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Each year more than 1.5 million critically ill adults receive invasive mechanical ventilation in the United States, at a cost of nearly $30 billion dollars annually. Recent research has dramatically improved patient safety during the maintenance, weaning, and liberation stages of invasive mechanical ventilation. In contrast, the optimal approach to the initiation of mechanical ventilation remains an important knowledge gap in the care of adults with respiratory failure. Among critically ill adults, life-threatening complications during tracheal intubation and initiation of invasive mechanical ventilation remain common. One in five patients experiences hypotension and one-in-forty experiences cardiac arrest during the two-minute tracheal intubation procedure Cardiovascular collapse is a peri-procedural outcome defined as severe hypotension, new or increased vasopressors, cardiac arrest or death. The occurrence of cardiovascular collapse during tracheal intubation of critically ill adults increases patients' risk of in-hospital mortality. Randomized trials examining intubation technique commonly target cardiovascular collapse as an outcome. Adherence to recommended best-practices for tracheal intubation (e.g., preoxygenation, optimization of patient positioning, and procedural checklists) are insufficient to prevent 20-40% of critically ill adults from experiencing cardiovascular collapse during tracheal intubation. Rapid sequence induction and tracheal intubation, the most common method of intubation for critically ill patients, is the nearly simultaneous administration of a sedative medication and neuromuscular blocking medication. The ideal sedative agent for rapid sequence intubation would rapidly provide a deep state of unconsciousness and analgesia without causing hemodynamic side effects. No available agent meets all of these criteria. The administration of any of the available sedative agents at a dose large enough to rapidly induce unconsciousness contributes to cardiovascular collapse through vasodilation, decreased cardiac filling pressures from sedation-induced venodilation, and decreased endogenous catecholamines. While all sedatives commonly used during emergency tracheal intubation of critically ill patients have been associated with unsatisfactory hypotension (21 CFR 50.24(a)(1)), ketamine and etomidate are the medications used most commonly in clinical practice due to their rapid onset and favorable hemodynamic profiles relative to the other available sedatives. Other sedatives that have been used in some settings during rapid sequence intubation include benzodiazepines, propofol, and barbiturates. Benzodiazepines do not provide any analgesia and are associated with an unsatisfactory degree of hypotension, with a drop in mean arterial blood pressure of 10 to 25 percent, even among healthy patients. At present, barbiturates are rarely used for tracheal intubation in the US because of unsatisfactorily high rates of post-intubation hypotension and evidence of negative cardiac ionotropy. While propofol is commonly used to induce anesthesia among healthy patients, and is commonly administered as a continuous infusion to maintain sedation for critically ill patients, it is used less commonly as a bolus during tracheal intubation of critically ill patients because it has been suggested to cause unsatisfactorily high rates of hypotension and cardiac depression, compared to ketamine or etomidate. Ketamine is a phencyclidine derivative that provides anesthesia via its effect at the NMDA receptors. Ketamine has been approved by the United States Food and Drug Administration (FDA) with approved indications including "use as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation" and "induction of anesthesia prior to the administration of other general anesthetic agents." In addition to sedation, ketamine provides significant amnesia and analgesia via action at the opioid receptors, and is commonly used for procedural sedation and as a continuous infusion to control pain. Ketamine activates the sympathetic nervous system, stimulating the release of catecholamines, which may increase heart rate and blood pressure during intubation and prevent peri-procedural cardiovascular collapse. Conversely ketamine has direct negative ionotropic effects, leading to myocardial depression. While the myocardial depression may be counteracted by increased catecholamine release, ketamine could cause cardiovascular collapse among patients with depleted catecholamine stores, and case reports of unexpected cardiac arrest during intubations with ketamine have been published. Despite stimulating the release of catecholamines, using ketamine as the induction agent during emergency tracheal intubation does not appear to frequently cause or worsen hypertensive urgency or emergency; however, the literature on this topic is limited to case reports. Historically, concerns have been raised that ketamine might increase intracranial pressure and cause deleterious decreases in cranial perfusion pressure. Recent studies have suggested, however, that ketamine may be associated with a beneficial increase in cranial perfusion pressure as a result of increased mean arterial pressure, and a recent, large before-after study showed no significant differences in clinical outcomes for trauma patients intubated with ketamine versus etomidate. Etomidate is an imidazole derivative that acts at gamma-aminobutyric acid "A" (GABA) receptors. Etomidate has been approved by the FDA with an indication for "induction of general anesthesia." In a recent review of more than 19,000 intubations by a large, multicenter emergency medicine registry, etomidate was the most commonly used sedative during emergency tracheal intubation. Etomidate causes less hemodynamic instability than propofol or midazolam, but the data regarding the relative risk of hemodynamical instability with etomidate, compared to ketamine, is unclear. It was initially suggested that ketamine might cause less hypotension than etomidate, given ketamine's ability to stimulate the release of catecholamines, but a recent observational study comparing ketamine and etomidate among nearly 7,000 critically ill adults undergoing tracheal intubation in emergency departments suggested that ketamine was independently associated with an increased risk of peri-intubation hypotension. Etomidate was initially used both for induction of anesthesia and as a continuous drip for maintenance of anesthesia. Its use as a continuous drip for maintenance of anesthesia was halted after it was discovered that prolonged use of etomidate causes inhibition of adrenal cortisol production by blockade of 11-β-hydroxylase, leading to adrenal insufficiency, and increased mortality. Etomidate use as a single bolus for induction of anesthesia has continued, but numerous studies have demonstrated that even a single dose of etomidate can cause transient adrenal insufficiency. The clinical significance of this relative adrenal insufficiency, however, remains unclear. Contrasting observational studies have suggested that etomidate may have positive, negative or neutral impacts on mortality. Two randomized trials have directly compared ketamine to etomidate for RSI among critically ill adults. The Ketased trial, published in 2009, was a 469-patient trial conducted across 12 emergency medical services and emergency departments in France. Because many patients were enrolled in the pre-hospital setting without continuous blood pressure monitoring, peri-procedural outcomes such as cardiovascular collapse were not collected, and the results were indeterminate, in regards to the primary outcome, average Sequential Organ Failure Assessment (SOFA) scores in the 72 hours after intubation. The results, however, demonstrated significant heterogeneity. Patients with trauma (for whom increased intracranial pressure from ketamine may be important) experienced a non-significant 4% absolute increase in mortality when intubated with ketamine compared to etomidate. All other patients experienced a non-significantly lower mortality when intubated with ketamine, particularly patients with sepsis who experienced a non-significant 7% absolute mortality benefit (and in whom adrenal insufficiency from etomidate may be particularly important). The EvK trial, published in January 2022, was a single-center, 801-patient trial conducted among hospitalized patients at a single hospital in Texas.61 Survival at 7 days, the primary outcome of the EvK trial, was higher in the ketamine group, compared to the etomidate group (85.1% vs 77.3%; p=0.005), but this difference was attenuated by day 28, at which point it was no longer significant (66.8% vs 64.1%, p=0.294). The conclusion of this single-center trial was that "there was no significant difference in survival by Day 28", however it was noted that this "could represent a small but durable long-term survival effect, one which our trial was under-powered to detect." Experts have pointed out that the currently available data on sedative choice during tracheal intubation of critically ill patients are inadequate and have called for additional randomized clinical trials. Because (1) cardiovascular collapse is common during tracheal intubation of critically ill adults (2) sedatives are a driver of cardiovascular collapse, (3) use of ketamine or etomidate varies between centers, specialties, and operators, and (4) prior data suggests the potential for ketamine to significantly decrease mortality for patients without trauma, a large, multicenter trial is needed to determine the effects of ketamine and etomidate on mortality in non-traumatic critical illness.