library services,
whereas etomidate may be the drug of choice for St. Joseph’s Healthcare, Hamilton, ON, Canada, for her
patients who are hemodynamically unstable at the assistance in performing the comprehensive search of
time of intubation. Further research addressing this the databases. Also, we thank Kaitryn Campbell (St.
question is needed to improve the precision of effect Joseph’s Healthcare, Hamilton, ON, Canada) for peer
estimates and there is currently an RCT underway review of the Ovid search strategy.
comparing ketamine and etomidate for emergent
endotracheal intubation (43). This study plans to 1 Department of Medicine, Division of Emergency Medicine,
examine several different hemodynamic outcomes in- McMaster University, Hamilton, ON, Canada.

cluding during the immediate peri-intubation period, 2 Department of Medicine, Division of Critical Care, McMaster
University, Hamilton, ON, Canada.
the first 24 hours and 28 days into ICU stay, in addi-
3 Dokuz Eylul University, İzmir, Turkey.
tion to mortality.
4 Department of Medicine, Sinai Health System;
This systematic review and meta-analysis has several Interdepartmental Division of Critical Care Medicine,
strengths including a pre-registered protocol, design University of Toronto, Toronto, ON, Canada.

8     www.ccmjournal.org XXX 2024 • Volume 53 • Number 00

Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
 Review Article

5 Leslie Dan Faculty of Pharmacy, University of Toronto, intubation in acutely ill patients: A multicentre randomised
Toronto, ON, Canada. controlled trial. Lancet 2009; 374:293–300
6 Division of Allergy, Pulmonary, and Critical Care Medicine, 9. Matchett G, Gasanova I, Riccio CA, et al: Etomidate versus ke-
Department of Medicine, Vanderbilt University Medical tamine for emergency endotracheal intubation: A randomized
Center, Nashville, TN. clinical trial. Intensive Care Med 2022; 1:14
7 Department of Health Research Methods, Evidence and 10. Albert SG, Ariyan S, Rather A: The effect of etomidate on ad-
Impact, McMaster University, Hamilton, ON, Canada. renal function in critical illness: A systematic review. Intensive
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Care Med 2011; 37:901–910

Supplemental digital content is available for this article. Direct
URL citations appear in the printed text and are provided in the 11. Mohr NM, Pape SG, Runde D, et al: Etomidate use is associ-
ated with less hypotension than ketamine for emergency de-
wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 12/09/2024

HTML and PDF versions of this article on the journal’s website

(http://journals.lww.com/ccmjournal). partment sepsis intubations: A NEAR cohort study. Academic
Emerg Med2020; 27:1140–1149
Drs. Greer, Sharif, Rochwerg, and Hewitt designed the study.
Drs. Greer, Hewitt, Khazaneh, and Ergan collected the data. Drs. 12. Fouche PF, Meadley B, St Clair T, et al: The association of ke-
Rochwerg and Sharif analyzed and interpreted the data. Drs. tamine induction with blood pressure changes in paramedic
Greer, Sharif, Hewitt, Burry, Rochwerg, and Semler contributed rapid sequence intubation of out-of-hospital traumatic brain
to the writing of the article. injury. Acad Emerg Med 2021; 28:1134–1141
13. Schenarts CL, Burton JH, Riker RR: Adrenocortical dysfunc-
Dr. Semler received support for article research from the
tion following etomidate induction in emergency department
National Institutes of Health. Dr. Sharif received funding from
patients. Acad Emerg Med 2001; 8:1–7
the McMaster University Department of Medicine Internal Career
Research Award. The remaining authors have disclosed that they 14. Bakhsh A, Alnashri M, Alawami F, et al: Changes in hemody-
do not have any potential conflicts of interest. namic parameters with the use of etomidate versus ketamine
induction in the emergency department. Signa Vitae 2021;
Drs. Rochwerg and Sharif contributed equally as senior authors.
17:85–92
For information regarding this article, E-mail: sameer.sharif@ 15. Stanke L, Nakajima S, Zimmerman LH, et al: Hemodynamic
medportal.ca effects of ketamine versus etomidate for prehospital rapid se-
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