Manual of Emergency Airway Management, 3rd Edition

26. RSI Using Nondepolarizing Agents

Ron M. Walls

The Clinical Challenge

Succinylcholine is the preferred agent for rapid sequence intubation (RSI) in the emergency department (ED), but certain patients have contraindications to its use, principally related to the risk of hyperkalemia for patients with certain pre-existing conditions or, rarely, to known prior adverse reactions. These are discussed in detail in Chapter 19. This chapter addresses the approach to patients for whom an alternative neuromuscular blocking agent (NMBA) is required for RSI.

Approach to the Airway

Of the nondepolarizing NMBAs, two have pharmacokinetic properties that support use during RSI: rocuronium (Zemuron) and vecuronium (Norcuron). Of these, rocuronium is clearly superior for emergency intubation because of its consistently rapid onset; it has been shown to produce intubating conditions almost identical to succinylcholine 60 seconds after administration when used with an adequate dose of an effective sedative induction agent. Rocuronium does not release histamine, is not a ganglionic blocking agent, and is devoid of cardiac muscarinic blocking effects, so it is virtually free of adverse effects. The biggest drawback to rocuronium, when compared to succinylcholine, is its relatively longer duration, which averages approximately 45 minutes when used in the recommended 1 mg/kg RSI dose. Sugammadex, the first of a novel class of reversal agents for competitive NMBAs, specifically reverses rocuronium. Unlike traditional reversal regimens, sugammadex can be given before any spontaneous muscular recovery occurs. With adequate dosing of sugammadex, early evidence indicates that full neuromuscular paralysis with rocuronium can be reversed sufficiently to permit adequate spontaneous ventilations within approximately 1 minute.

Vecuronium is a reasonable alternative to rocuronium for RSI, although it is a bit more complicated to use. Vecuronium is also devoid of any clinically significant side effects, but the time to achieve intubation-level relaxation is somewhat longer than with rocuronium (count on 75–90 seconds), even when the priming technique (described below) is used. The duration of action of vecuronium is significantly greater than for rocuronium, and there is presently no rapid reversal agent available.

Technique

When a nondepolarizing agent is used for RSI, the time to adequate relaxation for laryngoscopy and intubation is slightly prolonged when compared to that for succinylcholine. In general, time 45 seconds to begin laryngoscopy after succinylcholine, 60 seconds after rocuronium, and 75 to 90 seconds after vecuronium. One method to shorten the apparent time to paralysis for vecuronium is to reverse the order of administration of the induction agent and the NMBA, giving the vecuronium first, followed immediately by the induction agent. This approach is not necessary when rocuronium is used.

When vecuronium is used for RSI, its onset can be hastened by the administration of a small priming dose (0.01 mg/kg or one tenth of the paralyzing dose) 3 minutes before giving the large, intubating dose (0.15 mg/kg; almost twice the paralyzing dose). This is called the “priming principle,” and the small dose is referred to as the priming dose. The small priming dose serves to bind a small percentage of the motor end plate acetylcholine (ACh) receptors, such that clinical weakness is not experienced by the patient, yet the onset of action of the subsequent intubating dose is hastened. Using the priming principle, intubation-level paralysis can be achieved with vecuronium in 75 to 90 seconds. As is the case with other NMBAs, the intubating dose of vecuronium (i.e., the dose needed to achieve rapid paralysis for intubation) is significantly greater than the paralyzing dose. When using the priming principle, it is recommended that the paralytic dose be increased from the typical dose of 0.1 mg/kg (two times the effective dose that results in paralysis of 95% of the population, or ED₉₅) to 0.15 mg/kg (three times the ED₉₅).

There is another method for hastening the onset of vecuronium, called the “timing” method, in which the vecuronium is administered first, but the induction agent is withheld until the first sign of clinical weakness (ptosis) is observed, at which time the induction agent is then rapidly pushed. This timing method is advocated on the basis that it better aligns the onset of paralysis and hypnosis, minimizing the period that the patient is unconscious (but not yet paralyzed or intubatable) and, therefore, the risk of aspiration. We do not recommend the timing method for emergency intubation because it has the potential to cause severe distress for the patient, who experiences the onset of paralysis while still awake. This method also requires a level of patient observation, timing, and sequencing of drugs not used in any other RSI protocol, so seems prone to error.

Drug Dosage and Administration

Much research has been done on rocuronium to determine the appropriate dose for the most rapid and consistent onset of paralysis for RSI. The ED₉₅ of rocuronium is 0.3 mg/kg. Consequently, the most commonly studied dosages in the literature are multiples of that, namely, 0.6 mg/kg, 0.9 mg/kg, and 1.2 mg/kg. Pharmacokinetic studies have unequivocally identified 1.0 mg/kg as the best intubation dose for RSI. This dose allows for laryngoscopy and intubation to occur 45 to 60 seconds after administration and results in approximately 45 minutes of motor paralysis. Rocuronium is distributed as a solution in 50- and 100-mg vials, at a concentration of 10 mg/mL. Using the larger vial (100 mg) allows the dose for the average adult patient (70–80 mg) to be obtained from a single vial. Because reconstitution is not necessary, the drug can be drawn up and administered quickly during the RSI protocol. For RSI, rocuronium, 1.0 mg/kg, is simply substituted for succinylcholine 1.5 mg/kg. All other steps remain the same. The shelf-life of rocuronium at room temperature is only a month, and thus, refrigeration or active inventory control is required to avoid spontaneous degradation of the drug. A sample RSI using rocuronium is shown in Box 26-1.

Vecuronium is supplied as a lyophilized powder in 10-mg vials that must be reconstituted with normal saline before use. When the vial is mixed with 10 cc of saline, a solution of 1 mg/mL vecuronium is produced. When performing RSI using vecuronium, the priming principle should be used. This involves the administration of a small, nonparalyzing dose of vecuronium, followed a few minutes later by a larger, paralyzing dose to hasten onset of intubation-level paralysis. Many variations of priming dose, interval, and intubating dose have been studied and recommended. On balance, to achieve intubating conditions as consistently as possible in the emergency situation, we recommend that the patient receive 0.01 mg/kg (usually rounded to a full 1 mg in most adult patients of average weight), concordant with the pretreatment phase of RSI, followed 3 minutes later by 0.15 mg/kg of vecuronium, given by rapid intravenous administration, immediately before or after the sedative (induction) agent. In most circumstances, laryngoscopy can be initiated in 75 to 90 seconds. Because of the larger intubating dose, the duration of paralysis will be prolonged (approximately 40 minutes). When using the priming principle, the operator must be extremely vigilant of the patient because an elderly or severely debilitated patient or a patient with respiratory failure may experience significant motor paralysis after the priming dose alone and require bag-mask ventilation and accelerated movement to the paralysis/induction step of RSI. A sample RSI using vecuronium with the priming principle is shown in Box 26-2.

BOX 26-1 Rapid Sequence Intubation Using Rocuronium

BOX 26-2 Rapid Sequence Intubation Using Vecuronium with the Priming Principle

Postintubation Management

Postintubation management after RSI with a nondepolarizing NMBA is comparable to that of conventional RSI with succinylcholine, with an obvious exception. The duration of action of succinylcholine is so short that spontaneous recovery of neuromuscular function can be anticipated within 10 minutes. Paralysis with a competitive NMBA will be much longer, as described previously, necessitating appropriate use of generous doses of sedatives and analgesics (see Chapter 3) to ensure that the patient is not “paralyzed but awake.”

Tips and Pearls

· When succinylcholine is contraindicated, rocuronium is the preferred NMBA for RSI because it provides an earlier onset of paralysis than vecuronium.

· Rocuronium substitutes easily for succinylcholine in the RSI protocol, and it is supplied in solution, like succinylcholine, so it does not need to be reconstituted. It is neither advisable nor necessary to use the priming principle with rocuronium.

Evidence

1. What is the correct dose of rocuronium for RSI, and how fast does it work? Many studies performed in the operating room have shown that rocuronium can produce excellent intubating conditions within 60 seconds. The best analysis is that of Kirkegaard-Nielsen, et al. (1), who were able to use pharmacokinetic measurements to calculate the optimal intubating dose of rocuronium for RSI at 1.04 mg/kg. This dose provided for intubation at 60 seconds in 95% of patients with a 46-minute duration of action. This result strongly supports the use of 1.0 mg/kg of rocuronium for RSI, rather than the frequently recommended 0.6 mg/kg.

Perry, Lee, and Wells (2) performed a detailed meta-analysis of 26 randomized clinical trials, including 1,606 patients undergoing RSI with succinylcholine versus rocuronium and found that there was a statistically significant relative risk (0.87) of less favorable intubating conditions with rocuronium. In a subgroup analysis, when propofol was used as the induction agent, intubation conditions were found to be the same between succinylcholine and rocuronium. These data support the widely held notion that using a potent induction agent can significantly improve the intubation conditions during RSI. This is likely because when intubation is attempted, the NMBA has not reached its peak effect, and the additional relaxation produced by the induction agent thus further optimizes the intubation conditions. However, the differences between succinylcholine and rocuronium depend on the definitions and outcomes used, and much of the apparent superiority of succinylcholine over rocuronium depends on narrow definitions of “excellent” intubating conditions. Success rates were comparable in the two groups.

Studies have fairly consistently shown that succinylcholine is more rapid and of shorter duration than rocuronium, but many of these have not replicated true RSI conditions, and doses of both rocuronium and succinylcholine have varied (3). Nevertheless, for now, succinylcholine remains the drug of choice for emergency RSI.

Rocuronium does not require priming when used in the 1 mg/kg dose. A recent study in children found that 0.6 mg/kg of rocuronium resulted in much more rapid intubating conditions when it was divided, with 10% given as a priming dose and the remaining 90% given a minute later (4). However, this study also did not replicate true RSI conditions, and the duration of action was over 40 minutes, comparable to that when 1.0 mg/kg of rocuronium is used. As expected, priming does not prolong the action of rocuronium.

2. Are there any studies of rocuronium in the ED? Unfortunately, few ED-based studies exist because of the practical difficulties involved in carrying out pharmacological intubation studies in an uncontrolled setting on unstable patients with unplanned intubations. Over a 6-month period, Sakles et al. (5) studied 58 patients who received rocuronium for RSI in the ED, and found that a mean dose of 1.0 ± 0.2 mg/kg of rocuronium was used for intubation and that etomidate was the most frequently used induction agent. The time from rocuronium administration to the initiation of laryngoscopy was able to be timed in 34 patients and averaged 45 ± 15 seconds (range 20–90 seconds). Laurin et al. (6) studied 520 ED intubations in which succinylcholine or rocuronium was used for RSI over a 1-year period. In the 382 patients receiving succinylcholine, the mean onset time of paralysis was 39 ± 13 seconds, and in the 138 patients receiving rocuronium, the onset time was 44 ± 20 seconds. This difference has no statistical or clinical significance.

3. What is all the interest in sugammadex? There is a new class of drugs, called the selective relaxant binding agents (SRBAs), which are designed to reverse the effects of the competitive aminosteroid NMBAs. Each drug in this class is specific to a particular aminosteroid NMBA, and sugammadex, which encapsulates and disables rocuronium, is the first agent to come to clinical trials. Traditional reversal methods for competitive NMBA involve administration of a cholinesterase inhibitor, which greatly increases acetylcholine concentrations, allowing effective competition with the NMBA at the neuromuscular junction. The reversal is not effective, however, until significant spontaneous recovery has occurred, and the excess of acetylcholine causes muscarinic effects that require the concomitant administration of an antimuscarinic agent, such as atropine. SRBAs hold the promise of immediate (within a minute or two) reversal of aminosteroid NMBA without any prior recovery, so that even a long-acting NMBA could be quickly reversed, if necessary. Initial studies appear to demonstrate both safety and tolerance for sugammadex (7). Doses up to 16 mg/kg of sugammadex have been well tolerated by healthy adults (8), and Groudine et al. (9) recently demonstrated reversal of paralysis approximately 1 minute after administration of 8 mg/kg of sugammadex to healthy adult patients fully paralyzed with 1.2 mg/kg of rocuronium. Although additional studies are needed, sugammadex and its fellow SRBAs hold the promise of rapid reversal of competitive NMBA, which could open the door for widespread adoption of an aminosteroid NMBA, likely rocuronium, as the agent of choice for emergency RSI. With rapid reversal possible, rocuronium would have the advantages of succinylcholine (fast, consistent, effective, brief duration of action) without the potentially serious adverse effects, especially hyperkalemia, associated with succinylcholine in certain patients.

References

1. Kirkegaard-Nielsen H, Caldwell JE, Berry PD. Rapid tracheal intubation with rocuronium: a probability approach to determining dose. Anesthesiology 1999;91:131–136.

2. Perry JJ, Lee J, Wells G. Are intubation conditions using rocuronium equivalent to those using succinylcholine? Acad Emerg Med 2002;9:813–823.

3. Sluga M, Ummenhofer W, Studer W, et al. Rocuronium versus succinylcholine for rapid sequence induction of anesthesia and endotracheal intubation: a prospective, randomized trial in emergent cases. Anesth Analg 2005;101:1356–1361.

4. Bock M, Haselmann L, Böttiger BW, et al. Priming with rocuronium accelerates neuromuscular block in children: a prospective randomized study. Can J Anesth 2007;54:538–543.

5. Sakles JC, Laurin EG, Rantapaa AA, et al. Rocuronium for rapid sequence intubation of emergency department patients. J Emerg Med 1999;17:611–616.

6. Laurin EG, Sakles JC, Panacek EA, et al. A comparison of succinylcholine and rocuronium for rapid sequence intubation of emergency department patients. Acad Emerg Med 2000;7: 1362–1369.

7. Sorgenfrei IF, Norrild K, Larsen PB, et al. Reversal of rocuronium-induced neuromuscular block by the selective relaxant binding agent sugammadex: a dose-finding and safety study. Anesthesiology 2006;104:667–674.

8. Gijsenbergh F, Ramael S, Houwing N, et al. First human use of Org 25969, a novel agent to reverse the action of rocuronium bromide. Anesthesiology 2005;103:695–703.

9. Groudine SB, Soto R, Lien C, et al. A randomized, dose-finding, phase II study of the selective relaxant binding drug. Sugammadex, capable of safely reversing profound rocuronium-induced neuromuscular block. Anesth Analg 2007;104(3):555–562.