Ketamine or etomidate, whats your go-to agent for rapid sequence intubation? Are these agents always hemodynamically neutral? How should you approach dosing these agents for hemodynamically unstable patients?
Greetings Pharmers and Friends, Mark with PHARMWYZE. I'm a board certified emergency medicine pharmacist. I make clinical pharmacotherapy content on the social medias. Thanks for joining me on the Code Blue Debrief: A Clinical Pharmacotherapy YouTube & Podcast Series. Make sure to hit the follow, subscribe, and notification bell as we get into the episode's topic. We'll be discussing ketamine and etomidate for hemodynamically unstable patients for rapid sequence intubation?
Induction agents are an essential component of rapid sequence intubation. They work synergistically with neuromuscular blockers. As the paralytics relax the vocal cords for optimal conditions as the endotracheal tubes is being passed, induction agents provide amnesia and make the patient unconscious. That is an important thing to mention. How much drug does the patient really need when they're body is barely hanging on? There is such a thing as drug toxicities and we want to keep it safe. Let's briefly review these two agents.
Ketamine, a NMDA non-competitive antagonist, dissociates the brain from external stimuli. The NMDA receptor is a part of the glutamate receptor family, which contains neuroexcitatory properties. It is a potent anesthetic that offers unique features compared to other sedatives. Ketamine preserves respiratory drive and maintains hemodynamics. Additionally, it has secondary activity opioid mu receptors.
Ketamine provides two-fer properties, sedation and analgesia as a single agent. Transient hypertension and tachycardia can be seen with ketamine from inhibiting reuptake of catecholamines. One of ketamine's minor mechanism include negative inotropic properties. This has raised concern for use in catecholamine depleted patients as this may contribute to the more negative cardiovascular effects. The dosing range for RSI is 1 to 2 mg/kg IV with a rapid onset of action and duration of up to 10 minutes. The alpha and beta half-life elimination of 10 and 180 minutes, respectively.
Etomidate is a commonly used hypnotic agent used for induction. It is an imidazole-based agonist of the GABAa receptor to exert its potent sedative effects. Etomidate has been preferred given its cardiovascular neutral profile having minimal effects on blood pressure or heart rate. The weight-based dose for etomidate is 0.3 mg/kg IV with a rapid onset of onset. It has a reported half life of roughly 3 hours. . It is the more commonly used medication since it technically isn't classified as a controlled substance, making it more accessible in emergent situations.
Sounds like a great drug right? The known concern etomidate-induced adrenal adrenal insufficiency from 11 beta-hydroxylase inhibition. This enzyme is essential corticosteroid biosynthesis. A single dose can blunt adrenal function from 4 anywhere from 4 to 24 hours, and up to 72 hours in some cases.
Etomidate was used frequently until the mid 1980s when reports indicated a possible increased risk of mortality. Additionally, Mckee and Finlay conducted a trial in 1983 showing that cortisol replacement therapy reduced mortality in the setting of etomidate use. The effects on adrenal suppression make it unsuitable as a continuous infusion.
Evidence since this time has been conflicting on the actual clinical risk of etomidate. Etomidate has seen increased use over the past several years as the true risk of a single dose remains unclear. Let's briefly go over some recent studies that highlights operating in the greyzone and how it applies to your patient.
Ketamine
The hemodynamic and safety profile of induction agents is always a consideration with rapid sequence intubation.
April and colleagues analyzed ED intubation data from the National Emergency Airway Registry. The study included 25 EDs from 2016 through 2018. They excluded patients with a systolic less than 100 or had cardiac arrest before intubation.
Their primary outcome was peri-intubation hypotension defined by a systolic less than 100.
Several limitations to note about this retrospective trial; ketamine appeared to be more utilized at baseline in patients more likely to have bad outcomes, such as septic and trauma patients.
From their analysis, ketamine was associated with a higher incidence of peri-intubation hypotension.
They also analyzed differences in 1 vs 2 mg/kg of ketamine, which didn't show any differences in outcomes.
Foster and colleagues completed a trial in 2022 titled, "ketamine is not associated with more postintubation hypotension than etomidate in patients undergoing endotracheal intubation".
They performed a retrospective, single-center cohort trial in 358 patients undergoing emergent intubation and received either ketamine or etomidate.
The primary outcome was incidence of hypotension defined as SBP < 90 or MAP < 65. From their findings, ketamine was not associated with increased hypotension compared to etomidate.
Additionally, ketamine appeared to be more utilized in patients with a higher shock index. The mortality rate was the same in both cohorts and associated with higher shock index rather than agent selected.
Etomidate
The negative etomidate trials in the 1980s solidified the danger of being utilized as a maintenance continuous infusion for anesthesia and sedation. Comp
Several meta-analysis have gone back and forth associating etomidate with increased or no effects on mortality.
More recently, Kotani and colleagues completed a meta-analysis of randomized controlled trials to evaluate if etomidate impacted mortality in critically ill adults when compared with other induction agents.
From their findings, found a high probability that etomidate increases mortality when used as an induction agent in critically ill patients with a number needed to harm of 31.
Mortality is a really difficult outcome to statistically prove. Meta-analysis only provide effects based on association rather than causation. You're using aggregate numbers of the studies and lose the robustness of each individual trial. Let's review two fairly recent studies that gives you some insight on the discussion.
Srivilaithon and colleagues completed a single-center, single-blind, randomized, controlled trial in Pathum Thani, Thailand. Published this past year, they included 260 patients with suspected sepsis and required emergent intubation in the ED. Patients randomly received a single dose of 0.2 - 0.3 mg/kg of etomidate or ketamine 1 - 2 mg/kg as an IV push.
The primary outcome was 28-day survival with secondary outcomes assessing survival at different time-frames, in addition to vasopressor and fluid requirements. Limitations of this retrospective trial include a baseline difference in patients receiving neuromuscular blockers more in the ketamine group compared to etomidate.
They found no difference in their primary and most secondary outcomes. Although, they did associate etomidate with earlier vasopressor initiation and use of steroids in their secondary analysis.
Cagliani and colleagues conducted a single-center, prospective trial in a surgical ICU with patients who developed respiratory failure undergoing RSI. Their aim was to assess the prevelance of adrenal insufficiency and characterize risk factors in patients receiving etomidate. 34 patients who received etomidate were compared to 10 that did not. Adrenal insufficiency was defined as random cortisol levels less than 25 mcg/dL and/or with concurrent MAP < 65. This contains limitations similiar to other adrenal insufficiency analysis in baseline levels and catabolic patient population. There was no difference in the incidence of adrenal insufficiency in their primary outcome, nor secondary analysis which included mortality and LOS.
Cagliani and colleagues make a great statement, "Until we have conducted these high-quality studies that generate accurate results, we should analyze each patient on an individual basis, understand the risk factors for morbidity and mortality, make judgments based on evidence, and then decide our next course of treatment."
The biggest takeaway from our discussion today is there isn't a black and white answer. You should always consider what the intent of the medication you're giving to the patient. Not every patient who gets an emergent intubation requires full weight-based dosing. For example, if a patient presents obtunded and unresponsive, the full dose of etomidate or ketamine probably isn't needed. The purpose of our induction agents are to make the patient unconcious and amnestic to the emergent intubation. Consider giving a reduced doses if the patient condition doesn't match up.
Personally, I am grabbing the agent that makes most sense for the patient in front of me and whats most accessible. Etomidate is a perfectly find induction agent and likely more accessible to you in the department. Being classified as a non-controlled medication allows it to be more readily available. On the other hand, ketamine is a class III controlled substance, which limits access to secured locations. Cases I'd consider ketamine first would be anticipated airways and refractory status epilepticus.
I don't encourage avoiding certain medications based on dogma. Be familiar with all medications possible in your drug bank for more patient-centered options. Thanks for staying to the end of this episode. If you enjoyed the content today, make sure to give the video a like and check out my other clinical pharmacotherapy posts on the social medias. Hit the notification bell for the next video, and I hope you learned something new.
References
McKee JI, Finlay WE. Lancet . 1983 Feb 26;1(8322):484.
Watt I, Ledingham IM. Anaesthesia . 1984 Oct;39(10):973-81.
Dobrek L, Thor P. Postepy Hig Med Dosw (Online) . 2011 Jun 7:65:338-46.
Srivilaithon W et al. Sci Rep . 2023 Apr 19;13(1):6362.
April MD et al. 2020 Nov;27(11):1106-1115.
Cagliani JA et al. Cureus. 2021 Feb; 13(2): e13445.
Foster M et al. Am J Emerg Med . 2022 Nov:61:131-136.
Thompson Bastin ML, Baker SN, Weant KA. Hosp Pharm . 2014 Feb;49(2):177-83.
Albtert SG, Sitaula S. J Intensive Care Med . 2021 Oct;36(10):1124-1129.
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