Etomidate is an imidazole derivative that is primarily a hypnotic agent and has no analgesic activity. It is one of the most hemodynamically stable induction agents currently available. It enhances GABA activity at the GABA-receptor complex, making neurons less excitable by opening inhibitory chloride channels. Etomidate is cerebroprotective (although not as much as other agents like barbiturates), and it has general hemodynamic stability, which preserves cerebral perfusion pressure (CPP). Combined, etomidate is an excellent choice for patients with elevated intracranial pressure (ICP). In addition, etomidate is safe for use in patients with reactive airway disease. However, it lacks the direct bronchodilatory properties of ketamine or propofol.

Etomidate has become the induction agent of choice for most emergent intubations because of its rapid onset, hemodynamic stability, positive effect on CPP, and rapid recovery. Its dosage can be reduced in hemodynamically compromised patients who are refractory to resuscitation. Etomidate is a pregnancy category C drug. Etomidate is not FDA-approved for use in children, but many series report safe and effective use in pediatric patients.

In euvolemic and hemodynamically stable patients, the normal induction dose of etomidate is 0.3 mg per kg IV push. In compromised patients, the dose can be reduced commensurate with the patient’s clinical status; reduction to 0.1 to 0.15 mg per kg is usually sufficient to produce unconsciousness. In morbidly obese patients, the induction dose should be based on IBW.

Pain during injection can occur due to the diluent (propylene glycol) and can be decreased by injecting into a large vein with a fast-flowing IV solution. Myoclonus is a common side effect and is usually of no clinical consequence as it terminates promptly as the neuromuscular blocking agent (NMBA) takes effect.

Etomidate causes a transient, reversible inhibition of adrenal cortisol production by blockade of 11-β-hydroxylase, which decreases both serum cortisol and aldosterone levels for 12 to 24 hours and may extend as long as 72 hours in some patients.¹ Concern has been raised about the potential to harm patients in septic shock who are potentially reliant on endogenous cortisol,^2,3,4,5 and there is occasionally lingering debate as to the potential risks of etomidate. There are unlikely to be any significant clinical sequelae from the transient inhibition of adrenal hormonal synthesis in the critically ill patient.^2,6,7 Much of the literature that exists has emerged from small, observational studies, post hoc analyses, retrospective review articles, and meta-analyses. None of the articles used to raise suspicion about etomidate were designed or powered to look at its effects, and the current available literature shows opposing opinions supporting or refuting single-dose etomidate in the critically ill patient. It is clear that immediate, short-lived adrenal insufficiency occurs in many patients with critical illness who receive etomidate, and etomidate’s role in sepsis mortality remains unclear,⁸ but there is no significant evidence of any increase in mortality. The 2023 Society for Critical Care Medicine RSI guidelines state that there is no evidence of any difference between etomidate and any other sedative in terms of mortality, hypotension, or vasopressor use, and there is no evidence that empiric steroids with etomidate are useful.⁹

Ketamine is a phencyclidine derivative that provides significant analgesia, anesthesia, and amnesia, with minimal effect on respiratory drive. The amnestic effect is not as pronounced as that seen with the benzodiazepines. Ketamine interacts with the NMDA receptors at the GABA-receptor complex, as well as blocks glutamate receptors, causing neuroinhibition and subsequent anesthesia.^10,11 Interaction with opioid receptors accounts for its analgesic effect. Ketamine stimulates the release of catecholamines, augmenting heart rate and blood pressure (BP) in those patients who are not catecholamine-depleted secondary to the demands of their underlying disease. This results in an increase in mean arterial pressure (MAP) that may offset any rise in ICP, resulting in a relatively stable CPP. Ketamine also directly relaxes bronchial smooth muscle, producing bronchodilation.^12,13 Ketamine is primarily metabolized in the liver, producing one active metabolite, norketamine, which is metabolized and excreted in the urine.

Ketamine is an ideal induction agent for patients with reactive airway disease who require tracheal intubation, and is also an excellent induction agent for patients who are hypovolemic, hypotensive, or hemodynamically unstable, including those with sepsis.^2,14,15 In normotensive or hypertensive patients with ischemic heart disease, catecholamine release may adversely increase myocardial oxygen demand, but it is unlikely that this effect is detrimental in patients with significant hypotension, in whom additional catecholamine release may support the BP. Ketamine’s preservation of upper airway reflexes makes it appealing for awake laryngoscopy and intubation in the difficult airway patient where the dose is titrated to effect.

Concern has been raised regarding ketamine’s effect on ICP, especially in the head-injured patient. Ketamine has been noted to slightly increase ICP through increased cerebral blood flow (CBF) and excitatory effects on neurons. Brain injury can cause a loss of cerebral autoregulation, and CBF is largely dependent on CPP, which in turn is largely dependent on the patient’s MAP. This is particularly true in patients with polytrauma where traumatic brain injury and shock may coexist. The dangers of hypotension on the injured brain are well known, and avoiding hypotension in traumatic brain injury is a priority.^{15,16,17,18,19} Ketamine helps maintain CPP, inhibits NMDA receptor activation, and reduces the systemic inflammatory response to tissue injury, among other potential effects.^15,19 In the last few years, increasing clinical evidence of the safety of ketamine in brain-injured patients has emerged, and it is becoming increasingly clear that ketamine is likely not dangerous in brain-injured patients.

The pregnancy category of ketamine has not been established by the FDA, and so it is currently not recommended for use in pregnant women.

The induction dose of ketamine for RSI is 1 to 2 mg per kg IV. In patients who are catecholamine depleted, doses more than 2 mg per kg IV may cause myocardial depression and exacerbate hypotension.²⁰ Because of its generalized stimulating effects, ketamine enhances laryngeal reflexes and can increase pharyngeal and bronchial secretions. These effects may uncommonly precipitate laryngospasm,^20,21 and may interfere with upper airway examination during awake intubation, but are generally not an issue during RSI. Atropine 0.01 mg per kg IV or glycopyrrolate (Robinul) 0.005 mg per kg IV may be administered 15 minutes before ketamine to promote a drying effect for awake intubation, when feasible. Ketamine is available in three separate concentrations: 10, 50, and 100 mg per mL. Care should be taken to verify which concentration is utilized during RSI to avoid inadvertent over- or underdosing.