Pharmacologic Adjuncts to Intubation

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Chapter 5

Pharmacologic Adjuncts to Intubation

Richard B. Schwartz and Greene Shepherd

Endotracheal (ET) intubation in the emergency setting presents a challenge distinct from that associated with intubation of fasted, premedicated patients in the operating room (OR). Patients in the emergency department (ED) are frequently uncooperative and unstable and may have medical problems that are completely unknown to the treating clinician. It is challenging that within a matter of minutes and with scant data the clinician must assess and control the airway while diagnosing and managing the patient’s other life-threatening problems.

In 1979, Taryle and coworkers ¹ reported that complications occurred in more than half the patients intubated in a university hospital ED. They called for improved house officer training in ET intubation, including “more liberal use of the procedures and agents used in the operating room (OR), including sedatives and muscle relaxers.”¹ Since this report, the use of neuromuscular blockade and rapid-sequence intubation (RSI) has become the standard for emergency medicine practice.^2,3 In addition to RSI, emergency physicians now use airway devices such as videoscopes and flexible fiberoptic bronchoscopes to manage difficult and complex airways.

Clinicians must concentrate not only on the manual skills of airway management but also on selection of the appropriate drugs to achieve specific objectives. These objectives include (1) immediate airway control, including induction of unconsciousness and muscle paralysis; (2) analgesia and sedation in awake patients; and (3) minimization of the adverse physiologic effects of intubation, including systemic and intracranial hypertension.

This chapter reviews the mechanisms and strategic use of the drugs that are currently available to facilitate intubation in the ED.

Overview of Rapid-Sequence Intubation

The sequential process for quickly intubating a patient in an emergency situation is referred to as rapid-sequence intubation. The steps in performing RSI are often described by the six “P’s”: preparation, preoxygenation, pretreatment and induction, paralysis, placement of the tube, and postintubation management (Fig. 5-1). This sequential technique of rapidly inducing unconsciousness (induction) combined with muscular paralysis and optimal conditions for intubation has gained broad acceptance among ED clinicians. Obviously, many patients do not afford the clinician the time or opportunity to comply with the ideal scenario of trachael intubation described in this chapter. RSI, as described in this chapter, is the ideal method of emergency airway management for intubations not anticipated to be difficult.

Figure 5-1 The 6 “P’s” of rapid sequence intubation. IV, intravenous; RSI, rapid-sequence intubation.

Preparation occurs before and during preoxygenation. Assess the airway to determine the likelihood of a difficult intubation. Simultaneously, establish an intravenous (IV) line and connect the patient to cardiac, pulse oximetry, and end-tidal CO₂ monitors when available. Assemble all necessary drugs and equipment for oral intubation and the desired backup equipment for airway control, such as cricothyrotomy.

Begin RSI preoxygenation as soon as possible by administering 100% oxygen. The intent is to displace nitrogen from the lungs and replace it with an oxygen reserve that will last several minutes. Under optimal conditions, breathing 100% oxygen for 3 minutes has been demonstrated to maintain acceptable oxygen saturation for up to 8 minutes in previously healthy apneic individuals.⁴ Another method is to give four maximal breaths of 100% oxygen from a face mask, which can also maintain acceptable saturation for 6 minutes.⁴ Comparable results may not be expected in the ED setting, though, because of differences in the underlying health and cooperation of the patient population.

Pretreatment consists of the administration of medications to mitigate the potential untoward responses to intubation. Pretreatment during RSI usually occurs 2 to 3 minutes before induction of unconsciousness or muscular paralysis. Although preoxygenation should be maintained for as long as practical before beginning intubation, the ideal situation and circumstances are not always present, and clinical judgment is the deciding factor for this portion of RSI.

Paralysis and induction involve the induction of a state of unconsciousness with a sedative agent, followed immediately by muscle paralysis. A protocol for ED-based RSI is summarized in Box 5-1. ET intubation and RSI have also expanded beyond the ED into the prehospital setting. Prehospital RSI protocols use a sedative plus a paralytic for patients not in cardiac arrest, with success rates as high as 92% to 98% being demonstrated.^5–9 As in the ED setting, without a full complement of medications, prehospital intubation becomes significantly more difficult, and success rates drop to approximately 60%.¹⁰ Rates of misplaced ET tubes and complications by paramedics may be much higher than previously reported.^11,12 Recent studies indicate that outcomes may be worse for patients with traumatic brain injury intubated in the prehospital setting than in the ED.¹³ For these reasons many prehospital systems have moved away from the use of RSI.

Box 5-1 Rapid-Sequence Intubation Protocol

1. Preoxygenate (denitrogenate) the lungs by providing 100% oxygen by mask.

2. Assemble the equipment required:

• Bag-valve-mask device connected to an oxygen delivery system

• Suction with a Yankauer tip

• ET tube with an intact cuff, stylet, syringe, and tape

• Laryngoscope and blades, in working order

• Back up airway equipment

3. Check to be sure that a functioning, secure intravenous line is in place.

4. Continuously monitor cardiac rhythm and oxygen saturation.

5. Premedicate as appropriate:

• Fentanyl: 2 to 3 µg/kg given at a rate of 1 to 2 µg/kg/min intravenously for analgesia in awake patients

• Atropine: 0.01 mg/kg by intravenous push for children or adolescents (minimum dose of 0.1 mg recommended)

• Lidocaine: 1.5 to 2 mg/kg intravenously over a period of 30 to 60 seconds

6. Induce anesthesia with one of the following agents administered intravenously: thiopental, methohexital, fentanyl, ketamine, etomidate, or propofol. Apply cricoid pressure.

7. Give succinylcholine, 1.5 mg/kg by intravenous push (use 2 mg/kg for infants and small children).

8. Apnea, jaw relaxation, and/or decreased resistance to bag-mask ventilation (use only when oxygenation before rapid-sequence intubation cannot be optimized by spontaneous ventilation) indicates that the patient is sufficiently relaxed to proceed with intubation.

9. Perform ET intubation. If unable to intubate during the first 20-second attempt, stop and ventilate the patient with the bag-mask device for 30 to 60 seconds. Monitor pulse oximetry readings as a guide.

10. Treat bradycardia occurring during intubation with atropine, 0.5 mg by intravenous push (smaller dose for children; see item 5).

11. Once intubation is completed, inflate the cuff and confirm ET tube placement by auscultating for bilateral breath sounds and checking the pulse oximetry and capnography readings.

12. Release cricoid pressure and secure the ET tube.

ET, endotracheal.

The technique for proper ET tube placement is discussed in Chapter 2.^1–3 Postintubation monitoring should assess for proper tube placement, adequate tissue oxygenation, and response to previously administered drugs. After laryngoscopy, the clinician should ensure ongoing analgesic and anxiolytic therapy.

Pretreatment: preventing the Complications of Intubation

Numerous reports have highlighted the physiologic responses to tracheal intubation and attempted to define their immediate or long-term adverse effects and to offer interventions to ameliorate potential organ injury. It is certain that intubation and adjunctive medications have the potential to alter reflexes, intracranial pressure (ICP), blood pressure, and the pulse rate and may induce disturbances in cardiac rhythms, but the actual clinical consequences of these commonly observed changes are largely unknown. Clinical experience suggests that most transient alterations in physiology occurring with ED intubation produce no specific or readily documented long-term sequelae or are often consequences that cannot easily be monitored or prevented. Prudent clinicians are aware of the potential adverse effects of intubation and are cognizant of potential methods to minimize them. Careful monitoring of the postintubation condition will guide specific interventions. Overzealous attempts to suppress the physiologic responses that normally accompany airway manipulation may be counterproductive. It would be desirable to provide airway control under the best of circumstances and with the least amount of injury to the patient, but the ideal approach to the physiologic responses to intubation is simply unknown. Most information has been extrapolated from experimental animal models or from the anesthesia experience, and similar issues may not apply to the milieu of the ED experience. The following discussion serves as a general clinical guide to alterations in the physiologic response to intubation.

The Pressor Response

In addition to the ubiquitous sinus tachycardia, a number of dysrhythmias have been reported after intubation. They are primarily ventricular in origin and include ectopic beats, bigeminy, and short runs of ventricular tachycardia. Bradyarrhythmias have been reported uncommonly. Electrocardiographic changes suggestive of ischemia have been documented, particularly in patients with dramatic increases in blood pressure.14,15 In 1977, Fox and colleagues¹⁶ reported two patients, both of whom deteriorated after induction of anesthesia and orotracheal intubation. This report has been widely quoted as evidence that the pressor response should be prevented. No studies have reported comparative data, and none have established a direct relationship between the response and subsequent clinical deterioration in a large patient population. It is also unclear whether attenuation of the pressor response will prevent dysrhythmias or electrocardiographic evidence of ischemia, although it is prudent to avoid sudden increases in blood pressure in unstable patients with acute cardiac or vascular disease.

Multiple studies have evaluated procedures to pharmacologically block the pressor response. Lidocaine has been the most extensively evaluated, but the results of these studies are inconclusive.17–23 No standards are universally accepted. Although it appears that administration of lidocaine, 1.5 to 2 mg/kg intravenously before intubation, may blunt the response, it is not clear that the reductions reported (10 to 15 mm Hg and 20 beats/min) are of any clinical significance. Other drugs, including thiopental, sodium nitroprusside, labetalol, nitroglycerin, verapamil, nifedipine, clonidine, fentanyl, sufentanil, etomidate, and magnesium, have shown variable responses.^24–33

Of these drugs, fentanyl may be the most effective. It completely suppresses the pressor response at large anesthetic doses of 50 µg/kg,34–36 but considerably smaller doses may be effective. Two studies have shown marked suppression of the pressor response at doses of 5 to 6 µg/kg, although in both studies patients also received 5 mg/kg of thiopental.^18,37 Fentanyl has blunted the pressor response when administered in conjunction with etomidate.³² The 1998 SHRED (Sedatives and Hemodynamics during Rapid-Sequence Intubation in the Emergency Department) study evaluated the pressor response to RSI and compared thiopental, fentanyl, and midazolam as induction agents.³⁸

Midazolam, which is associated with the poorest intubating conditions and the most attempts required for intubation, showed a mean increase in heart rate of 17 beats/min. Thiopental, probably because of its direct myocardial depressant and venodilatory effects, decreased mean arterial pressure by about 40 mm Hg. Fentanyl recipients maintained a relatively neutral hemodynamic profile during intubation. Use of paralytics during intubation did not appear to alter the hemodynamic response associated with each sedative agent. One study isolated the effect of laryngoscopy from the effect of tube passage into the trachea. Adachi and colleagues ³⁹ found that pretreatment with 2 µg/kg of fentanyl could blunt the hemodynamic effects of tracheal tube passage, but not the hemodynamic effects of laryngoscopy.

It is important to note that even studies demonstrating blunting of the pressor response failed to show that this provided any real benefit to patients. It is likely that the pressor response is innocuous in the vast majority of patients, but it may be exaggerated and potentially harmful in those with preexisting hypertension, cardiovascular disease,⁴⁰ or other vascular comorbid conditions, in whom sudden changes in hemodynamics may be detrimental.⁴¹ The pressor response may contribute to the rise in ICP that follows laryngoscopy, and it is potentially harmful in patients with intracranial pathology. Administration of lidocaine or fentanyl to blunt the pressor response may be appropriate in these subsets of patients, but no universal standards exist.

Intracranial Hypertension

Physical stimulation of the respiratory tract by maneuvers such as laryngoscopy, tracheal intubation, and ET suctioning is commonly associated with a brief rise in ICP. The exact mechanism responsible for this rise is unknown. One potential mechanism is the coughing and gagging that frequently follow manipulation of the upper airway and subsequent transmission of intrathoracic pressure to the cerebral circulation. An alternative explanation is the release of catecholamine that accompanies laryngoscopy, which causes a rise in mean arterial pressure and cerebral perfusion pressure. A small rise in ICP has been reported after the administration of succinylcholine. The value of pretreatment with defasciculating doses of neuromuscular blockers (NMBs) to prevent rises in ICP is unknown.⁴²

Although the exact significance of a transient rise in ICP is not known, it is logical to assume that it may be detrimental in patients with head trauma or intracranial hypertension. A number of drugs, including lidocaine, succinylcholine, and the majority of the anesthesia induction agents, have been studied to determine whether their use prevents this response. Many of the existing clinical data are not particularly relevant to the ED setting because they are derived from patients in various stages of general anesthesia, which often incorporates a wide variety of drug combinations and doses.

Good evidence suggests that deep general anesthesia prevents the rise in ICP associated with intubation. Depending on the drug used, anesthesia may compromise cardiovascular performance and critically reduce cerebral blood flow.43–45 Consequently, the ideal anesthetic agents to facilitate intubation of patients with acute intracranial pathology may be those that have minimal effects on cardiovascular performance, such as etomidate or fentanyl. Etomidate has been demonstrated to prevent changes in both cerebral perfusion pressure and ICP after tracheal intubation of patients with space-occupying intracranial lesions.⁴⁶

At the present time the clinical consequences of intubation-induced physiologic changes are not thoroughly understood. The role of drugs in preventing these changes is equally unclear. Despite this lack of data, it may be intuitively reasonable to attempt to protect patients at theoretical risk. The approach outlined in Box 5-2 is recommended.

Induction Agents

After premedication, a sedative agent is used to induce loss of consciousness. A number of diverse drugs are available in the ED to induce unconsciousness before intubation, including barbiturates, benzodiazepines, etomidate, ketamine, opiates, and propofol. The choice of a particular induction agent depends on the experience and training of the clinician, the patient’s clinical status, drug characteristics, and institutional protocols (Box 5-3).

Box 5-3

Recommendations for Sedation of Patients Undergoing Rapid-Sequence Intubation in Specific Circumstances

The most appropriate medications for sedation before rapid-sequence intubation are based on evaluation of the clinical scenario, and no specific recommendations are appropriate for all circumstances. Different situations, too complex to list here, lend themselves to the use of certain agents (see text). There are no specific standards that must be followed, and the medical literature can be confusing, contradictory, or inadequate. The following conditions and sedation agent recommendations may guide the clinician. Note that appropriate paralytic drugs should also be used.

Head Injury or Potentially Elevated Intracranial Pressure

Pretreatment with the various medications described in text are appropriate but of unproven value. Adequate cerebral perfusion pressure should be maintained to prevent secondary brain injury. Etomidate is suggested for induction of these patients. For hypotensive patients, etomidate or ketamine may be used. Ketamine should probably be avoided in patients with severe hypertension or if elevated intracranial pressure is caused by spontaneous cerebral hemorrhage.

Status Epilepticus

Midazolam or thiopental may be used for induction. Reduced doses should be used in the unusual circumstance of seizure with hypotension. Etomidate may be used when the patient is hemodynamically compromised. Propofol is acceptable. Ketamine has been reported for the treatment of status epilepticus.

Hemodynamically Stable Patient with Severe Bronchospasm

Induction with ketamine or propofol is suggested. Etomidate and midazolam are acceptable alternatives. In hemodynamically unstable patients with severe bronchospasm, ketamine or etomidate is suggested. Thiopental should not be used in these patients because it provokes release of histamine and can induce or exacerbate bronchospasm.

Patients with Cardiovascular Compromise

Etomidate is suggested because of the hemodynamic stability that it provides. If the patient is in shock or severely hypotensive, ketamine and/or etomidate is suggested. If etomidate is used in a patient with sepsis who has associated hypotension refractory to treatment with fluid resuscitation and a vasopressor, a single dose of hydrocortisone (100 mg intravenously) may be given (value unproven).

For an “Awake Look” before Intubation

Ketamine is suggested, but it may not be appropriate when these patients have cardiovascular disease or hypertension.

Adapted from Caro D, Walls RM, Grayzel J. Sedation or induction agents for rapid sequence intubation in adults. Up To Date. Based on Literature through February 2012. Queried 4/12/12.

Considerable evidence indicates that the sedative agent selected influences the quality of intubation conditions and the rapidity of their attainment. These effects persist even when paralytic agents are used. Commonly used drugs and their doses are summarized in Table 5-1.

TABLE 5-1

ICP, intracranial pressure; IV, intravenously; RAD, reactive airway disease; SE, status epilepticus.

^*Any of these can drugs be used before the administration of a neuromuscular blocking agent to induce anesthesia (see text).

Barbiturates: Thiopental and Methohexital

The barbiturates, particularly thiopental, have been the traditional agents used for induction in the OR setting, but their use in the ED is minimal. The ultrashort-acting barbiturates thiopental and methohexital are the most suited for ED RSI, but, their potential hemodynamic effects require cautious use in the ED setting. Barbiturates are central nervous system (CNS) depressants capable of producing effects ranging from mild sedation to deep coma. They do not block afferent sensory input to a significant extent and should be used in conjunction with an analgesic agent such as fentanyl if a painful procedure is to be performed. It is common practice to intubate patients who have received only barbiturates as the induction agent without an analgesic.

The barbiturates rapidly cross the blood-brain barrier and induce unconsciousness in less than a minute. They are rapidly redistributed and then ultimately degraded in the liver. After a single IV dose of thiopental, anesthesia lasts 5 to 10 minutes, as compared with 4 to 6 minutes for methohexital.47,48 The recommended dose of thiopental is 3 to 5 mg/kg intravenously administered over a 60-second period. Methohexital is dosed at 1 to 1.5 mg/kg intravenously over a 30- to 60-second period.

Advantages of barbiturates as induction agents include their high potency, rapid onset, and short duration of action. They reduce cerebral metabolism, oxygen consumption, cerebral blood flow, and ICP.49,50 For this reason, thiopental is considered the agent of choice for induction of anesthesia and maintenance of long-term anesthesia in patients with elevated ICP. Short-term use of barbiturates during RSI has not been shown to have a protective effect on the CNS. Barbiturate use in hypovolemic patients may lead to systemic hypotension and impaired cerebral perfusion pressure, which may offset any cerebral-protective characteristics.³⁸ Some evidence indicates that for ED RSI, thiopental may produce the best intubating conditions when used in conjunction with succinylcholine.⁵¹

The most significant complication of barbiturate therapy is depression of the vasomotor center and myocardial contractility, which can lead to significant hypotension. One study showed the average decrease in mean arterial pressure during RSI with thiopental to be 40 mm Hg.³⁸ This is particularly pronounced in the presence of hypovolemia or cardiovascular disease.

Barbiturates also depress the brainstem respiratory centers when given rapidly or in large doses. This effect may be accelerated by simultaneous treatment with opioids. Patients with asthma or chronic bronchitis may experience bronchospasm. Laryngospasm may occur in patients who were anesthetized lightly with barbiturates during manipulation of the upper airway. This complication usually responds to positive pressure ventilation or neuromuscular blockade. The high pH of the barbiturate solution can cause tissue necrosis after extravascular administration and severe pain, vessel spasm, and thrombosis after intraarterial infusion.

Etomidate

Etomidate is an ultrashort-acting nonbarbiturate hypnotic agent that has been used successfully as an anesthesia induction agent in Europe since the mid-1970s and in the United States since 1983. A significant benefit of etomidate in the emergency setting is its lack of cardiodepressant effects.52,53 Several case series have now demonstrated its safety and effective use in ED RSI.^54–58 Extensive experience with this agent now exists in both pediatric⁵⁹ and adult patients, and it is an agent of choice for most ED intubations.

Etomidate is a carboxylated imidazole that is both water and lipid soluble. The drug reaches peak brain concentrations within 1 minute of IV infusion ⁶⁰ and induces unconsciousness within 30 seconds of administration. Its effects last less than 10 minutes after a single bolus dose.¹⁰ Redistribution of the drug is quite rapid, which accounts for its short duration of action. Etomidate is rapidly hydrolyzed in the liver and plasma and forms an inactive metabolite excreted primarily in urine.⁶⁰ The recommended dose is 0.3 mg/kg via rapid IV bolus. There is virtually no accumulation of the drug, and anesthesia may be maintained through repeated doses; however, etomidate should not be used as an infusion or in repeated bolus doses for maintenance of sedation after intubation in the ED.⁶¹

Etomidate acts on the CNS by stimulating γ-aminobutyric acid (GABA) receptors and depressing the reticular activating system. It produces electroencephalographic changes similar to those produced by barbiturates as patients pass rapidly through light to deep levels of surgical anesthesia. Because etomidate has no analgesic activity,⁶⁰ it should be used in conjunction with a parenteral analgesic when painful conditions are being treated, although it is most commonly used as a sole induction agent for intubation. Etomidate decreases cerebral oxygen consumption, cerebral blood flow, and ICP but appears to have minimal effects on cerebral perfusion pressure.⁴⁶ Most importantly in the ED setting, etomidate is characterized by hemodynamic stability without significant changes in mean arterial pressure,^53,54,57 although a slightly increased heart rate may be observed.⁶¹ Etomidate is suggested for induction of patients with significant cardiovascular disease requiring RSI. The hemodynamic stability that it provides and the absence of induced hypertension make it preferable to other sedatives. This hemodynamic stability persists even in patients with preexisting hypotension.⁶² The most common immediate side effects of etomidate are pain on injection, nausea, vomiting, and myoclonic jerks.⁶³ Pain on injection is reported in up to two thirds of patients. Use of a large vein, simultaneous saline infusion, and opioid premedication can reduce the discomfort in appropriate situations.⁶⁴ Myoclonic activity has been reported in about one third of cases and is believed to be caused by disinhibition of subcortical activity rather than CNS stimulation and does not represent seizure activity.⁶⁰ This sometimes dramatic effect can be avoided through the use of NMBs and is rarely seen in the ED, where paralytic agents are regularly used with RSI. No treatment of myoclonus is usually necessary, and it is generally of no clinical significance. If persistent, an intravenous benzodiazepine may be administered. Etomidate need not be avoided in patients with seizure disorders, status epilepticus, head injury, or stroke.

Some degree of altered adrenal function has been demonstrated even after a single dose of etomidate.65,66 The true clinical effect is unknown, but because the alteration in adrenal function appears to persist for 12 to 24 hours, there is theoretical concern about potential clinical consequences.^10,67,68 Etomidate is a reversible inhibitor of 11β-hydroxylase, the enzyme that converts 11-deoxycortisol to cortisol. Although cortisol levels do not fall below the normal physiologic range, even a single induction dose of etomidate causes a measurable decrease in the level of circulating cortisol that occurs in response to the administration of exogenous adrenocorticotropic hormone (ACTH). Despite concerns regarding the safety of etomidate in the specific setting of adrenal insufficiency related to sepsis, no well-designed, prospective trial has shown adverse effects from a single dose of etomidate used for intubation in patients with sepsis or septic shock. Overall, however, the literature on this subject provides conflicting results.^69–86

When comparing etomidate with ketamine, a multicenter randomized trial of critically ill patients requiring emergency intubation found no significant difference in organ failure score, 28-day mortality, or intubating conditions between patients given etomidate for induction and those given ketamine.⁸³ No serious, drug-related adverse events were reported with either medication. Even though adrenal insufficiency occurred at a higher rate in the etomidate group (86%), it also developed in approximately 48% of patients receiving ketamine.

Although historically no individual study is sufficiently powered to detect differences in mortality from the adrenal effects of etomidate, a systematic review of 20 studies in which etomidate was given in a bolus dose as part of induction for tracheal intubation found that etomidate does not have a significant proven effect on mortality.⁸⁴ Declines in serum cortisol concentration were more prevalent in etomidate recipients than in those who did not receive etomidate in the large majority of studies, but the effect did not persist beyond 5 hours. When intubating a critically ill patient with possible adrenal insufficiency, the clinician must weigh the theoretical risk of cortisol suppression against the hemodynamic instability that may be caused by alternative induction agents. Overall, the mixed results in the current literature do not justify recommendations to avoid using etomidate for induction in patients with sepsis. Pending more definitive studies and subject to change as additional evidence is forthcoming, etomidate is an acceptable induction agent for patients with severe sepsis.⁸⁷

Clinicians performing ACTH stimulation testing should be aware that the results may be affected by prior administration of etomidate. The empirical administration of glucocorticoids for the first 24 hours after a dose of etomidate has been given to patients with sepsis is not supported by outcome studies. However, some clinicians treating patients with sepsis who have received etomidate for RSI will administer a single dose of glucocorticoid (e.g., hydrocortisone, 100 mg intravenously) if the hypotension is refractory to treatment with aggressive fluid resuscitation and vasopressors. Though yet unproven and seemingly an ever-changing recommendation, this approach is consistent with that used for septic patients who have not received etomidate.

Ketamine

Unique among anesthetic agents and probably underused in the ED, ketamine produces a dissociative anesthesia characterized by excellent analgesia and amnesia despite the appearance of wakefulness. As a drug that is potent and relatively safe with a rapid onset and brief duration of action, ketamine fits the profile of an agent that could be used effectively to facilitate intubation. Ketamine has also been advocated for pharmacologic control of undifferentiated agitated and violent patients with excited delirium. It does possess some pharmacologic properties that theoretically limit its use in selected circumstances.

Ketamine is a water- and lipid-soluble drug that rapidly penetrates into the CNS. Like the barbiturates, ketamine accumulates rapidly and then undergoes redistribution with subsequent degradation in the liver.⁸⁸ The recommended dose of ketamine before intubation is 1 to 2 mg/kg administered intravenously over a 1-minute period. Anesthesia occurs within 1 minute of completing the infusion and lasts 5 to 10 minutes. A smaller additional dose (0.5 to 1 mg/kg) may be given 5 minutes after the initial dose if needed to maintain anesthesia. Simultaneous administration of succinylcholine and midazolam is recommended to provide adequate muscle relaxation and to decrease the incidence of postanesthesia emergence reactions, respectively. The intramuscular dose for intubation has not been well studied, but a suggested dose is 4 to 5 mg/kg. Onset of action occurs within 2 to 3 minutes. Because of its good vascularity, the anterior thigh muscle is theoretically the preferred site for administration.

Unlike other anesthetic agents that depress the reticular activating system, ketamine acts by interrupting association pathways between the thalamocortical and limbic systems. Characteristically, the eyes remain open, and patients exhibit spontaneous, though not purposeful movements. Increases in blood pressure, heart rate, cardiac output, and myocardial oxygen consumption are seen, most likely mediated through the CNS. In vitro studies indicate that ketamine is a myocardial depressant, but the CNS-mediated pressor effects generally mask the direct cardiac effects,89,90 thus making it potentially useful in patients with hemorrhagic shock or hypotension. Respirations are initially rapid and shallow after ketamine administration, but they soon return to normal.

Other features of ketamine anesthesia include increased skeletal muscle tone, preservation of the laryngeal and pharyngeal reflexes, hypersalivation, and relaxation of bronchial smooth muscle. Discussions exist regarding the use of ketamine in patients with head injury or potentially elevated ICP. Ketamine can cause a rise in ICP through sympathetic stimulation, thereby potentially exacerbating the condition of such patients with elevated ICP. When ketamine is used with a GABA agonist, however, this rise in ICP may not occur. Ketamine may benefit patients with a neurologic injury by increasing cerebral perfusion.

In one study, eight patients with traumatic brain injury and elevated ICP who were sedated with propofol were given different doses of ketamine (1.5, 3, or 5 mg/kg).⁹¹ Ketamine did not alter cerebral hemodynamics at any time. In another study, researchers randomly assigned 25 patients with traumatic brain injury to sedation with either ketamine and midazolam or sufentanil and midazolam.⁸⁵

Other studies suggest that ketamine does not interfere with cerebral metabolism or increase cerebral oxygen consumption and does not reduce regional glucose metabolism.⁸⁶ Ketamine can also offset any decrease in mean arterial pressure caused by fentanyl, a drug commonly used as part of RSI in patients with a head injury.⁹²

Overall, evidence suggesting that ketamine elevates ICP to any significant clinical extent is weak, and evidence that harm might ensue is weaker. Based on current evidence it is reasonable to conclude that ketamine is an appropriate induction agent for RSI in patients with suspected elevated ICP and normal blood pressure or hypotension. In patients with hypertension and suspected ICP elevation, ketamine should be avoided because of its tendency to further increase blood pressure.

The most promising use of ketamine as an intubation adjunct has been in the setting of acute bronchospastic disease. Ketamine relaxes bronchial smooth muscle either directly through enhancement of sympathomimetic effects or indirectly through inhibition of vagal effects. Ketamine also increases bronchial secretions and may decrease the incidence of mucous plugging, which is commonly seen in decompensating asthmatic patients.⁹³ Clinical reports have demonstrated a reduction in airway resistance and an increase in pulmonary compliance within minutes of ketamine administration.^88,94 Bronchospastic patients struggling to breathe and unable to tolerate oxygen masks or bronchodilators because of hypoxic encephalopathy will continue to breath deeply and rapidly with ketamine anesthesia, thereby allowing the maximum delivery of oxygen before a more elective intubation (Fig. 5-2).

Figure 5-2 This asthmatic is diaphoretic, confused, and agitated and cannot tolerate inhaled bronchodilators. He is about to suffer respiratory arrest and cannot be preoxygenated before intubation. Pulse oximetry shows an oxygen saturation of 82% to 84%. Within 60 seconds following intravenous administration of ketamine (100 mg), he stopped fighting but kept breathing rapidly. A non-rebreathing oxygen mask was tolerated and oxygen saturation rose to 98%, after which he was electively intubated under controlled preoxygenated conditions. A ketamine infusion (1 mg/kg/hr) was maintained for a few hours.

A potential side effect that has raised some concern about the use of ketamine for RSI is its tendency to produce postanesthesia emergence reactions, a characteristic that it shares with the structurally similar drug phencyclidine. The reemergence phenomenon, such as disturbing dreams as patients emerge from ketamine-induced anesthesia, is much less of a concern when the drug is used for RSI. In fact, there are no convincing data indicating that when used for RSI, ketamine produces unpleasant reemergence reactions that are significant or common enough to limit its use for this purpose. One study found that although dreams occurred frequently following sedative doses of ketamine, they were generally pleasant and the frequency of reemergence phenomena and delirium was markedly reduced by the concomitant use of a benzodiazepine.⁹⁵ Rarely, reactions may be marked and distressing, with symptoms including floating sensations, dizziness, blurred vision, out-of-body experiences, and vivid dreams or nightmares. The true incidence of emergence reactions following RSI is unknown, and clinical experience suggests that it is not an issue for RSI in the ED. Such reactions are less common in children than in adults and may be suppressed with benzodiazepines. Both diazepam and lorazepam appear to be useful in adults, but the latter is more effective, most likely because of its enhanced amnestic effect. Midazolam is effective in adult patients at doses of 0.07 mg/kg⁹⁶ and may be the preferred agent because it has potent amnestic effects and a short duration of action. Studies in children have failed to show a reduction in the rate of emergence reactions in those treated with both ketamine and midazolam.^97,98

Despite preservation of pharyngeal and laryngeal reflexes in patients sedated with ketamine, aspiration can still occur.99,100 Ketamine does not relax skeletal muscles, and production of the desired intubating conditions requires the simultaneous administration of a paralytic agent, thereby removing all upper airway reflexes.

Propofol

Propofol is a popular drug among anesthesiologists for OR-based induction and is ideal for ED use. Multiple reports have demonstrated the safety and efficacy of propofol for ED procedural sedation.101,102 Although some ED clinicians now intubate only with propofol, eschewing longer-acting agents and paralysis, its role as an adjunct to intubation in the ED is undergoing evolution.

Propofol is an alkylphenol sedative-hypnotic used for induction and maintenance of general anesthesia. The drug has no analgesic activity, but it does exert a powerful amnestic effect. Propofol also tends to decrease vomiting through an unknown antiemetic effect. It produces dose-dependent depression of consciousness ranging from light sedation to coma. Propofol is a highly lipophilic, water-insoluble compound that undergoes rapid uptake by vascular tissues, including the brain, followed soon afterward by redistribution to muscle and fat. The drug is metabolized by the liver and excreted in urine.103,104 After an induction dose of 2 mg/kg intravenously, unconsciousness occurs within 1 minute and lasts for 5 to 10 minutes. A smaller dose (1 to 1.5 mg/kg) is recommended in the elderly and when simultaneously administering other CNS depressants. Because propofol has a short duration of action and patients rapidly regain consciousness, repeat boluses are not a practical way to maintain a desired level of sedation.^103,104 Therefore, a slow drip infusion of 3 to 5 mg/kg/hr titrated to effect is preferred.

Propofol reduces airway resistance, which renders it a useful induction agent for patients with bronchospasm. Its neuroinhibitory effects make propofol a good induction agent for patients with intracranial pathology, provided that they are hemodynamically stable. The propofol-induced decrease in mean arterial pressure, generally about 10 mm Hg, can reduce cerebral perfusion pressure, thereby theoretically exacerbating CNS injury.

Propofol does not prolong the QT interval. Although the manufacturer lists egg or soybean allergy as a contraindication to the use of propofol, significant allergic reactions to the newer preparation of the drug are extremely rare.

Propofol suppresses sympathetic activity, thereby causing myocardial depression and peripheral vasodilation, particularly in the elderly or hypovolemic patients and when administered simultaneously with opioids. Hypotension can be minimized with fluid loading or reversal with 5 to 10 mg of IV ephedrine. Propofol reduces cerebral blood flow and may cause mild CNS excitatory activity (e.g., myoclonus, tremors, hiccups) during induction. Pain on injection occurs commonly, even when the drug is infused slowly.103,104 Pretreating the infusing vein with 3 mL of 1% lidocaine (30 mg) injected over a 30-second period or choosing a large antecubital vein will ameliorate this pain.

Benzodiazepines (Midazolam)

The benzodiazepines are a widely used class of drugs characterized by anxiolytic, hypnotic, sedative, anticonvulsant, muscle relaxant, and amnestic effects. Several of these properties make the benzodiazepines appealing adjuvant agents for intubation, particularly when used in combination with opioids. It is important to remember that benzodiazepines do not have analgesic effects. Although they may produce excellent sedation and impair the patient’s memory of an unpleasant experience, they will not prevent the pain associated with intubation.

Midazolam has replaced diazepam as a preoperative sedative agent, even in elderly patients.105–109 When compared with diazepam, the primary advantages of midazolam include a twofold increase in potency, shorter half-life, and decreased potential for cardiorespiratory depression. Midazolam is water soluble in an acid medium and does not require suspension in propylene glycol like other benzodiazepines. It is rarely associated with phlebitis and can be given intramuscularly when a very rapid onset of action is not required. At physiologic pH, midazolam is lipophilic and rapidly accumulates in the CNS, with onset of sedation occurring in as little as 1 to 2 minutes. Outside the CNS it accumulates in fatty tissue and extensively binds to plasma, which accounts for the paucity of non-CNS side effects. Its half-life of elimination is 1 to 4 hours and is dependent on release of the drug from adipose tissue and protein-binding sites. The period of sedation after a single IV dose is considerably shorter. Emergence from a 0.15-mg/kg dose occurs in 15 to 20 minutes.¹¹⁰

Clinical experience using midazolam with or without fentanyl for procedural sedation is considerable, and it is considered both safe and effective in the ED setting. The recommended dose for moderate sedation with midazolam is 0.05 to 0.1 mg/kg given in 1-mg boluses and not exceeding 2.5 mg over a period of 2 minutes. Doses upward of 0.1 mg/kg are often needed to produce good conditions for intubation.38,06

The potential for adverse effects with midazolam is similar to that with other benzodiazepines. A small increase in heart rate is seen frequently, as is a small decrease in systolic blood pressure.¹¹¹ Changes in blood pressure may be exaggerated in the presence of hypovolemia.¹¹² An ED-based study reported a mean 10% decrease in systolic blood pressure, with 19% of intubated patients having systolic blood pressure lower than 90 mm Hg.¹¹¹ The cardiac index and coronary artery blood flow are not generally affected. In the prehospital setting, hypotension with midazolam was found to be dose related,¹¹³ and it should be used cautiously in patients with hypovolemia or traumatic brain injury. Respiratory depression may occur even at standard doses, but it most often follows rapid administration of an excessive dose. Respiratory depression is also more likely to occur in debilitated or elderly patients and in those simultaneously receiving opioids. The effects of midazolam are rapidly reversed by administration of the benzodiazepine antagonist flumazenil. A study of various induction agents for ET intubation suggested that the use of midazolam alone for RSI may be associated with suboptimal intubating conditions and increased difficulty.⁵¹ Other induction agents may be preferred over midazolam alone during RSI.

Opioids (Fentanyl)

Although any of several opioids administered intravenously could be used to induce unconsciousness, fentanyl has significant advantages over other opioid agents. A synthetic opioid, it has been widely used since its introduction in 1968. Its favorable pharmacologic properties include rapid serum clearance, high potency, and minimal release of histamine.114–117 Fentanyl quickly crosses the blood-brain barrier and produces analgesia in as little as 1 to 2 minutes. Serum levels decline rapidly from peak concentrations because of extensive tissue uptake.^118,119 Unlike morphine, the brain concentration of fentanyl falls in conjunction with the serum level. The duration of analgesic action is 30 to 40 minutes, although at high doses a second peak of activity may be seen several hours later because of release of the bound drug from tissue stores. Fentanyl is about 50 to 100 times as potent as morphine.¹²⁰ This unique combination of potency and short half-life permits the administration of numerous small doses that can be titrated to the desired clinical effect. Similar to other opioids, fentanyl is competitively reversed with naloxone.

The relative safety of fentanyl permits considerable latitude in dosing. When used as a primary anesthetic agent for major surgical procedures, doses ranging from 50 to 100 µg/kg produce minimal side effects.¹²¹ Comparatively tiny doses produce sedation, and 3 to 5 µg/kg, given at a rate of 1 to 2 µg/kg/min, is generally an effective analgesic dose. More rapid administration will cause greater depression of the level of consciousness. Mostert and coworkers¹¹⁴ reported successful awake intubation in 99 of 103 patients who were administered an average cumulative dose of 3.7 µg/kg. Most of these patients were able to follow commands, and many recalled events surrounding the intubation. A small percentage could not be intubated even after receiving 500 µg of fentanyl.

Larger doses, perhaps up to 25 µg/kg, may be needed to produce ideal intubating conditions, although if given rapidly, 10 µg/kg is usually adequate. Even this lower dose is more likely to produce unconsciousness than a lesser depth of sedation, and it may cause a longer period of unresponsiveness than is desirable. It is preferable to use a low dose of fentanyl (2 to 3 µg/kg) for analgesia combined with a paralytic agent (e.g., succinylcholine) to produce adequate muscle relaxation and a sedative (e.g., midazolam) to reduce anxiety and produce amnesia for the event.

Unlike other opioids, fentanyl causes little or no release of histamine, and its use is seldom associated with emesis or hypotension. It is probably the safest opioid to use in hypovolemic patients. Fentanyl also has significantly fewer emetic effects than other opioids do. Adverse effects that have been reported with fentanyl are few and primarily follow the rapid IV infusion of very large doses. Like other opioids, fentanyl may cause rigidity of the skeletal musculature, including the chest wall and diaphragm. Rigidity occurs with doses in excess of 15 µg/kg, but it has also been reported with doses as low as 10 µg/kg and may also be related to rapid administration.114,122 The muscular rigidity may be prevented or treated with standard doses of succinylcholine or naloxone.¹²³ The most common significant complication with fentanyl is respiratory depression, and it generally occurs when fentanyl is given in combination with other CNS depressants or in excessive amounts.¹²⁴

Neuromuscular Blocking Agents

NMBs are used to achieve muscle relaxation for intubation. They permit complete airway control and greatly simplify visualization of the vocal cords. This is particularly important when intubation must be performed quickly under less than ideal circumstances. Sedatives may provide some muscle relaxation, but this requires rapid administration of large doses, which poses a risk for depression of the cardiovascular system. The combination of a paralytic agent and a sedative or analgesic agent is generally superior to the use of either agent alone. A 1999 report showed an 18% failure-to-intubate rate with a sedative alone versus a 0% failure rate for sedatives plus paralytics.¹²⁵ Procedural complication rates such as significant airway trauma and aspiration were also markedly higher in the group receiving sedation only.

The only absolute contraindication to the use of NMBs is the inability to manage the airway once the patient becomes apneic. Though not absolutely contraindicated, it is considered inhumane to paralyze and intubate an alert patient. A sedative or an analgesic agent should always be administered simultaneously if the patient is able to perceive pain.

NMBs are classified as either depolarizing or nondepolarizing. Depolarizing agents mimic the action of acetylcholine (ACh) and produce sustained depolarization of the neuromuscular junction, during which time muscle contractions cannot occur. Nondepolarizing agents competitively block the action of ACh at the neuromuscular junction and prevent depolarization and therefore muscle contractions. Commonly used NMBs and their dosages and characteristics are listed in Table 5-2.

TABLE 5-2

Commonly Used Neuromuscular Blocking Agents

Succinylcholine

The standard depolarizing agent currently in use is succinylcholine.¹²⁶ It has a chemical structure similar to that of ACh and depolarizes the postjunctional neuromuscular membrane. Administration is followed by a brief period of muscle fasciculations that correspond to the initial membrane depolarization and muscle fiber activation. Unlike ACh, which is released in minute amounts and hydrolyzed in milliseconds, succinylcholine requires several minutes for breakdown to occur. During this time the neuromuscular junction remains depolarized, but the muscles relax and will not contract again until the neuromuscular end plate and adjacent sarcoplasmic reticulum return to the resting state and are again depolarized. Relaxation proceeds from the small, distal, rapidly moving muscles to the proximal, slowly moving muscles. The diaphragm is one of the last muscles to relax.¹²⁷

Succinylcholine is rapidly degraded in serum by the enzyme pseudocholinesterase, and the duration of action of a single dose is 3 to 5 minutes. Relaxation may be maintained by repeated IV injections. Prolonged or repeated use of the drug enhances its vagal stimulatory effects, thereby resulting in bradycardia, hypotension, and other muscarinic effects. These effects may be seen even at normal doses, particularly in children.¹²⁸ For this reason, atropine pretreatment at a dose of 0.02 mg/kg has been recommended in all small children and for adults receiving multiple doses, although the need and optimal dose are still in question.¹²⁸ Repeated dosing of succinylcholine may produce a desensitization blockade and create a scenario in which the neuromuscular membrane returns to the resting state and becomes resistant to further depolarization by succinylcholine.^129,130 In general, there is little need for repeated doses of succinylcholine if appropriately dosed the first time. If paralysis in excess of 3 to 5 minutes is desired, longer-acting, nondepolarizing agents such as vecuronium or pancuronium should be used.

The recommended dose of succinylcholine is 1 to 1.5 mg/kg given intravenously. Dosages at the upper end of this range are suggested to guarantee complete relaxation and avoid the need for repeated dosing. Dosage calculations should also be based on actual, not lean body mass because of alterations in both volume of distribution and pseudocholinesterase activity.¹³¹ Neonates and infants require a slightly higher dose of succinylcholine (2 mg/kg intravenously) as a result of their higher volume of distribution.^61,132 It is crucial that succinylcholine be administered as a rapid bolus because slow administration may lead to incomplete relaxation. Use of a rapid 20- to 30-mL saline flush after IV administration may enhance its desired effect.

There are a number of potential adverse effects of the use of succinylcholine ranging from minor to life-threatening. Muscle fasciculations accompany the initial depolarization of the neuromuscular membrane. Fasciculations are most prominent in muscular patients and create deep, aching muscle pain that may last for days.¹³³ It is unclear whether any regimen will totally prevent the succinylcholine-induced fasciculations (seen in 73% to 100% of patients) and myalgias (seen in 10% to 83% of patients), with varying effects reported after numerous interventions.¹³⁴ Interestingly, higher doses of succinylcholine may be associated with less myalgia. Traditionally, fasciculations have been prevented by the preadministration of a defasciculating dose (0.01 mg/kg) of pancuronium or vecuronium. The evidence available does not suggest that succinylcholine worsens outcomes in at-risk patients, nor does any evidence suggest that defasciculation improves outcomes in at-risk patients.¹³⁵

A major consideration in the use of succinylcholine is its propensity to cause hyperkalemia. This electrolyte disturbance is believed to occur secondary to asynchronous depolarization of muscle cells and resulting cellular injury. Elevation in serum potassium occurs in normal patients after standard doses but is typically clinically inconsequential, with increases of less than 0.5 mmol/L (mEq/L).¹³⁶ Increases in potassium are not prevented with defasciculating doses of nondepolarizing agents. Marked hyperkalemia is associated with increased extrajunctional muscle ACh receptors, which develop in patients with prolonged diseases of the neuromuscular system. Susceptibility may occur within as little as 5 to 7 days and persist indefinitely. In these cases the hyperkalemic response may be as much as 5 mmol/L (mEq/L). Such conditions include late severe burns,¹³⁷ major muscle trauma,¹³⁸ spinal cord injury, muscular dystrophy, multiple sclerosis, and other upper motor neuron diseases^139,140 such as amyotrophic lateral sclerosis. These large elevations occur only in patients who have had significant tissue injury or muscle denervation for several days or weeks before the use of succinylcholine. Importantly, succinylcholine is not contraindicated in the initial management of patients with acute injuries, including burns, major crush injuries, and spinal cord injuries. Succinylcholine is also not contraindicated in normokalemic patients with renal failure because the magnitude of the rise in serum potassium is the same as in patients with normally functioning kidneys.¹⁴¹ A retrospective review of the use of succinylcholine in 38 operative cases with moderate pre-RSI hyperkalemia (5.6 to 7.6 mmol/L) suggested that the risk for hyperkalemia-related complications may be lower than feared.¹⁴² In a review of more than 41,000 intubations (38 patients had hyperkalemia with a mean serum potassium level of 5.9 mmol/L), Schow and colleagues¹⁴² concluded that it is safe to administer succinylcholine to patients with a potassium level of 5.5 to 6.0 mEq/L. Regardless, succinylcholine is best avoided (if other equally effective pharmacologic options such as rocuronium exist) in the setting of known or suspected preexisting hyperkalemia (e.g., renal failure patients not receiving regular dialysis or demonstrating a wide QRS complex). Concern has also been raised over the use of succinylcholine in the pediatric population because of rare case reports of hyperkalemic cardiac arrest after administration to children with undiagnosed myopathies. Succinylcholine is currently recommended for use in pediatric patients only under emergency circumstances when the airway must be secured rapidly.¹³²

Malignant hyperthermia is a rare complication with an autosomal dominant inheritance pattern that is triggered by multiple anesthetic agents, including succinylcholine. Most provocative agents, such as halothane, are not used in the ED setting, and it is extremely rare for the ED physician to encounter this complication. It occurs in approximately 1 in 15,000 children and 1 in 50,000 adults.¹⁴³ The clinical syndrome consists of high fever, tachypnea, tachycardia, cardiac arrhythmias, hypoxia, acidosis, myoglobinuria, and impaired coagulation. Unabated muscle contractions mediated by abnormal calcium channels are the physiologic basis for this condition.¹⁴⁴ Treatment includes aggressive cooling measures, volume replacement, and correction of hypoxia and acid-base and electrolyte abnormalities. Dantrolene sodium, a direct-acting skeletal muscle relaxant, is thought to be effective in reducing the muscle hypermetabolism that causes the dramatic hyperpyrexia.¹⁴⁵ An associated abnormal response to succinylcholine is isolated masseter spasm,¹⁴⁶ but it can occur in isolation or portend the subsequent development of malignant hyperthermia. Though rare, it has been reported in the emergency medicine literature.¹⁴⁷ In this condition, forcible sustained contraction of the masseter muscles occurs and prevents mouth opening and oral intubation. Management is controversial, with recommendations ranging from use of a bag valve mask, securing a surgical airway until the contraction abates, to attempting to suppress the contractions through administration of a nondepolarizing NMB.

Prolonged paralysis after the administration of succinylcholine may occur in clinical conditions that result in decreased pseudocholinesterase levels and subsequent decreased metabolism of succinylcholine. Physiologic states associated with this condition include hepatic disease, anemia, renal failure, organophosphate poisoning, pregnancy, chronic cocaine use, advanced age, bronchogenic carcinoma, and connective tissue disorders. Patients with these conditions experience a twofold to threefold increase in the duration of apnea.¹⁴⁸ Patients with cocaine intoxication may also experience prolonged muscle relaxation because cocaine is competitively metabolized by the cholinesterases. An inherited deficiency of pseudocholinesterase is also present in about 0.03% of the population and can lead to prolonged paralysis from the administration of succinylcholine.¹⁴⁵

Succinylcholine can also result in an increase in ICP, but the magnitude and significance of the increase in ICP remains controversial.149–153 Increases in the range of 5 to 10 mm Hg have been reported by several investigators, but other researchers have shown no increase. There is no evidence of neurologic deterioration associated with these transient elevations in ICP. Mechanisms that have been proposed to explain the elevated ICP include (1) a direct effect of fasciculations, (2) an increase in cortical electrical activity with a resultant increase in cerebral blood flow and blood volume, and (3) sympathetic postganglionic stimulation. Limited studies have been performed to evaluate the significance of this rise in ICP in a brain-injured human patient population. These studies have shown no significant change in electroencephalographic activity or ICP with succinylcholine, but the small size of the studies limits the ability to draw conclusions about clinical outcomes.^132,154,155

Questions concerning the safety of succinylcholine in the setting of acute intracranial pathology do not have clear answers. The drug has been used widely and successfully in this setting, and its continued use is supported by this experience. The very real risk for airway compromise and secondary cerebral insult because of hypoxia from delayed or failed intubation must always be weighed against the theoretical harmful effects. Succinylcholine, despite its many potential side effects, is currently the most frequently used agent for neuromuscular blockade with RSI because of its rapid onset and offset and reliable muscle relaxation characteristics.

Nondepolarizing Agents

Nondepolarizing agents act in a competitive manner to block the effects of ACh at the neuromuscular junction. Drugs in this class include pancuronium, atracurium, vecuronium, mivacurium, and rocuronium. These drugs, particularly the intermediate-acting agents, have fewer side effects than succinylcholine does and the potential for reversal. They generally have a longer onset and duration of action than succinylcholine does, thus making them less attractive choices for RSI because of the delay in muscle relaxation. In most instances, succinylcholine remains the agent of choice to facilitate emergency intubation, and nondepolarizing agents are indicated to maintain paralysis after intubation. Knowledge of appropriate nondepolarizing NMBs is important for situations when succinylcholine may be contraindicated.

Because nondepolarizing agents act competitively at neuromuscular junction receptors, increasing the concentration of ACh may reverse their effects. Cholinesterase inhibitors such as neostigmine or edrophonium may be used but will not be effective until some spontaneous signs of reversal are seen. The concept of reversal is of limited clinical importance in the ED with rare exceptions, such as performance of a neurologic examination on a previously paralyzed patient. When reversal is required, neostigmine, 0.02 to 0.04 mg/kg, is given by slow IV push. An additional dose of 0.01 to 0.02 mg/kg may be given in 5 minutes if reversal is incomplete, but the total dose should not exceed 5 mg in adults. Atropine, 0.01 mg/kg (with a minimum dose of 0.1 mg in children and a maximum dose of 1 mg in adults), should be given concurrently with neostigmine to block its systemic cholinergic effects.156–158 Another potential reversing agent, sugammadex, binds directly to the aminosteroid NMB rather than to cholinesterases.¹⁵⁹ For reversal of shallow or profound neuromuscular blockade, 2 or 4 mg/kg intravenously, respectively, is recommended. Unfortunately, no studies currently address its use in emergency situations. It is approved for use in Europe but not the United States.

Long-Acting Agents: Pancuronium

Pancuronium is an aminosteroid that is primarily excreted in urine within 1 hour of IV administration.¹⁵⁹ Classified as a long-acting agent, its onset and duration of action are dose related. After a typical IV dose of 0.1 mg/kg, paralysis occurs within 2 to 5 minutes and lasts approximately 60 minutes. Paralysis may be maintained safely by repeated bolus or drip infusion. Because the effects of the drug are cumulative, repeating the original dose significantly lengthens the duration of paralysis.

Relatively few adverse effects are associated with the use of pancuronium. Many patients experience an increase in heart rate, blood pressure, and cardiac output because of the vagolytic effect of the drug. Ventricular tachycardia and severe hypertension have been reported but are quite rare.160,161 Pancuronium may cause release of histamine resulting in bronchospasm or anaphylactic reactions.¹⁶² Prolonged paralysis may occur, primarily in patients with myasthenia gravis or with significant impairment in renal function. One consensus panel recommended pancuronium for maintaining paralysis, except in patients with cardiac disease or hemodynamic instability, for whom they recommended vecuronium.¹⁶³

Intermediate-Acting Agents: Vecuronium, Atracurium, Mivacurium, and Rocuronium

Vecuronium and atracurium are intermediate-acting agents with an onset of action of approximately 3 minutes and a duration of action of 30 minutes. Mivacurium has an onset of action of 2 to 3 minutes and a duration of action of 15 to 20 minutes. Rocuronium has an onset of action within 1 to 1.5 minutes and a duration of action of 20 to 75 minutes (longer in geriatric patients). These drugs have minimal cardiovascular effects, cause little release of histamine (with the exception of mivacurium),¹³² and lack cumulative effects.¹⁶⁴

The recommended doses of vecuronium, atracurium, mivacurium, and rocuronium are listed in Table 5-2. Use of larger doses hastens the onset of action but greatly prolongs the period of paralysis. For example, vecuronium at a dose of 0.25 mg/kg intravenously will cause paralysis in as little as 1 minute, but the period of paralysis will last 1 to 3 hours.^165,166 Because a rapid onset of action comparable to that of succinylcholine is achieved at high doses of intermediate-acting agents, they may be used as the sole agents to facilitate intubation, particularly if a long period of paralysis is desired after intubation. The use of succinylcholine before intubation and an intermediate-acting agent at a normal dose after intubation provides rapid intubating conditions and better control over the duration of paralysis. The paralysis induced by vecuronium or atracurium may be maintained by repeated boluses or drip infusion. Unlike both pancuronium and succinylcholine, these agents have no side effects specifically related to repeated dosing in the ED. A repeated dose of 0.01 to 0.02 mg/kg of vecuronium will extend the period of paralysis 12 to 15 minutes.

Rocuronium, a structural analogue of vecuronium, is emerging as a desirable alternative agent for RSI when succinylcholine is contraindicated. At doses of 0.6 to 1.2 mg/kg, rocuronium consistently provides good to excellent intubating conditions within 1 minute of administration. Its duration of action is dose dependent and ranges from 20 to 75 minutes.167,168 Smaller anesthesia and ED-based studies have demonstrated its clinical utility and safety in RSI protocols.^55,167–173 However, a 2003 Cochrane review¹⁷⁴ found that except when used in conjunction with propofol, the intubation conditions produced by rocuronium tend to be inferior to those produced by succinylcholine for RSI.

The “Sedated Look” Evaluation of the Airway before Rapid-Sequence Intubation

In selected stable patients, conditions may exist that preclude the immediate use of RSI, and the more prudent approach would be to assess the airway and intubation needs or potential complications before using paralytics. Examples are patients with angiotensin-converting enzyme inhibitor–induced angioedema or smoke inhalation, where clinical issues of RSI and intubation can be assessed by directly visualizing the larynx. This approach, referred to as a “sedated look” or “awake look,” is used when the clinician suspects a difficult intubation. This approach allows the clinician to verify that the laryngeal structures are indeed visible and accessible before committing to paralysis. This technique allows the patient to maintain respiratory drive during analysis of the airway. This approach is distinct from the practice of intubation with sedation alone or non-paralytic RSI, in which the patient receives a full induction dose of a sedative agent but no neuromuscular blocking agent. This older practice may create a vulnerable and compromised patient in whom intubating conditions are then problematic.

Traditionally in the OR, topical anesthesia (e.g., nebulized 4% lidocaine) along with moderate sedation has been used to allow a view into the airway while enabling the patient to maintain respiratory drive and protective airway reflexes. Although more research is needed to determine which medications are best for sedated looks in the ED, ketamine may be ideal in this circumstance by allowing the patient to maintain respiratory drive while providing analgesia, amnesia, and sedation. Ketamine’s analgesic properties allow it to be used as the sole agent in patients with a bloody traumatized airway, for which topical anesthesia is unlikely to work effectively. Other options are discussed in the following section.

Awake Intubation

An alternative to induction of unconsciousness in patients requiring intubation is the use of local anesthetic and sedative agents in conscious patients. The availability of relatively effective and safe induction agents makes this a less attractive alternative than in the past, but these techniques may be desirable in specific patients, such as for fiberoptic intubation of a predicted difficult airway. Awake intubation offers a number of potential advantages over RSI. The natural airway is maintained along with spontaneous respiration and a degree of protection from aspiration. The use of sedative agents to produce a state of mild or moderate sedation and adequate topical anesthesia are the principal components needed for awake intubation.

Thomas ¹⁷⁵ likened standard laryngoscopy in an awake patient to the “mouth being held open with a wrench.” Awake nasotracheal intubation and fiberoptic intubation can also be an extremely unpleasant experience. The upper airway is richly innervated by sensory branches of the 5th, 7th, 9th, and 10th cranial nerves. In addition to pain fibers, there are stretch receptors that stimulate the coughing and gagging reflexes with even minor airway manipulation. It is essential that adequate analgesia be provided before intubation in all but the most extreme circumstances. Treatment options include topical application of anesthetic agents to the pharyngeal and tracheal mucosa and IV infusion of analgesic or sedative agents.

Local or topical anesthesia techniques may be used in patients who are awake, either in place of or as a supplement to IV analgesia or sedation. They are particularly useful as adjuncts to nasotracheal and fiberoptic intubation but do not generally provide the degree of analgesia or relaxation desirable for traditional laryngoscopy. In addition, the time required to achieve good topical anesthesia may limit the usefulness of these techniques in emergency situations. Topical anesthesia may be achieved by direct application, by cricothyroid membrane puncture, or by inhalation of a nebulized anesthetic.

Direct Application

Achieving anesthesia of the oral and pharyngeal mucosa is a relatively simple procedure that involves the use of commonly available agents such as 4% lidocaine or a combination such as 14% benzocaine, 2% butamben, and 2% tetracaine (Cetacaine). Achieving anesthesia of the hypopharynx is more difficult because optimal results require application of the anesthetic to the epiglottis and vocal cords.

This procedure begins with spraying the tongue and pharynx with a topical agent. Use of atomization devices that attach to standard syringes (e.g., Mucosal Atomization Device [MAD], Wolfe Tory Medical, Inc., Salt Lake City) can provide effective drug dispersal without a forceful spray (Fig. 5-3). The more forceful pressurized canister sprays commonly provoke a cough reflex. After allowing at least 2 to 3 minutes to achieve numbing of the tongue and pharynx, the epiglottis and vocal cords can be sprayed with the MAD device. A malleable extension tube allows the tip of the MAD to pass around the base of the tongue, thereby permitting direct spraying of the epiglottis and vocal cords. This is generally well tolerated. An alternative method is to visualize the epiglottis and vocal cords with a laryngoscope and directly spray with the anesthetic agent. The use of a laryngoscope to visualize the vocal cords is much more stimulating to the patient and often not well tolerated. Another alternative is percutaneous injection of an anesthetic agent into the trachea at the level of the cricothyroid membrane.^176,177

Figure 5-3 The Mucosal Atomization Device. (Courtesy of Wolfe Tory Medical, Inc., Salt Lake City.)

Cricothyroid Membrane Puncture

Direct application of topical anesthetics to the subglottic region can also be achieved through cricothyroid membrane puncture (Fig. 5-4). In this procedure, identify the cricothyroid membrane immediately below the thyroid cartilage. After antiseptic skin preparation, puncture the overlying tissue and membrane with a 22-gauge needle in the midline and just above the superior border of the cricoid cartilage. Take care to maintain the needle in the midline at all times to avoid injury to the recurrent laryngeal nerves. Advance the needle until air can be aspirated, which indicates placement of the tip in the trachea. Inject a 2-mL volume of 4% lidocaine rapidly. If the 4% concentration is not available, use 3 to 4 mL of 1% to 2% lidocaine. Typically, this will precipitate a cough and distribute the anesthetic over the upper part of the trachea, vocal cords, and epiglottis.