Emergency physicians have established expertise in the field of rapid sequence intubation (RSI). All emergency physicians must be facile not only with the skill of intubation, but also with the different pharmacologic agents appropriate for unique airway scenarios. Ultimately, by maximizing pharmacologic resources, the emergency physician will maximize the potential for success during RSI.

The pharmacology of RSI can be deconstructed into four phases: 1) premedication, 2) sedation, 3) paralysis, and 4) postintubation. The emergency physician’s armamentarium must have enough options to adapt each step to all clinical presentations. This article will focus in detail on each phase of RSI pharmacology.

Premedication

When intubating a patient, manipulation of the hypopharynx, larynx, and trachea cause a reflex sympathetic response to laryngoscopy (RSRL). The physiologic response caused by RSRL leads to a catecholamine-mediated increase in blood pressure, heart rate, and intracranial pressure (ICP).¹ Different case scenarios will dictate how clinically relevant these reflexes are to airway management. Premedication allows the emergency physician to minimize the deleterious effects of laryngoscopy and RSI medications. Classically, the four agents used for premedication have been described by the acronym LOAD (lidocaine, opioids, atropine, and a defasciculating dose). These agents must be given 3-5 minutes prior to sedation and paralysis.

When used as a pretreatment agent, lidocaine is dosed at 1.5 mg/kg intravenously, and the duration of action is approximately 10-20 minutes.1 Lidocaine offers protection in two clinical scenarios: 1) prevention of increase in ICP caused by RSRL, and 2) bronchodilation in reactive airway disease. Robinson and Clancy in the Emergency Medicine Journal published a literature review showing that although this agent does blunt the RSRL-caused ICP increase, there is no evidence of improved neurologic outcome when using lidocaine in head-injured patients.² However, current recommendations are to premedicate with lidocaine in patients with suspected increases in ICP. Use of lidocaine should be avoided in patients with bradydysrhythmia or hypotension, and in those allergic to amide.

Fentanyl as a pretreatment agent is dosed at 1-3 mcg/kg IV, and the duration of action is approximately 30-60 minutes. Fentanyl is effective at attenuating the catecholamine surge described in RSRL, which can be harmful in patients with increased ICP, ischemic heart disease, abdominal aortic aneurysm, or aortic dissection.^3,4 Although dose-related respiratory depression is a concern, this adverse effect becomes less relevant in the setting of RSI. Also, fentanyl should be avoided in patients in shock states and in children.¹

In the past, atropine and defasciculating doses of nondepolarizing neuromuscular blocking agents (NMBAs) were considered mainstays of premedication. Theorized to prevent reflex bradycardia seen in the pediatric population, atropine was dosed at 0.02 mg/kg IV. A 2007 review article in Emergency Medicine Journal reevaluating the use of atropine in pediatric RSI revealed that no evidence supports the routine use of atropine to decrease the incidence of bradycardia.⁵ Further, atropine complicates an already high-stress environment of pediatric RSI, while also having the potential to induce dysrhythmias. Atropine has now fallen out of favor as a pretreatment agent.¹

Defasciculating doses of a nondepolarizing NMBA were used to prevent the theoretical rise in ICP created by fasciculations caused by succinylcholine use. Classically, rocuronium, vecuronium, or pancuronium were administered at one-tenth of the paralytic dose. A randomized, controlled trial showed no differences in fasciculations in head-injured patients when comparing pretreatment with pancuronium versus pretreatment with mini-dose succinylcholine when paralyzing with succinylcholine. The ultimate conclusion is that succinylcholine alone is an acceptable intubating agent in head-injured patients.⁶ Further, a literature review by Clancy and colleagues in Emergency Medicine Journal found no definitive evidence that succinylcholine causes a rise in ICP.⁷ Evidence does not suggest that succinylcholine worsens outcomes in at-risk patients, nor does evidence suggest that defasciculation improves outcomes in at-risk patients. Currently, defasciculation is no longer recommended.¹

Sedation

After premedication, sedation is the next step in RSI pharmacology. This step allows the emergency physician to induce a state of unconsciousness and amnesia. An ideal sedative would have a rapid onset of action, short duration, and a hemodynamically neutral profile. Unfortunately, most sedatives will cause apnea, myocardial depression, and hypotension to varying degrees. As with pretreatment agents, the emergency physician will be able to customize the sedative to the clinical circumstance (Table 1).

Because of its positive hemodynamic profile, etomidate has become the sedative of choice for RSI. Etomidate is an imidazole derivative dosed at 0.3 mg/kg IV; the time of onset is 15-30 seconds, and the duration of action is approximately 3-12 minutes.¹ Its minimal effects on blood pressure and heart rate, combined with its rapid onset, makes this drug safe in most RSI situations.⁸ Etomidate may have deleterious effects in two disease states: sepsis and seizures. During EEG monitoring, etomidate use has been shown to increase seizure activity.⁹ With other options available, etomidate should be avoided in status epilepticus.

In sepsis patients, etomidate has become an increasingly controversial agent secondary to its transient cortisol suppression.¹⁰ Further, increased mortality has been observed in sepsis patients relative to the degree of adrenal dysfunction.¹¹ Although etomidate is known to suppress cortisol, outcome trials in sepsis syndrome are still lacking, and a cause-effect relationship has yet to be determined.^12,13 Currently, no guidelines state that etomidate is a contraindicated agent in sepsis, but the emergency physician may consider another induction agent in this clinical scenario.

Ketamine is a phencyclidine derivate dosed at 1.5 mg/kg IV; the time of onset is 45-60 seconds, and the duration of action is approximately 10-20 minutes.¹ Ketamine acts as an amnestic, anesthetic, and analgesic agent. Also, ketamine possesses unique bronchodilatory properties that make it the induction agent of choice in patients with reactive airway disease.^14,15 Ketamine also produces a catecholamine surge that increases heart rate and mean arterial pressure. This characteristic makes ketamine a viable alternative to etomidate, especially in sepsis management. Recently, a randomized, controlled trial published in Lancet comparing induction with etomidate versus ketamine in acutely ill patients demonstrated no difference in outcomes, while showing higher rates of adrenal insufficiency in the etomidate arm.¹⁶ However, because of this catecholamine release, ketamine remains relatively contraindicated in normo- or hypertensive patients who have underlying ischemic cardiac disease.¹

Medical dogma previously dictated that ketamine is contraindicated in patients who have the potential for increased ICP. The traditional theories suggested that ketamine causes a further rise in ICP; however, emerging literature has begun to discount prior teachings. While ketamine is not the drug of choice for the head-injured patient, this agent may no longer be absolutely contraindicated in this patient population.^17,18,19

Propofol is an alkylphenol derivate dosed at 1.5 mg/kg IV; the time of onset is 15-45 seconds, and the duration of action is approximately 5-10 minutes.¹ Propofol is an appropriate agent for induction for the hemodynamically stable seizure patient, as this medication potentiates GABA activity. This agent also has bronchodilatory properties and can be considered for patients with reactive airway disease.²⁰ However, propofol can cause profound hypotension and must be used judiciously.

Thiopental is a barbiturate dosed at 3 mg/kg IV; the onset of action is 30 seconds, and the duration of action is approximately 5-10 minutes. The pharmacologic profile of thiopental is similar to that of propofol, as both agents decrease ICP at the expense of cerebral perfusion pressure and possess GABA-enhancing activity. As with all barbiturates, thiopental causes myocardial depression and venodilation. Expert recommendation is to decrease the dose of thiopental to 1-2 mg/kg IV in hypotension, but avoidance of this agent in this scenario would be preferable. Thiopental must also be avoided in patients with reactive airway disease, as barbiturates will cause a secondary histamine release.¹

Midazolam is a benzodiazepine dosed at 0.2-0.3 mg/kg IV; the onset of action is 60-90 seconds, and the duration of action is approximately 15-30 minutes.¹ Midazolam has direct negative effects on systemic vascular resistance and the myocardium. In a prospective study comparing midazolam versus etomidate, Choi and colleagues observed a 10% reduction in mean systolic blood pressure in patients receiving midazolam.²¹ The poor side effect profile and slow onset of action make midazolam an unfavorable induction agent.

Paralysis

Paralytics are divided into two NMBA classes: noncompetitive and nondepolarizing. Succinylcholine (SCh) is a noncompetitive NMBA dosed at 1.5-2 mg/kg IV or 4 mg/kg IM; the onset of action is 45 seconds, and the duration of action is approximately 6-8 minutes. SCh is the most popular paralytic among emergency physicians, as it boasts a short onset and relatively quick return of airway reflexes.

A large disadvantage of SCh is the potential for life-threatening hyperkalemia in at-risk patient populations. Traditionally, patients with renal failure have been listed in this at-risk cohort. However, multiple case series and meta-analyses yielded no reports of dysrhythmias or adverse events in the setting of SCh use in renal failure. Also, the mean increase in potassium was approximately 0.5 meq/L.^22,23,24 While not recommended, inadvertent SCh administration in the setting of renal failure appears to be safe. Fatal hyperkalemia is seen in receptor upregulation (e.g., burns, crush injuries, upper or lower motor neuron injuries, and prolonged ICU stays) and myopathies (e.g., muscular dystrophy). SCh use in myopathies causes a significantly higher mortality (30%) than does its use in receptor upregulation (11%).²⁵

SCh has also been associated with bradycardia, especially in repeat dosing. This bradycardia has not been shown to be prevented by prophylactic atropine; however, when bradycardia occurs, the phenomenon is atropine responsive.⁵ Fasciculations are another known complication of SCh, but the clinical relevance of the fasciculations is debated.^6,7 Malignant hyperthermia is a notorious but rare complication of SCh use. To date, no emergency department cases of malignant hyperthermia have been reported; the treatment for this disorder is cooling, sedation, and administration of dantrolene at 1 mg/kg IV.²⁶

When SCh is contraindicated (Table 2), a nondepolarizing NMBA should be used for paralysis. Rocuronium is dosed at 1 mg/kg IV; the time of onset is 60 seconds, and duration of action is approximately 40-60 minutes.¹ A Cochrane Review article comparing SCh and rocuronium showed that both agents provided clinically acceptable intubating conditions, but SCh was superior.²⁷

Vecuronium is an alternative nondepolarizing NMBA to rocuronium. Vecuronium is dosed at 0.01 mg/kg IV to prime 3 minutes before an intubating dose of 0.15 mg/kg IV. This time of onset is 75-90 seconds, and the duration of action is approximately 60-75 minutes.^1,28

Nondepolarizing NMBAs are not as popular as SCh because the duration of action remains significantly longer. Sugammadex is a new agent available in Europe that is capable of reversing the paralysis of rocuronium.^29,30 If this product shows continuing promise, rocuronium could soon become the agent of choice in RSI pharmacology.

Postintubation

The postintubation phase of RSI pharmacology is as important as the prior steps. Once the emergency physician has successfully completed laryngoscopy, the patient must have appropriate analgesia and anxiolysis. The same agents used for sedation during RSI can be used for postintubation care; all agents should be titrated to a standardized sedation scale (Table 3).³¹ In the American Journal of Emergency Medicine, Bonomo and colleagues brought to light the fact that emergency physicians are providing inadequate anxiolysis and analgesia after intubation.³² A retrospective study in the Journal of Trauma showed that 25% of patients received analgesia within 30 minutes of intubation; the mean time to receiving analgesia was 57 minutes.³³

The emergency physician must also be wary of postintubation hypo­volemia, which can be caused by decreased venous return secondary to positive-pressure ventilation or pneumothorax, choice of induction agent, and/or decrease in sympathetic drive. Initial management should revolve around crystalloid resuscitation and evaluation for pneumothorax.

Summary

Rapid sequence intubation is a procedure that is mechanically and mentally complicated. The pharmacology behind this process is multifaceted and requires careful planning. The evidence for use of tailored agents for specific clinical scenarios is very compelling and lends credence to expanding our repertoire beyond the traditional cocktail of etomidate and succinylcholine.

References

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