A Review of Rapid Sequence Intubation Pharmacology

Eli Brennan MS3
EMRA MSC Northeast 2 Representative, 2025

Edited by
Olivia Voltaggio, OMS III
EMRA MSC Editor, 2025

Rapid Sequence Intubation (RSI) is an emergency airway management technique where sedative and neuromuscular blocking agents are administered in rapid succession to allow endotracheal intubation. This procedure is performed in a variety of settings, most commonly in the emergency department or operating room. RSI rapidly renders the patient paralyzed and unresponsive, allowing the physical passage of an endotracheal tube into the trachea while the patient remains sufficiently unresponsive to be unable to react to this stimulating procedure and jeopardize the loss of the airway. RSI is considered the standard of care for urgent airway control, especially in scenarios in which a patient is unable to protect their own airway or is in imminent danger of respiratory failure but still conscious.  

In this article, we will review the medications that are most frequently used in RSI and highlight the reasons a physician may or may not choose them. 

Induction Agents 

An ideal induction agent for rapid sequence intubation (RSI) has a rapid onset and short duration of action, providing deep sedation or anesthesia for a limited time. The pharmacokinetic properties of RSI drugs are critical to their effectiveness. While deep sedation and paralysis are necessary for successful intubation, in the event of a failed attempt, it is advantageous to have used an agent with a short duration to avoid prolonged impairment of airway reflexes or spontaneous ventilation, which can complicate rescue efforts (1). 

The choice of induction agent depends on many patient factors, such as hemodynamics, neurological status, and airway reactivity (1). Physician preference is also relevant in the choice, as it is not uncommon for physicians within various specialties such as anesthesia and emergency medicine to prefer different drugs depending on their training and level of comfort. Common induction agents include etomidate, ketamine, and propofol. Midazolam is also used in certain scenarios, but less frequently, as will be discussed. (1,2).

Etomidate

Etomidate is a sedative that is very frequently used as an induction agent both in emergent and non-emergent airway control (3). It potentiates the action of gamma-aminobutyric acid (GABA), causing a net inhibitory effect on the central nervous system (3). Etomidate is often the preferred induction agent due to its hemodynamic stability; it typically does not cause significant hypotension, which should be a main consideration in unstable patients. However, etomidate transiently suppresses cortisol synthesis by inhibiting 11β-hydroxylase (4). This can be of particular concern in patients with adrenal dysfunction due to known disease or due to the adrenal suppression, which is common in unstable intensive care patients. Studies have shown that etomidate may worsen patient outcomes in septic patients and particular care should be shown when utilizing the medication (4). However, given its rapid onset and minimal cardiovascular effects, many physicians consider the benefits of etomidate to outweigh its potential risks and often employ it for use in RSI situations. 

Propofol 

Propofol induces unconsciousness by potentiating GABA-A receptors. It is frequently used in surgical patients due to its potent hypnotic effects. It has an extremely rapid onset and short duration of action (1). Propofol also reduces intracranial pressure and has anti-seizure and anti-emetic properties (1). However, it causes significant peripheral vasodilation and can be extremely dangerous if used on hypotensive patients. While in a stable operating room this can be generally well managed, unstable patients may not be ideal candidates due to the risk of hypotensive shock. 

Ketamine

Ketamine is an NMDA receptor antagonist that provides both sedation and analgesia. It has been the subject of intense interest in recent years as a sedative, analgesic, and due to its role in treating a variety of psychiatric disorders (5).  Uniquely among induction agents, ketamine has sympathomimetic effects that stimulate an increased heart rate and blood pressure, which can be beneficial in hemodynamically unstable patients, but dangerous in those with underlying arrhythmia or myocardial contractility concerns (5). Additionally, ketamine is known to increase tracheobronchial secretions which can contribute to airway instability (6). However, pretreatment with atropine has been shown to provide a significant decrease in secretions (6). Although ketamine is highly effective, physicians may choose to avoid using it in patients where excessive secretions are already a concern or if atropine could pose additional risk, such as in those with marked tachycardia.

Midazolam 

Benzodiazepines act by increasing the frequency of chloride channel opening at the GABA-A receptor, thereby enhancing inhibitory neurotransmission. (7). Historically they have been extremely popular for a variety of situations requiring sedation. In modern medicine, benzodiazepines are less commonly used as sole induction agents for intubation due to their relatively slow onset and prolonged duration of action (7). Additionally, there is growing awareness of the risks associated with their use in patients with a history of benzodiazepine use, alcohol use disorder, or in the elderly. Studies have shown that when midazolam is used for intubation, it is often under-dosed (8), which may be due to concerns about these adverse effects and can result in inadequate sedation. 

Neuromuscular Blocking Agents (Paralytics)

Induction drugs are neuromuscular blocking agents that induce muscular paralysis, allowing the use of laryngoscopy and tube placement without patient movement interference. Paralytics do not inherently have sedative or analgesic effects, as they act to prevent transmission of impulses specifically in motor units without impacting the CNS. This is why they are to be given with a sedative to prevent awareness. In today’s clinical practice, the most commonly used paralytics for RSI are succinylcholine and rocuronium (1).

Succinylcholine

  Succinylcholine is a depolarizing neuromuscular blocker that acts as an acetylcholine receptor agonist. By depolarizing the neuromuscular junction (NMJ), the transmission of impulses is impeded, thereby impairing motor movement (9). It has an extremely fast onset and a short duration of action (9). This profile is very favorable for RSI situations, however, succinylcholine can lead to several critical adverse events. A classic example is malignant hyperthermia, a genetic alteration of ryanodine receptors leading to dysregulated calcium transmission in motor units, and a subsequent hypermetabolic crisis (10). Additionally, patients who have upregulation of acetylcholine receptors (those with neuromuscular disorders or chronic paralysis) can have large releases of potassium when given succinylcholine, leading to cardiac arrhythmia and even arrest (10). Even with its potential for adverse issues, it is still commonly used due to its rapid onset and duration of action as well as its reliability for providing sufficient paralysis. 

Rocuronium

Rocuronium is a non-depolarizing neuromuscular blocker that competitively inhibits acetylcholine receptors at the motor endplate. It typically has a rapid onset comparable to succinylcholine but a longer duration of action (11). This is often ideal for use in non-emergent patients in the operating room, but less desirable in RSI situations. Due to its long duration of action, if the intubation attempt fails, subsequent ventilation can be more difficult. Sugammadex is a selective binding agent developed to rapidly reverse rocuronium-induced paralysis. It functions by encapsulating free rocuronium molecules in the plasma, creating a concentration gradient that draws rocuronium away from nicotinic receptors at the neuromuscular junction. Once in the plasma, sugammadex complexes with rocuronium, effectively neutralizing it (12). While highly effective and fast-acting, sugammadex is expensive and may not be available in all clinical settings.

Overall, while some drawbacks exist to rocuronium, studies have shown that when rocuronium and succinylcholine are compared in RSI situations, there are no statistical differences between the incidence of oxygen desaturations or first-pass failed intubation attempts (13). As such, both are valid choices for RSI.  

In Conclusion

Rapid Sequence Intubation is a critical procedure that demands careful consideration of pharmacologic agents to maximize success and minimize risk. The selection of the induction and paralytic agents is extremely important and may significantly impact patient outcomes. Each medication has pronounced advantages and limitations and physicians should carefully educate themselves on their pharmacokinetic profiles. 

As research and clinical experience continue to evolve, it reinforces a lesson every physician learns early in training: never stop reading.

References

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