The Randomized Trial of Sedative Choice for Intubation

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.