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Malignant Hyperthermia, Coexisting Disorders, and Enzymopathies: Risks and Management Options

Benca, Joan, MD; Hogan, Kirk, MD, JD

doi: 10.1213/ane.0b013e3181adca28
Pediatric Anesthesiology: Special Article
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Clinical episodes and abnormal laboratory tests compatible with a diagnosis of malignant hyperthermia have been observed in patients with a diversity of syndromes, enzymopathies, and coexisting disorders thereby raising the likelihood of causal associations and heightened perioperative risk in others carrying a shared diagnosis. In the present review, we survey available published series, case reports, and the results of contracture testing in patients identified by others to be potentially predisposed to malignant hyperthermia. For most conditions, evidence for a causal relationship with malignant hyperthermia susceptibility is weak. The review concludes with suggestions for clinical management when evidence for or against an association is uncertain.

From the Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

Accepted for publication April 9, 2009.

Address correspondence and reprint requests to Joan Benca, MD, Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, B6/319 Clinical Science Center, 600 Highland Ave., Madison, WI 53792-3272. Address e-mail to jfbenca@wisc.edu or joan.benca@gmail.com.

The diseases, enzyme defects, and clinical syndromes we will present have been reported in association with malignant hyperthermia (MH) susceptibility by clinical event or abnormal laboratory test result with an incidence more than might be expected by chance alone. Although it is rarely possible to provide a blanket recommendation to guide the anesthetic management for all individuals with a specific disorder, to stratify anesthetic risk, and inform management options, it is helpful to review reported cases of MH and contracture test results that have been published in the context of coexisting conditions and syndromes (Table 1). We reviewed published manuscripts and provide recommendations for anesthetic management when the evidence for or against an association with MH may not be fully persuasive. Caffeine halothane contracture test (CHCT) results in patients with coexisting disease, but in the absence of published descriptions of clinical MH, are especially difficult to interpret. CHCT thresholds distinguishing MH-susceptible (MHS) individuals from MH negative individuals have been determined in the absence of other recognized muscle disease, indicating that CHCT results may have reduced specificity, sensitivity, and predictive value in patients with coexisting neuromuscular diseases and enzymopathies.

Table 1

Table 1

For most uncommon syndromes and diseases, there may never be a definitive resolution to the possibility of MHS. In view of the rarity of most conditions under consideration, and even rarer episodes of MH and MH-like events in patients with these conditions, no scoring system is available that quantifies risk using an agreed-upon metric. For our purposes, we adopted the simplest possible categories ranging from no evidence for an association with MH (e.g., to our knowledge, there is no report of an increased risk for MH in association with multiple sclerosis, amyotrophic lateral sclerosis, myasthenia gravis, or many other neuromuscular disorders) to weak evidence for an association and to strong evidence for an association.

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NOONAN SYNDROME

Noonan syndrome is an inherited clinical condition with wide phenotypic variation, most often including short stature, webbed neck, low set ears, pectus excavatum, cryptorchidism, and sometimes hearing loss or bleeding diathesis. The incidence is 1:1000-1:2500, with sporadic or autosomal dominant inheritance. Fifty percent of patients have protein-tyrosine phosphatase, nonreceptor-type II (PTPN 11) mutations. There is one convincing case report of MH in a series of 60 patients with Noonan syndrome having scoliosis surgery.1 During induction, the patient exhibited muscle rigidity, a rapid increase in temperature to 40°C, and metabolic acidosis with a pH of 7.18. Contracture testing was not done, and there was no indication of dantrolene treatment. There are no other reports or genetic studies linking Noonan syndrome to MH. In another series of 27 patients with Noonan syndrome, random serum creatine kinase (CK) levels were measured.2 One patient had mildly elevated serum CK, despite multiple uneventful anesthetics with halothane and succinylcholine. Noonan syndrome may be confused with King-Denborough syndrome (see below), possibly accounting for past concerns regarding MH predisposition. Accordingly, the evidence for MHS in Noonan syndrome is weak (a single case report of a possible association).

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OSTEOGENESIS IMPERFECTA

Osteogenesis imperfecta (OI) is a group of genetic disorders causing extreme bone fragility. The incidence is 1 in 30,000 births, with mutations in Type I collagen COL1A1, COL1A2, CRTAP, and LEPRE1 genes resulting in at least eight different types of OI. The clinical syndrome is variable and may include blue sclera, hearing loss, cardiovascular involvement, bleeding diathesis, and neurologic deficits. There is one convincing case report of MH in a patient with OI who received halothane for repair of a fractured mandible. The patient developed increasing muscle rigidity, a temperature of 42°C, with arterial blood gas values of pH 6.86, Pco2 18.2 kPa (136.8 mm Hg), and base excess −13.8 mEq/L.3 The patient had a therapeutic response to 2 mg/kg dantrolene and active cooling measures. Intraoperative hyperthermia and metabolic acidosis may be observed in patients with OI but is most often responsive to standard cooling measures and is not associated with other signs and symptoms of hypermetabolism or overt MH. This association has been discussed in a number of reports.4–9 One series describes normal CHCT results in patients with perioperative hyperthermia and OI.4 In another series of five patients with OI reported by Rosenberg, one was positive on CHCT.10 There are no reports of MH in OI patients that have subsequently been confirmed with positive contracture testing. Evidence for an association between the syndrome of OI and MHS is weak (one convincing case report). However, hyperthermia in OI patients during surgery with general anesthesia is well recognized and usually resolves with standard cooling measures.

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ARTHROGRYPOSIS

Arthrogryposis, a condition characterized by multiple joint contractures of prenatal onset, is associated with a variety of diseases and syndromes. Arthrogryposis may be divided into categories of central and neuromuscular disease. Distal arthrogryposis is caused by mutations in the TPM2 gene, which encodes β-tropomyosin. The incidence of arthrogryposis is sporadic and does not clearly follow a Mendelian pattern of inheritance. Two reports of MH-like events in children with arthrogryposis have been published, both with well-documented acidosis and therapeutic responses to dantrolene. However, only one of the two had contracture testing, with negative results.11,12 Hyperthermia and hypermetabolism in children with arthrogryposis that is not associated with skeletal muscle destruction has been reported. Accordingly, the evidence for an association between arthrogryposis syndrome and MH is weak (two case reports).13 Avoiding succinylcholine in patients with arthrogryposis seems warranted in light of the two reported cases of MH-like events and the risk of hyperkalemia in an immobile patient.

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KING-DENBOROUGH SYNDROME

King-Denborough syndrome is characterized by the combination of Noonan-like dysmorphic features (see above), congenital myopathy with proximal weakness, and susceptibility to MH.14 Inheritance of King-Denborough syndrome is unclear, and most cases are sporadic. Approximately one half of patients with King-Denborough syndrome demonstrate baseline elevated serum CK levels.15 A recent report of King-Denborough syndrome and MHS describes a novel mutation in the gene encoding the skeletal muscle calcium release channel ryanodine receptor (RYR1), the locus of MHS in approximately one half of all patients lacking coexisting diseases.16 Patients with King-Denborough syndrome should be considered MHS and should not receive triggering drugs.

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ENZYMOPATHIES OF SKELETAL MUSCLE

Carnitine Palmitoyltransferase II Deficiency

Mutations in the gene encoding carnitine palmitoyltransferase II (CPT II) give rise to abnormal long-chain fatty acid oxidation most often inherited as an autosomal recessive trait, with men more likely to be affected than women (Fig. 1). Rare neonatal forms are typically lethal. The adolescent form is usually milder and manifests episodic myalgia, muscle stiffness, and rhabdomyolysis induced by exercise, stress, and infectious disease or fasting.17 There is one case report of a malignant MH-like syndrome in a patient with heterozygous for a CPT II amino acid substitution.18 After receiving succinylcholine and halothane, the patient developed fever (39°C), acidosis (base excess −11.3 mEq/L), and elevated CK (10,000 U/L), with full recovery after dantrolene and cooling.18a There are two case reports of rhabdomyolysis with anesthesia.19,20 No CHCT data are available from patients with well-described CPT II deficiency. Palmitoylcarnitine, the substrate of CPT II, accumulates with decreased enzyme activity, passively diffuses from the mitochondrion to the cytoplasm, and is able to specifically activate (i.e., open) the calcium release channel (RYR1) of the sarcoplasmic reticulum of skeletal muscle.21 Accordingly, the association between CPT II deficiency and MH is plausible but unproven by virtue of the rarity of the two conditions. The evidence for an association between CPT II deficiency and MH susceptibility is weak (a single case report of a possible association). Because patients with CPT II deficiency may exhibit rhabdomyolysis, it appears prudent to avoid drugs that may facilitate muscle membrane breakdown (e.g., succinylcholine and inhaled anesthetics), whether it is classified as MH or muscle membrane fragility.

Figure 1.

Figure 1.

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Myophosphorylase Deficiency (McArdle Disease)

Myophosphorylase deficiency, also known as glycogen storage disease Type V, is caused by reduced activity of the enzyme needed to convert glycogen to lactate in skeletal muscle, which results in glycogen accumulation and myopathy (Fig. 2). The disease is rare, with an incidence between 1/100,000 and 1/600,000, and usually presents between 10 and 30-yr-of-age with exercise-induced weakness, cramping, myoglobinuria, hyperCKemia, hyperkalemia, and acute renal failure. There are no case reports of MH with myophosphorylase deficiency. However, positive CHCT results in eight patients with myophospohorylase deficiency have been published from three sources.22–24 The evidence for an association between myophosphorylase deficiency and MHS is weak (no case reports, eight positive contracture test reports). Interpretation of CHCT results in the setting of a coexisting myopathy (e.g., myophosphorylase deficiency) and in the absence of one or more reports describing a clinical trigger is unresolved.

Figure 2.

Figure 2.

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Myoadenylate Deaminase Deficiency

Experts disagree whether myoadenylate deficiency exists as a distinct pathophysiologic entity.25 Advocates believe that myoadenylate deaminase deficiency presents in adulthood with exercise-induced fatigue, myalgia, and muscle cramps. There is profound deficiency of the enzyme in 2% of the population who may be asymptomatic. There are no reports of MH in patients with isolated myoadenylate deaminase deficiency, but positive CHCT results in 10 patients with reduced or absent myoadenylate deaminase activity have been described.26,27 Accordingly, the evidence for an association between myoadenylate deaminase deficiency and MHS is weak (no case reports, 10 positive contracture test results).

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Brody Disease

Brody disease is an extremely rare (1/10,000,000 births) muscle disease resulting in progressive exercise-induced impairment of muscle relaxation secondary in most cases to reduced influx of calcium into the sarcoplasmic reticulum via Ca2+-ATPase (SERCA1) during exertion. The clinical symptoms include stiffening, cramps, myalgias, rhabdomyolysis, and cold intolerance. Inheritance may be autosomal dominant or recessive with mutations in ATP2A1, the gene encoding SERCA1, and at least two other loci apparently causal for Brody disease. Although there are no reports of MH in patients with Brody disease, there are three reports of positive CHCT tests in patients with Brody disease.28,29 Accordingly, the evidence for an association between Brody disease and MHS is weak (no case reports, three positive contracture tests). Inhibition of SERCA1 activity by cyclopiazonic acid enhances halothane and caffeine-induced contractures in MHS and MH-equivocal muscle bundles from patients without Brody disease.30 Because the mechanism of Brody disease is abnormal intracellular calcium regulation, which is also present in MH, it is reasonable to treat patients with Brody disease as MHS in the absence of evidence to the contrary. The lack of case reports may be a reflection of the rarity of the disorder rather than lack of susceptibility to MH.

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Asymptomatic HyperCKemia

Management of patients with elevated serum CK in the absence of a diagnosed clinical syndrome or enzyme defect is problematic. In some patients, the CK elevation may fluctuate, and in others, it may be a normal variant. Episodes of MH and MH-like events in patients with isolated elevation in CK have not been reported. Lingaraju and Rosenberg31 report positive CHCT results in three of seven individuals with persistently elevated CK levels. In a larger series, positive contracture test results were documented in 28 of 49 patients with elevated baseline CK.32 Another series of 37 patients with persistent elevated CK levels disclosed one patient MHS by CHCT and one patient MH equivocal by CHCT.33 There is no evidence that brief, i.e., <15 min, exposure to modern inhalation anesthetics is harmful in these patients or in patients with enzyme defects, nor is proof available that propofol is safe. Accordingly, the evidence for an association between asymptomatic hyperCKemia and MHS is weak (no case reports, 29 positive in vitro contracture test).

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APPROACH TO PATIENTS WITH ASSOCIATED CONDITIONS AND ENZYMOPATHIES WHEN EVIDENCE FOR AN ASSOCIATION WITH MHS IS WEAK

Whenever a patient with an associated condition or enzyme deficiency requires an anesthetic, it is essential to follow an organized approach. Reviewing the most recent information by accessing the Online Mendelian Inheritance in Man web site, contacting the Malignant Hyperthermia Association of the United States (online or by telephone), and reviewing the literature using a medical search engine are excellent and not mutually exclusive first steps. Consultation with genetic, neurologic, and metabolic specialists to define the patient’s disease and severity as clearly as possible, and confirmation that their reports are documented in the patient’s chart before the surgery, is always worthwhile. Familiarity with information available to parents and caregivers helps to allay their concerns about the anesthetic. Management plans and options should be discussed with the parents, and the plan clearly documented, including the balance of risks, safety precautions, and alternate approaches. It is wise to inform the surgical and the postoperative care teams of the content of these consultations and discussions and to document these communications as well.

There is no case report of MH or an MH-like event in patients with the disorders considered above receiving nontrigger anesthetics. There is also no case report of MH or an MH-like event in patients with rare enzyme deficiencies and weak association with MHS receiving brief exposure (i.e., the time it takes for inhaled induction of anesthesia and placement of an IV catheter) to the newer potent inhaled anesthetics, sevoflurane and desflurane, although these drugs are certainly MH triggers in patients who are MHS from other causes, i.e., mutations in the skeletal muscle calcium release channel RYR1 genes. Therefore, with due care in consultation, communication, monitoring, and preparation, in patients with the rare enzyme defects for which the association with MH is weak, it may be an option to perform an inhaled induction to secure IV access and then to change over to a nontriggering anesthetic technique for anesthetic maintenance. If the choice is to maintain a general anesthetic with triggering drugs in these patients, it is imperative to discuss the rationale and plan with the patient’s family and other caregivers (surgeon, pediatrician, and subspecialty consultants), use monitoring commensurate with the magnitude and duration of the procedure, and be prepared to diagnose and treat at the first sign of MH. When faced with an emergency procedure in a patient with a rare syndrome, time taken to document the assessment of the risk of MH, anesthetic plan and a back-up plan, and the discussion with family and surgeon is well spent.

Because of the rarity of the disorders and their underlying genetic heterogeneity, absolute certainty with regard to MHS may never be established. Those encountering patients with myopathies and enzymopathies who display MH or MH-like reactions to anesthesia are encouraged to document the case in the medical literature or reports to the North American MH Registry (www.mhreg.org). As noted above, CHCT thresholds distinguishing MHS from MH-negative have been determined in the absence of other recognized muscle disease, suggesting that contracture test results may have decreased specificity, sensitivity, and predictive value in patients with other coexisting neuromuscular diseases and enzymopathies. It must be remembered that MH is itself a syndrome, with multiple underlying molecular causes, just as many of the diseases considered above are syndromes, with a variety of underlying genetic defects, many of which are unknown. Patient safety must be the overriding concern when dealing with patients with rare diseases, but without the expectation that there is a guaranteed safe anesthetic drug or technique available for all circumstances.

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