HYPERKALEMIA and rhabdomyolysis after the use of succinylcholine and potent inhalation anesthetic agents has been reported in patients with Duchenne (DMD) and Becker muscular dystrophy (BMD). 1,2In addition, some patients with DMD are susceptible to malignant hyperthermia (MH) based on positive results of in vitro the halothane–caffeine contracture test (IVCT). 2,3
We report an unusual case of hyperkalemic cardiac arrest and rhabdomyolysis in an 18-yr-old man with a history of muscular dystrophy, after a 6-h orthognathic procedure conducted with use of isoflurane and rocuronium. Subsequently, the results of the IVCT were positive and muscle dystrophin analysis confirmed the diagnosis of BMD.
An 18-yr-old man weighing 127 kg was admitted for elective orthognathic surgery. Family history was unremarkable. At the age of 5 yr he began to develop muscle fatigue and weakness. His creatine kinase (CK) was elevated to approximately 10,000 U/l. Muscle biopsy showed mild myopathic changes and DMD was suspected. However, his weakness did not progress and subsequent muscle biopsy at age 12 yr was unchanged, leaving the diagnosis unclear. He underwent hernia repair (agents unknown) at age 6 yr without problems. Medical history was otherwise unremarkable and the patient was not prescribed medication. Preoperative CK level was 3,053 U/l, and results of blood gas analysis were normal.
Anesthesia was induced with use of thiothal, rocuronium, and isoflurane. Standard monitoring was used, including end-tidal capnography and esophageal temperature recording. The 6-h surgery was uneventful, without hypotension, rigidity, or hyperthermia. End-tidal carbon dioxide remained in the range of 30–36 mmHg throughout the surgery. Blood transfusion was not necessary. In the recovery room, the patient woke up, was hemodynamically stable, and started moving his extremities to command. Two minutes later, while he was still intubated, heart rate decreased to the range of 40 beats/min and he became unresponsive. Atropine, 0.5mg, was administered, along with carotid massage. Cardiopulmonary resuscitation was started immediately. Initial electrocardiography showed wide complex tachycardia and standard advanced cardiac life support (ACLS) protocol was followed, with defibrillation and administration of epinephrine, lidocaine, and bretylium. Vasopressors, including dopamine, epinephrine, and norepinephrine bitartrate, were administered, and 1 mEq/kg sodium bicarbonate was injected.
Initial measurement of arterial blood gases showed metabolic acidosis and hypercapnia, despite adequate oxygenation (table 1). Hyperkalemia, hypocalcemia, hyperphosphatemia, and increasing CK levels also were found. The patient was immediately treated using glucose, insulin, and calcium and the rhythm converted to sinus tachycardia. Based on the evidence of muscle hypermetabolism and rhabdomyolysis, MH was suspected. Dantrolene sodium (720 mg) was administered and continued for 12 h to a total of 10 mg/kg. Resuscitation was performed for 2 h 20 min until the patient was hemodynamically stable; he was then transferred to the intensive care unit. Renal failure developed and the patient’s urine became dark; results of myoglobin testing were positive. Eight hours after the onset of cardiac arrest, CK was greater than 50,000 U/l, and his temperature increased to 40.9°C (table 1). No evidence of infection was seen after chest radiography or blood or urine culturing.
Severe weakness in all extremities was noted, and CK level remained increased more than 50,000 U/l for 1 week before it decreased gradually. Five days after cardiac arrest, hemodialysis was necessary until renal function recovered 2 weeks later. Muscle strength improved gradually and the patient was extubated 2 weeks after the event. He was transferred to a rehabilitation facility 1 month later and baseline neurologic status returned within 3 months. Subsequent muscle biopsy with IVCT was requested.
Diagnostic vastus lateralis muscle biopsy was performed during local anesthesia and was processed for histopathologic evaluation and frozen histochemistry using standard techniques. Mild variation in fiber size and a small number of central nuclei and split fibers were found, consistent with early myopathic changes. Western blot analysis of muscle dystrophin (Athena Diagnostics Inc., Worcester, MA) showed decreased molecular size and quantity (20–100% of normal), typical for BMD.
Malignant Hyperthermia Testing
Muscle samples were removed for MH contracture testing as previously described. 4The muscle initially was adjusted to a resting tension of 2 g and stimulated supramaximally with use of a pulse generator to confirm viability. Ten viable muscle strips were exposed to increasing concentrations of halothane (1–3%), and the maximal response within 5 min was recorded. Subsequently, additional strips were exposed to incremental doses of caffeine (0.125–16 mm). Skeletal muscle strip response to halothane was greater than 2 g (normal, < 0.7 g), and to caffeine 0.4 g (normal, < 0.3 g).
The sudden onset of hyperkalemia and rhabdomyolysis is remarkable in a patient with BMD after anesthesia using a potent inhalation agent and a nondepolarizing muscle relaxant. In previously reported similar cases the onset of hyperkalemia almost invariably followed succinylcholine administration. 2,5–7Rhabdomyolysis developed in a few DMD patients without the use of succinylcholine, 8–11cardiac arrest occurred only in a child with BMD during anesthetic induction with halothane. 12It therefore appears that at least some patients with dystrophinopathy, including BMD, are at risk of the same muscle destruction and hyperkalemia after anesthesia with potent volatile inhalation agents alone as with the addition of succinylcholine. The mortality rate is potentially high. 13
Malignant hyperthermia–like episodes of unusually late onset have been reported previously. 1,10,11Similar to the current patient, cardiac arrest in one case occurred 10 min after the patient regained consciousness from anesthesia. 11Perhaps the absence of muscle activity during anesthesia restricted the release of calcium from the sarcoplasmic reticulum. At awakening, increased muscle activity, in combination with residual anesthesia, potentiated calcium release and the cascade of metabolic effects. 1,14
During typical episodes of MH, rigidity may be absent in 25% of patients, and actual hyperthermia develops in only one third. 1,2Moreover, dantrolene may prevent or delay the onset of these symptoms. Unlike typical MH, hyperkalemia during or after anesthesia in patients with dystrophinopathies may manifest suddenly, without the typical MH increase in end-tidal carbon dioxide. 5,6However, in some patients with muscular dystrophy, muscle rigidity that is more typical of MH developed after administration of succinylcholine. 2,3In the current patient, postanesthesia onset of cardiac arrest, biochemical evidence of acute muscle hypermetabolism and rhabdomyolysis, lack of rigidity, and delayed onset of hyperthermia, led to the classification as an MH-like event.
The positive response to IVCT, as is typically seen with true MH susceptibility, is unusual in BMD. We previously documented such responses in some patients with DMD. 2,3Results of the IVCT were negative in a BMD patient after a clinical episode of rhabdomyolysis and masseter spasm, 2but they were positive in another BMD patient without an MH-like episode. 2The result of the IVCT, with a specificity of approximately 80% using the North American protocol, 15may represent a false-positive response in our patient. Elevated myoplasmic calcium levels, increased calcium release at baseline, and impaired mechanisms that resequester calcium have been found in dystrophin-deficient muscle. 16Increased intracellular calcium levels may be caused by failure of calcium adenosine triphosphatase or dystrophin-related structural membrane alterations affecting calcium channel function. 17Potent inhalation agents increase calcium release from the sarcoplasmic reticulum, 18exacerbating the baseline abnormality. These factors may lead to uncontrolled elevation of myoplasmic calcium, causing a hypermetabolic state, membrane breakdown, and rhabdomyolysis. 1,14
Another explanation for both the clinical event and the positive response to the IVCT in this case could be the coexistence of BMD and MH. This seems to be less likely because of different inheritance patterns and lack of family history. However, it cannot be excluded because genetic testing for MH was not possible in this family. More than 50% of MH in susceptible families has been linked to the RYR1 gene on chromosome 19q13, which encodes the ryanodine receptor, with more than 20 known mutations. 14,19Several other genetic loci may be involved in MH. 19Despite the progress in the molecular genetics of MH, replacement of the IVCT by genetic testing is not possible because of the enormous size of the RYR1 gene and emerging genetic heterogeneity. 19Further improvement in the diagnostic accuracy of the IVCT is necessary. The use of 4-chloro-m-cresol may be promising. 20
This case also raises the question whether patients with myopathies who experience hyperkalemic arrest in the perioperative period should be administered dantrolene as part of the resuscitation. Primary attention always should be directed to the restoration of circulatory effectiveness and correction of hyperkalemia. 1However, unexplained metabolic acidosis and hypercapnia that indicates muscle hypermetabolism, along with evidence of rhabdomyolysis, should raise the possibility of true MH or an MH-like episode. 14Dantrolene administration is appropriate in both cases. Regardless of the underlying molecular genetic mechanism, classic MH and MH-like events associated with other myopathies seem to share the common final pathway of calcium-induced muscle hypermetabolism, 1,14,19which can be reversed by dantrolene.
Routine testing for MH susceptibility is not necessary in every patient with dystrophinopathy. However, as this case shows, MH-susceptible patients have a greater risk of MH-like episodes, and potent inhalation anesthetics and succinylcholine should be avoided. If an MH-like event occurs, full evaluation should be considered with use of muscle biopsy when clinically indicated, the IVCT, and genetic testing for MH-associated mutations.