Malignant Hyperthermia Testing in Patients with Persistently Increased Serum Creatine Kinase Levels

Abstract

We describe 49 neurologically asymptomatic patients with persistently increased serum creatine kinase (CK) levels (idiopathic hyperCKemia or IHCK) who were referred to our institution for diagnostic muscle biopsy, including malignant hyperthermia (MH) susceptibility testing between 1979 and 1993.Muscle biopsy samples of the vastus lateralis were obtained for histologic analysis and MH contracture testing with halothane and caffeine. From 1979 to November 1987, patients were tested for MH in accordance with a standardized institutional protocol. After November 1987, contracture testing was performed according to the recently adopted North American MH Group protocol. In both protocols, a patient was considered to be MH susceptible (MHS) if one or more muscle strip demonstrated an abnormal contracture response after exposure to 3% halothane, 2% halothane, or caffeine alone. Twenty-four of the 49 IHCK patients (49%) had positive contracture tests. No significant correlation was found between the magnitude of CK increase and the incidence of MHS or histologic abnormalities. Unexplained persistently increased CK levels in an otherwise healthy patient should alert the anesthesiologist to the possibility of MHS and/or myopathy.

(Anesth Analg 1997;84:1038-41)

Malignant hyperthermia (MH) is an autosomally dominant inherited skeletal muscle disorder. Its basic pathophysiologic mechanism involves a defective calcium release channel in the sarcoplasmic reticulum. Upon exposure to "triggering" anesthetics, the defective channel remains open, leading to excessive release of calcium, which results in a catabolic state and rhabdomyolysis. A clinical MH crisis is characterized by hypermetabolism with variable signs and symptoms, including generalized or localized muscle rigidity, hypercarbia, fever, acidosis, myoglobinuria, tachycardia, increased serum levels of creatine kinase (CK), hyperkalemia, arrhythmias, and, potentially, cardiac arrest and death if untreated. Although MH is believed to represent a disorder of skeletal muscle, patients rarely have clinical symptoms of muscle abnormalities or histologic evidence of muscle disease.

Increased serum levels of CK represent increased membrane permeability of CK-containing cells (primarily skeletal muscle). CK elevation can be related to many unrelated conditions, including muscular trauma, ischemia, inflammation, drugs, genetic diseases, and idiopathic causes. The significance of chronically increased serum CK levels in the absence of demonstrated neuromuscular disease or muscle damage is unclear. While it was once suggested that increased CK levels are a marker for susceptibility to MH and could be used as an MH screening test, further study and experience have not supported this ^[1]. We describe 49 patients with persistent idiopathic hyperCKemia (IHCK) who were referred to our institution for diagnostic muscle biopsy, which included contracture testing for MH susceptibility.

Methods

Forty-nine patients with persistently increased serum CK levels who were referred to the Mayo Clinic for evaluation of a neuromuscular disorder underwent diagnostic muscle biopsy in the 14 yr between 1979 and 1993. IHCK was defined as at least three serum CK levels more than twice normal, which remained increased over at least 3 mo in patients with no evidence of neuromuscular disease. Although neurologically asymptomatic, patients had had their CK level checked for a variety of reasons. The most common reason for patients to have their CK level measured was to further evaluate a complaint of chronic muscle soreness and/or cramps. Many patients had an increased CK level discovered after a routine blood chemistry panel was performed for an employment physical exam or preoperative evaluation. Several patients had their CK level checked because they had a family history of increased CK levels. Muscle specimens from the vastus lateralis (and one gastrocnemius) were obtained for histologic analysis and contracture testing with halothane and caffeine for MH susceptibility (MHS). From 1979 through 1987, patients were tested in accordance with a standardized institutional protocol ^[2]. After 1987, contracture testing was performed according to the North American MH Group protocol ^[3]. In both protocols, a patient was considered to be MHS if one or more of their muscle strips demonstrated an abnormal contracture response after exposure to 3% halothane, 2% halothane, or caffeine alone. Prior to 1987, based on control patients tested in our laboratory, a 7% rise in baseline tension at 2 mM caffeine or less or a 0.5-g increase with 2% or 3% halothane was considered a positive response. Current cutoffs to establish a positive response for the North American MH Group protocol are a contracture greater than 0.5-0.7 g upon exposure to 3% halothane or a contracture greater than 0.2-0.3 g at a caffeine concentration of 2 mM or less. Histology and histochemistry were interpreted by the same consultant.

Patients' charts were reviewed for information pertaining to anesthetic history (both personal and family), history of muscle pain or cramps, history of rhabdomyolysis or heat stroke, baseline neurologic evaluations, prebiopsy medications, and family history of elevated CK or neurologic problems.

Statistical analysis was performed using Fisher's exact test. An unpaired t-test was used to compare the incidence of positive contractures between muscle bundles exposed to 2% and 3% halothane in MHS patients using 500 mg as the upper limit of normal contracture strength. Data are expressed as mean +/- SD. A P value less than 0.05 was considered significant.

Results

The patients ranged in age from 3 to 59 yr (mean 33 +/- 13.6 yr). Thirty-six patients were male (73%) and 13 were female (27%). Demographic data and neurologic history and evaluation for patients in the MHS and MH negative (MHN) groups are presented in Table 1.

Table 1: MHS versus MHN: Patient Findings

Three MHS patients in our study presented with either heat stroke or myoglobinuria. In the two patients who presented with heat stroke, one had a contracture test that was positive with 2% and 3% halothane exposure only, and the other had positive contractures upon exposure to both 3% halothane and caffeine. The patient who presented with myoglobinuria had a normal contracture response to 3% halothane and an abnormal response to caffeine. His mother subsequently tested strongly positive to both 3% halothane and caffeine.

Twenty-four of the 49 IHCK patients (49%) had positive contracture tests. In these MHS patients, a total of 99 muscle bundles were tested with either 2% or 3% halothane. Of these 99 bundles, 44 (44%) had positive contractures. Of the 97 total muscle bundles exposed to caffeine, 38 (39%) had positive responses. The mean increased tension in positive bundles was 1.3 +/- 0.7 g for 2% halothane and 1.5 +/- 0.9 g for 3% halothane. The range of contracture responses for 2% and 3% halothane in both the MHS and MHN groups is presented in Figure 1 and Figure 2. Using 500 mg as the cutoff for normal contracture responses in the MHS patients, the number of positive muscle bundles was significantly greater when exposed to 3% halothane compared with 2% halothane.

Figure 1: Comparison of muscle bundles exposed to 2% and 3% halothane at various contracture strengths in malignant hyperthermia susceptible patients. MHS = Malignant hyperthermia susceptible. *P < 0.05 versus 3% halothane, dagger P = 0.05 versus 3% halothane.

Figure 2: Comparison of muscle bundles exposed to 2% and 3% halothane at various contracture strengths in patients with negative contracture tests. MHN = Malignant hyperthermia negative.

Discussion

Persistently increased CK in the absence of neuromuscular signs and symptoms is a nonspecific finding. There are numerous causes of increased CK. Most of these causes, however, do not result in a persistent increase in CK. It is therefore essential to test the patient with increased CK more than once (e.g., three measurements at monthly intervals). It is also important to question the patient about strenuous exercise routines and muscle trauma.

The association of IHCK with MHS in the absence of a clinical or family history of anesthetic problems remains unresolved. Britt et al. ^[4] found that 80% of MH survivors had increased CK levels and that an increase in CK was of diagnostic value in 45% of families with a history of MH. McPherson and Taylor ^[5] studied individuals who, on the basis of family history alone, had a 50% probability of MHS. They reported that an increased CK level increased the risk to 94%, while a normal CK level decreased it to 17%. However, in a review of CK levels in patients undergoing MH testing, Ellis et al. ^[6] concluded that CK levels could not be used as a screening test for MHS unless the patient belonged to a family in which high CK levels correlated with MHS. This conclusion was supported by Paasuke and Brownell ^[7], who found normal serum CK levels in 34 patients whose in vitro muscle contracture testing showed susceptibility to MH. When used as an MH screening test for 1800 healthy ambulatory surgery patients, Amaranath et al. ^[8] reported that of the two patients who were MHS (one by history, one by clinical episode), only one had an increased CK level. In light of these studies, CK is of no value as a screening test for MH in patients with no clinical or family history of MH, and, even in patients who are at risk of MHS, CK is poorly sensitive and nonspecific.

None of the patients in our study had a history of anesthetic complications, although 57% had had uneventful general anesthesia in the past. In the few patients who had a history of anesthetic difficulties or elevated CK in family members, there was no significant difference between the MHS and MHN groups. Furthermore, the degree of CK increase was not found to correlate with the incidence of MHS.

Both exertional heat stroke ^[9] and rhabdomyolysis ^[10,11] have been associated with MH. Two teenage males included in our study presented with heat stroke. The first patient presented with headache, nausea, and vomiting after playing tennis on a hot day. His CK level at that time was noted to be approximately 25,000 U/L. Two years later, during a routine blood screen after a tennis match, his CK level was 21,760 U/L. A recheck showed a CK level of 3,000 U/L. The patient denied a history of myoglobinuria or muscle cramping and had no anesthetic history; there was no family history of anesthesia or muscle problems. On contracture testing, one of two muscle bundles exposed to 2% halothane tested positive for MH, and all four bundles exposed to 3% halothane were positive. None of the seven bundles exposed to caffeine alone showed a positive response. Histology and histochemistry revealed a mild myopathy. The second patient with heat stroke was admitted to the hospital with a complaint of weakness, fever, and nausea after working outdoors on a hot day. His oral temperature was noted to be approximately 103 degrees F, and his CK level was 396 U/L (upper limit of normal 195 U/L). His CK level remained increased when tested 10 days and again 4 months later. He also had no anesthetic or family history. On contracture testing, one of three muscle bundles exposed to 3% halothane tested positive for MH. Two of three bundles exposed to caffeine alone showed a positive response. Histology and histochemistry revealed no diagnostic abnormality. The patient's father underwent contracture testing 4 months later, with negative results. His mother did not undergo testing.

Another patient included in our study presented with rhabdomyolysis. He was an 11-yr-old boy who came to the emergency room with a complaint of bilateral thigh pain after playing football. His CK level peaked the following day at 43,400 U/L, and both serum and urine myoglobin levels were increased. The patient had a congenital club foot. He had had four general anesthetics with triggering agents (two with halothane alone and two with halothane and succinylcholine) at our institution without difficulty. 1There was no family history of anesthetic complications. He denied a history of muscle cramps. On contracture testing, three bundles exposed to 3% halothane showed a normal response. One of three bundles exposed to caffeine showed a positive response. Histology and histochemistry revealed no diagnostic abnormality. Two months later, the patient's mother underwent contracture testing. Her CK level was normal and she had had several general anesthetics in the past without complication. She denied a history of muscle cramps or weakness. She had a history of strabismus. On contracture testing, all three muscle bundles exposed to 3% halothane and all three bundles exposed to caffeine alone were strongly positive. Histology and histochemistry revealed a slight myopathy.

The in vitro halothane caffeine contracture test is considered the "gold standard" for a diagnosis of MH. Although the in vitro contracture test is thought to be highly sensitive, its low specificity (demonstrated to be approximately 78%) makes interpretation of a positive result in an IHCK patient difficult ^[12]. A comparison of 2% halothane contracture response with 3% halothane contracture response in our MHS patients using 500 mg as the cutoff for normal contracture response revealed 3% halothane to be a more sensitive test than 2% halothane for determining MH susceptibility (Figure 1). However, the increased sensitivity of 3% halothane for determining MH susceptibility is tempered by its lack of specificity.

The clinical presentation of MH can be highly variable ^[13]. It has been shown that this variability in clinical expression is associated with genetic heterogeneity ^[14,15]. It may be that patients with IHCK represent yet another point on the clinical spectrum of MH expression. However, 57% of our patients were exposed to general anesthesia prior to testing with no evidence of anesthesia complications suggestive of MH. It is possible that patients with IHCK have a subclinical myopathy characterized by persistently elevated CK levels, which results in a false-positive response to contracture testing. Other genetic myopathies, such as Duchenne muscular dystrophy, central core disease, and myotonia congenita have been associated with abnormal contracture test results, and some of these neuromuscular disorders have been linked to clinical episodes that have features of MH ^[16]. Only half of our IHCK patients tested positive, and only 38% of those with positive contracture testing had a myopathy diagnosed on pathology examination, the same number as those with negative contracture responses.

The decision to perform MH contracture testing on IHCK patients remains controversial. We recommend that these patients undergo a thorough neurologic examination, and, if muscle biopsy is advised, in vitro contracture testing for MHS can be considered. These patients often request an intensive evaluation, and, in many of our patients, only the MH contracture test was positive, with very few having a definitive diagnosis on histology and histochemistry or neurologic examination. Although a positive contracture test may represent a false-positive result, we counsel the patient to take anesthetic precautions. We do not recommend MH contracture testing for family members of IHCK patients who have tested positive unless they have a history suggestive of increased MH risk. We do, however, recommend that family members receive nontriggering agents when undergoing anesthesia and wear Medic Alert tags.

In summary, 49% of 49 IHCK patients undergoing MH contracture testing in our institution were found to be MHS. Unexplained persistently increased CK levels in an otherwise healthy patient should alert the anesthesiologist to the possibility of MHS and/or underlying myopathy. Consultation with a neurologist regarding the advisability of neurologic examination and muscle biopsy should be considered for these patients.