What is the ideal induction agent, between ketamine, etomidate, or benzodiazepines, for delayed sequence intubation in an adult patient with a potentially difficult airway or at high risk of rapid desaturation?

Ketamine is the Ideal Induction Agent for Delayed Sequence Intubation

Ketamine at 1-2 mg/kg IV is the preferred induction agent for delayed sequence intubation (DSI) because it uniquely provides dissociative sedation while preserving spontaneous respirations and airway reflexes, allowing safe preoxygenation in agitated patients who would otherwise not tolerate preparation—the fundamental purpose of DSI. 1, 2

Why Ketamine is Specifically Designed for DSI

Preservation of Respiratory Drive

• Ketamine maintains spontaneous ventilation and protective airway reflexes during the dissociative state, which is essential for the preoxygenation phase of DSI 1, 2
• This allows patients to continue breathing through high-flow oxygen or noninvasive positive pressure ventilation (NIPPV) while achieving adequate oxygen saturation before paralysis 2
• In a prospective multicenter study of 62 patients undergoing DSI, oxygen saturations increased from a mean of 89.9% before ketamine administration to 98.8% after preoxygenation, representing an 8.9% improvement (95% CI 6.4%-10.9%) 2

Dissociative Properties Enable Cooperation

• Ketamine produces a dissociative state that allows previously agitated or combative patients to tolerate preoxygenation procedures without requiring immediate paralysis 1, 2
• Among 62 DSI patients, 39 required ketamine specifically to allow NIPPV, 19 to allow nonrebreather mask, and 4 for nasogastric tube placement—all procedures impossible without sedation 2
• Critically, 32 patients with pre-DSI saturations ≤93% all increased their saturations post-ketamine, with 29 (91%) achieving saturations >93% before intubation 2

Why Etomidate Fails in the DSI Context

Immediate Loss of Consciousness and Respiratory Drive

• Etomidate causes rapid loss of consciousness within 30-60 seconds with significant respiratory depression, making it unsuitable for the preoxygenation phase of DSI 3
• The FDA label explicitly warns that etomidate causes "a slight elevation in arterial carbon dioxide tension (PaCO2)" indicating respiratory compromise 3
• Etomidate requires immediate airway management after administration, defeating the entire purpose of DSI which is to allow time for optimization 3

Mortality Concerns in Critically Ill Patients

• A 2025 Brazilian multicenter cohort study of 1,810 critically ill adults undergoing RSI found that etomidate was associated with higher 28-day mortality compared to ketamine (60.5% vs 54.4%; RR 1.14,95% CI 1.03-1.27; risk difference 7.6%) 4
• Seven-day mortality was also significantly higher with etomidate (35.2% vs 30.1%; RR 1.19,95% CI 1.04-1.35) 4
• A 2024 Bayesian 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) 5

Why Benzodiazepines Are Inadequate

Prolonged Onset and Hemodynamic Instability

• Benzodiazepines (particularly midazolam) have a significantly longer onset of action compared to ketamine, making them impractical for DSI where timely progression to intubation is critical 6
• Midazolam is a potent venodilator at RSI doses, causing significant hypotension in already compromised patients 6
• Benzodiazepines provide no hemodynamic support through sympathomimetic properties, unlike ketamine 6

Lack of Evidence for DSI

• No published studies support benzodiazepine use for DSI, whereas ketamine has prospective multicenter validation 2
• The Society of Critical Care Medicine guidelines recommend ketamine or etomidate as first-line induction agents, not benzodiazepines 7, 6

Practical DSI Protocol with Ketamine

Dosing Algorithm

• Administer ketamine 1-2 mg/kg IV for dissociative sedation 6, 1, 2
• Use the lower end of dosing (1 mg/kg) in patients with cardiovascular compromise, chronic hypoxemia, or suspected catecholamine depletion 6, 8
• Consider antisialagogue pretreatment (glycopyrrolate 0.2 mg or atropine 0.5 mg) 3-5 minutes before ketamine to prevent excessive secretions 8, 9

Preoxygenation Phase

• After ketamine administration, apply high-flow nasal oxygen (HFNO) or NIPPV depending on severity of hypoxemia 7, 2
• Use NIPPV in patients with severe hypoxemia (PaO2/FiO2 < 150) 6
• Allow 3-5 minutes for adequate preoxygenation while monitoring oxygen saturation 2

Transition to Intubation

• Once adequate preoxygenation is achieved (SpO2 >93% or FeO2 >90%), administer neuromuscular blocking agent 7, 6
• Use succinylcholine 1-1.5 mg/kg or rocuronium 1.0-1.2 mg/kg 6
• Wait 60 seconds after paralytic administration before attempting intubation 6

Critical Pitfalls to Avoid

Paradoxical Hypotension with Ketamine

• Despite ketamine's sympathomimetic properties, paradoxical hypotension can occur in critically ill patients with depleted catecholamine stores from prolonged shock, severe hypoxemia, or adrenal exhaustion 6, 8, 10
• Have vasopressors immediately available during DSI, as observational data shows post-intubation hypotension rates of 18.3% with ketamine 7, 6
• Higher ketamine doses (>2 mg/kg) are associated with significantly increased adverse events including hypotension (OR 7.0,95% CI 3.0-16.6), laryngospasm (OR 10.8), and bradycardia (OR 7.5) 11

Secretion Management

• Ketamine significantly increases upper airway secretions, which can complicate laryngoscopy 8, 9
• The FDA label states that "due to the potential for salivation during ketamine administration, administer an antisialagogue prior to induction" 9
• Ensure aggressive suctioning capability is immediately available 8

Aspiration Risk

• While ketamine preserves some airway reflexes, the FDA warns that "vomiting and aspiration may occur with ketamine" and it is "not recommended for use in patients who have not followed nil per os guidelines" 9
• Position patients in semi-Fowler position (head and trunk elevated) during DSI to reduce aspiration risk 6

Avoiding Etomidate in Specific Populations

• Never use etomidate in pediatric patients with septic shock, as guidelines explicitly recommend against it due to adrenal suppression and increased mortality 6, 10
• The American College of Critical Care Medicine states that even one dose of etomidate is independently associated with increased mortality in septic shock 10

Comparative Safety Profile

No Mortality Difference in General Populations

• The 2023 Society of Critical Care Medicine guidelines found no significant mortality difference between etomidate and ketamine in general critically ill populations undergoing standard RSI (not DSI specifically) 7, 6
• However, the most recent 2025 evidence suggests ketamine may reduce mortality in critically ill adults 4, 5

Hemodynamic Considerations

• Mixed results exist regarding peri-intubation hemodynamics between agents, with some studies showing higher hypotension rates with ketamine (18.3% vs 12.4% for etomidate) while others show the opposite 7
• These discrepancies likely reflect patient selection bias, as ketamine is often chosen for patients with more difficult airways and higher baseline risk 7
• Duration of vasopressor use shows no difference between agents 7, 6