What is the mechanism of action (MOA) of Rapid Sequence Intubation (RSI) drugs?

Mechanism of Action of Rapid Sequence Intubation Drugs

RSI employs two drug classes administered in rapid succession: sedative-hypnotic agents that induce unconsciousness and neuromuscular blocking agents (NMBAs) that produce complete muscle paralysis, facilitating optimal intubating conditions while minimizing aspiration risk. 1

Core Pharmacologic Components

Sedative-Hypnotic Induction Agents

The sedative-hypnotic agent must always be administered when an NMBA is used to prevent awareness during paralysis. 1 These agents work through distinct mechanisms:

Etomidate (0.2-0.3 mg/kg)

• Mechanism: Enhances GABA-A receptor activity in the central nervous system, producing rapid unconsciousness with minimal cardiovascular depression 1
• Key property: Inhibits 11-beta-hydroxylase (adrenal enzyme), though single-dose use shows no mortality difference compared to other agents 1
• Hemodynamic profile: Most favorable for unstable patients, preserving blood pressure better than alternatives 1, 2

Ketamine (1-2 mg/kg)

• Mechanism: NMDA receptor antagonist producing dissociative anesthesia with sympathomimetic properties 1, 3
• Key properties: Maintains respiratory drive, increases catecholamine release, preserves cerebral perfusion pressure 1, 4
• Critical caveat: In critically ill patients with depleted catecholamine stores, direct myocardial depression may cause paradoxical hypotension or cardiac arrest 1
• Special use: Preferred for medication-assisted preoxygenation in agitated patients, increasing oxygen saturation by mean 8.9% 2, 4

Propofol (1.5-2.5 mg/kg)

• Mechanism: GABA-A receptor agonist with rapid onset and short duration 1, 5
• Limitation: Most profound vasodilatory and negative inotropic effects, limiting use in hemodynamically unstable patients 1

Midazolam

• Mechanism: Benzodiazepine enhancing GABA-A receptor activity 1
• Limitation: Longer onset of action and potent venodilation at RSI doses make it less desirable 1

Neuromuscular Blocking Agents

An NMBA must be administered when a sedative-hypnotic agent is used for intubation (strong recommendation). 1, 2

Succinylcholine (1-1.5 mg/kg)

• Mechanism: Depolarizing NMBA that binds nicotinic acetylcholine receptors at the neuromuscular junction, causing initial fasciculations followed by flaccid paralysis 6, 7
• Onset: Approximately 45-60 seconds to optimal intubating conditions 7
• Duration: 5-10 minutes due to rapid hydrolysis by plasma cholinesterase 7, 8
• Advantage: Shortest duration allows faster return of spontaneous ventilation if intubation fails 7

Rocuronium (0.9-1.2 mg/kg for RSI)

• Mechanism: Non-depolarizing competitive antagonist at nicotinic acetylcholine receptors, preventing depolarization without initial fasciculations 5, 7
• Onset at high dose (1.2 mg/kg): Comparable to succinylcholine at 60-90 seconds 5
• Duration: 30-60 minutes, significantly longer than succinylcholine 5
• Critical requirement: Sugammadex must be immediately available for reversal in "cannot intubate/cannot oxygenate" scenarios 2, 4
• Standard dose (0.6 mg/kg): Provides intubating conditions in median 1 minute with 31 minutes clinical duration 5

Evidence-Based Drug Selection Algorithm

For Hemodynamically Stable Patients:

• Either etomidate or ketamine as induction agent 1, 2
• Either succinylcholine or rocuronium (1.0-1.2 mg/kg) as NMBA when no contraindications exist 2, 4

For Hemodynamically Unstable/Shock Patients:

• Etomidate preferred based on retrospective evidence showing less hypotension than ketamine in shock/sepsis 3
• Alternative: Reduced-dose etomidate (0.15 mg/kg) in severe hemodynamic compromise 1

For Agitated/Uncooperative Patients:

• Ketamine for medication-assisted preoxygenation (delayed sequence intubation) before administering NMBA 2, 4

NMBA Selection Considerations:

• Choose succinylcholine when: Shorter duration desired, concern for difficult airway, no contraindications present 2, 7
• Choose rocuronium when: Succinylcholine contraindicated (hyperkalemia risk, malignant hyperthermia history, neuromuscular disease) 2, 5

Critical Timing and Administration

The defining characteristic of RSI is rapid succession administration: sedative-hypnotic immediately followed by NMBA with immediate endotracheal tube placement before assisted ventilation begins. 1, 2, 8 This differs from traditional intubation by avoiding mask ventilation between induction and intubation to minimize aspiration risk, though this practice is evolving based on hypoxemia risk. 1, 2

Common Pitfalls and How to Avoid Them

• Administering NMBA without sedative-hypnotic: Always give induction agent first to prevent awareness during paralysis 1
• Inadequate dosing in obese patients: Dose based on actual body weight, not ideal body weight, as IBW dosing produces inadequate intubating conditions 5
• Using rocuronium without available sugammadex: Ensure reversal agent immediately accessible before administering rocuronium 2, 4
• Delayed post-intubation sedation with rocuronium: Its 30-60 minute duration creates prolonged awareness risk if post-intubation analgosedation delayed 4
• Ketamine in catecholamine-depleted patients: Despite sympathomimetic properties, direct myocardial depression may cause cardiovascular collapse in severely depleted patients 1