The important adverse drug reactions associated with succinylcholine include anaphylaxis, prolonged drug effect, hyperkalemia, acute rhabdomyolysis in patients with muscular dystrophy, MH in susceptible patients, muscle spasms or trismus in patients with myotonia congenita, and cardiac dysrhythmias.
The effects of succinylcholine may last for several hours if metabolism is slowed because of decreased PChE concentration, abnormal PChE activity (genetic variant or drug inhibition), or a phase II block.17 Acquired PChE deficiency may be caused by hepatic disease, malnutrition, plasmapheresis, or pregnancy.17 Inactivation of PChE may be caused by fluoride poisoning, organic phosphorus compounds, and carbamates. However, even with only 20% to 30% of normal PChE activity, the clinical duration of succinylcholine is less than doubled.31
Many genetic variants of PChE are known. The most common atypical PChE (atypical type, homozygous; incidence 1:3000) can be assayed by its resistance to inhibition by the local anesthetic dibucaine.85 A history of uneventful exposure to succinylcholine excludes the possibility of atypical PChE except in the case of hepatic transplantation. Dibucaine inhibits the ability of normal PChE to hydrolyze benzoylcholine by more than 70% (ie, dibucaine number >70), heterozygous atypical PChE by 40% to 60%, and homozygous atypical PChE by 30% or less. Fresh-frozen plasma or PChE concentrates may be infused to hasten recovery in the case of a genetic enzyme defect or an acquired PChE deficiency. However, to avoid the risks of transfusion, it is best to simply keep the patient sedated, intubated, and ventilated until the drug is metabolized. In this setting, spontaneous reversal usually occurs within 3 to 4 hours, although in rare cases, full recovery requires up to 12 hours.17 When the duration of succinylcholine is very prolonged, blood samples should be drawn for measurement of PChE concentration and activity.
Prolonged nondepolarizing block may occur when unusually large IV doses of succinylcholine (3–5 mg/kg) are given over minutes.62 This is called phase II block, and it can be partially reversed by neostigmine.
Succinylcholine 1 mg/kg IV typically causes serum K+ concentration to increase within minutes by approximately 0.5 mEq/L both in normal individuals and in persons with kidney failure. The acute hyperkalemic response to succinylcholine is greatly exaggerated with coexisting myopathy or proliferation of extrajunctional muscle ACh receptors. However, the mortality is highest (approaching 30%) when rhabdomyolysis is present.39 Severe, precipitous, potentially life-threatening hyperkalemia also occurs after succinylcholine administration in several conditions associated with proliferation of ACh receptors. These conditions include denervation (head or spinal cord injury, stroke, neuropathy, prolonged use of NDNMBs), muscle pathology (direct trauma, crush or compartment syndrome, muscular dystrophy), critical illness (hemorrhagic shock, neuropathy, myopathy, prolonged immobility), thermal burn or cold injury, and sepsis lasting several days (eg, intraabdominal infections). After a neurologic injury, susceptibility to hyperkalemia begins within 4 to 7 days and may persist indefinitely. In patients who have been in the ICU for more than one week, a prudent course is to avoid succinylcholine altogether because of the risk of hyperkalemic cardiac arrest, which is associated with a mortality rate of at least 19%.6,8,39 Severe hyperkalemia is modified, but not prevented, by a dose of an NDNMB sufficient to prevent succinylcholine-induced muscle fasciculations.
Severe or even fatal hyperkalemia is reported in a few patients who received succinylcholine immediately after exsanguinating hemorrhage or massive trauma. The mechanism for this condition differs from that after neurologic injury because of inadequate time for proliferation of extrajunctional ACh receptors. Succinic acid, a tricarboxylic acid cycle intermediate (which is also a metabolite of succinylcholine), facilitates activation of voltage-gated sodium channels in a dose-dependent fashion, increasing skeletal muscle excitability.41 In hemorrhagic shock, accumulation of succinic acid as a result of cell breakdown and anaerobic metabolism possibly augments the potassium-releasing effect of succinylcholine.
Severe hyperkalemia rarely occurs in the absence of a clinical history that readily discloses an obvious risk factor, with one important exception. Acute or delayed onset of rhabdomyolysis, hyperkalemia, ventricular dysrhythmias, cardiac arrest, and death are reported in apparently healthy children who subsequently were found to have an undiagnosed myopathy.58 Since March 1995, a black box warning on the package insert has stated that succinylcholine should be avoided in elective surgery in children, particularly in children younger than 8 years of age, because of the small risk of a previously undiagnosed skeletal myopathy, especially Duchenne muscular dystrophy. Sudden cardiac arrest occurring immediately after succinylcholine administration should always be assumed to be caused by hyperkalemia. If fever, muscle rigidity, hyperlactatemia, or metabolic and respiratory acidosis also is present, the presumptive diagnosis of MH should prompt immediate therapy with dantrolene.
MH is a syndrome characterized by extreme skeletal muscle hypermetabolism. It is most often initiated after exposure to an anesthetic that triggers a cycle of abnormal calcium release from the skeletal muscle sarcoplasmic reticulum, and it can have a variable presentation.90 Although MH is strongly associated with certain myopathies, especially King-Denborough syndrome, central core disease, and multiminicore disease, the disorder is also associated with certain enzyme deficiencies (McArdle disease, carnitine palmitoyltransferase type II, and myoadenylate deaminase deficiency), myopathies (eg, Duchenne muscular dystrophy, hyperCKemia), and some myotonias. MH typically affects individuals who are otherwise healthy and most have had prior uneventful anesthesia.56 It is inherited as an autosomal dominant trait with variable penetrance.69 Triggering xenobiotics that can precipitate an attack of MH include succinylcholine and volatile inhalational anesthetics (the prototypical xenobiotic is halothane). In individuals who are considered MH susceptible (MHS), xenobiotics that can be administered safely include NDNMBs, nitrous oxide, propofol, ketamine, etomidate, benzodiazepines, barbiturates, opioids, and local anesthetics.
In human MH, there is a causal association with several unique defects involving a skeletal muscle receptor/regulatory protein, especially defects involving the calcium-activated calcium release channel found in skeletal muscle: the type 1 ryanodine receptor (or RYR-1, chromosome 19q13.1). Mutations of the RYR-1 receptor are detected in 50% to 70% of patients with MH, and more than 200 different mutations are described10,44 (Fig. 69–1). The structurally distinct type 2 ryanodine receptor (RYR-2) is the primary type expressed in cardiac muscle, and this could explain why the myocardium is relatively spared in the early phase of MH (with the exception of an acute hyperdynamic response).89 Of practical importance, the existence of multiple mutations across multiple alleles means that genetic testing is not likely to prove useful in detecting all MHS individuals or in excluding the risk of MH.
Although the prevalence of a genetic disorder associated with MH is one in 3000 to one in 8500, the observed incidence of fulminant MH in patients exposed to general anesthesia when triggering anesthetic agents are used is one in 62,000 to one in 84,000.83,90 Each year in the United States, there are an estimated 700 cases of MH.55 In the MHS population, after exposure to anesthesia with known triggers, clinical manifestations develop less than half the time. For this reason, a previous uneventful anesthetic exposure does not preclude development of MH on a subsequent exposure.3 In the operating room, MH most often presents abruptly soon after initial exposure to a triggering anesthetic, but the onset of MH may be delayed several hours during the anesthesia,76 or it may occur as long as 12 hours after surgery. In addition, recrudescence of MH can occur within 24 to 36 hours after an initial episode in up to 25% of patients.
The immediate systemic manifestations of MH result from extreme skeletal muscle hypermetabolism. The uncontrolled release of calcium from the terminal cisternae of the sarcoplasmic reticulum causes skeletal muscle contraction. Although generalized muscular rigidity is a specific sign of MH, it is only observed in 40%; masseter spasm is a sensitive finding observed in 27% of MH patients.56 Futile calcium cycling by sarcoplasmic Ca2+-ATPase rapidly depletes intracellular ATP and leads to anaerobic metabolism. Clinically, MH presents as skeletal muscle hypermetabolism with an increase in cardiac output and sinus tachycardia. Increased CO2 production causes hypercapnia. Increased O2 consumption can cause mixed venous O2 desaturation (below the normal value of 75%), arterial hypoxemia, anaerobic metabolism, metabolic acidosis, and elevation of lactate concentration, cyanosis, and skin mottling. Excess heat production leads to a rapid increase in core temperature with hyperthermia.42 Other clinical findings include tachycardia, cardiac dysrhythmias, hyperkalemia, rhabdomyolysis, and disseminated intravascular coagulopathy.
The earliest signs of MH include an early and rapid increase in CO2 production, causing an increase in arterial, venous, and end-tidal CO2. This is followed by or associated with tachycardia, tachypnea, hypertension or labile blood pressure, and skeletal and jaw muscle rigidity. Despite the name of the syndrome, hyperthermia is not a universal finding in MH, and moreover, it may be a late sign.101 Acute potassium release from skeletal muscle cells may produce life-threatening hyperkalemia. Subsequent rhabdomyolysis may exacerbate the elevation of potassium by causing acute kidney injury. In late-stage MH, cardiac decompensation results from hyperkalemia, heart failure, vascular collapse, or myocardial ischemia (especially with coexisting coronary artery disease). A standardized MH clinical grading scale based on patient history, clinical observations, and laboratory studies is commonly used to rank the qualitative likelihood (ranging from “almost never” to “almost certain”) that an adverse event represents a true episode of MH.57 Points are assigned based on the clinical likelihood that observations are inappropriate for a given patient (eg, respiratory acidosis occurring abruptly despite sustained mechanical ventilation).
The differential diagnosis of MH includes antipsychotic malignant syndrome, propofol infusion syndrome, serotonin syndrome, thyroid storm, pheochromocytoma, baclofen withdrawal, malignant syndrome during withdrawal of dopaminergic drugs to treat Parkinson disease, tetanus, meningitis, poisoning by salicylates, amphetamines, cocaine, or antimuscarinics, unintentional intraoperative hyperthermia, heat stroke, and transfusion reactions. Of note, early septic shock is also associated with hypermetabolism, increased cardiac output, and fever, however, in contrast to MH, early septic shock is associated with an elevated mixed venous O2 saturation (typically >75%).
Rarely, MH is triggered by severe exercise in a hot climate, IV potassium (which depolarizes the muscle membrane), antipsychotics, or infection.20,47 There is increased awareness of a possible link between MH and exertional heat illness or exertional rhabdomyolysis (ER; eg, a patient with ER who at a later time developed MH).12,13 Most patients with heat-related illness do not have MH, even if, on occasion, some patients have demonstrated a favorable response to dantrolene. Furthermore, a presumptive diagnosis of heat related illness does not necessarily exclude the diagnosis of MH and one must maintain clinical suspicion for possible MH, especially since environmental factors can be a sole precipitating factor in the absence of anesthetics.44
One theory of the pathogenesis of MH suggests that MH-triggering xenobiotics interact with an abnormal RYR-1 channel, causing it to stay in a prolonged open state and leading to rapid efflux of calcium from the skeletal muscle sarcoplasmic reticulum into the myoplasm. Succinylcholine prolongs muscle depolarization, leading to elevated myoplasmic calcium concentration. This action initiates accelerated calcium-activated calcium release from the myoplasmic reticulum.39 However, not all cases of MH can be explained by an RYR-1 mutation.32 For example, MH is also associated with defects in the CACNA1S protein that encodes a subunit of the skeletal muscle L-type calcium channel (known as the dihydropyridine receptor) and possibly with certain disorders of sodium channels (observed in the myotonic disorders).32,75
The antidote for MH is dantrolene, and the key aspects of MH therapy are rapid initial diagnosis, discontinuation of triggering anesthetics, and immediate therapy with dantrolene (within minutes). By partially blocking calcium release from skeletal muscle sarcoplasmic reticulum, dantrolene rapidly reverses the signs and symptoms of hypermetabolism (Antidotes in Depth: A21). The precise mechanism of dantrolene activity is not known, but it modulates several calcium pathways.44 Before the introduction of dantrolene, the mortality rate of MH was 64%.55 When patients with an acute phase MH are treated immediately with dantrolene, removal of triggering agents, and supportive measures (volume resuscitation, active cooling, control of hyperkalemia), the mortality rate is less than 5%.55 Factors associated with an increase in mortality are a muscular body habitus, development of disseminated intravascular coagulation, and a longer duration of anesthesia before the peak in end-tidal carbon dioxide.55 Even if administration is delayed for hours or days, dantrolene may still improve survival after an acute phase of MH. Patients with significant dysrhythmias can be treated with standard antidysrhythmics; however, calcium channel blockers must not be given with dantrolene because they may precipitate hyperkalemia and severe hypotension91 (Table 69–3).
TABLE 69–3.Suggested Therapy for Malignant Hyperthermia (MH) ||Download (.pdf) TABLE 69–3. Suggested Therapy for Malignant Hyperthermia (MH)
Acute Phase Treatment of MH
Call for help. Immediately summon experienced help when MH is suspected.
Discontinue triggers volatile inhalational anesthetics and succinylcholine.
Hyperventilate with 100% O2 with flow ≥10 L/min and monitor end-tidal CO2.
Halt procedure as soon as possible, and continue sedation and analgesia with nontriggering agents (eg, opioids and benzodiazepines).
Administer dantrolene sodium, initial IV bolus of 2–3 mg/kg followed by additional boluses (every 15 minutes), until signs of MH are controlled (tachycardia, rigidity, increased end-tidal CO2, hyperthermia). Typically, a total dose of 10 mg/kg IV controls symptoms, but occasionally 30 mg/kg may be required.
Monitor core temperature closely (tympanic membrane, nasopharynx, esophagus, rectal, or pulmonary artery) and actively cool the patient with core temperature >39°C, (immersion in ice-water slurry, peritoneal or gastric lavage can also be useful, surface cool and/or surface cooling).
Hyperkalemia is common and should be treated aggressively with hyperventilation, IV calcium gluconate or chloride, sodium bicarbonate, IV dextrose, and insulin. Hypokalemia should be treated with caution because of the potential for rhabdomyolysis induced hyperkalemia.
Sodium bicarbonate. Consider 1–2 mEq/kg if blood gas values not yet obtained, or if clinically indicated.
Monitor continuously: electrocardiogram, pulse oximetry, end-tidal CO2, core temperature, central venous pressure, urine output; and serially measure: arterial and mixed venous blood gases, metabolic profile (especially potassium), calcium, CBC, coagulation indices, and creatine kinase.
Dysrhythmias usually respond to dantrolene and correction of acidosis and hyperkalemia. If dysrhythmias persist or are life threatening, standard antidysrhythmics may be used including amiodarone, magnesium, and procainamide
Ensure adequate urine output by hydration and/or administration of mannitol or furosemide. Insert a urinary bladder catheter and consider central venous or pulmonary artery catheterization.
For emergency consultation, refer to the Malignant Hyperthermia Association of the United States (MHAUS) at http://www.mhaus.org/. Call the MH Emergency Hotline:
Inside United States or Canada, call 800-MH-HYPER (800-644-9737)
Outside the United States and Canada, call 001 315-464-7079
Postacute Phase Treatment of MH
Observe the patient in an ICU setting for at least 24 hours because recrudescence of MH occurs in 25% of cases, particularly after a fulminant case resistant to treatment. Observe for pulmonary edema, renal failure, and compartment syndrome.
Administer dantrolene 1 mg/kg IV q4–6h or 0.25 mg/kg/h by infusion for at least 24 hours after the episode.
Serially monitor arterial blood gases, metabolic profile, CBC, creatine kinase, calcium, phosphorus, coagulation indices, urine and serum myoglobin, and core body temperature until they return to normal values.
Counsel the patient and family regarding MH and further precautions.
For nonemergency patient referrals, contact MHAUS at 800-644-9737, 1 North Main Street, PO Box 1069, Sherburne, NY 13460.
Report patients who have had an acute MH episode to the North American MH Registry of MHAUS at 888-274-7899.
Alert family members to the possible dangers of MH and anesthesia.
Recommend an MH medical ID tag or bracelet for the patient, which should be worn at all times.
Persons who have experienced a possible episode of MH or have a positive family history should be referred to the Malignant Hyperthermia Registry and may be considered for muscle biopsy and muscle testing. The fresh tissue specimen is placed in a tissue bath perfused with Krebs solution, and halothane or caffeine is added. According to the North America Malignant Hyperthermia Group, an MH-susceptible individual is one who demonstrates a positive muscle contraction in response to either halothane or caffeine.
Masseter muscle rigidity (MMR) was observed in 0.3% to 1.0% of children when general anesthesia was induced with succinylcholine and halothane (a technique now obsolete), and, at present, it is much less frequently encountered. MMR is clinically significant because it may complicate airway management and herald the onset of MH.82
When administered to persons genetically predisposed to myotonia, succinylcholine may precipitate tonic muscular contractions, ranging from trismus (which may prevent orotracheal intubation) to severe generalized myoclonus and chest wall rigidity28 (which may prevent ventilation). Because the myotonic contractions are independent of neural activity, they cannot be aborted by an NDNMB. Usually the contractions are self-limited, but occasionally they can be life-threatening if an airway cannot be established and hypoxemia ensues.