RAPID SEQUENCE INTUBATION & PHARMACOLOGY

OVERVIEW
Rapid sequence induction intubation (RSI) has become the gold standard for management of the airway in trauma and critical illness. The technique of RSI has been demonstrated to increase success rates for intubation and reduce complications compared to pre-RSI techniques in a variety of emergent settings. (Kovacs, G., 2004) (Pearson, S., 2003) (Bair AE, 2002)
Rapid sequence intubation is not without risk, and the decision to employ RSI must be preceded by a risk-benefit analysis based upon proficiency with non-intubating airway maintenance skills, RSI pharmacology, and emergent intubation. Rapid sequence intubation can be divided into five phases: (1) preparation of patient and equipment; (2) preoxygenation; (3) premedication; (4) paralysis; and (5) placement of the tube.

Preparation

Although significant injury with physiologic instability may preclude prolonged preparation for RSI, all efforts should be made to allow for individualized assessment of comorbid conditions, airway status, predictors of difficult intubation, and anticipated pharmacologic regimen.

Preoxygenation

Although not originally considered an essential component of RSI, preoxygenation is mandatory if the oxygenation, ventilation, and hemodynamic status of the patient permit. The purpose of preoxygenation is to replace the nitrogen-dominant room air occupying the pulmonary functional residual capacity with a 100% oxygen reservoir, such that saturation of arterial hemoglobin (SaO2) is prolonged. This can be accomplished by gently assisting spontaneous respirations with 100% oxygen or simply allowing the patient to breathe 100% oxygen. An optimally preoxygenated healthy 70-kg adult will maintain SaO2 over 90% for approximately 8 minutes, an obese adult less than 3 minutes, and a 10-kg child less than 4 minutes. (Walls RM, 2004) More importantly, the desaturation from 90% SaO2 to 0% occurs much more rapidly than the fall from 100% to 90%. The approximate PaO2 at 90% SaO2 is 60 mmHg, and this decreases to 27 mmHg at an SaO2 of 50%. An injured patient with little compensatory reserve can decline from 90% to 0% literally in seconds.
It is imperative that providers caring for the injured be facile with all pharmacologic agents utilized for RSI, including both barbiturate and nonbarbiturate hypnotics, neuromuscular blocking agents, benzodiazepines, dissociative agents, and opiates. each patient should be individualized based upon type and mechanism of injury, comorbidities, and potential for adverse events. The majority of trauma patients, however, can be effectively intubated using a generalized pharmacologic regimen.

PREMEDICATION

Airway stimulation, including laryngoscopy and placement of an endotracheal tube, results in the pressor response, an intense autonomic sympathetic discharge producing tachycardia, hypertension, and increased intracranial pressure. (Reynolds SF, 2005) (Singh S, 2003)A common mnemonic for the preinduction regimen is LOAD, which includes Lidocaine, Opiates, Atropine, and a Defasciculating agent, although atropine is typically utilized in pediatric populations only.
Opioids. Depth of sedation may correlate with speed of intubation in RSI. (Sivilotti ML, 1998) The sedative and analgesic effects of opioids may provide benefit to the injured patient prior to induction. A commonly used opioid for RSI in the prehospital and emergency department setting is fentanyl, which at a dose of 5.0 mcg/kg has been shown to be hemodynamically neutral compared to midazolam and thiopental during RSI. (Sivilotti ML, 1998) Fentanyl effectively blunts airway reactivity (Tagaito Y, 1998) and confers the significant added benefit of analgesia in the injured patient.

Benzodiazepines

Benzodiazepines, a family of gamma aminobutyric acid (GABA) agonists, have been utilized in RSI for sedation. Midazolam is the most widely studied agent, having favorable pharmacokinetics for RSI, including rapid onset and short half-life. Advantages include hemodynamic neutrality and retrograde amnesia, although onset is slower than comparable agents and the intubation reflex is not attenuated. (Sivilotti ML, 1998) Therefore, it is less commonly used in RSI protocols than opioids.

Antiarrhythmics

Despite a great deal of controversy regarding the potential benefits of lidocaine during RSI, it is a preinduction agent common to RSI protocols (Robinson N, 2001) and is advocated in many emergency airway courses. Lidocaine has a number of theoretical beneficial preintubation effects, including abrogation of airway reactivity following placement of the endotracheal tube, the tachycardic response to intubation, and succinylcholine-induced myalgia and fasciculations. (Lev R, 1994), (Schreiber JW, 2005) The two primary potential benefits of use of lidocaine in RSI are to avoid reflex bronchospasm and increased intracranial pressure. The decision to use lidocaine in RSI becomes a potential benefit versus risk analysis. Although definitive data are lacking regarding effects on intracranial pressure, the potential benefits outweigh the negligible side effects of the RSI dose.

Defasciculation Paralytic Agents

Succinylcholine, the standard neuromuscular blocking agent utilized for RSI, produces significant myoclonal fasciculations, prompting a rise in intracranial pressure. Therefore, a defasciculating dose of a competitive neuromuscular blocking is administered during RSI. Common defasciculating agents include vecuronium and rocuronium, and, less commonly, pancuronium. Defasciculating doses are administered as 10% of the paralyzing dose, given 3 to 5 minutes prior to administration of succinylcholine. It is unusual for defasciculating doses of neuromuscular blockers to cause apnea. As patient weight is commonly an estimate during RSI following injury, however, preparations to assist with ventilation should be made.


Induction Agents

The purpose of induction agents in RSI is to induce rapid loss of consciousness to facilitate endotracheal intubation. The perfect induction agent would possess rapid onset and elimination, render the patient unconscious but also amnestic, possess analgesic properties, and have negligible side effects. In injured and critically ill patients, the ideal agent would produce little cardiovascular effects and maintain cerebral perfusion pressure. Regrettably, such an agent does not yet exist. Because many agents produce side effects, including myocardial depression with the potential for hypoperfusion, careful attention should be dedicated to the selection of individual agents, focusing on clinical presentation and patient specific characteristics.

Etomidate

Etomidate is a short acting carboxylated imidazole hypnotic agent frequently utilized for rapid sequence induction. Etomidate possesses ideal characteristics for urgent and emergent RSI in trauma patients, including rapid onset and clearance, reduction in cerebral metabolic rate, (Rodricks MB, 2000) and negligible effects on hemodynamics. This favorable pharmacokinetic profile has led to the widespread use of etomidate for RSI in patients with injury to the brain and hemodynamically labile patients. The most significant side effect of etomidate relates to adrenal insufficiency, as it produces a reversible blockade of adrenal 11-beta-hydroxylase. In patients at risk for adrenal insufficiency, including brain injured, mechanically ventilated, and septic populations, etomidate has been independently correlated with reductions in serum cortisol. (Jackson, 2005) (Malerba G, 2005) (Cohan P, 2005) The controversial question relates to whether transient adrenal suppression produces lasting effects on outcome. Further studies are warranted to determine the long-term safety of etomidate for RSI; however, given the multiple favorable characteristics of the drug, etomidate will remain the standard induction agent in most RSI protocols.

Propofol

Propofol is a nonbarbiturate hypnotic agent that rapidly induces deep sedation and significant relaxation of laryngeal musculature.28 When used for induction, propofol produces intubation conditions equal to thiopental (El-Orbany MI, 2003)and equal to or superior to etomidate. (Sivilotti ML F. M., 2003) Propofol should be used with caution in patients with injury to the brain or hemodynamically labile patients due to a consistent hypotensive effect and potential reduction of cerebral blood flow. Therefore, it should be considered an alternative agent in RSI.

Barbiturates

Thiopental is the most commonly used barbiturate for RSI. Like other induction agents used in RSI, thiopental has rapid onset and clearance. In the aeromedical setting, thiopental has been shown equally efficacious to etomidate as an adjunct to RSI. (Sonday CJ, 2005) Similarly, in an evaluation of 2380 RSI procedures, patients were more likely to be successfully intubated using thiopental or propofol as compared to etomidate or a benzodiazepine. (Sivilotti ML F. M., 2003) In addition, thiopental reduces cerebral oxygen consumption and exhibits anticonvulsant effects, rendering it useful in patients with injury to the brain. The significant limitation of thiopental use for RSI in trauma relates to inhibition of the sympathetic response of the central nervous system. Therefore, thiopental reduces myocardial contractility and systemic vascular resistance, and causes hypotension. Therefore, it is best reserved for patients who are euvolemic and normotensive, limiting its application in injured and critically ill patients.

Dissociative Agents

Ketamine, a rapid onset dissociative sedative and anesthetic agent, is frequently used for RSI in the pediatric population (Lee BS, 2001) and in adults with chronic obstructive pulmonary disease. (Marvez E, 2003)In addition to its sedative effects, ketamine exhibits the beneficial properties of potent analgesia and a partial amnesia. As a sympathomimetic agent, ketamine may induce tachycardia and increase blood pressure. In addition, ketamine induces cerebral vasodilatation, potentially exacerbating intracranial hypertension. Trauma patients with documented or potential injury to the brain should not undergo induction for RSI with ketamine. Given the sympathomimetic properties of ketamine, it is best reserved for patients with proven reactive airway disease and hypovolemia when injury to the brain has been definitively excluded.

Neuromuscular Blocking Agents

Pharmacologic paralysis represents an integral component of RSI, facilitating emergent intubation for more than three decades. (Thompson JD, 1982) (Brown EM, 1979) Paralysis of facial musculature facilitates optimal visualization during laryngoscopy, confers total control of the patient, and reduces complications during intubation. Prehospital neuromuscular blockade has been demonstrated to be safe (Zonies DH, 1998) (Rotondo MF, 1993), and to improve the success of intubation in injured patients undergoing RSI. (Bozeman WP, 2006) (Davis DP, 2003).

Succinylcholine

Succinylcholine, a depolarizing acetylcholine dimer, acts noncompetitively at the acetylcholine receptor in a biphasic manner to produce muscular paralysis at the motor end plate. Succinylcholine stimulates all muscarinic and nicotinic cholinergic receptors of both parasympathetic and sympathetic systems. Initial brief depolarization results in clinically notable muscular fasciculations, followed by sustained myocyte depolarization. Succinylcholine degradation is dependent on hydrolysis by pseudocholinesterase, and it is resistant to acetylcholinesterase. Due to rapid onset of action and a short half-life, succinylcholine remains the gold standard for RSI in patients not at risk for adverse events. The standardized dose of succinylcholine for RSI is 1.0 mg/kg, although the optimal dose for RSI is under evaluation. Recent data suggest that a smaller dose of 0.5-0.6 mg/kg is sufficient for RSI, (Naguib M, 2003) facilitating more rapid resumption of spontaneous respiration. Because complete paralysis represents an integral component of RSI, it is better to err toward complete paralysis when dosing in patients not at risk for adverse events. Intramuscular injection of succinylcholine has been described, although the required dose, 4 mg/kg is higher and onset is slower than with intravenous injection. (Schuh, 1982) Intramuscular injection should be absolutely reserved for the injured patient in whom a delay associated with intravenous or intraosseous access would be life-threatening.
A clear understanding of the potential adverse effects of succinylcholine is critical to its appropriate use in RSI. Contraindications are primarily related to existing hyperkalemia or conditions which accentuate the hyperkalemic effects of succinylcholine, as it normally produces a 0.5-1.0 mEq/L elevation of serum potassium. Contraindications related to hyperkalemia include a thermal injury greater than 24 hours old, (MacLennan N, 1998) although upregulation of receptors likely does not become clinically relevant until postburn day 5. Therefore, it is safe to use succinylcholine for RSI in most acute burns. It is contraindicated in patients with crush injury or rhabdomyolysis with hyperkalemia, (Gronert, 2001) congenital or acquired myopathies, conditions of subacute and chronic upper and motor neuron denervation including paralysis and polyneuropathy of critical illness, (Reynolds SF, 2005) a history of malignant hyperthermia and pseudocholinesterase deficiency. In addition, succinylcholine is reported to raise intragastric and intracranial pressure due to muscle fasciculations and may contribute to increased intraocular pressure. It should be used with caution in patients with injury to the brain and penetrating injury to the globe, although the evidence that succinylcholine raises intraocular pressure is anecdotal at best. (Vachon CA, 2003)

Nondepolarizing Agents

Nondepolarizing NMBAs, through competitive blockade of acetylcholine transmission at postjunctional, cholinergic nicotinic receptors, provide a paralytic alternative for those injured patients in whom succinylcholine is contraindicated. The aminosteriod compounds, including rocuronium, pancuronium, and vecuronium, represent the commonly used NMBAs for RSI and postintubation paralysis. Nondepolarizing agents for RSI are selected based upon the ability to best approximate the rapid onset and elimination of succinylcholine. The most intensively studied nondepolarizing agent utilized for RSI is rocuronium, which exhibits short onset and intermediate duration of action. In a recent Cochrane Database analysis comparing rocuronium to succinylcholine during RSI, rocuronium use was associated with inferior production of "excellent" intubating conditions, but equal "acceptable" conditions. (Perry J, 2003)Similarly, in a recent prospective, randomized comparative trial under emergent conditions, succinylcholine produced more rapid intubation and superior intubating conditions. (Sluga M, 2005) Despite the reported inferiority compared to succinylcholine, rocuronium has been shown to produce superior intubating conditions in comparison to vecuronium in the prehospital environment. (Bulger EM, 2002) When contraindications to succinylcholine exist, rocuronium produces acceptable intubating conditions and should remain in the RSI armamentarium as an alternative to succinylcholine.

REFERENCES

Bair AE, F. M. (2002). The failed intubation attempt in the emergency department: Analysis of prevalence, rescue techniques, and personnel. Journal of Emergency Medicine, 23(2), 131-140.
Bozeman WP, K. D. (2006). A comparison of rapid-sequence intubation and etomidate-only intubation in the prehospital air medical setting. Prehospital Emergecny Care, 10, 8.
Brown EM, K. D. (1979). A comparison of rapid-sequence intubation and etomidate-only intubation in the prehospital air medical setting. Canadian Anaesthia Society, 26, 489.
Bulger EM, C. M. (2002). An analysis of advanced prehospital airway management. Journal of Emergency Medicine , 23(2), 183-189.
Cohan P, W. C. (2005). Acute secondary adrenal insufficiency after traumatic brain injury: A prospective study. Critical Care Medicine, 33, 2358.
Davis DP, O. M. (2003). Paramedic administered neuromuscular blockade improves prehospital intubation success in severely head-injured patients. Journal of Trauma, 54, 444.
El-Orbany MI, W. Y. (2003). Does the choice of intravenous induction drug affect intubation conditions after a fast-onset neuromuscular blocker? Journal of Clinical Anesthesia, 15, 9.
Gronert, G. (2001). Cardiac arrest after succinylcholine: Mortality greater with rhabdomyolysis than receptor upregulation. Anesthesiology, 94, 523.
Jackson, W. (2005). Should we use etomidate as an induction agent for endotracheal intubation in patients with septic shock?: A critical appraisal. Chest, 127, 1031.
Kovacs G, L. J. (2004). Acute airway management in the emergency department by non-anesthesiologists. Canadian Journal of Anasthesia, 51, 174.
Lee BS, G.-H. M. (2001). Pediatric Airway Management. CPEM, 2, 91.
Lev R, R. P. (1994). Prophylactic lidocaine use preintubation: A review. 12(4), 499-506.
MacLennan N, H. D. (1998). Anesthesia for major thermal injury. Anesthesiology, 89, 749.
Malerba G, R.-G. F. (2005). Risk factors of relative adrenocortical deficiency in intensive care patients needing mechanical ventilation. Intensive Care Medicine, 31, 388.
Marvez E, W. S. (2003). Predicting adverse outcomes in a diagnosis-based protocol system for rapid sequence intubation. Americain Journal of Emergency Medicine, 21-23.
Naguib M, S. A. (2003). Optimal dose of succinylcholine revisited. Anesthesiology, 99, 1045.
Pearson, S. (2003). Comparison of intubation attempts and completion times before and after the initiation of a rapid sequence intubation protocol in an air medical transport program. Air Medical Journal, 22(6), 28-33.
Perry J, L. J. (2003). Rocuronium versus succinylcholine for rapid sequence induction intubation. Cochrane Database Syst Rev 1:CD002788.
Reynolds SF, H. J. (2005). Airway management of the critically ill patient rapid-sequence intubation. Chest, 127(4), 1397-1412.
Robinson N, C. M. (2001). In patients with head injury undergoing rapid sequence intubation, does pretreatment with intravenous lignocaine/lidocaine lead to an improved neurologic outcome? A review of the literature. Emergency Medicine Journal, 18(6), 453-457.
Rodricks MB, D. C. (2000). Emergent airway management: Indications and methods in the face of confounding conditions. Critical Care Clinics, 16, 389.
Rotondo MF, M. M. (1993). Urgent paralysis and intubation of trauma patients: Is it safe? Journal of Trauma, 34, 242.
Schreiber JW, L. C.-B. (2005). Prevention of succiny-lcholine-induced fasciculation and myalgia: A meta-analysis of randomized trials. Anesthesiology, 103(4), 877-884.
Schuh, F. (1982). The neuromuscular blocking action of suxamethonium following intravenous and intramuscular administration. Int J Clin Pharmacol Ther Toxicol, 20, 399.
Singh S, S. J. (2003). Cardiovascular changes after the three stages of nasotracheal intubation. British Journal of Anaesthesia, 91(5).
Sivilotti ML, D. J. (1998). Randomized, double-blind study on sedatives and hemodynamics during rapid-sequence intubation in the emergency department: The SHRED study. The Annals of Emergency Medicine, 31(3), 313-324.
Sivilotti ML, F. M. (2003). Does the sedative agent facilitate emergency rapid sequence intubation? Achedemic Emergency Medicine, 10, 612.
Sluga M, U. W. (2005). Rocuronium versus succinylcholine for rapid sequence induction of anesthesia and endotracheal intubation: A prospective, randomized trial in emergent cases. Anesth Analg, 101, 1356.
Sonday CJ, A. J. (2005). Thiopental vs. etomidate for rapid sequence intubation in aeromedicine. Prehospital Disaster Medicine, 20, 324.
Tagaito Y, I. S. (1998). Upper airway reflexes during a combination of propofol and fentanyl anesthesia. 88(6), 1459-1466 .
Thompson JD, F. S. (1982). Succinylcholne for endotracheal intubation. Annals of Emergency Medicine, 526.
Vachon CA, W. D. (2003). Succinylcholine and the open globe. Tracing the teaching. Anesthesiology, 99, 220.
Walls RM, (2004). Manual of Emergency Airway Management (2nd ed.). Philadelphia: Lippincott, Williams & Wilkins.
Zonies DH, R. M. (1998). The safety of urgent paralysis and intubation (UPI) in the trauma admitting area (TAA):A review of 570 consecutive patients. Journal of Trauma, 43, 431.