Ketamine and Etomidate: Into the Void

We’re increasingly cognizant of the physiological importance of maintaining specific hemodynamics during resuscitation. Practice patterns vary broadly, so we’ve done a deep dive into the various evidence around the use of ketamine and etomidate in specific clinical scenarios.

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Physiology of the rapid sequence intubation

Rapid sequence intubation (RSI) is the nearly simultaneous administration of a potent sedative agent (induction) and neuro-muscular blocking agent, after a period of pre-oxygenation and cardiopulmonary optimization for tracheal intubation.(1) This technique was developed to safely and effectively intubate patients while minimizing the risk of aspiration of gastric contents via avoidance of bag-mask ventilation (BMV). RSI is the most widely used method of emergency department (ED) intubation, and while it is designed to minimize risk, some complications can still arise. A recent study investigating risk factors for peri-intubation cardiovascular collapse for critically ill patients identified the following risk factors:(2)

• Older age
• Pre-induction tachycardia
• Pre-induction hypotension
• Pre-induction hypoxia
• Use of propofol as an induction agent

Even in patients with stable vitals prior to induction, post-intubation hypotension can still occur, with some studies showing up to 22%.(3) This remains significant, as it has been well documented that post-intubation hypotension increases in-hospital mortality, and our induction agent(s) of choice can have an impact as well.(2,4)

Pharmacodynamics of etomidate and ketamine

Etomidate

Etomidate is a sedative-hypnotic anesthetic agent acting via the GABA receptor complex, with no analgesic properties.(5) Etomidate has an onset of action within 30 to 60 seconds, and a total duration of action of approximately five minutes.(5,6) A typical induction dose in an RSI is between 0.2 – 0.3mg/kg. Intracranially, etomidate is thought to be “cerebroprotective” as it reduces intracranial pressure, cerebral blood flow, and cerebral oxygen consumption while maintaining cerebral perfusion pressure.(7) Etomidate is renowned for its hemodynamic stability, as it does not influence cardiovascular parameters such as heart rate, blood pressure, systemic vascular resistance, or mean arterial pressure.(6) It can safely be used in settings of left ventricular dysfunction and does not have any bronchodilatory effects. Some key adverse effects include myoclonic jerks, pain on injection, and transient adrenal suppression. Given the rapid duration of action of etomidate, it is crucial to promptly initiate post-intubation sedation before next steps in patient care, to minimize the potential risk of awareness under anesthesia.  

Ketamine

Ketamine is a dissociative anesthetic agent that acts as an NMDA receptor antagonist to induce a cataleptic state instead of a true unconscious state.(1) Ketamine has an onset of action between 30 to 45 seconds and a clinical duration of 15 minutes.(1) In RSI, doses ranging between 1 and 2mg/kg are frequently cited for induction. The cerebral effects of ketamine are still not fully understood, and its effects on ICP have been long debated. Some studies hypothesize that ketamine may in fact be neuroprotective, by either maintaining neutral or decreased ICP in association with increases in CPP.(8,9) From a hemodynamics perspective, ketamine primarily acts as a myocardial depressant, but these effects are counteracted by its secondary systemic sympathomimetic effect resulting in systemic catecholamine release and vagal suppression.(10) Therefore, in hemodynamically stable patients, ketamine preserves cardiac output. However, for those who are hemodynamically unstable and are catecholamine depleted, ketamine may increase the risk of hemodynamic complications as its secondary sympathomimetic effect cannot counteract its myocardial depressant effects.(11) (12) Otherwise, ketamine is known to preserve ventilatory drive while also having some bronchodilatory effects.(1)

Main takeaway #1: Etomidate is typically dosed at 0.3mg/kg with caution in renally impaired patients, and has a comparable onset of action to ketamine. It is a hemodynamically neutral, and cerebroprotective, with no analgesic properties. Given its rapid duration of action, it is crucial to promptly start post-intubation sedation infusions on patients to minimize the risk of awareness under paralysis.

Etomidate vs Ketamine as induction agents:

Key outcomes: incidence of post-induction hypotension and mortality

One systematic review and meta-analysis conducted in 2022 by Sharda et al, in which the primary outcome was focused on comparing the safety of etomidate vs ketamine as induction agents for RSI in critically ill patients with respect to post-induction hypotension in the ED and prehospital setting.(13) Data was pooled from six studies, totaling 12,000 patients and through their pooled results, they found etomidate use was associated with a significantly decreased risk of post-induction hypotension compared to ketamine.

However, this review had fairly significant limitations. Firstly, there is an overall lack of randomized evidence, let alone high-quality randomized evidence; the two RCT’s included consisted of data available from a published abstract, and data available from a clinical trial registry, and neither were blinded.(14,15). Secondly, the remaining four included studies were observational, which increases the overall selection bias. Lastly, the study authors report significantly high heterogeneity (I² = 68%) which further calls into question the validity of these results.  

In contrast to the above review, a few RCT’s have been conducted and report similar results. The largest of the three, Matchett et al, investigated outcomes relating to emergent intubations performed by a mobile anesthesia-trained airway team.(16) They compared the use of ketamine (range 1-2mg/kg) and etomidate (0.2-0.3mg/kg) and reported a statistically significant increase in 7-day survival in those receiving ketamine, but no other differences in 28-day survival or serial SOFA scores. The study also reported small, yet significant differences in exploratory outcomes, with higher observed rates of cardiovascular collapse in the ketamine group. Likewise, Jabre et al, a multi-center French study, also reported no statistically significant differences in maximum SOFA score within three days of admission, early complications of intubation (change in BP parameters, change in O2, etc.), as well as 28-day mortality, comparing ketamine (2mg/kg) and etomidate (0.3mg/kg).(17) Lastly, Knack et al, compared the use of ketamine (2mg/kg) vs etomidate (0.3mg/kg) in 143 patients undergoing RSI and report similar findings to the above studies: no differences in maximum SOFA score within three days of admission, incidence of post-intubation hypotension, and 30-day mortality.(18) However, a majority of patients in this trial were intubated for airway protection, rather than a clear medical etiology, and the trial was not adequately powered to detect clinically meaningful differences in their secondary outcomes.

Key populations: septic patients

Very limited research exists investigating the overall mortality of septic patients receiving a single dose of etomidate in the ED. This population is of particular importance, given the adrenal suppressant effects of etomidate. Only one single-centre RCT exists directly the use of etomidate (0.2-0.3mg/kg) and ketamine (1-2mg/kg) in septic patients undergoing RSI, which found no statistically significant difference in mortality at 28 days, 7 days, and 24 hours and no difference in post-intubation hypotension incidence.(19) A recent sepsis-specific meta-analysis further supports the results of the above RCT, reporting an increased risk of adrenal insufficiency in the etomidate group, but no increase in overall patient mortality, in comparison to a range of induction agents.(20) In addition to this, Jabre et al included a specific subgroup analysis comparing outcomes between septic and trauma patients and found no overall differences in outcomes.(17)

Key populations: trauma patients

There is no high-quality randomized evidence, and very limited observational evidence specifically evaluating the use of etomidate and ketamine as RSI induction agents in traumatically injured patients, which is not surprising given both have individually been shown to be safe in patients with concern for raised ICP. Only one observational study has specifically investigated this question, conducted out of a Korean level one trauma centre on all traumatically injured patients requiring intubation. They found that while those receiving ketamine had higher rates of tachycardia and hypotension post-induction, there were no overall differences in mortality.(21) Therefore, no clear recommendations can be drawn due to the lack of data.

Do higher or lower doses matter?

Once again, very few studies have directly compared outcomes between high and low doses of etomidate and ketamine in the RSI setting. Two observational studies have reported conflicting results; One reported significantly increased rates of post-intubation hypotension in patients receiving high doses of ketamine (>2mg/kg) compared to low dose (<2mg/kg) in the pre-hospital setting. The second study reported no dose-related association of hypotension with either high or low-dose etomidate or ketamine (>0.3mg/kg, <0.3mg/kg, >1mg/kg, and <1mg/kg respectively).(22,23)

Main take away #2: There is very limited high-quality, randomized evidence assessing the safety and adverse effects of etomidate and ketamine as RSI induction agents. Within the existing evidence, there does not seem to be a clear association of etomidate causing increased mortality or post-intubation hypotension when compared to ketamine and is therefore currently a safe alternative to the use of ketamine. While data remains limited with regards to specific patient populations, there is no evidence suggesting harm of either agent in traumatically injured populations or septic populations, nor is there evidence to suggest one ideal dosing range.

Etomidate and adrenal suppression – pathophysiology:

To briefly review, our hypothalamic-pituitary-adrenal (HPA) axis, is responsible for mediating the synthesis of cortisol throughout the body. In response to a stressor, the hypothalamus stimulates the release of corticotropin-releasing hormone (CRH), which in turn stimulates the anterior pituitary to release ACTH, which then acts on the adrenal cortex to release cortisol. In settings of critical illness such as sepsis, relative adrenal insufficiency can develop; with dysregulation of the HPA axis, resultant alterations in cortisol metabolism occur, which in turn creates tissue resistance to glucocorticoids. Additionally, some of the key enzymes involved in the peripheral conversion and production of cortisol are suppressed due to inflammation, such as 11-beta hydroxylase.(24)

One would logically assume that if the body lacks endogenous steroids in states of critical illness, supplementation with exogenous corticosteroids would help improve outcomes. However, this effect has not held true within randomized trials, such as the landmark CORTICUS study, by Sprung et al. This RCT sought to evaluate the efficacy and safety of low-dose hydrocortisone therapy in patients with septic shock, via primary outcome of death at 28 days. They reported no significant difference in mortality between patients receiving 50mg of IV hydrocortisone compared to placebo for five days.(25) The findings of this study remain relatively consistent with current literature, with a recent meta-analysis of 50 RCT’s reporting similar findings, with no effects on 28-day mortality.(26)  

Etomidate has been shown to inhibit adrenal mitochondrial 11-beta hydroxylase in a dose-dependent fashion. Even a single induction dose of etomidate causes a reversible relative adrenal insufficiency by suppressing steroidogenesis for up to 72 hours.(27) However, the overall clinical significance of this relative, reversible adrenal insufficiency has been heavily debated and continues to remain unanswered.  

Circling back to the meta-analysis conducted by Gu et al, we can see that through their robust results, there is no difference in mortality in patients with sepsis receiving etomidate or ketamine.(20) It is also worth noting that through subgroup analyses of some of the previously outlined RCT’s, no mortality differences were found in septic patients as well. However, the results of this review do contrast two systematic reviews that preceded it; these were both methodologically flawed, with primarily observational data.

The Society of Critical Care Medicine recently published clinical practice guidelines for the RSI in the critically ill adult patient.(28) There are two key clinical recommendations to draw from these guidelines:

1. They suggest no difference between etomidate and other induction agents administered for RSI with respect to mortality, the incidence of hypotension, or the incidence of vasopressor use in the peri-intubation period and through hospital discharge (conditional recommendation, moderate quality of evidence).
2. We suggest against administering corticosteroids following RSI with etomidate for the purpose of counteracting etomidate-induced adrenal suppression (conditional recommendation, low quality of evidence).

And based on the studies that have been reviewed so far, this makes sense.

Main takeaway #3: Etomidate causes transient, reversible, relative adrenal suppression. Although evidence is limited, there is no current data to suggest that etomidate causes an increase in mortality when used in septic patients as a result. Knowing this, the prophylactic use of corticosteroids in conjunction with etomidate is not recommended.

Etomidate and ketamine in the neuroprotective intubation:

Historically, ketamine was thought to increase ICP and was traditionally taught to be avoided as an induction agent for patients with concern for raised ICP based on evidence that dated back to the 1970’s. These studies were primarily based on patients undergoing anesthesia for elective surgical procedures which showed increases in ICP, cerebral blood flow, and CPP, but without any subsequent neurologic sequelae.(29,30) Since then, observational studies have remained relatively divided; recent systematic reviews evaluating the use of ketamine in both traumatic and non-traumatic acute brain injury have not shown any significant differences in mortality or neurologic outcomes, despite ketamine’s intracranial mechanisms of action not yet being fully understood.(31–33)

Another key component of the “neuroprotective intubation” aims to blunt the sympathetic response of laryngoscopy to prevent any further increases in MAP and HR. This has typically been achieved with the administration of a short-acting opioid such as fentanyl approximately 3-5 minutes prior to induction, at a dose of 3mcg/kg.(34) This practice is based on few randomized trials conducted in the 1990’s, reporting that fentanyl is effective in attenuating rises in heart rate and BP during laryngoscopy and RSI.(35–37) Conversely, a small body of literature exists potentially suggesting an increase in ICP with the use of opioids, however, this has not been reproduced with recent, larger, high-quality trials.  

When considering the administration of opioid pre-treatment in the appropriate patient population, it is important to be aware of any potential complications that can arise during this period before RSI. As we know, opioids can cause respiratory depression and hypotension, and it is recommended to administer fentanyl pre-treatment over a period of 30-60 seconds to attempt to minimize this risk.(34) Despite this, apnea may still occur, and we must be prepared to intervene should this occur, as in certain patient populations, even short periods of apnea can have detrimental physiologic effects. In rare cases, fentanyl can cause a phenomenon referred to as “rigid chest syndrome” or “wooden chest syndrome” in which apnea occurs and the patient is unable to be adequately ventilated via bag-mask ventilation. Case reports detailing this typically involve patients receiving cumulative infusion doses, or much larger doses of fentanyl than those given in an emergency RSI.(34,38) UpToDate recommends abolishing this by administering an NMBA promptly and proceeding with RSI.(34)

Putting together all that has been reviewed with regards to the pharmacodynamics of each agent, a refined approach to the neuroprotective intubation is suggested. These recommendations are based on a combination of information from UpToDate, local expert consensus, and a few studies:(34,39)

In a hypotensive patient with concern for raised ICP, it may be reasonable to use ketamine. These patients may not necessarily be catecholamine depleted and therefore may benefit from the systemic catecholamine increase ketamine produces. However, it is important to keep in mind the importance of resuscitating before intubating and avoiding induction in a very hypotensive patient if possible. Some previous studies recommend against the use of opioid pre-treatment in a hypotensive patient, due to the concern that any opioid agents may contribute to further hypotension.

For patients who are normotensive or hypertensive and with a concern for raised ICP, the use of etomidate is recommended in conjunction with opioid pre-treatment, given that etomidate has no analgesic properties. Etomidate will not alter hemodynamics and will therefore not contribute to any further increase in heart rate, blood pressure, or systemic catecholamine release on top of the stimulation of laryngoscopy. For these patients, opioid pre-treatment is recommended regardless of the induction agent used, as even with the analgesic effects of ketamine, this is not enough to blunt the sympathomimetic effects of both ketamine and laryngoscopy combined.