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Date: January 16th, 2022

Reference: Matchett, G. et al. Etomidate versus ketamine for emergency endotracheal intubation: a randomized clinical trial. Intensive Care Med 2021

Guest Skeptic: Missy Carter, former City of Bremerton Firefighter/Paramedic, currently a professor of Emergency Medical Services at Tacoma Community College’s paramedic program. Missy is currently working in a community emergency department as a physician assistant and recently accepted a critical care position in Tacoma Washington.

Case: You respond to a rapid response on the floor for a 58-year-old woman in septic shock who is requiring emergent rapid sequence intubation (RSI). As you prepare to intubate the pharmacist asks if you would prefer ketamine or etomidate for induction in this patient.

Background: We have covered the issue of intubation multiple times on the SGEM. This has included looking at supraglottic airways for out-of-hospital cardiac arrests (SGEM#247), video vs. direct laryngoscopy (SGEM#95), tracheal intubation for in-hospital cardiac arrests (SGEM#197), apneic oxygenation (SGEM#186) and confirming intubation with POCUS (SGEM#249). One thing we have not covered is the choice of induction agent for intubation.

There has been much debate regarding the use of etomidate verses ketamine for induction in the critically ill [1-4]. A 2009 randomized control trial conducted in French ICUs supported the use of ketamine in this patient population [5]. Both agents are considered hemodynamically stable, but any induction agent may precipitate shock in the critically ill.

There is some conflicting evidence as to which agent is preferred for patients who are at high risk of peri intubation complications. Historically there has been concern about adrenal insufficiency caused by etomidate being harmful for patients with sepsis but this has not been shown to cause increased mortality in the literature [6, 7].

Ketamine has emerged as a reasonable alternative but in recent years there has been concern about increased cardiovascular collapse with ketamine especially in those with sepsis or a high shock index [1, 8].   

Clinical Question: Which induction agent has a better day 7 survival for critically ill patients requiring emergency endotracheal intubation, ketamine or etomidate?

Reference: Matchett, G. et al. Etomidate versus ketamine for emergency endotracheal intubation: a randomized clinical trial. Intensive Care Med 2021

  • Population: Adults 18 years of age and older in need of emergency endotracheal (ET) intubation
    • Exclusions: Children, pregnant patients, patients needing ET intubation without sedation or allergic to one of the agents being used
  • Intervention: Ketamine 1-2mg/kg IV
  • Comparison: Etomidate 0.2-0.3mg/kg IV
  • Outcome:
    • Primary Outcome: 7-day survival
    • Secondary Outcomes: 28-day survival, duration of mechanical ventilation, ICU length of stay, need for vasopressor use, SOFA scores and an assessment of a new diagnosis of adrenal insufficiency by the treating critical care teams.
  • Trial: Prospective, randomized, parallel-assignment, open-label, single-center trial (NCT02643381)

Authors’ Conclusions: While the primary outcome of Day 7 survival was greater in patients randomized to ketamine, there was no significant difference in survival by Day 28.”

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. No
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Unsure
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Unsure
  11. The treatment effect was large enough and precise enough to be clinically significant. Unsure
  12. Lack of conflicts of interest. No

Results: The cohort consisted of 801 critically ill patients that required ET. The mean age was 55 years, 38% female, 69% were in the MICU, and 51% had diagnosis of sepsis.

Key Result: Day 7 survival was statistically higher in the ketamine arm compared to the etomidate arm

  • Primary Outcome: 7-day survival favored
    • Ketamine (85.1%) vs etomidate (77.3%), difference − 7.8, (95% CI; − 13 to − 2.4) p = 0.005
  • Secondary Outcomes: There was no statistical difference in 28-day survival between groups (ketamine 66.8% vs etomidate 64.1%)

1. Selection Bias: These were not consecutive patients. The manuscript says physicians were “encouraged to consider screening and enrolling patients whenever clinical circumstances reasonably permitted but were under no obligation to do so.”

When you look at the number of patients excluded due to “clinical circumstances, clinician preference for usual care” in each arm of trial they were similar (n =396 for etomidate, and n = 398 for Ketamine). The reasons for these exclusions are unclear and may have biased the results towards whichever medication the physician favored. How these exclusions would ultimately impact the over-all results is also unclear.

2. Blinding: This was an open label trial. The authors said: “After extensive discussions with hospital and community stakeholders, we were unable to arrive at a satisfactory plan for masking.” This lack of blinding could have been responsible for the reported higher level of adrenal insufficiency was found in the etomidate arm. Having knowledge of group allocation may have led clinicians to more testing for adrenal insufficiency in the etomidate arm verses the ketamine arm.

3. Outcome Measure: The authors recognize that selecting 7 day survival is an unconventional outcome measure in an RCT of critically ill patients. They chose one Constantine unit (7 days) as the outcome because of their quality improvement data and to have the endpoint close to randomization. While the 7 day mortality was statistically better in the ketamine group compared to the etomidate group, there was not statistical difference reported at 28 days. Also, a more patient oriented outcome would be survival with good neurologic status.

4. External Validity: This trial was a single center trial including largely ICU patients who were intubated by an anesthesia lead airway team. This airway team uses the Montpellier Intubation protocol which includes the presence of two skilled operators, head-up positioning, deliberate preoxygenation, routine use of neuromuscular blocking agents and intubating stylets and frequent use of VL. They use EtCO2 detection for tube confirmation and are focused on prompt treatment of post intubation hypotension with vasopressors and IVF. This practice produced a 91% first pass success rate and likely contributed to standardized care in each group. The practice may not be generalizable to other centers who do not use such standardized protocols.

5. Hypothesis Generating: There were some interesting secondary outcomes regarding hemodynamics and cardiovascular collapse that are thought provoking and hypothesis generating. Ketamine had higher rates of vasopressors use, more frequent post intubation CPR, and higher incidence of post induction cardiovascular collapse compared to etomidate. This is very interesting given the 7-day mortality was better with ketamine. It may be that the airway team was so aggressive about post intubation management that they were able to overcome these complications.

This circles back to nerdy point #4 and raises another question about generalizability. If these complications are encountered in other practice settings, such as the pre-hospital setting where there are less resources, would the patient receive the same aggressive post intubation management for these complications and might that change the outcomes.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors conclusion.

SGEM Bottom Line: It likely does not make a patient-oriented difference whether you use ketamine or etomidate for emergency endotracheal induction in most critically ill patients.

Case Resolution: You tell your pharmacist you would like to use etomidate at a half dose but prior to intubation. First you would like to optimize hemodynamics and oxygenation and have a vasopressor ready in case you encounter post intubation hypotension.

Missy Carter

Clinical Application: Both ketamine and etomidate have similar hemodynamic stability, but both should be used with caution in the critically ill patient. There may be certain patient populations who might benefit from one medication over the other, but more research is needed on this topic. Regardless of which agent used there should be a focus on optimizing patient physiology by aggressively resuscitating before you intubate. Considering lower dosing for either induction agent in the critically ill may be further protective.

What Do I Tell the Patient? You tell the patients family she is requiring a breathing tube to keep her safe while we manage her illness. She will be given medications to make them comfortable during and after the procedure. Although complications are possible, we will be doing everything we can to reduce her risk and keep her safe and comfortable.

Keener Kontest: Last weeks’ winner was Dr. Paul Ehlers a PGY4 from UCSF. He knew the Rak Su singer who suffered a hemothorax was Myles Stephenson.

Listen to the SGEM podcast for this weeks’ question.  If you know, then send an email to thesgem@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References:

  1. Lynde GC, Jabaley CS (2018) Etomidate is a first-line induction agent in critically ill patients. Crit Care Med 46(9):1492–1494. https://doi.org/10. 1097/CCM.0000000000003290
  2. Katz J, Greenberg S (2018) etomidate is not a first-line induction agent in critically ill patients: primum non nocere-above all, do no harm. Crit Care Med 46(9):1495–1496. https://doi.org/10.1097/CCM.0000000000003291
  3. Ray DC, McKeown DW (2012) Etomidate for critically ill patients. Pro: yes we can use it. Eur J Anaesthesiol 29(11):506–510. https://doi.org/10.1097/ EJA.0b013e32835819b0
  4. de la Grandville B, Arroyo D, Walder B (2012) Etomidate for critically ill patients. Con: do you really want to weaken the frail? Eur J Anaesthesiol 29(11):511–514. https://doi.org/10.1097/EJA.0b013e32835819ca
  5. Jabre P, Combes X, Lapostolle F, Dhaouadi M, Ricard-Hibon A, Vivien B, Bertrand L, Beltramini A, Gamand P, Albizzati S, Perdrizet D, Lebail G, Chollet-Xemard C, Maxime V, Brun-Buisson C, Lefrant JY, Bollaert PE, Megarbane B, Ricard JD, Anguel N, Vicaut E, Adnet F; KETASED Collaborative Study Group. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial. Lancet. 2009 Jul 25;374(9686):293-300. doi: 10.1016/S0140-6736(09)60949-1. Epub 2009 Jul 1. PMID: 19573904.
  6. April MD, Arana A, Schauer SG, Davis WT, Oliver JJ, Fantegrossi A, Summers SM, Maddry JK, Walls RM, Brown CA, NEAR Investigators (2020) Ketamine versus etomidate and peri-intubation hypotension: a national emergency airway registry study. Acad Emerg Med 27(11):1106–1115. https://doi.org/10.1111/acem.14063
  7. Bruder EA, Ball IM, Ridi S, Pickett W, Hohl C (2015) Single induction dose of etomidate versus other induction agents for endotracheal intubation in critically ill patients. Cochrane Database Syst Rev 1(1):CD010225. https:// doi.org/10.1002/14651858.CD010225.pub2
  8. Mohr NM, Pape SG, Runde D, Kaji AH, Walls RM, Brown CA 3rd (2020) Etomidate use is associated with less hypotension than ketamine for emergency department sepsis intubations: a NEAR Cohort Study. Acad Emerg Med 27(11):1140–1149. https://doi.org/10.1111/acem.14070