What is the preferred agent for induction in a critically ill or injured patient requiring delayed sequence intubation, comparing ketamine, benzodiazepines (e.g. midazolam) and etomidate?

Ketamine is the Preferred Agent for Delayed Sequence Intubation

For delayed sequence intubation (DSI) in critically ill or injured patients, ketamine (1-2 mg/kg IV) is the preferred induction agent over benzodiazepines or etomidate because it uniquely preserves spontaneous respirations and airway reflexes while providing dissociative sedation, allowing safe preoxygenation in agitated patients. 1

Why Ketamine is Superior for DSI

Preservation of Respiratory Drive

• Ketamine maintains spontaneous ventilation during the preoxygenation phase, which is the fundamental advantage that makes DSI possible. 1
• This allows 3 minutes of effective preoxygenation in agitated, hypoxemic patients who would otherwise not tolerate mask ventilation or high-flow oxygen. 2
• In a randomized trial of 200 critically injured patients, DSI with ketamine reduced peri-intubation hypoxia from 35% to 8% compared to standard rapid sequence intubation (P = .001). 2

Hemodynamic Stability

• Ketamine's sympathomimetic properties help maintain blood pressure during the high-risk peri-intubation period, making it suitable for hemodynamically unstable patients. 1, 3
• The Society of Critical Care Medicine recommends ketamine as a first-line induction agent alongside etomidate for critically ill patients. 1, 4

Dosing Protocol for DSI

• Administer ketamine 1-2 mg/kg IV as a dissociative dose. 1, 2
• Wait 3 minutes while providing preoxygenation with high-flow nasal oxygen or noninvasive positive pressure ventilation. 1, 2
• Then administer neuromuscular blocking agent (succinylcholine 1-1.5 mg/kg or rocuronium 1.0-1.2 mg/kg) and proceed with intubation. 1, 2

Why NOT Benzodiazepines

• Benzodiazepines are not recommended as sole induction agents for DSI or RSI in critically ill patients. 5
• They cause respiratory depression and loss of airway reflexes, defeating the purpose of DSI which requires preserved spontaneous ventilation during preoxygenation. 5
• Guidelines specifically recommend hypnotic agents (etomidate, ketamine, propofol) rather than benzodiazepines for induction. 5

Why NOT Etomidate for DSI

• Etomidate causes immediate loss of consciousness and respiratory drive, making it unsuitable for the preoxygenation phase of DSI. 5
• While etomidate (0.3 mg/kg) is an excellent choice for standard rapid sequence intubation due to hemodynamic stability, it cannot be used for DSI because patients cannot cooperate with preoxygenation after administration. 1
• Etomidate is reserved for the final induction step in standard RSI, not for the dissociative sedation phase of DSI. 5

Critical Pitfalls to Avoid

Catecholamine Depletion

• In patients with prolonged septic shock, severe cardiogenic shock, or adrenal exhaustion, ketamine may paradoxically cause hypotension despite its sympathomimetic properties. 1, 4
• Always have vasopressors immediately available during any intubation with ketamine. 1, 3

Timing and Neuromuscular Blockade

• Never administer the neuromuscular blocking agent before ketamine—this causes awareness during paralysis, which occurs in 2.6% of emergency intubations. 1, 3
• Wait the full 3 minutes after ketamine administration to allow adequate preoxygenation before giving the paralytic. 2
• After administering rocuronium, wait at least 60 seconds before attempting intubation to ensure adequate neuromuscular blockade. 1

Evidence Quality and Comparative Outcomes

Mortality Data

• Recent meta-analysis of 2,978 patients showed an 83.2% probability that ketamine reduces mortality compared to etomidate (RR 0.93,95% CrI 0.79-1.08). 6
• A 2025 systematic review of 23,926 patients found no significant difference in 30-day survival between ketamine and etomidate (OR 0.92,95% CI 0.68-1.24 for RCTs). 7

Hemodynamic Considerations

• Ketamine was associated with higher post-intubation vasopressor requirements (OR 0.71,95% CI 0.53-0.96) but no difference in cardiovascular collapse. 7, 8
• Post-induction hypotension occurred in 18.3% with ketamine versus 12.4% with etomidate in emergency department RSI, though this difference was not statistically significant in all studies. 3, 8

First-Pass Success

• DSI with ketamine achieved 83% first-attempt success versus 69% with standard RSI (P = .02). 2

Clinical Decision Algorithm

Use ketamine for DSI when:

• Patient is agitated, combative, or delirious preventing adequate preoxygenation
• Severe hypoxemia (PaO2/FiO2 < 150) requiring extended preoxygenation time
• Hemodynamically stable to moderately unstable patients

Have vasopressors ready and consider lower ketamine dose (1 mg/kg) when:

• Prolonged septic shock with likely catecholamine depletion
• Severe cardiogenic shock
• Known adrenal insufficiency

Avoid DSI entirely and proceed directly to RSI with etomidate or ketamine when:

• Patient is already apneic or in extremis
• Immediate airway control needed without time for preoxygenation phase