Specific sedative hypnotic agents, administered to facilitate endotracheal intubation (ETI) in critically ill adults, may lead to adverse outcomes such as peri-intubation cardiovascular collapse. However, little is known from systematic investigations of the impact these individual agents have on cardiovascular function or other clinical outcomes.
Data sources
MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, Scopus and Web of science databases.
Study selection
We conducted a systematic search for randomized and non-randomized studies that evaluated adult (≥18 years) critically ill patients who were sedated to facilitate ETI with ketamine, propofol, ketamine/propofol, etomidate, or a benzodiazepine and who had data on peri-intubation hemodynamics and at least one other outcome involving acute kidney injury, delirium, opioid use, intubation difficulty, sequential organ failure assessment, length of stay, or mortality. Eighty-five studies were identified for eligibility assessment with 23 included in the analysis.
Data extraction
Two reviewers independently screened articles, extracted data from selected articles, and assessed risk of bias using ROBINS-I for observational studies and revised Cochrane Risk of Bias tool for randomized controlled trials.
Data synthesis
Acute cardiovascular dysfunction (peri-intubation hemodynamic instability and/or cardiac arrest) was similar between etomidate and ketamine with more events seen when propofol versus non-propofol sedation was administered. However, exploratory meta-analysis demonstrated no difference between etomidate and ketamine (OR 1.05 [95%CI 0.60-1.84]) or between etomidate and propofol (OR 0.91 [95%CI 0.33-2.46]). Compared to ketamine, etomidate demonstrated lower survival to hospital discharge in the included studies in exploratory meta-analysis OR 0.76 (95%CI 0.62-0.92). Limited data existed for other outcomes with no discernible differences between sedative agents.
Conclusions
Acute cardiovascular dysfunction was more common when propofol, as compared to non-propofol sedation, was administered, although not statistically significant in exploratory meta-analysis. In addition, etomidate conferred lower survival to hospital discharge versus non-etomidate sedation, which was confirmed in exploratory meta-analysis of etomidate versus ketamine.
SmischneyNKashyapRSeisaMSchroederDDiedrichD. Endotracheal intubation among the critically ill: Protocol for a multicenter, observational, prospective study. JMIR Res Protoc. 2018;7(12):e11101. doi:https://doi.org/10.2196/11101
2.
JaberSAmraouiJLefrantJ-Y, et al.Clinical practice and risk factors for immediate complications of endotracheal intubation in the intensive care unit: A prospective, multiple-center study. Crit Care Med. 2006;34(9):2355‐2361. doi:https://doi.org/10.1097/01.CCM.0000233879.58720.87
3.
De JongAJungBJaberS. Intubation in the ICU: We could improve our practice. Crit Care. 2014;18:209. doi:https://doi.org/10.1186/cc13776
4.
SmischneyNJKashyapRKhannaAK, et al.Risk factors for and prediction of post-intubation hypotension in critically ill adults: A multicenter prospective cohort study. PLoS ONE. 2020;15(8):e0233852. doi:https://doi.org/10.1371/journal.pone.0233852
5.
RussottoVMyatraSNLaffeyJG, et al.Intubation practices and adverse peri-intubation events in critically ill patients from 29 countries. JAMA. 2021;325(12):1164‐1172. doi:https://doi.org/10.1001/jama.2021.1727
6.
GreenRSTurgeonAFMcIntyreLA, et al.Postintubation hypotension in intensive care unit patients: A multicenter cohort study. J Crit Care. 2015;30(5):1055‐1060. doi:https://doi.org/10.1016/j.jcrc.2015.06.007
7.
SimpsonGDRossMJMcKeownDWRayDC. Tracheal intubation in the critically ill: A multi-centre national study of practice and complications. Br J Anaesth. 2012;108(5):792‐799. doi:https://doi.org/10.1093/bja/aer504
8.
CookTMWoodallNHarperJBengerJ. Major complications of airway management in the UK: Results of the fourth national audit project of the royal college of anaesthetists and the difficult airway society. Part 2: Intensive care and emergency departments. Br J Anaesth. 2011;106(5):632‐642. doi:https://doi.org/10.1093/bja/aer059
9.
SmischneyNJSuraniSRMontgomeryA, et al.Hypotension prediction score for endotracheal intubation in critically ill patients: A post hoc analysis of the HEMAIR study. J Intensive Care Med. 2022;37(11):1467‐1479. doi:https://doi.org/10.1177/08850666221085256
10.
HeffnerACSwordsDKlineJAJonesAE. The frequency and significance of postintubation hypotension during emergency airway management. J Crit Care. 2012;27(4):417.e9‐13. doi:https://doi.org/10.1016/j.jcrc.2011.08.011
11.
SunshineJEDeemSWeissNS, et al.Etomidate, adrenal function, and mortality in critically ill patients. Respir Care. 2013;58(4):639‐646. Doi:https://doi.org/10.4187/respcare.01956
12.
GuWJWangFTangLLiuJC. Single-dose etomidate does not increase mortality in patients with sepsis: A systematic review and meta-analysis of randomized controlled trials and observational studies. Chest. 2015;147(2):335‐346. doi:https://doi.org/10.1378/chest.14-1012
13.
SmischneyNJNicholsonWTBrownDR, et al.Ketamine/propofol admixture vs etomidate for intubation in the critically ill: KEEP PACE randomized clinical trial. J Trauma Acute Care Surg. 2019;87(4):883‐891. doi:https://doi.org/10.1097/TA.0000000000002448
14.
BruderEABallIMRidiSPickettWHohlC. Single induction dose of etomidate versus other induction agents for endotracheal intubation in critically ill patients. Cochrane Database Syst Rev. 2015;1(1):CD010225. doi:https://doi.org/10.1002/14651858.CD010225.pub2
15.
JabrePCombesXLapostolleF, et al.Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: A multicentre randomised controlled trial. Lancet. 2009;374(9686):293‐300. doi:https://doi.org/10.1016/S0140-6736(09)60949-1
16.
PageMJMcKenzieJEBossuytPM, et al.The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Br Med J.2021;372:n71. doi:https://doi.org/10.1136/bmj.n71
17.
DeeksJJHigginsJPTAltmanDGMcKenzieJEVeronikiAA. Chapter 10: Analysing data and undertaking meta-analyses [last updated November 2024]. In: HigginsJPTThomasJChandlerJCumpstonMLiTPageMJWelchVA, eds. Cochrane Handbook for Systematic Reviews of Interventions version 6.5. 2024. www.training.cochrane.org/handbook.
18.
SterneJAHernánMAReevesBC, et al.ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions. Br Med J.2016;355:i4919. doi:https://doi.org/10.1136/bmj.i4919
19.
SterneJACSavovićJPageMJ, et al.Rob 2: A revised tool for assessing risk of bias in randomised trials. Br Med J.2019;366:l4898. doi:https://doi.org/10.1136/bmj.l4898
20.
McGuinnessLAHigginsJPT. Risk-of-bias VISualization (robvis): An R package and Shiny web app for visualizing risk-of-bias assessments. Res Synth Methods. 2021;12(1):55‐61. doi:https://doi.org/10.1002/jrsm.1411
21.
ElsharkawyAMAl-AwadySMHelmyTA. Postintubation hypotension and its association with prolonged ICU length of stay and ICU mortality. The Egyptian Journal of Critical Care Medicine. 2020;7(1):26‐32. doi:https://doi.org/10.1097/EJ9.0000000000000008
22.
MatchettGGasanovaIRiccioCA, et al.Etomidate versus ketamine for emergency endotracheal intubation: A randomized clinical trial. Intensive Care Med. 2022;48(1):78‐91. doi:https://doi.org/10.1007/s00134-021-06577-x
23.
ZettervallSLSirajuddinSAkstS, et al.Use of propofol as an induction agent in the acutely injured patient. Eur J Trauma Emerg Surg. 2015;41(4):405‐411. doi:https://doi.org/10.1007/s00068-014-0479-3
24.
FathySHasaninAMostafaM, et al.The benefit of adding lidocaine to ketamine during rapid sequence endotracheal intubation in patients with septic shock: A randomised controlled trial. Anaesth Crit Care Pain Med. 2021;40(1):100731. doi:https://doi.org/10.1016/j.accpm.2020.06.017
25.
CinarOPiratAZeynelogluP, et al.Hemodynamic and metabolic responses to ketamine and etomidate seals during endotracheal intubation in critical patients. J Turk Soc Intens Care. 2011;9(3). doi:https://doi.org/10.4274/tybdd.09.15
26.
Gallo de MoraesARacedo AfricanoCJHoskoteSS, et al.Ketamine and propofol combination (“ketofol”) for endotracheal intubations in critically ill patients: A case series. Am J Case Rep. 2015;16:81‐86. doi:https://doi.org/10.12659/AJCR.892424
27.
KnackSKSPrekkerMEMooreJC, et al.The effect of ketamine versus etomidate for rapid sequence intubation on Maximum sequential organ failure assessment score: A randomized clinical trial. J Emerg Med. 2023;65(5):e371‐e382. doi:https://doi.org/10.1016/j.jemermed.2023.06.009
28.
LeouKMendezDHoraniG, et al.Effects of etomidate on postintubation hypotension, inflammatory markers, and mortality in critically ill patients with COVID-19: An international, multicenter, retrospective study. J Intensive Care Med. 2023;38(10):922‐930. doi:https://doi.org/10.1177/08850666231173847
29.
JungBClavierasNNougaretS, et al.Effects of etomidate on complications related to intubation and on mortality in septic shock patients treated with hydrocortisone: A propensity score analysis. Crit Care. 2012;16(6):R224. doi:https://doi.org/10.1186/cc11871
30.
Diaz-GuzmanEMireles-CabodevilaEHeresiGABauerSRArroligaAC. A comparison of methohexital versus etomidate for endotracheal intubation of critically ill patients. Am J Crit Care. 2010;19(1):48‐54. doi:https://doi.org/10.4037/ajcc2010562
31.
BakhshAAlnashriMAlawamiF, et al.Changes in hemodynamic parameters with the use of etomidate versus ketamine induction in the emergency department. Signa Vitae. 2021;17(2):85‐92. doi:https://doi.org/10.22514/sv.2021.005
32.
AldayNJJonesGMKimmonsLAPhillipsGSMcCallisterJWDoepkerBA. Effects of etomidate on vasopressor use in patients with sepsis or severe sepsis: A propensity-matched analysis. J Crit Care. 2014;29(4):517‐522. doi:https://doi.org/10.1016/j.jcrc.2014.02.002
33.
Van BerkelMAExlineMCCapeKM, et al.Increased incidence of clinical hypotension with etomidate compared to ketamine for intubation in septic patients: A propensity matched analysis. J Crit Care. 2017;38:209‐214. doi:https://doi.org/10.1016/j.jcrc.2016.11.009
34.
PerierFChateauneufALJacqG, et al.Comparison of etomidate and sodium thiopental for induction during rapid sequence intubation in convulsive status epilepticus: A retrospective single-center study. Seizure. 2018;61:170‐176. doi:https://doi.org/10.1016/j.seizure.2018.08.022
35.
RussottoVTassistroEMyatraSN, et al.Peri-intubation cardiovascular collapse in patients who are critically ill: Insights from the INTUBE study. Am J Respir Crit Care Med. 2022;206(4):449‐458. doi:https://doi.org/10.1164/rccm.202111-2575OC
36.
DennisCJChungKKHollandSR, et al.Risk factors for hypotension in urgently intubated burn patients. Burns. 2012;38(8):1181‐1185. doi:https://doi.org/10.1016/j.burns.2012.07.004
37.
KunkelSLenzT. Hemodynamics in helicopter emergency medical services (HEMS) patients undergoing rapid sequence intubation with etomidate or ketamine. J Emerg Med. 2022;62(2):163‐170. doi:https://doi.org/10.1016/j.jemermed.2021.10.004
38.
KuzaCMToJChangA, et al.A retrospective data analysis on the induction medications used in trauma rapid sequence intubations and their effects on outcomes. Eur J Trauma Emerg Surg. 2022;48(3):2275‐2286. doi:https://doi.org/10.1007/s00068-021-01759-0
39.
StankeLNakajimaSZimmermanLHCollopyKFalesCPowersW4th. Hemodynamic effects of ketamine versus etomidate for prehospital rapid sequence intubation. Air Med J. 2021;40(5):312‐316. doi:https://doi.org/10.1016/j.amj.2021.05.009
40.
GamageW. Endotracheal intubation in critically ill patients, practices, complications and factors associated with post intubation hypotension: A study in national hospital Sri Lanka. Sri Lankan Journal of Anesthesiology. 2020;28(2):101‐107. doi:https://doi.org/10.4038/slja.v28i2.8569
41.
AsfarPMezianiFHamelJF, et al.High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583‐1593. doi:https://doi.org/10.1056/NEJMoa1312173
42.
LamontagneFMeadeMOHébertPC, et al.Higher versus lower blood pressure targets for vasopressor therapy in shock: A multicentre pilot randomized controlled trial. Intensive Care Med. 2016;42(4):542‐550. doi:https://doi.org/10.1007/s00134-016-4237-3
43.
KhannaAKMaheshwariKMaoG, et al.Association between mean arterial pressure and acute kidney injury and a composite of myocardial injury and mortality in postoperative critically ill patients: A retrospective cohort analysis. Crit Care Med. 2019;47(7):910‐917. doi:https://doi.org/10.1097/CCM.0000000000003763
44.
SmischneyNJShawADStapelfeldtWH, et al.Postoperative hypotension in patients discharged to the intensive care unit after non-cardiac surgery is associated with adverse clinical outcomes. Crit Care. 2020;24(1):682. doi:https://doi.org/10.1186/s13054-020-03412-5
45.
GreerAHewittMKhazanehPT, et al.Ketamine versus etomidate for rapid sequence intubation: A systematic review and meta-analysis of randomized trials. Crit Care Med. 2025;53(2):e374‐e383. doi:https://doi.org/10.1097/CCM.0000000000006515
46.
Armengol de la HozMRangasamyVBrenes BastosA, et al.Intraoperative hypotension and acute kidney injury, stroke, and mortality during and outside cardiopulmonary bypass: A retrospective observational cohort study. Anesthesiology. 2022;136(6):927‐939. doi:https://doi.org/10.1097/ALN.0000000000004175
47.
ShawADKhannaAKSmischneyNJ, et al.Intraoperative hypotension is associated with persistent acute kidney disease after noncardiac surgery: A multicentre cohort study. Br J Anaesth. 2022;129(1):13‐21. doi:https://doi.org/10.1016/j.bja.2022.03.027
48.
GregoryAStapelfeldtWHKhannaAK, et al.Intraoperative hypotension is associated with adverse clinical outcomes after noncardiac surgery. Anesth Analg. 2021;132(6):1654‐1665. doi:https://doi.org/10.1213/ANE.0000000000005250
49.
LehmanLWSaeedMMoodyGMarkR. Hypotension as a risk factor for acute kidney injury in ICU patients. Comput Cardiol. 2010;37:1095‐1098.
50.
PanwarRTarvadeSLanyonN, et al.Relative hypotension and adverse kidney-related outcomes among critically ill patients with shock. A multicenter, prospective cohort study. Am J Respir Crit Care Med. 2020;202(10):1407‐1418. doi:https://doi.org/10.1164/rccm.201912-2316OC
51.
CarayannopoulosKLPiduttiAUpadhyayaY, et al.Mean arterial pressure targets and patient-important outcomes in critically ill adults: A systematic review and meta-analysis of randomized trials. Crit Care Med. 2023;51(2):241‐253. doi:https://doi.org/10.1097/CCM.0000000000005726
52.
MaheshwariKAhujaSKhannaAK, et al.Association between perioperative hypotension and delirium in postoperative critically ill patients: A retrospective cohort analysis. Anesth Analg. 2020;130(3):636‐643. doi:https://doi.org/10.1213/ANE.0000000000004517
53.
NguyenDNHuyghensLParraJSchiettecatteJSmitzJVincentJL. Hypotension and a positive fluid balance are associated with delirium in patients with shock. PLoS One. 2018;13(8):e0200495. doi:https://doi.org/10.1371/journal.pone.0200495
54.
WuTTKoSKookenRvan den BoogaardMDevlinJW. Exploring ketamine analgosedation use and its effect on incident delirium in critically ill adults. Crit Care Explor. 2021;3(10):e0544. doi:https://doi.org/10.1097/CCE.0000000000000544
55.
TarwadePSmischneyNJ. Endotracheal intubation sedation in the intensive care unit. World J Crit Care Med. 2022;11(1):33‐39. doi:https://doi.org/10.5492/wjccm.v11.i1.33
56.
RohGUSongYParkJKiYMHanDW. Effects of propofol on the inflammatory response during robot-assisted laparoscopic radical prostatectomy: A prospective randomized controlled study. Sci Rep. 2019;9(1):5242. doi:https://doi.org/10.1038/s41598-019-41708-x
57.
ChenRMChenTGChenTL, et al.Anti-inflammatory and antioxidative effects of propofol on lipopolysaccharide-activated macrophages. Ann N Y Acad Sci. 2005;1042(1):262‐271. doi:https://doi.org/10.1196/annals.1338.030
HelmySAAl-AttiyahRJ. The immunomodulatory effects of prolonged intravenous infusion of propofol versus midazolam in critically ill surgical patients. Anaesthesia. 2001;56(1):4‐8. doi:https://doi.org/10.1046/j.1365-2044.2001.01713.x
60.
ParkHYLeeYLimCYKimMParkJLeeT. Effects of etomidate use in ICU patients on ventilator therapy: A study of 12,526 patients in an open database from a single center. Korean J Anesthesiol. 2021;74(4):300‐307. doi:https://doi.org/10.4097/kja.20509
61.
AlbertSGSitaulaS. Etomidate, adrenal insufficiency and mortality associated with severity of illness: A meta-analysis. J Intensive Care Med. 2021;36(10):1124‐1129. doi:https://doi.org/10.1177/0885066620957596
62.
KorokiTKotaniYYaguchiT, et al.Ketamine versus etomidate as an induction agent for tracheal intubation in critically ill adults: A Bayesian meta-analysis. Crit Care. 2024;28(1):48. doi:https://doi.org/10.1186/s13054-024-04831-4
63.
WunschHBoschNALawAC, et al.Evaluation of etomidate use and association with mortality compared with ketamine among critically ill patients. Am J Respir Crit Care Med. 2024;210(10):1243‐1251. doi:https://doi.org/10.1164/rccm.202404-0813OC
64.
SrivilaithonWBumrungphanithawornADaorattanachaiK, et al.Clinical outcomes after a single induction dose of etomidate versus ketamine for emergency department sepsis intubation: A randomized controlled trial. Sci Rep. 2023;13(1):6362. doi:https://doi.org/10.1038/s41598-023-33679-x
65.
PowersWF. Evaluating the Hemodynamic Effects of Ketamine Versus Etomidate During Rapid Sequence Intubation (Ket-RSI). June 4, 2018. ClinicalTrials.gov, National Library of Medicine. Available from: https://clinicaltrials.gov/study/NCT03545503.
HeffnerACSwordsDSNussbaumMLKlineJAJonesAE. Predictors of the complication of postintubation hypotension during emergency airway management. J Crit Care. 2012;27(6):587‐593. doi:https://doi.org/10.1016/j.jcrc.2012.04.022
68.
SmischneyNJDemirciODiedrichDA,et al.Incidence of and risk factors for post-intubation hypotension in the critically ill. Med Sci Monit. 2016;22:346‐355. doi:https://doi.org/10.12659/msm.895919
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
