Clinical Question: During my time in emergency medicine, I had the opportunity to see a code being run for a patient who came in unresponsive. It was a very interesting case to witness because I was able to see the systematic approach that is taken before someone can be intubated. There is a checklist that the providing team goes through before they can intubate. One of the things that I noticed was their choice of induction agent for the rapid sequence intubation which was ketamine. Recently, it has been said that ketamine is being preferred over traditional choices of induction agents because it is believed to have less hemodynamic effects.
PICO Question: Does the use of ketamine in trauma patients needing rapid sequence intubation have less associated risk for adverse effects compared to etomidate?
PICO search terms:
| P | I | C | O |
| Rapid sequence intubation | ketamine | etomidate | morbidity |
| RSI | Adverse effects | ||
| risks | |||
| Hemodynamic effects |
Search tools and strategy used:
Please indicate what databases/tools you used, provide a list of the terms you searched together in each tool, and how many articles were returned using those terms and filters. Explain how you narrow your choices to the few selected articles.
PubMed
- Ketamine AND etomidate AND rapid sequence intubation 33
- Full text & last 10 years 33
- Systematic review, meta-analysis, RCT 3
- Full text & last 10 years 33
ScienceDirect
- Ketamine AND etomidate AND intubation 2,109
- Last 10 years 849
- American Journal of Emergency Medicine 39
- Last 10 years 849
Google Scholar
- Ketamine vs etomidate in RSI 3,100
- Last 10 years 1,940
When it came to narrowing down my search, I wanted to try and stick to using only systematic reviews, meta-analysis, and retrospective cohort studies. Randomized control trials weren’t going to be ideal or readily available because my question is looking for outcomes based on a treatment that has already been given specifically in an emergency setting. I also excluded any studies whose original language wasn’t English, so I focused my search on studies done in the US. Once my search was refined using those filters, I looked for articles published in the last 10 years. The articles that I chose directly answered my question.
Articles Chosen:
Article 1
| Citation:Baekgaard, J. S., Eskesen, T. G., Sillesen, M., Rasmussen, L. S., & Steinmetz, J. (2019). Ketamine as a Rapid Sequence Induction Agent in the Trauma Population: A Systematic Review. Anesthesia and analgesia, 128(3), 504–510. https://doi.org/10.1213/ANE.0000000000003568Link:https://journals.lww.com/anesthesia-analgesia/Fulltext/2019/03000/Ketamine_as_a_Rapid_Sequence_Induction_Agent_in.17.aspx |
| Abstract:The choice of drug used to facilitate endotracheal intubation in trauma patients during rapid sequence induction (RSI) may have an impact on survival. Ketamine is commonly used in the hemodynamically unstable trauma patient although it has been associated with side effects. This review sought to investigate whether ketamine should be preferred over other induction agents for RSI in trauma patients. PubMed, Embase, and the Cochrane Library were systematically searched on September 19, 2016 for studies reporting RSI of adult trauma patients with ketamine compared with another induction agent (etomidate, propofol, thiopental, or midazolam). No language restrictions were applied. The primary outcome was 30-day mortality, and secondary outcomes included information on blood transfusions, length of hospital stay, and hospital mortality. Risk of bias was assessed using the Cochrane Risk of Bias assessment tool for randomized trials and the Risk of Bias in Non-Randomized Studies of Interventions for nonrandomized studies of intervention. A total of 4 studies were included. A cohort study from 1976 compared thiopental (n = 26) with ketamine (n = 14) for RSI in trauma patients. The primary outcome was number of blood transfusions, and no significant difference was found. Risk of bias was judged to be serious. A randomized controlled trial from 2009 compared etomidate (n = 57) with ketamine (n = 47) and found no significant difference in 28-day mortality (odds ratio [OR], 0.8 [0.4–2.0]). The trial was judged to have a low risk of bias. Two cohort studies from 2015 and 2017 also compared etomidate (n = 116 and n = 526) with ketamine (n = 145 and n = 442). No significant difference in hospital mortality between the groups was observed (OR, 1.11 [0.38–3.27] and OR, 1.41 [0.91–2.16], respectively). Both studies were judged to have a moderate risk of bias, thus excluding the possibility of a meaningful meta-analysis. The study from 2017 also reported number of units of blood transfused during the first 48 hours after trauma and length of hospital stay. No significant differences were observed (OR, 1.14 [0.87–1.49] and OR, 1.1 [0.95–1.27], respectively). Extremely few studies have compared induction agents for RSI in trauma patients. No significant differences have been found in mortality, length of hospital stay, or number of blood transfusions after induction with ketamine compared to other induction agents, but a clinically relevant benefit or harm cannot be excluded. (Anesth Analg 2019;128:504–10) |
Article 2
| Citation:Sharda, S. C., & Bhatia, M. S. (2022). Etomidate Compared to Ketamine for Induction during Rapid Sequence Intubation: A Systematic Review and Meta-analysis. Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine, 26(1), 108–113. https://doi.org/10.5005/jp-journals-10071-24086Link:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8783236/ |
| Abstract:Aims and objectives: The objective of the study was to compare the safety and efficacy of etomidate and ketamine as induction agents for rapid sequence intubation (RSI) in acutely ill patients in emergency department and prehospital settings with respect to post-induction hypotension and first-pass intubation success during RSI.Materials and methods: For this systematic review and meta-analysis, we searched PubMed, Embase, Cochrane, and ClinicalTrials.gov between database inception and June 1, 2021. Articles were included if they compared safety and efficacy of etomidate vs ketamine as induction agents, in patients undergoing RSI in emergency department and prehospital settings, without any restrictions on study design. The outcome measures were incidence of post-induction hypotension and first-pass intubation success. The dichotomous outcomes were assessed for odds ratio (OR) with 95% confidence interval (CI) using random-effects meta-analysis.Results: Of 87 records identified, 9 were eligible, all assessed as having a low to moderate risk of overall bias. Six studies, including 12,060 patients from prehospital emergency medical services, air medical transport, and emergency department settings, compared post-induction hypotension incidence between etomidate and ketamine groups. The meta-analysis showed that etomidate was associated with decreased risk of post-induction hypotension compared to ketamine (OR: 0.53; 95% CI: 0.31–0.91; I2 = 68%). Seven studies, including 15,574 patients, reported on the rate of first-pass intubation success with etomidate vs ketamine. In the pooled analysis, no differences were seen in first-pass intubation success during RSI using etomidate vs ketamine as the induction agent (OR: 1.13; 95% CI: 0.95–1.36; I2 = 16%).Conclusion: The use of etomidate for induction during RSI is associated with a decreased risk of post-induction hypotension as compared to the use of ketamine, without an impact on the first-pass intubation success rate. |
Article 3
| Citation: Stanke, L., Nakajima, S., Zimmerman, L. H., Collopy, K., Fales, C., Powers, W. (2018). 984: Hemodynamic effects of ketamine versus etomidate for prehospital rapid sequence intubation. Critical Care Medicine, 46(1), 475–475. https://doi.org/10.1097/01.ccm.0000528991.40952.53Link:https://www.sciencedirect.com/science/article/abs/pii/S1067991X21000973 |
| Abstract: Objective: Rapid sequence intubation (RSI) is often required in managing critically ill patients in the prehospital setting. Although etomidate is a commonly used induction agent for RSI, ketamine has gained new interest in prehospital management with reported neutral hemodynamic effects. Limited data exist to support keta- mine as an alternative to etomidate, particularly in the prehospital setting. The purpose of this study was to evaluate hemodynamic changes after the administration of ketamine versus etomidate in prehospital RSI. Methods: This retrospective study evaluated adult patients undergoing prehospital RSI over 13 months within a regional emergency transport medicine service. Hypotension was defined as a 20% decrease in systolic blood pressure (SBP) within 15 minutes of receiving ketamine or etomidate. Hemodynamic data were collected 15 minutes before and 15 minutes after administration or until additional sedative medications were given. Data were analyzed using SPSS software (Version 21; IBM Corp, Armonk, NY), with P < .05 considered significant.Results: One hundred thirteen patients met the inclusion criteria (ketamine, n = 33; etomidate, n = 80), with the primary reasons for intubation being respiratory failure and trauma. There was no difference between the incidence of patients who experienced a 20% decrease in SBP (16% etomidate vs. 18% ketamine, P = .79). There were no significant differences in SBP pre- to post-administration between ketamine and etomidate. Conclusion: No hemodynamic differences occurred between patients who received ketamine versus etomidate for prehospital RSI. Neither drug was associated with an increased need for additional sedatives, and neither drug was associated with an increased first-pass intubation success rate. Larger, prospective, powered studies are required to identify patients who may benefit from either ketamine or etomidate. |
Article 4
| Citation: Foster, M., Self, M., Gelber, A., Kennis, B., Lasoff, D. R., Hayden, S. R., Wardi, G. (2022). Ketamine is not associated with more post-intubation hypotension than etomidate in patients undergoing endotracheal intubation. The American Journal of Emergency Medicine, 61, 131–136. https://doi.org/10.1016/j.ajem.2022.08.054Link:https://www-sciencedirect-com.york.ezproxy.cuny.edu/science/article/pii/S0735675722005587 |
| Abstract:Introduction: Emergency department (ED) patients undergoing emergent tracheal intubation often have multiple physiologic derangements putting them at risk for post-intubation hypotension. Prior work has shown that post- intubation hypotension is independently associated with increased morbidity and mortality. The choice of induction agent may be associated with post-intubation hypotension. Etomidate and ketamine are two of the most commonly used agents in the ED, however, there is controversy regarding whether either agent is superior in the setting of hemodynamic instability. The goal of this study is to determine whether there is a difference in the rate of post-intubation hypotension who received either ketamine or etomidate for induction. Additionally, we provide a subgroup analysis of patients at pre-existing risk of cardiovascular collapse (identified by pre- intubation shock index (SI) > 0.9) to determine if differences in rates of post-intubation hypotension exist as a function of sedative choice administered during tracheal intubation in these high-risk patients. We hypothesize that there is no difference in the incidence of post-intubation hypotension in patients who receive ketamine versus etomidate.Methods: A retrospective cohort study was conducted on a database of 469 patients having undergone emergent intubation with either etomidate or ketamine induction at a large academic health system. Patients were identified by automatic query of the electronic health records from 1/1/2016–6/30/2019. Exclusion criteria were patients <18-years-old, tracheal intubation performed outside of the ED, incomplete peri-intubation vital signs, or cardiac arrest prior to intubation. Patients at high risk for hemodynamic collapse in the post-intubation period were identified by a pre-intubation SI > 0.9. The primary outcome was the incidence of post-intubation hypotension (systolic blood pressure < 90 mmHg or mean arterial pressure < 65 mmHg). Secondary outcomes included post-intubation vasopressor use and mortality. These analyses were performed on the full cohort and an explor- atory analysis in patients with SI > 0.9. We also report adjusted odds ratios (aOR) from a multivariable logistic regression model of the entire cohort controlling for plausible confounding variables to determine independent factors associated with post-intubation hypotension.Results: A total of 358 patients were included (etomidate: 272; ketamine: 86). The mean pre-intubation SI was higher in the group that received ketamine than etomidate, (0.97 vs. 0.83, difference: −0.14 (95%, CI -0.2 to −0.1). The incidence of post-intubation hypotension was greater in the ketamine group prior to SI stratification (difference: −10%, 95% CI −20.9% to −0.1%). Emergency physicians were more likely to use ketamine in patients with SI > 0.9. In our multivariate logistic regression analysis, choice of induction agent was not associated with post-intubation hypotension (aOR 1.45, 95% CI 0.79 to 2.65). We found that pre-intubation shock index was the strongest predictor of post-intubation hypotension.Conclusion: In our cohort of patients undergoing emergent tracheal intubation, ketamine was used more often for patients with an elevated shock index. We did not identify an association between the incidence of post-intubation hypotension and induction agent between ketamine and etomidate. Patients with an elevated shock index were at higher risk of cardiovascular collapse regardless of the choice of ketamine or etomidate. |
Summary of Evidence:
| Author (Date) | Level of Evidence | Sample/Setting (# of subjects/studies, cohort definitions etc.) | Outcome(s) Studied | Key Findings | Limitations and Biases |
| Baekgaard, J. S., Eskesen, T. G., Sillesen, M., Rasmussen, L. S., & Steinmetz, J. (2019) | Systematic Review | – total # of participants: 1,333- adults >16 y/o intubated in pre-hospital setting or in ED within 1 hr of arrival- 4 studies included: 3 observational and 1 RCT- ISS: Injury Severity Score-GCS; Glasgow Coma Scale-Cromartie: 50 participants from Vietnam War; compared Ketamine to Thiopental in non-randomized manner; study period from Jan-Oct 1971- Jabre et al: 104 participants from France; compared Ketamine to Etomidate; study period April 2007-Feb 2008-Lyon et al: 211 participants from UK; compared Ketamine to Etomidate; study period July 2007-Oct 2008Upchurch et al: 968 participants from USA; compared Ketamine to Etomidate; study period Jan 2011-Dec 2012 (etomidate) & Dec 2012-2014 (Ketamine) | Primary: 30-day mortalitySecondary: In-hospital mortality, information on blood transfusions, and length of hospital stay | – no differences were found for mortality, length of hospital stay or number of blood transfusions after induction with ketamine compared to other induction agents-Cromartie study reported # of blood transfusions was 3.4 in thiopental group and 10.6 in ketamine group- Jabre et al study found no differences in 28-day mortality- Lyon et al study showed no difference in hospital mortality- Upchurch et al study showed no difference in # of packed RBC units transfused during 1st 48 hrs of admissions, in days to hospital discharge, or in-hospital mortality- groups intubated w/ ketamine had significantly higher ISS as well as lower GCS and showed no difference in hospital mortality adjusted for ISS, GCS, age and sex | – small sample sizes- none of the articles included timing of induction in relation to traumatic incident, which doesn’t allow to explore the relationship or association between the timing and choice of induction agents and its effects on hemodynamics- one study did not include information on TBI and ISS and failure to provide this info poses an issue because certain drugs can increase ICP- one study used rocuronium instead of succinylcholine as a neuromuscular agent decreasing comparability between studies |
| Sharda, S. C., & Bhatia, M. S. (2022) | Systematic Review & Meta-Analysis | – total # of participants: 20,283- Source of participants: ED, Air medical transport, pre-hospital emergency medical service – 9 studies included: 6 retrospective, 2 RCTs, and 1 prospective, comparative- 6 studies (n=12,060) looked at post-induction hypotension & 7 studies (n=15,574) contained information for 1st pass intubation success- all studies included were set in the USA- immediate post-induction hypotension was defined as </= 1hr after procedure- over delayed hypotension was defined as hypotension at any time point during 24 hrs- first-pass success: successful placement of ET tube on the 1stlaryngoscopy attempt- interventions compared in all studies only included Etomidate vs Ketamine | – first-pass intubation success – incidence of post-induction hypotension | – Etomidate use was associated with a significantly decreased risk of post-induction hypotension compared to ketamine.- Meta-analysis of outcomes of the seven studies showed no difference in first-pass intubation success during RSI using etomidate vs ketamine as the induction agent.- The occurrence of adverse effects and successful intubation can also be influenced by operator-related factors and selection of airway agents.- The results of the meta-analysis favor etomidate for a significant reduction of post-induction hypotension compared to those of ketamine during RSI in acutely ill patients | – Small sample sizes- majority of the studies included are mostly observational in nature- only 2 RCTs were included and for one of them only trial registry data were available-lack of blinding of personnel and outcome assessment |
| Stanke, L., Nakajima, S., Zimmerman, L. H., Collopy, K., Fales, C., Powers, W. (2018) | Retrospective Cohort Study | – total # of participants: 113 patients (ketamine, n=33; etomidate, n=80)- participants were patients >18 years old who received etomidate or ketamine for RSI outside of hospital setting- study period: Dec 2015-Jan 2017- Shock index: HR/SBP; < 0.7= normal, >0.9 = increased morbidity & mortality- incidence of hypotension after induction was defined as 20% or greater decrease in SBP from baseline- MAP and shock index calculated- vital signs, indication & time of intubation, # of intubation attempts, induction agent & dose, adjunctive sedatives, pain meds, vasopressor and fluids were recorded- vital signs were documented w/I 15 min before intubation and up to 15 min after intubation- post-induction vital signs were grouped as recorded w/I 0-7 min and 8-15 min of induction agent administration- additional sedative doses, including fentanyl, hydromorphone, or midazolam, administered w/I 30 min of induction were also recorded- vasopressor requirements were defined as a vasopressor initiation or a rate increase w/I 15 min of ketamine or etomidate administration- a sample size of 75 pts in each group was needed to provide a statistically significant result- dose of 0.3 mg/kg for etomidate given- 1.5-2mg/kg dose given for ketamine- most pts received succinylcholine as neuromuscular blockade | – Primary: incidence of a 20% or greater decrease in SBP within 15 min of receiving ketamine or etomidate- Secondary: quantification of additional sedative requirements & the assessment of 1st pass intubation success | – The incidence of hypotension after induction, defined as a 20% or greater decrease in SBP from baseline, did not differ between group-Postinduction SBP did not differ between the ketamine and etomidate groups when separated into 0 to 7 minutes and 8 to 15 minutes- there was no difference in the overall percent change in pre-induction SBP to post-induction SBP- The advantages of etomidate include minimal cardiovascular effects and decreased intracranial pressure due to decreased cerebral blood flow- Advantages of ketamine are that it can be used for intubation, agitation, pain and sedation, while etomidate does not provide analgesia which can explain the more significant hypertensive response in that group- Changes in other hemodynamic measurements including MAP and HR from preinduction to postinduction did not differ- Rates of hypotension caused by induction agent are also affected by the patient’s condition, such as in sepsis. – One of studies discussed provided evidence that ketamine is equally as unsafe as etomidate in critically ill patients. | – small sample size- number of pts required in each group to reach statistical significance was lower than 75-retrospective nature – In 2 studies, pre-intubation sedatives and analgesics were given that could have decreased the potential hypertensive response to ketamine- another study discussed – use of different protocols for induction agents – Provider selection of induction agent with a preference for etomidate which could be attributed to lack of experience with ketamine or the simple fact that etomidate is listed 1st on the protocol- some post-intubation vitals were recorded after additional sedatives & analgesics were given for pt comfort which can affect post-intubation hemodynamics |
| Foster, M., Self, M., Gelber, A., Kennis, B., Lasoff, D. R., Hayden, S. R., Wardi, G. (2022) | Retrospective Cohort Study | – total # of participants: 358 (272, etomidate; 86, ketamine); no difference in age or gender- identified pts at a large academic medical system from Jan 2016-June 2019 that included 2 separate hospitals using automatic query of the electronic health records-SOFA score: sequential organ failure assessment which indicates illness severity – baseline vital signs were defined as the 1stvital sign recording upon ED arrival- post-intubation hypotension was defined as SBP <90 mmHg or MAP <65 recorded <20 min after intubation- Shock index: HR/SBP; < 0.7= normal, >0.9 = increased morbidity & mortality | – Primary: development of post-intubation hypotension- Secondary: post-intubation vasopressor administration and in-hospital mortality; incidence of peri-intubation cardiac arrest in patients identified having received CPR within 20min of ET intubation- secondary analysis was conducted of patients at pre-existing risk of cardiovascular collapse in the post-intubation phase which were selected if they had a pre-intubation SI >/= 0.9 | – Patients at pre-existing risk of cardiovascular collapse in the post-intubation phase were also analyzed- Prior to stratification by shock index, post-intubation hypotension occurred in 28% of ketamine inductions and 18% of etomidate inductions- In patients with an SI >0.9, ketamine administration was no longer associated with a higher rate of post-intubation hypotension- There was no association between induction agent administered and hospital mortality, irrespective of SI- in the full cohort, the ketamine group was more likely to receive vasoactive medications, but the difference between groups was no longer statistically significant once subgrouping by SI was done- the strongest predictor of post-intubation hypotension was pre-intubation SI >/= 0.9 suggesting that appropriate resuscitation is more important than sedative selection prior to intubation- in pts with a pre-intubation SI > 0.9, there was no significant difference in the incidence of post-intubation hypotension and vasopressor use between etomidate and ketamine- ketamine group had a higher average SI, higher percentage of patients with an SI of >0.9, lower average BP values, and higher average SOFA score | – small sample size- small sample size impaired ability to assess peri-intubation cardiac arrest- numbers for peri-intubation cardiac arrest rate were low- retrospective in nature-vital sign recordings regarding intubation time were not standardized and at various times- data was only analyzed from two EDs over 3 years and the results may not be applicable to other centers |
Weight of evidence:
I weighed the evidence based on the year published, sample size, relevance, how much of the studies included in each studied were conducted in the US, and organization of the data as it applied to my patient scenario. I weighted them in the following order: Sharda & Bhatia, Baekgaard et al., Foster et al., and Stanke et al. While Baekgaard et al. – a systematic review – only included one US study, it had the largest sample size compared to the other 3 studies combined. Also, that study in particular did not compare the two interventions in question making it irrelevant for my patient scenario; however, the rest of the studies did. In addition, the ultimate result concluded was only regarding the two interventions in question, not the two induction agents they compared; it only reported the outcomes for blood transfusions.
Conclusions:
Article 1:
Baekgaard et al. conclude that there is no advantage of using ketamine over other induction agents based on the evidence collected, however, that is not to say that there are no benefits to using it or any harms for that matter. In the statistical analysis of the article, it was noted that each group needed to have a total of 906 patients to detect a clinically relevant difference in mortality of 5% with 80% power at the 0.05 significance level. The only study that had enough patients was the one conducted in the US which had 968 participants.
Article 2:
Sharda & Bhatia suggest that etomidate has better outcomes in regard to decreased risk of post-induction hypotension during rapid sequence intubation compared with ketamine. However, neither of the induction agents was associated with first-pass intubation success. The conclusion was that the use of etomidate provides better hemodynamic stability in critically ill patients.
Article 3:
Stanke et al. found no hemodynamic differences between those who received ketamine or etomidate for pre-hospital RSI, although, each induction agent may provide different advantages based on the patient’s diagnosis. They also concluded that there were no differences in additional sedative use or first-pass intubation success rate.
Article 4:
Foster et al. conclude that neither ketamine or etomidate was associated with hospital mortality or post-intubation hypotension, meaning that both have comparable hemodynamic stability. However, pre-intubation SI >0.9 was associated with an increased risk cardiovascular collapse irrespective of induction agent suggesting that appropriate resuscitation should be considered more urgent than sedative selection prior to intubation.
Overall conclusion:
Overall, most of the articles agree that there is no significant difference in outcomes – specifically post-induction hypotension – between the two induction agents. Both ketamine and etomidate demonstrate hemodynamic stability. The conclusion from Sharda and Bhatia may be due to two studies that were included which had small sample sizes which didn’t allow for detection of significant differences between the groups, as well as the observational nature of the studies included, and other confounding variables.
What is the clinical “bottom line” derived from these articles in answer to your question?
The clinical bottom line is that ketamine isn’t superior to etomidate for rapid sequence induction for the purpose of reducing risk of adverse effects. Most of these articles focused specifically on post-induction hypotension, which is one of the more common adverse effects associated with use of induction agents. The issue is that more large-scale studies are needed to come to a better and more accurate conclusion. There are also other factors that should be consider, such as a patient’s pre-existing cardiovascular risk which could affect the outcome. The dosage of an induction agent is another consideration that must be factored in, as well as the timing of induction. An ideal induction agent should have a rapid onset, short duration of action, insignificant hemodynamic effects, minimal side effect profile, and provide some analgesia. Between ketamine and etomidate, ketamine is the only one to provide analgesic effect. Regardless of the two induction agents in question, in a clinical environment there are other variables that sometimes can’t be controlled such as, the skill and experience of the provider intubating or induction agents available. All in all, ketamine continues to be a choice of induction agent regardless of associated risk or benefits that are yet to be studied and has comparable hemodynamic stability to etomidate.
