David A. Caro
Erik G Laurin
Introduction
Neuromuscular blocking agents (NMBAs) are the cornerstone of rapid sequence intubation (RSI) and are used to facilitate rapid endotracheal intubation while minimizing the risks of aspiration or other adverse physiological events. NMBAs are used in conjunction with a sedative-induction agent for RSI because the NMBAs do not provide analgesia, sedation, or amnesia. Similarly, appropriate sedation is essential when neuromuscular blockade is maintained postintubation.
The pharmacology of NMBAs is based on their effects at the postjunctional cholinergic nicotinic receptors in the neuromuscular junction. Under normal circumstances, the nerve synthesizes acetylcholine (ACH) and stores it in small packages (vesicles). Nerve stimulation results in these vesicles migrating to the nerve surface, rupturing and discharging ACH into the junctional clefts between the nerve and the muscle as well as into those clefts that invaginate into the muscle fiber. The ACH attaches to ACH receptors, promoting muscle fiber depolarization that culminates in a muscle cell action potential and muscle cell contraction. Once the ACH diffuses away from the cleft, some undergoes reuptake into the prejunctional neuron, although most is hydrolyzed by acetylcholinesterase (ACHE). NMBAs are either agonists (depolarizers of the motor end plate) or antagonists (“nondepolarizers”). The antagonists attach to the receptors and competitively block ACH from accessing ACH receptors. Because they are in competition with ACH for the motor end plate, they can be displaced from the end plate by increasing concentrations of ACH, the end result of reversal agents (cholinesterase inhibitors such as neostigmine, edrophonium, and pyridostigmine) that inhibit ACHE and allow acetylcholine to accumulate and reverse the block.
In clinical practice, there are two classes of NMBAs: the noncompetitive or depolarizing NMBAs, of which succinylcholine (Anectine) is the prototype and the only one in common clinical use. The competitive or nondepolarizing agents are divided into two main classes: the benzylisoquinolinium compounds and the aminosteroid compounds. The benzylisoquinolines, d-tubocurarine (Tubarine), dimethyltubocurarine (Metocurine), atracurium (Tracrium), cisatracurium (Nimbex), and mivacurium (Mivacron) share common properties. The aminosteroids, vecuronium (Norcuron), pancuronium (Pavulon), and rocuronium (Zemuron) also share common attributes, which are distinct from those of the benzylisoquinolines.
Depolarizing (Competitive) NMBA: Succinylcholine
|
Intubating dose (mg/kg) |
Onset (sec) |
t1/2α (min) |
Duration (min) |
t1/2α (hr) |
Pregnancy Category |
|
1.5 |
45 seconds |
<1 minute |
6–10 |
5 |
C |
The ideal muscle relaxant to facilitate tracheal intubation would have a rapid onset of action, rendering the patient paralyzed within seconds; a short duration of action, returning the patient's normal protective reflexes within 3 to 4 minutes; no significant adverse side effects; and metabolism and excretion independent of liver and kidney function. Unfortunately, such an agent does not exist. Succinylcholine (SCh) comes closest to meeting these desirable goals. Despite the historic and well-known adverse effects of SCh and the continuous advent of new competitive NMBAs, SCh remains the drug of choice for emergency RSI in both adults and children.
A. Clinical pharmacology
SCh is actually two molecules of ACH linked back to back by an ester bridge, and as such, is chemically similar to ACH. It stimulates all nicotinic and muscarinic cholinergic receptors of the sympathetic and parasympathetic nervous system, not just those at the neuromuscular junction. Stimulation of cardiac muscarinic receptors can cause bradycardia, especially when repeated doses are given to small children. Although SCh can be a negative inotrope, this effect is so minimal as to have no clinical relevance. SCh also releases trace amounts of histamine, but this effect is also not clinically significant. Once SCh reaches the neuromuscular junction, it binds tightly to the ACH receptors, resulting in depolarization that manifests initially as fasciculations, then subsequent paralysis. The onset, activity, and duration of action of SCh are resistant to ACHE and dependent on rapid hydrolysis by pseudocholinesterase, an enzyme of the liver and plasma not present at the neuromuscular junction. Therefore, diffusion away from the neuromuscular junction motor end plate and back into the vascular compartment is ultimately responsible for SCh metabolism. This extremely important pharmacological concept explains why only a fraction of the initial intravenous (IV) dose of SCh ever reaches the motor end plate to promote paralysis. More important, it is for this reason that larger, rather than smaller, doses of SCh should always be given in emergency RSI. Incomplete paralysis may jeopardize the patient by compromising respiration and may not provide adequate relaxation to facilitate otherwise easy endotracheal intubation. Succinylmonocholine, the initial metabolite of SCh, sensitizes the cardiac muscarinic receptors in the sinus node to repeat does of SCh, which may then cause bradycardia that will respond to atropine. At room temperature, SCh retains 90% of its activity for up to 3 months. Refrigeration mitigates this degradation. Therefore, if SCh is stored at room temperature, it should be dated and regularly exchanged to the operating room, where it will be rapidly used.
B. Indications and contraindications
SCh remains the NMBA of choice for emergency RSI because of its rapid onset and relatively brief duration of action. A personal or family history of malignant hyperthermia is an absolute contraindication to the use of SCh. Inherited disorders that lead to abnormal or insufficient cholinesterases contraindicate SCh use in elective anesthesia, but are not an issue in emergency airway management. Certain conditions place patients at risk for SCh-related hyperkalemia and represent absolute contraindications to SCh. These patients should be intubated using a competitive, nondepolarizing NMBA. Relative contraindications to the use of SCh are dependent on the skill and proficiency of the intubator and the individual patient's clinical circumstance. The role of difficult airway assessment in the decision regarding whether a patient should undergo RSI is discussed in Chapters 2 and 7.
C. Dosage and clinical use
In the normal-size adult patient, the recommended dose of SCh for emergency RSI is 1.5 mg/kg IV. In a rare, life-threatening circumstance when SCh must be given intramuscularly (IM) because of inability to secure venous access, a dose of 4 mg/kg IM may be used. Absorption and delivery of drug will be dependent on the patient's circulatory status. Intramuscular administration may result in a prolonged period of vulnerability for the patient, during which respirations will be compromised, but relaxation is not sufficient to permit intubation. Active bag-mask ventilation will usually be required before laryngoscopy in this circumstance.
Although length-based drug dosing will lead to the correct dose of SCh for children, adults, including obese adults, are dosed on a total body weight basis (see Chapter 35). In the emergency department, it may be impossible to know the exact weight of a patient, and weight estimates, especially of supine patients, have been shown to be notoriously inaccurate. In those uncertain circumstances, it is better to err on the side of a higher dose of SCh to ensure adequate patient paralysis. The serum half-life of SCh is less than 1 minute, so doubling the dose theoretically increases the duration of block by only 60 seconds. The margin of safety in dosing SCh is up to a cumulative dose of 6 mg/kg. At doses greater than 6 mg/kg, the typical phase 1 depolarization block of SCh becomes a phase 2 block, which changes the pharmacokinetic displacement of SCh from the motor end plate; that is, it becomes competitive rather than noncompetitive. This may prolong the duration of paralysis but is otherwise clinically irrelevant. The risk of an inadequately paralyzed patient who is difficult to intubate because of an inadequate dose of SCh greatly outweighs the minimal potential for adverse effects from excessive dosing.
In children younger than 10 years of age, length-based dosing is recommended, but if weight is used as the determinant, the recommended dose of SCh for emergency RSI is 2 mg/kg IV, and in the newborn (younger than 12 months of age), the appropriate dose is 3 mg/kg IV. Some practitioners routinely administer atropine to children younger than 12 months old who are receiving SCh, but there is no high-quality evidence to support this practice. There is similarly no evidence that it is harmful, so it is considered optional. When adults or children of any age receive a second dose of SCh, bradycardia may occur, and atropine should be readily available.
D. Adverse effects
The recognized side effects of SCh include fasciculations, hyperkalemia, bradycardia, prolonged neuromuscular blockade, malignant hyperthermia, and trismus/masseter muscle spasm. Each is discussed separately.
1. Fasciculations
Fasciculations are believed to be produced by stimulation of the nicotinic ACH receptors. Fasciculations occur simultaneously with increases in intracranial pressure (ICP), intraocular pressure, and intragastric pressure, but these are not the result of concerted muscle activity. Of these, only the increase in ICP is potentially clinically important.
The exact mechanisms by which these effects occur are not well elucidated. The use of nondepolarizing agents to pretreat fasciculations in an attempt to prevent increases in ICP has been emphasized in the past. A systematic review failed to show sufficient evidence for this practice in acute brain injury, but did show level II evidence of a modest effect in patients undergoing neurosurgery with brain tumors.
The relationship between muscle fasciculation and subsequent postoperative muscle pain is controversial. Studies have been variable with respect to prevention of fasciculations and subsequent muscle pain. The theoretical concern in open globe injury is extrusion of vitreous, but there has not been a single published report of this. In fact, many anesthesiologists continue to use SCh as a muscle relaxant in cases of open globe injury, with or without an accompanying defasciculating agent. Similarly, the increase in intragastric pressure that has been measured has never been shown to be of any clinical significance, perhaps because it is offset by a corresponding increase in the lower esophageal sphincter pressure.
2. Hyperkalemia
Under normal circumstances, serum potassium increases minimally (0–0.5 mEq/L) when SCh is administered. In certain pathological conditions, however, a rapid and dramatic increase in serum potassium can occur in response to SCh. These pathological hyperkalemic responses occur by two distinct mechanisms: receptor upregulation and rhabdomyolysis. In either situation, potassium increase may approach 5 to 10 mEq/L within a few minutes and result in hyperkalemic dysrhythmias or cardiac arrest.
Two forms of postjunctional receptors exist: mature (junctional) and immature (extrajunctional). Each receptor is composed of five proteins arranged in a circular fashion around a common channel. Both types of receptors contain two alpha subunits. ACH must attach to both alpha subunits to open the channel and effect depolarization and muscle contraction. When receptor upregulation occurs, the mature receptors at and around the motor end plate are gradually converted over a 4- to 5-day period to immature receptors that propagate throughout the entire muscle membrane. Immature receptors are characterized by low conductance and prolonged channel opening times (four times longer than mature receptors), resulting in increasing release of potassium. Most of the entities associated with hyperkalemia during emergency RSI are the result of receptor upregulation. Interestingly, these same extrajunctional nicotinic receptors are relatively refractory to nondepolarizing agents, so larger doses of vecuronium, pancuronium, or rocuronium may be required to produce paralysis. This is not an issue in emergency RSI, where full intubating doses several times greater than the ED95 for paralysis are used.
Rhabdomyolysis is the other mechanism by which hyperkalemia may occur. It is most often associated with myopathies, especially inherited forms of muscular dystrophy. When severe hyperkalemia occurs related to rhabdomyolysis, the mortality approaches 30%, almost three times higher than that in cases of receptor upregulation. This mortality increase may be related to coexisting cardiomyopathy. SCh is a toxin to unstable membranes in any patient with a myopathy and should be avoided.
Patients with the following conditions are at risk of SCh-induced hyperkalemia:
a. Burns
In burn victims, the extrajunctional receptor sensitization becomes clinically significant 5 days postburn. It lasts an indefinite period of time, at least until there is complete healing of the burned area. If the burn becomes infected or healing is delayed, the patient remains at risk for hyperkalemia. It is prudent not to administer SCh to burned patients beyond day 5 post-burn if any question exists regarding the status of their burn. The percent of body surface area burned does not correlate well with the magnitude of hyperkalemia. Significant hyperkalemia has been reported in patients with as little as 8% total body surface area burn (less than the surface of one arm), but this is rare. Most emergency intubations for burns are performed well within the safe 5-day window after the burn occurs, but if later intubation is required, rocuronium or vecuronium provide excellent alternatives for emergency RSI in these situations (see Chapter 26).
b. Denervation
The patient who suffers a denervation event, such as spinal cord injury or stroke, is at risk for hyperkalemia from approximately the fifth day post event until there is healing or total muscle fiber atrophy (generally 6 months post event). Patients with progressive neuromuscular disorders such as multiple sclerosis or amyotrophic lateral sclerosis are perpetually at risk for hyperkalemia. Likewise, patients with transient neuromuscular disorders such as Guillain-Barré syndrome or wound botulism can develop hyperkalemia after day 5, depending on the severity of their disease. As long as the neuromuscular disease is dynamic, there will be augmentation of the extrajunctional receptors and the risk for hyperkalemia. The hyperkalemic response cannot be attenuated by administering defasciculating doses of nondepolarizing NMBAs, and therefore, these specific clinical situations should be considered absolute contraindications to SCh during the designated time periods.
c. Crush injuries
The data regarding crush injuries are scant. The hyperkalemic response begins about 5 days postinjury, similar to denervation, and persists for several months after healing seems complete. The mechanism appears to be receptor upregulation.
d. Severe infections
This entity seems to relate to established, serious infections, usually in the intensive care unit environment. The mechanism is receptor upregulation, but the initiating event is not established. Total body disuse atrophy and chemical denervation of the ACH receptors, particularly if muscle relaxants are chronically infused, appear to drive the pathological receptor changes. Again, the at-risk time period is 5 days after initiation of the infection and continues indefinitely as long as the disease process is dynamic. Intra-abdominal sepsis has most prominently been identified as the culprit, but any serious, prolonged, debilitating infection should prompt concern.
e. Prolonged Immobility
Hospitalized patients who are bedbound and relatively immobile for long periods can develop severe SCh-related hyperkalemia from disuse atrophy, as described previously. Another common setting is the elderly patient who has been ill and immobile (e.g. “found down”) for several days at home, then enters the emergency care system and RSI is performed as part of the stabilization efforts.
f. Myopathies
SCh is absolutely contraindicated in patients with inherited myopathies, such as muscular dystrophy. Myopathic hyperkalemia can be devastating because of the combined effects of receptor upregulation and rhabdomyolysis. This is a particularly difficult problem in pediatrics, when a child with occult muscular dystrophy receives SCh. SCh has a black box warning advising against its use in elective pediatric anesthesia, but it continues to be the muscle relaxant of choice for emergency intubation. Any patient suspected of a myopathy should be intubated with nondepolarizing muscle relaxants rather than SCh.
g. Pre-existing hyperkalemia
The risk of SCh-induced cardiac dysrhythmias in patients who are hyperkalemic prior to SCh administration is not clearly determined. Although there is widespread belief that patients with acute hyperkalemia, such as from acute renal failure or diabetic ketoacidosis, are more likely to exhibit cardiac disturbances from SCh than patients with chronic or recurrent hyperkalemia, such as chronic renal failure, there is no evidence to support this. Most likely, the severity of pre-existing hyperkalemia dictates the response because these patients are subject to the same potential rise of 0 to 0.5 mEq/L of potassium. The only study evaluating the use of SCh in large numbers of patients with chronic renal failure, including those with hyperkalemia prior to intubation, failed to identify any adverse effects. A reasonable approach is to assume that SCh is safe to use in patients with renal failure unless the ECG (either monitor tracing or 12-lead ECG) shows evidence of acute hyperkalemia (high T waves or prolongation of QRS).
3. Bradycardia
The controversy regarding bradycardia following the administration of SCh in young children is discussed in Chapter 20. In both adults and children, repeated doses of SCh may produce bradycardia, and administration of atropine may become necessary.
4. Prolonged neuromuscular blockade
Prolonged neuromuscular blockade may result from an acquired pseudocholinesterase (PCHE) deficiency, a congenital absence of PCHE, or the presence of an atypical form of PCHE, any of the three of which will delay the degradation of SCh and prolong paralysis. Acquired PCHE deficiency may be a result of liver disease, pregnancy, burns, oral contraceptives, metoclopramide, bambuterol, or esmolol. Atypical or abnormal genetic variants of PCHE can be disclosed by testing the patient's PCHE against dibucaine. A 20% reduction in normal levels will increase apnea time about 3 to 9 minutes. The most severe variant (0.04% of population) will prolong paralysis for 4 to 8 hours.
5. Malignant hyperthermia
A personal or family history of malignant hyperthermia (MH) is an absolute contraindication to the use of SCh. MH is a myopathy characterized by a genetic skeletal muscle membrane abnormality of the Ry1 ryanodine receptor. It can be triggered by halogenated anesthetics, SCh, vigorous exercise, and even emotional stress. Following the initiating event, its onset can be acute and progressive or delayed for hours. Generalized awareness of MH, earlier diagnosis, and the availability of dantrolene (Dantrium) have decreased the mortality from as high as 70% to less than 5%. Acute loss of intracellular calcium control results in a cascade of rapidly progressive events manifested primarily by increased metabolism, muscular rigidity, autonomic instability, hypoxia, hypotension, severe lactic acidosis, hyperkalemia, myoglobinemia, and disseminated intravascular coagulation. Temperature elevation is a late manifestation. The presence of more than one of these clinical signs is suggestive of MH. Masseter spasm has been claimed to be the hallmark of MH. However, SCh can promote isolated masseter spasm as an exaggerated response at the neuromuscular junction, especially in children. Therefore, masseter spasm alone is not pathognomonic of MH.
The treatment for MH consists of discontinuing the known or suspected precipitant and the immediate administration of dantrolene sodium (Dantrium). Dantrolene is essential to successful resuscitation and should be given as soon as the diagnosis is seriously entertained. Dantrolene is a hydantoin derivative that acts directly on skeletal muscle to prevent calcium release from the sarcoplasmic reticulum without affecting calcium reuptake. The initial dose is 2.5 mg/kg IV and is repeated every 5 minutes until muscle relaxation occurs or the maximum dose of 10 mg/kg is administered. Dantrolene is free of any serious side effects. In addition, measures to control body temperature, acid–base balance, and renal function must be used. All cases of MH require constant monitoring of pH, arterial blood gases, and serum potassium. Immediate and aggressive management of hyperkalemia with the administration of calcium gluconate, glucose, insulin, and sodium bicarbonate may be necessary. Interestingly, full paralysis with nondepolarizing NMBAs will prevent SCh-triggered MH. MH has never been reported related to use of SCh in the emergency department. The MH emergency hotline number is 1–800-MH-HYPER 1-800-644-9737 (U.S. and Canada) or 315-464-7079, 24 hours a day, 7 days a week. Ask for “index zero.” The e-mail address for the Malignant Hyperthermia Association of the United States (MHAUS) is mhaus@norwich.net, and the Web site is www.mhaus.org.
6. Trismus/masseter muscle spasm
SCh can transiently raise mandibular muscle tone. This is not true spasm, and laryngoscopy is usually unaffected. On occasion, SCh may cause transient trismus/masseter muscle spasm, especially in children. This is manifested as jaw muscle rigidity associated with limb muscle flaccidity. Pretreatment with defasciculating doses of nondepolarizing NMBAs will not prevent masseter spasm. If masseter spasm interferes with intubation, an intubating dose of a competitive nondepolarizing agent (e.g., rocuronium 1 mg/kg) should be administered and will relax the involved muscles. The patient may require bag-mask ventilation until relaxation is complete and intubation is possible. In such circumstances, serious consideration should be given to the diagnosis of MH (see previous discussion).
Nondepolarizing (Competitive) NMBA
A. Clinical pharmacology
The nondepolarizing NMBAs actually compete with and block the action of ACH at the postjunctional cholinergic nicotinic receptors in the neuromuscular junction. The blockade is accomplished by competitively binding to one or both of the alpha subunits in the receptor, preventing ACH access to both alpha subunits, which is required for muscle depolarization. This competitive blockade is characterized by the absence of fasciculations and the reversal of paralysis by ACHE inhibitors that prevent metabolism of ACH and allow its reaccumulation and retransmission at the motor end plate, promoting a muscle contraction. These drugs are metabolized and eliminated by Hoffman degradation, liver metabolism, and renal excretion.
The nondepolarizing NMBAs are divided into two groups: the benzylisoquinolinium compounds (e.g., d-tubocurarine, atracurium, mivacurium) and the aminosteroid compounds (e.g., vecuronium, pancuronium, rocuronium). Of the two groups, the aminosteroid compounds are the only agents used commonly for emergency RSI and postintubation paralysis.
In general, the aminosteroid compounds do not release histamine and do not cause ganglionic blockade. They vary inversely regarding their potency and time to onset (more potent agents require longer time to onset), and they exhibit differences in their vagolytic effects (i.e., moderate in pancuronium, slight in rocuronium, absent in vecuronium).
These compounds are further subdivided based on their duration of action, which is determined by their metabolism and excretion. None has the brief duration of action of SCh. Pancuronium is longer lasting than vecuronium or rocuronium. Although pancuronium is excreted primarily by the kidney, 10% to 20% is metabolized in the liver. Vecuronium is more lipophilic, hence more easily absorbed. It is eliminated primarily in the bile and is very stable cardiovascularly. Rocuronium is lipophilic and excreted in the bile. We recommend only rocuronium or vecuronium for emergency RSI (see Chapter 26).
The nondepolarizing NMBAs can be reversed by administering ACHE inhibitors such as neostigmine (Prostigmine) 0.06 to 0.08 mg/kg IV after significant (40%) spontaneous recovery has occurred. Atropine 0.02 mg/kg IV or glycopyrrolate (Robinul) 0.2 mg IV should be given to block excessive muscarinic stimulation. Reversal of blockade with neostigmine is rarely, if ever, indicated following emergency airway management. A new selective rocuronium reversal agent, called sugammadex (Org 25969), is in phase III studies at the time of this writing. Its hollow, cone-shaped molecular structure encapsulates rocuronium and promotes dissociation of the rocuronium from the ACH receptor, thereby reversing the neuromuscular block without the muscarinic side effects of the ACHE inhibitors. Spontaneous breathing is restored in approximately 1 minute, compared to more than 5 minutes with the ACHE inhibitors. In addition, sugammadex is rapidly effective, regardless of the extent of the neuromuscular block, and it is not necessary for any spontaneous recovery to occur before reversal is initiated. A rapid reversal agent such as this may be clinically useful in emergency RSI, especially if rapid reversal is desired for a failed airway. See Evidence section for details.
B. Indications and contraindications
The nondepolarizing NMBAs serve a multipurpose role in emergency airway management. They have been widely used as pretreatment agents to attenuate increases in ICP that occurs in response to succinylcholine administration, but we no longer recommend them for this purpose. Rocuronium or vecuronium can be used for emergency RSI when SCh is contraindicated (see Chapter 26), and any of the competitive agents is appropriate for maintenance of postintubation paralysis, when this is desired (see Chapter 3). There are no known contraindications to nondepolarizing NMBAs. Patients with myasthenia gravis are sensitive to NMBAs and may experience greater, or more prolonged, paralysis at any given dose.
|
Intubating dose (mg/kg) |
Time to intubation level paralysis (sec) |
Duration (min) |
|
|
Vecuronium |
0.01 to prime, then 0.15 |
75–90 |
60–75 |
|
Rocuronium |
1 |
60–75 |
40–60 |
C. Dosage and clinical use
1. For RSI when SCh is contraindicated, the drug of choice is rocuronium 1.0 mg/kg IV, which produces intubation-level paralysis consistently within 60 seconds, especially when an adequate dose of induction (sedative) agent is used. If rocuronium is not available, vecuronium can be given using a modified priming regimen. A priming dose of 0.01 mg/kg is given, followed 3 minutes later by an intubating dose of 0.15 mg/kg. Pancuronium is not recommended for emergency RSI (see Chapter 26).
2. For postintubation management when continued neuromuscular blockade is desired, vecuronium 0.1 mg/kg IV or pancuronium 0.1 mg/kg IV is appropriate, in concert with adequate sedation (see Chapter 3).
Table 19-1 lists the onset and duration of action for routine paralyzing doses of all commonly used NMBAs. The onset times and durations are for the specific doses listed, which are lower than the doses used for intubation, and vary with dose for each agent.
D. Adverse effects
Of the three aminosteroid compounds, pancuronium is the least expensive but may be less desirable because it has a tendency to produce tachycardia. Vecuronium and rocuronium are more expensive but do not cause tachycardia. All competitive NMBAs are generally less desirable for intubation than SCh because of either delayed time to paralysis, prolonged duration of action, or both. Their onset can be shortened by administering the rather larger intubating dose (as opposed to the ED95 dose (Table 19-1) used for surgical paralysis), but this further prolongs the duration of action. Availability of rapidly effective reversal agents, such as sugammadex, may greatly expand the role of competitive NMBAs in emergency RSI.
|
Table 19.1 Onset and Duration of Action of Neuromuscular Blocking Drugs |
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Evidence
1. What is the advantage to RSI with an NMBA versus intubation with deep sedation alone? RSI with a paralytic agent is the current standard of care for routine emergency intubation. NMBAs have been safely and successfully used in the emergency setting since the late 1970s to provide paralysis for intubation (1,2,3). Cicala and Westbrook (4) demonstrated an improved intubation success rate with neuromuscular blockade over deep anesthesia without neuromuscular blockade. This finding has been replicated many times, most recently by Naguib and his colleagues in two separate studies. In one study, patients received doses of SCh ranging from 0 to 2 mg/kg, after induction with propofol and fentanyl. Seventy percent of the group receiving no SCh had poor intubating conditions or failed intubation, despite full induction of general anesthesia (5). By comparison, more than 80% of the patients receiving 1.5 mg/kg or more of SCh had excellent intubating conditions. In an earlier study, the same investigators found acceptable intubating conditions in more than 95% of patients receiving SCh versus only 30% of those undergoing general anesthesia without neuromuscular blockade (6). The same results have been observed when rocuronium is used for intubation. In one study, 65% of patients who received general anesthesia without rocuronium had unacceptable intubating conditions, compared to zero patients who received rocuronium (7). In a study by Bozeman et al. (8), comparing etomidate-alone intubation to RSI using etomidate and SCh in an air medical setting, good or acceptable intubating conditions occurred in 79% of the RSI group versus 13% of the etomidate group. Success rates were 92% for RSI, 25% for etomidate alone (8). Multiple prospective studies confirm the high success rate of RSI with NMBAs when performed by experienced operators (9,10,11), with a lower rate of complications compared to sedatives alone (12,13).
2. Are any of the nondepolarizing NMBAs as good as SCh for emergency RSI? Multiple studies have compared SCh to rocuronium and vecuronium for intubation, but only a few have approximated the conditions and circumstances of an emergency RSI (9,14,15). Three review articles compared intubation success rates and intubating conditions for SCh versus rocuronium, and all three concluded that the two drugs are similar but not identical (16,17,18). SCh produces slightly better intubating conditions and has a statistically significant reduced number of intubation attempts when compared to intubating doses of rocuronium (19). A recent Cochrane review of rocuronium versus SCh for RSI concluded that, in adults, SCh produced “excellent” intubating conditions more often than rocuronium, but “adequate” (“excellent or good”) intubating conditions were produced equally with either NMBA (20). In a subgroup analysis, the intubating conditions were equivalent only if propofol was used as the sedative agent. In children, the conclusion was that SCh and rocuronium produced equivalent intubating conditions, but the studies were few and varied in design. The Cochrane review included 26 papers, of which only two used true RSI (intubation in <60 seconds), and none were done by emergency physicians in the emergency department. There are little data comparing SCh and rocuronium for emergency department RSI by emergency physicians, but one study of 520 intubations found SCh produced slightly better intubating conditions than rocuronium (16). The mean onset time of paralysis for SCh was 39 ± 13 seconds, and for rocuronium was 44 ± 15 seconds, which was neither statistically nor clinically significant. Importantly, the dose of rocuronium is critical to the success of rapid intubation. This has been elegantly studied, and the correct dose of rocuronium for RSI is 1.0 mg/kg, not 0.6 mg/kg as is commonly recommended. The duration for the 1.0 mg/kg dose is 46 minutes (18,21,22). SCh has been repeatedly shown to produce better intubating conditions at 45 to 60 seconds compared to pancuronium, vecuronium, and atracurium in well-designed prospective studies (23,24,25).
3. Can I give an NMBA intramuscularly? IV administration of NMBAs is vastly preferred to other routes, but infrequently a situation arises in which IV or intraosseous access cannot be obtained. IM administration of NMBAs has been described, with multiple agents (SCh, rocuronium, and mivacurium) studied. Invariably, the onset to paralysis is delayed. Schuh (26) performed a prospective comparison of SCh via IM and IV routes and found that the IM dose required is 3.0 to 4.0 mg/kg and time to onset is 5 to 6 minutes. Sutherland, Bevan, and Bevan (27) performed a prospective study that demonstrated obliteration of muscle twitch at 4.0 ± 0.6 minutes with an IM dose of 4 mg/kg. Each of the studies assessing IM rocuronium combines it with prior halothane use, which is not applicable to the emergency airway management situation. Reynolds et al. (28,29) prospectively demonstrated that deltoid injection of 1.0 mg/kg in infants and 1.8 mg/kg in children created adequate or good intubating conditions in 2.5 and 3.0 minutes, respectively. Kaplan et al. (30), however, found that equivalent doses gave inadequate intubating conditions at 2.5 and 3.0 minutes, and only half of the children receiving these doses had adequate intubating conditions at 3.5 and 4 minutes. The majority of patients had adequate conditions only after 7 to 8 minutes. Although IM administration of NMBAs has been described, its use in the emergent situation should be limited to the rare situation when absolutely no IV or intraosseous access can be obtained.
4. What is the correct dose of SCh for RSI? Although recent studies have demonstrated acceptable intubating conditions with doses of SCh as low as 0.3 mg/kg, these studies have not replicated the conditions extant for emergency RSI (6,31). Intubating conditions appear directly related to the dose of SCh used, with excellent intubating conditions in more than 80% of patients receiving 1.5 mg/kg or more of SCh (5). Increasing the dose of SCh from 0.5 mg/kg to 2 mg/kg increased the duration of action only from 5.2 to 7.5 minutes, reinforcing the notion that the half-life of SCh in vivo is about 1 minute, as shown by Kato et al. (5,32). Earlier studies have also shown that 1.0 mg/kg of SCh provides better intubating conditions than does placebo, 0.3 mg/kg or 0.5 mg/kg (6,33). In addition, use of 1.5 mg/kg of SCh is associated with less muscle fasciculation and myalgia than the 1.0 mg/kg dose (31). There is sufficient evidence that decreasing doses of succinylcholine produce inferior intubating conditions; hence, our firm recommendation that 1.5 mg/kg be considered the dose for emergency RSI.
5. What is the correct dose of rocuronium for RSI? Rocuronium has been studied in the context of intubation, although not precisely in the setting of RSI. Most studies induce general anesthesia, then compare escalating doses of rocuronium and, occasionally, succinylcholine. Early studies suggested that rocuronium doses of 0.6 mg/kg are inferior to doses of 0.9 to 1.2 mg/kg (15). The most valuable information, however, is provided by Kirkegaard-Nielsen et al. (7), who randomized patients to various doses of rocuronium for intubation at 60 seconds and showed that 1.0 mg/kg is the optimal dose.
6. SCh use in patients with open eye injuries. SCh has been linked to increases in intraocular pressure. Concern has been raised about its use in penetrating eye injuries (34). However, there has never been a case report of vitreous extrusion following the use of SCh in a patient with an open globe injury (35). The more pressing concern for the protection of the injured eye is the prevention of stimuli associated with laryngoscopy (36). Pretreatment with a nondepolarizing NMBA is recommended in patients with open globe injuries, but without supporting evidence.
7. Timing of hyperkalemia after significant (> 5% body surface area) burns. Schaner et al. (37) and Gronert et al. (38) found the greatest risk 18 to 66 days postburn in two studies in 1969 and 1975, and Viby-Mogensen et al. (39) found dangerous rises in serum potassium as early as 9 days postburn. SCh can be safely used within the first week of a burn, but should be withheld after the first week through clinical healing of the burn wound. We recommend a 5 day post-burn cut-off.
8. SCh use in denervation injuries (stroke, Guillain-Barré syndrome, polio, spinal cord trauma, myasthenia gravis, etc.). Denervation injuries cause a change in the number and function of junctional and extrajunctional ACH receptors at 4 to 5 days postinjury (40,41). This can result in massive serum potassium increases that can cause cardiac arrest. SCh can be safely used up to 5 days postdenervation and not again until complete muscle atrophy has occurred or the event is no longer dynamic.
9. SCh use in myopathic patients (muscular dystrophy, rhabdomyolysis, crush injuries, prolonged immobility, etc.). Myopathies cause hyperkalemia by a similar mechanism as denervation, that is, changes in ACH receptor function and density (42). Congenital myopathies are considered an absolute contraindication to SCh; its use with the myopathies can result in rhabdomyolysis and resuscitation-resistant hyperkalemic arrest (43,44). Hyperkalemia and occult, undiagnosed myopathy must be considered in children who experience cardiac arrest after SCh (45,46). When a patient with known rhabdomyolysis is encountered, SCh should be avoided.
10. SCh use in patients with pre-existing hyperkalemia. There are few studies of the risk of SCh administration in hyperkalemic patients (47,48). Unfortunately, no studies examine the outcome of large numbers of patients with pre-existing hyperkalemia. In fact, even the prevalence of pre-existing hyperkalemia in emergency department patients undergoing RSI is rarely described (16). In a meta-analysis, Thapa and Brull (49) identified only four controlled studies of patients with and without renal failure, and there were no cases in which serum potassium rose by more than 0.5 mEq/L. In two cases series, 22 of 23 patients with chronic renal failure had maximum serum potassium increases of 0.7 mEq/L. The other patient had an increase of 1.2 mEq/L, which resolved without treatment in a few minutes (49). The largest series, involving more than 40,000 patients undergoing general anesthesia, identified 38 adults and children with hyperkalemia (5.6–7.6 mEq/L) at the time they received SCh. None of the 38 had an adverse event, and the authors calculated that the maximum likelihood of an adverse event related to SCh in hyperkalemic patients is 7.9% (50). The long-held dogma to avoid SCh in any patient with renal failure is not valid, and SCh's independence of renal excretion makes it an excellent agent to consider when renal function is impaired (51,52). Some small studies have shown no instances of cardiac arrest when using SCh in the setting of renal failure (49,53), as long as the pre-SCh potassium was not elevated. We recommend that when hyperkalemia is present, or believed to be present (e.g., patient with end-stage renal disease), and the ECG shows stigmata of hyperkalemia (peaked T waves or increased QRS duration), an alternative agent, usually rocuronium, should be used for RSI. Otherwise, renal failure, or nominal hyperkalemia (i.e., without ECG changes), is not a contraindication to SCh.
11. SCh use in patients with severe (especially intraabdominal) infections. Intra-abdominal infections lasting longer than 1 week are susceptible to SCh-induced hyperkalemia (54). SCh-induced hyperkalemia risk increases with increasing severity of infection (55).
12. Treatment for SCh-induced MH. Discontinue any anesthetic use. Dantrolene, 2 mg/kg IV, is the recommended therapy, and it can be repeated every 5 minutes to a total dose of 10 mg/kg (56). In a review of 21 patients with presumed MH, 11 patients immediately treated with dantrolene survived, and 3 of 4 patients who did not receive treatment until 24 hours later died (6 patients were excluded because of insufficient evidence that MH was the cause of decompensation) (57).
13. Sugammadex evidence. The molecular shape of sugammadex allows it to encapsulate rocuronium and reverse neuromuscular blockade (58,59). Early studies demonstrate safe and effective reversal of rocuronium neuromuscular blockade in less than 2 minutes (60,61,62,63). (See also Chapter 26.)
Acknowledgment
The authors wish to recognize the significant contributions made by Robert Schneider, MD, to versions of this chapter in previous editions of this manual.
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