Koroki et al.

Critical Care (2024) 28:48 Critical Care

https://doi.org/10.1186/s13054-024-04831-4

RESEARCH Open Access

Ketamine versus etomidate as an induction

agent for tracheal intubation in critically ill
adults: a Bayesian meta‑analysis
Takatoshi Koroki1, Yuki Kotani1,2,3*, Takahiko Yaguchi1, Taisuke Shibata1, Motoki Fujii1, Stefano Fresilli2,
Mayuko Tonai1, Toshiyuki Karumai1, Todd C. Lee4, Giovanni Landoni2,3 and Yoshiro Hayashi1

Abstract
Background Tracheal intubation is a high-risk intervention commonly performed in critically ill patients. Due to its
favorable cardiovascular profile, ketamine is considered less likely to compromise clinical outcomes. This meta-analysis
aimed to assess whether ketamine, compared with other agents, reduces mortality in critically ill patients undergoing
intubation.
Methods We searched MEDLINE, Embase, and the Cochrane Library from inception until April 27, 2023, for ran-
domized controlled trials and matched observational studies comparing ketamine with any control in critically ill
patients as an induction agent. The primary outcome was mortality at the longest follow-up available, and the sec-
ondary outcomes included Sequential Organ Failure Assessment score, ventilator-free days at day 28, vasopressor-free
days at day 28, post-induction mean arterial pressure, and successful intubation on the first attempt. For the primary
outcome, we used a Bayesian random-effects meta-analysis on the risk ratio (RR) scale with a weakly informative
neutral prior corresponding to a mean estimate of no difference with 95% probability; the estimated effect size will
fall between a relative risk of 0.25 and 4. The RR and 95% credible interval (CrI) were used to estimate the probability
of mortality reduction (RR < 1). The secondary outcomes were assessed with a frequentist random-effects model. We
registered this study in Open Science Framework (https://​osf.​io/​2vf79/).
Results We included seven randomized trials and one propensity-matched study totaling 2978 patients. Etomidate
was the comparator in all the identified studies. The probability that ketamine reduced mortality was 83.2% (376/1475
[25%] vs. 411/1503 [27%]; RR, 0.93; 95% CrI, 0.79–1.08), which was confirmed by a subgroup analysis excluding studies
with a high risk of bias. No significant difference was observed in any secondary outcomes.
Conclusions All of the included studies evaluated ketamine versus etomidate among critically ill adults requiring
tracheal intubation. This meta-analysis showed a moderate probability that induction with ketamine is associated
with a reduced risk of mortality.
Keywords Systematic review, Meta-analysis, Ketamine, Intubation, Mortality, Intensive care units, Bayes theorem

*Correspondence:
Yuki Kotani
[email protected]
Full list of author information is available at the end of the article

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Koroki et al. Critical Care (2024) 28:48 Page 2 of 9

Graphical abstract

Background To further the discussion on potential benefits of keta-

Tracheal intubation is a high-risk procedure commonly mine, we performed an updated systematic review and
performed in intensive care units (ICUs) [1]. Peri- Bayesian meta-analysis to estimate the probability that
intubation complications are common and are associ- ketamine as an induction agent would reduce mortality
ated with an increased risk of mortality in critically ill in critically ill patients requiring tracheal intubation.
patients [2]. Therefore, improving the quality of care
in the peri-intubation period may result in better out- Methods
comes of these high-risk patients. We performed a systematic review and meta-analysis
Rapid sequence intubation (RSI), facilitated by rapidly according to the Preferred Reporting Items for System-
acting agents, is often used among critically ill patients atic Reviews and Meta-Analyses (PRISMA) guidelines [8]
who are deteriorating quickly. Clinical practice guide- (see PRISMA checklist in Additional file 1) and registered
lines for RSI suggest ketamine, etomidate, and propo- the review protocol on Open Science Framework (regis-
fol as induction agents [3, 4]. Among the three drugs, tration link: https://​osf.​io/​2vf79/) on March 30, 2023.
propofol is an independent risk factor for cardiovas- Our review question was built using the PICOS (Popu-
cular collapse during the procedure [5], and etomidate lation, Intervention, Comparison, Outcome, and Study
carries a major risk of adrenal insufficiency due to inhi- design) framework: adult critically ill patients requir-
bition of 11-beta hydroxylase in the adrenal glands [6]. ing emergency tracheal intubation (P); ketamine (I); any
Notably, a recent meta-analysis showed that etomidate other comparator (C); all-cause mortality at the longest
was associated with significantly increased mortality in follow-up available (O); and in randomized controlled
critically ill patients requiring tracheal intubation [7]. trials and matched studies (S).
Given ketamine’s favorable hemodynamic effects and
absence of the adverse effects exhibited by other agents, Search strategy and selection criteria
it may represent the optimal option in this particular Two investigators independently searched MEDLINE,
context. Indeed, in a subgroup analysis of a prior meta- Embase, and Cochrane Library for relevant studies from
analysis, etomidate had numerically increased mortal- inception to April 27, 2023. We considered eligible RCTs
ity when compared to ketamine although this was not and matched studies comparing ketamine versus other
statistically significant (risk ratio [RR], 1.07; 95% confi- sedatives as an induction agent for tracheal intubation
dence interval [CI] 0.94–1.22; P = 0.30) [7]. in critically ill adults. We defined critically ill adults as
patients requiring emergency tracheal intubation due to
Koroki et al. Critical Care (2024) 28:48 Page 3 of 9

critical illness, regardless of where the intubation was Data analysis

performed (e.g., prehospital, emergency department, For the primary outcome, we used a Bayesian ran-
and intensive care unit). Critical illness was defined as dom-effects meta-analysis on the RR scale. We chose a
a state of ill health with vital organ dysfunction and a weakly informative neutral prior for mu (N ~ [0,0.712])
high risk of imminent death if care is not provided [9]. corresponding to a mean estimate of no difference with
We only included the studies assessing the efficacy of a 95% probability; the estimated effect size fell between
administrating ketamine as induction agent for critically a RR of 0.25 and 4 [15]. This type of prior recognizes
ill adults during tracheal intubation. We excluded non- that: (1) There is no strong prior knowledge suggesting
randomized trials, observational studies without match- that ketamine is superior to other therapies; (2) there is
ing, systematic reviews, commentaries/editorials and not a demonstrable difference between most interven-
literature reviews, and studies not addressing our review tions in medicine; and (3) that the effect size of almost
question. The complete search strategy is provided in all interventions in medicine will be modest at best
Additional file 2. and so not all RRs are equally likely. For the between-
Two investigators independently screened eligibil- study standard deviation (SD) parameter (tau), we used
ity based on study titles and abstracts after removing an informative prior based on the predictive distribu-
duplicates. Finally, we selected eligible studies based tion derived from hundreds of Cochrane meta-analyses
on full-text manuscripts. Disagreements were resolved that reported all-cause mortality [16]. Analysis was
through discussion under the supervision of one senior conducted using the bayesmeta package in R version
investigator. 4.2.2 (R Foundation for Statistical Computing, Vienna,
Austria) [17]. Upon model fitting, we estimated the
posterior probabilities of any benefit (RR < 1) and of
Data collection and risk of bias assessment meaningful clinical effect (a priori defined as a 1%
Two investigators independently extracted data from absolute risk reduction) based on the weighted control
included studies using a standardized data collection event rate by generalized linear mixed model and the
form. We resolved disagreements by consensus or by metaprop package. We considered a 1% absolute risk
involving a third senior author. Data such as first author, reduction as clinically meaningful difference because,
year of publication, country, study design, setting (hospi- among millions of critically ill patients undergoing tra-
tal or other settings at enrollment), and primary and sec- cheal intubation annually in the world [18], even such a
ondary outcomes were collected. If data ware missing for subtle difference could potentially impact thousands of
this meta-analysis or if the authors reported only short- lives from a public health perspective.
term mortality, we contacted the first or corresponding We performed two subgroup analyses for the primary
author to request further information. outcome: exclusion of high-risk of bias studies and
We assessed the risk of bias for randomized studies by inclusion of randomized trials. A sensitivity analysis for
using the Cochrane risk of bias tool for randomized tri- the primary outcome was also performed using a Man-
als version 2 (RoB 2) [10] and for propensity-matched tel–Haenszel random-effects model with a frequentist
studies by using risk of bias in non-randomized studies approach.
of interventions (ROBINS-I) tool [11]. We assessed the For the secondary outcomes, frequentist analyses
overall certainty of the evidence based on the Grading were conducted using Review Manager version 5.4 [19].
of Recommendations Assessment, Development, and We calculated RR and 95% CIs using a Mantel–Haen-
Evaluation (GRADE) methodology [12]. We prepared szel random-effects model. A P value less than 0.05 was
the GRADE evidence profile tables using the GRADEpro considered statistically significant.
software [13]. The presence of publication bias and small We also performed a trial sequential analysis (TSA)
study effects on the primary outcome was investigated by [20] for the primary outcome with a diversity-adjusted
visual estimation of funnel plot. information size calculated using a two-sided alpha
of 0.05, a power of 80%, an anticipated relative risk
decrease of 10%, and the actual control event rate.
Outcomes We used the TSA Viewer software (Version 0.9 0.5
The primary outcome was all-cause mortality at the long- 0.10 Beta. Copenhagen Trial Unit, Centre for Clinical
est follow-up available. The secondary outcomes included Intervention Research, Rigshospitalet, Copenhagen,
Sequential Organ Failure Assessment (SOFA) score [14], Denmark).
ventilator-free days at day 28, vasopressor-free days at
day 28, post-induction mean arterial pressure (MAP),
and successful intubation on the first attempt.
Koroki et al. Critical Care (2024) 28:48 Page 4 of 9

mortality data, we received no responses. The included

studies were published between 2009 and 2023; four
RCTs [23–26] and one propensity-matched study [28]
were performed in the US, one RCT in France [21], one
RCT in the Netherlands [22], and one in Thailand [27].
All but one study was single centered [22–28].
The dose of ketamine was 1–2 mg/kg [21, 23–28],
except for one trial which used a combination of 0.5 mg/
kg of ketamine with 0.5 mg/kg of propofol [22]. All stud-
ies used etomidate as the comparator [21–28]. The char-
acteristics of the included studies are summarized in
Table 1. Among the included studies, seven were judged
at low risk of bias and one at some concerns of bias
(Additional file 14: Table S2).
Table 2 summarizes the outcome data. We estimated
the probability that ketamine reduced mortality com-
pared with etomidate at 83.2% (Fig. 2; 376/1475 [25%]
vs. 411/1503 [27%]; RR, 0.93; 95% credible interval,
0.79–1.08) and that the probability of 1% absolute risk
reduction was 62.2% (Figs. 2 and 3). The visual inspec-
Fig. 1 Flowchart of study selection
tion of the funnel plot did not suggest considerable pub-
lication bias, and the TSA confirmed inconclusiveness
of the findings and need for further research (Additional
Results file 3: Fig. S1 and Additional file 4: Fig. S2). When con-
We included seven randomized controlled trials (RCTs) fining the analysis to RCTs, the probability of RR < 1 was
[21–27] and one propensity-matched study [28] com- 68.6% (Table 2; Additional file 5: Fig. S3 and Additional
prising a total of 2978 critically ill adult patients file 6: Fig. S4). None of the included studies had a high
(Fig. 1), with major exclusions and reasons for exclusion risk of bias; therefore, a sensitivity analysis excluding
detailed in Additional file 13: Table S1. Despite contact- studies at high risk of bias yielded the same result as the
ing the corresponding authors of the studies without primary analysis (Table 2). A sensitivity analysis using a

Table 1 Characteristics of included studies

First author, year Country No. of centers Study design Patients Ketamine Comparator Timepoint
dose, mg/ of mortality
kg assessment

Jabre [21] France 65 RCT​ Adult patients requiring emer- 2 Etomidate 28 days
gency intubation
Punt [22] Netherlands 1 RCT​ Critically ill adult patients intu- 0.5 Etomidate 28 days
bated in the ICU
Van Berkel [28] US 1 PS-matched Septic patients requiring prehos- 1.8 Etomidate Hospital discharge
pital intubation
Smischney [23] US 1 RCT​ Critically ill adults who admitted 0.5a Etomidate Hospital discharge
to ICU and required emergency
intubation
Driver [24] US 1 RCT​ Adult trauma patients undergo- 2 Etomidate 30 days
ing RSI in the ED
Powers [25] US 1 RCT​ Adult patients requiring RSI 2 Etomidate Hospital discharge
Matchett [26] US 1 RCT​ Adults requiring emergency 1–2 Etomidate 28 days
intubation
Srivilaithon [27] Thailand 1 RCT​ Adult patients with suspected 1–2 Etomidate 28 days
sepsis requiring intubation
in the ED
ED Emergency department; ICU Intensive care unit; PS Propensity score; RCT​Randomized controlled trial; and RSI Rapid sequence intubation
a
Ketamine/propofol mixture = 0.5 mg/kg of ketamine plus 0.5 mg/kg of propofol
Koroki et al. Critical Care (2024) 28:48 Page 5 of 9

Table 2 Effects of ketamine on primary and secondary outcomes

Outcome No. of No. of patients Effect measure 95% CI Probability of I2
studies (RR or MD) benefit

Primary outcome
Mortality at the longest follow-up available 8 2978 0.93 0.79–1.08a 83.2%
Randomized controlled trials only 7 2748 0.96 0.81–1.13a 68.6%
Exclusion of high risk of bias studies 8 2978 0.93 0.79–1.08a 83.2%
Secondary outcome
SOFA score 4 1633 − 0.30 − 0.69–0.08 0%
Vasopressor-free days (to day 28) 4 1704 0.07 − 0.27–0.41 67%
Ventilator-free days (to day 28) 4 1555 1.2 − 1.4–3.7 55%
Post-induction mean arterial pressure, mmHg 2 929 − 3.1 − 6.4–0.2 0%
Successful intubation on the first attempt 3 1204 1.00 0.96–1.04 0%
RR Risk ratio; MD Mean difference; CI Confidence interval; and SOFA Sequential organ failure assessment
a
Indicates values are for credible interval

All Studies
Ketamine Comparator Risk ratio
Study (Year) Died Total Died Total with 95% CI

Jabre P (2009) 87 327 93 328 0.94 [ 0.73, 1.20]

Punt CD (2014) 54 140 61 161 1.02 [ 0.76, 1.36]
Van Berkel MA (2017) 36 115 49 115 0.73 [ 0.52, 1.04]
Smischney NJ (2019) 25 84 26 76 0.87 [ 0.55, 1.37]
Driver BE (2019) 8 70 15 73 0.56 [ 0.25, 1.23]
Power WF (2021) 0 208 0 220 1.06 [ 0.02, 53.05]
Matchett G (2022) 131 401 142 400 0.92 [ 0.76, 1.12]
Srivilaithon W (2023) 35 130 25 130 1.40 [ 0.89, 2.20]

Overall Bayesian - Median [95%CrI] 0.93 [ 0.79, 1.08]

Heterogeneity: τ = 0.091 [0.016-0.227] Favors ketamine Favors comparator

0.25 0.50 1 2 4
Fig. 2 Forest plot for mortality at the longest follow-up available

frequentist approach showed no significant difference − 0.2–0.41 days; P = 0.69; I2 = 67%), post-induction MAP
between the two groups (Additional file 7: Fig. S5). (MD, − 3.1 mmHg; 95% CI − 6.4–0.2 mmHg; P = 0.07;
The SOFA score was reported in three RCTs and one I2 = 0%), or successful intubation on the first attempt (RR,
matched study [21, 24, 26, 28], ventilator-free days at day 1.00; 95% CI 0.96–1.04; P = 0.99; I2 = 0%) (see Additional
28 in four RCTs [21, 23, 24, 26], vasopressor-free days file 8: Fig. S6, Additional file 9: Fig. S7, Additional file 10:
at day 28 in four RCTs [21, 22, 24, 26], post-induction Fig. S8, Additional file 11: Fig. S9, and Additional file 12:
MAP in two RCTs [23, 26], and successful intubation on Fig. S10). The GRADE assessment is described in Addi-
the first attempt in three RCTs [24, 26, 27]. The pooled tional file 15: Table S3.
data detected no statistically significant between-group
differences in SOFA score (MD, − 0.30; 95% CI − 0.69– Discussion
0.08; P = 0.12; I2 = 0%), ventilator-free days at day 28 Key findings
(MD, 1.2 days; 95% CI − 1.4–3.7 days; P = 0.38; I2 = 55%), This Bayesian meta-analysis of seven RCTs and one
vasopressor-free days at day 28 (MD, 0.07 days; 95% CI propensity-matched study found a moderate probability
Koroki et al. Critical Care (2024) 28:48 Page 6 of 9

Fig. 3 Probability density functions for combined posterior distributions of the difference in mortality in the overall population

that ketamine as an induction agent for tracheal intuba- P = 0.02) [29], the present meta-analysis showed no
tion was associated with improved survival in critically ill significant difference in post-induction MAP. The dif-
patients. The likelihood of survival benefits was reduced ferent results may be mainly attributable to different
when the analysis was restricted to randomized trials eligibility criteria. In the previous meta-analysis, no
alone. No statistically significant difference was observed restriction on study design was placed, leading to a
in any secondary outcome. predominance of retrospective observational studies in
the included articles [29], while the current meta-anal-
ysis selected only randomized and propensity-matched
Relationship with the previous literature
studies.
Ketamine and etomidate are suggested in clinical guide-
Since etomidate was the only comparator in this
lines as induction agents for RSI because of their rela-
meta-analysis, its common adverse effect of adrenal
tively modest cardiovascular effects [3, 4]; however, few
insufficiency might have affected the mortality result.
meta-analyses have focused on comparing these two
A recent meta-analysis showed that the risk of adre-
agents [7, 29]. In a previous meta-analysis of randomized
nal insufficiency was significantly higher in the etomi-
trials of etomidate in critically ill patients, a subgroup
date group than the ketamine group [7]. The diagnosis
analysis suggested an increased mortality risk of eto-
of adrenal insufficiency following etomidate admin-
midate compared with ketamine (six RCTs with 2399
istration typically is made several hours to a day after
patients; RR, 1.18; 95% CI 1.02–1.37) [7]. The present
induction, which is different from observation timing
meta-analysis increased the sample size by adding one
for SOFA score (1–3 days) [21, 24, 26, 28] and for post-
recent RCT [27] and one propensity-matched study [28],
induction MAP (within 1 h) [23, 26]. Therefore, adrenal
and found a moderate probability of mortality reduction
insufficiency might have contributed to the mortality
with ketamine. However, the inconclusive TSA results
findings without affecting the secondary outcomes.
and the reduced probability of benefit in the RCT sub-
In addition to ketamine and etomidate, propofol
group leave substantial equipoise surrounding the effect
is also listed among induction agents for critically ill
of ketamine on mortality.
patients [3, 4]. Although we identified no randomized
Hypotension is the most common peri-intubation
or matched study that compared ketamine with propo-
complication in critically ill patients [2]. While eto-
fol, a secondary analysis of a recent international large
midate was associated with less risk of post-intuba-
cohort study found induction with propofol as an inde-
tion hypotension compared to ketamine in a previous
pendent risk factor for peri-intubation hemodynamic
meta-analysis (odds ratio, 0.53; 95% CI 0.31–0.91;
complications in critically ill patients [5].
Koroki et al. Critical Care (2024) 28:48 Page 7 of 9

Implications for clinical practice and future research which could have improved the quality of evidence. Fur-
One important aspect of this meta-analysis is the use thermore, Bayesian meta-analysis for mortality allowed
of Bayesian analysis for mortality. Unlike a frequentist for flexible inferences, which cannot be made with a
approach, whose conclusion always falls into a dichoto- frequentist approach. Furthermore, the addition of TSA
mous yes or no based on the 95% CI (i.e., in this case, provided another perspective to assess the robustness of
ketamine does not reduce mortality), Bayesian analysis the currently available evidence. The TSA suggested that
can provide a more nuanced interpretation concerning not only is the impact of ketamine on mortality currently
the potential magnitude and direction of the treatment inconclusive, but also that more evidence is needed to
effect. When considering the relationship between dif- reach a definitive conclusion.
ferent types of sedatives and mortality, such treatment We should acknowledge several limitations. First,
effects may be small, which, in turn, would require large among the eight studies included in this meta-analysis,
sample sizes. However, due to the urgent nature of per- etomidate was the only comparator. As a result, no con-
forming tracheal intubation in critically ill patients, clusion is available regarding the comparison of ketamine
conducting large-scale randomized trials would prove with other induction agents. Second, peri-intubation
challenging. Furthermore, the high severity and con- interventions other than induction agents (e.g., opioids,
siderable heterogeneity in critically ill patients make it neuromuscular blockades, and vasopressors) were not
challenging to detect a statistically significant mortality always standardized within each study and were heterog-
difference attributable to a specific intervention. Given enous among different studies. In addition, most studies
this context, we decided to perform a Bayesian analysis to were single centered. However, randomized or matched
allow for probabilistic interpretation about ketamine and design have minimized potential biases that may have
mortality. The Bayesian approach is also beneficial from arisen. Third, the rarity of reported psychological adverse
a global public health perspective. Considering the vast events has hindered the evaluation of this critical out-
number of critically ill patients undergoing tracheal intu- come. Therefore, future research should investigate this
bation annually [18], even a minor mortality difference relevant patient-reported outcome, particularly given
could potentially have a considerable impact. that nightmare is a typical adverse event associated with
In addition, the present meta-analysis highlights the ketamine use [31].
need for further investigation comparing the two key
induction agents for tracheal intubation in intensive care Conclusions
settings. In fact, one ongoing multicenter RCT (N = 2324; This meta-analysis identified seven randomized trials and
trial registration: NCT05277896) will add important evi- one propensity-matched study which assessed ketamine
dence to this meta-analysis. as an induction agent compared to etomidate among crit-
For clinical practice, this meta-analysis cannot sup- ically ill adults requiring tracheal intubation. We found a
port a clear recommendation regarding the choice of moderate probability that induction with ketamine, com-
induction agents. Recent guidelines for RSI suggested no pared to etomidate, was associated with a reduced risk of
difference regarding the effects of induction agents on mortality. Further research is required to determine the
mortality or hypotension [30]. However, a moderate like- potential beneficial effects of ketamine on clinically rel-
lihood toward decreased mortality with ketamine com- evant outcomes.
pared with etomidate shown in our meta-analysis may
help clinical decision making when the treating clinician
has experience with both drugs. Of note, etomidate is not Abbreviations
CI Confidence interval
available in several countries. For clinicians working in CrI Credible interval
such countries, our study findings cannot be generalized, ICU Intensive care unit
and future research is necessary to evaluate other induc- PRISMA  Preferred Reporting Items for Systematic Reviews and
Meta-Analyses
tion agents with clinical equipoise. RCT​ Randomized controlled trial
RR Risk ratio
RSI Rapid sequence intubation
TSA Trial sequential analysis
Strengths and limitations
This meta-analysis provides updated mortality data
Supplementary Information
of ketamine compared with etomidate in critically ill
The online version contains supplementary material available at https://​doi.​
patients. The inclusion of only randomized and pro- org/​10.​1186/​s13054-​024-​04831-4.
pensity-matched studies increased the sample size and
statistical power while preserving the quality of eligi- Additional file 1. PRISMA checklist.
ble studies. Most of them were judged low risk of bias, Additional file 2. Search strategy.
Koroki et al. Critical Care (2024) 28:48 Page 8 of 9

Author details
Additional file 3: Fig. S1. Funnel plots for mortality at the longest follow- 1
Department of Intensive Care Medicine, Kameda Medical Center, 929
up available. Higashi‑cho, Kamogawa 296‑8602, Japan. 2 Department of Anesthesia
Additional file 4: Fig. S2. Trial sequential analysis for mortality at the and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy. 3 School
longest follow-up available. Alpha error = 5%, power = 80%, relative risk of Medicine, Vita-Salute San Raffaele University, Milan, Italy. 4 Division of Infec-
decrease = 10%, and diversity = 0%. tious Diseases, Department of Medicine, McGill University, Montreal, QC,
Canada.
Additional file 5: Fig. S3. Forest plot for mortality at the longest follow-
up available in randomized controlled trials.
Received: 14 December 2023 Accepted: 10 February 2024
Additional file 6: Fig. S4. Probability density functions for combined
posterior distributions. The difference in mortality at the longest follow-up
available in randomized controlled trials.
Additional file 7: Fig. S5. Forest plot for mortality at the longest follow-
up available using a frequentist approach.
Additional file 8: Fig. S6. Forest plot for Sequential Organ Failure Assess- References
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