Malignant hyperthermia (MH), also called malignant hyperpyrexia, is an autosomal dominant genetic disorder of the skeletal muscle. This condition is a pharmacogenetic syndrome that variably expresses itself on exposure to triggering agents, which include inhaled volatile anesthetics (e.g., halothane, isoflurane, enflurane, and sevoflurane) and depolarizing muscle relaxants (e.g., succinylcholine).1–3
MH is characterized by signs of hypermetabolism caused by the release of calcium from the sarcoplasmic reticulum,2–4 increased oxygen consumption, and increasing and unexplained increase in end-tidal CO2 that does not decrease with increasing minute ventilation, tachycardia, muscle rigidity, hyperthermia, and respiratory and metabolic acidosis.2–4 Other signs of MH may include disseminated intravascular coagulation, cardiac arrhythmias, hyperkalemia, hyperphosphatemia, hypocalcemia, rhabdomyolysis, myoglobinuria, and mottled skin.2–4
A clinical grading scale for MH was developed in 1994 to create a standard clinical case definition and, in part, to allow comparisons between groups of patients that were defined by similar characteristics.5 The laboratory diagnosis of MH susceptibility is based on the contracture response of biopsied vastus muscle to graded concentrations of halothane or caffeine.3,6–9 More recently, a DNA-based test has been introduced, but the diagnostic utility of the test has not been adequately assessed.
Estimates of MH incidence and prevalence have varied greatly. For example, separate epidemiologic studies with selected patient groups have found incidence rates of MH ranging from 1 in 200 to 1 in 50,000 anesthetics for patients aged 18 years and older.10–12 A study in Denmark found a prevalence of MH susceptibility of 1 in 250,000.13 In France, a study cites 1 in 10,000 as the estimated prevalence for MH susceptibility due to anesthesia, but given 6 loci and 2 genes associated with MH and the incomplete penetrance of the MH trait, the authors contend that a prevalence between 1 in 2000 to 1 in 3000 may be a better approximation of MH susceptibility.14 In Japan, Ibarra et al.15 estimate the prevalence of the MH genotype to be as high as 1 in 2000.
Although there is substantial variation in estimated prevalence of MH susceptibility and incidence in other countries, MH risk based on epidemiologic data in the United States is not well documented. One recent study used the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 995.86 (MH due to anesthesia) to identify MH due to anesthesia in a 20 percent sample of US hospital discharges from 2000 to 2005 and found a prevalence of 11.2 per million hospitalizations.16 Risk factors associated with MH include young age, male sex, orthopedic or ear, nose, and throat surgeries, and central core myopathy.2,3 MH susceptibility has also been documented in individuals with heat stroke and exercise-induced rhabdomyolysis.2
Although MH is a relatively rare occurrence, the case fatality rate for MH was about 80% in the 1970s. Present estimates of case fatality for MH range from 4% to 10%.2,17–20 This decrease in MH mortality has been attributed to (1) increased MH awareness resulting in the review of patients' and their families' medical histories for MH; (2) routine monitoring of patients for signs and symptoms of MH (e.g., measuring end-tidal CO2 and temperature monitoring); (3) the availability and increased use of anesthetics that are nontriggering for MH; and (4) Food and Drug Administration approval of administration of dantrolene sodium for the treatment of MH in 1979.21
Thus, to better understand the epidemiology of MH related to exposure to anesthesia in the United States, we performed a study using the Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases (SID) files for New York State from 2001 to 2005. Specifically, we examined the prevalence and clinical outcome of MH due to anesthesia (ICD-9-CM code 995.86) in patients treated in New York hospitals during 2001–2005.
Description of Data
HCUP SID files for New York State from 2001 to 2005 were used in this study. The New York SID files are maintained by the Agency for Healthcare Research and Quality, and were constructed from the New York State Department of Health's Statewide Planning and Research Cooperative System Master File.* Scheduled submission of data is required for hospital inpatients in New York State. The New York SID files contain inpatient discharge records for acute care hospitals, excluding long-term care units of short-term hospitals and federal hospitals. Clinical and nonclinical variables in the hospital discharge data files include, but are not limited to principal and secondary diagnoses and procedures, admission and discharge status, patient demographics (e.g., gender, age, and race), and hospitalization characteristics (e.g., scheduled admission, admission type).
The study protocol was reviewed and found exempt by the Columbia University Medical Center institutional review board. The study sample was composed of all hospital discharge records in New York State from 2001 to 2005 (n = 12,749,125). Cases of MH related to exposure to anesthesia were ascertained from patients who were assigned ICD-9-CM diagnosis code 995.86. We calculated the prevalence of MH related to exposure to anesthesia based on four denominators: (1) all hospital discharges; (2) hospital discharge with a surgical diagnosis-related group (DRG) or surgical ICD-9 procedure code listed;†‡§ (3) all hospital discharges with any recorded indication of anesthesia administration (reported anesthesia variable or billed anesthesia charge); and (4) nonsurgical therapeutic procedures requiring anesthesia, including placement or insertion of endotracheal and Eustachian tubes (ICD-9 procedure codes 96.04, 20.8), use of mechanical ventilation (ICD-9 procedure codes 96.71, 96.72), esophagoscopy (ICD-9 procedure code 42.23), and catheterization (ICD-9 procedure codes 37.22, 38.93). These nonsurgical therapeutic procedures requiring anesthesia were identified from the principal and secondary procedures listed in medical abstracts of MH cases and then were used to identify all patients who received any of these procedures to form the denominator. The surgical DRG or procedure and the nonsurgical therapeutic anesthetic procedure risk groups were mutually exclusive. The other risk groups were not mutually exclusive.
Statistical analysis was performed using SAS version 9.1.3. Prevalence of MH related to exposure to anesthesia and 95% confidence intervals were calculated using four different denominators, one for each at-risk group. Prevalence of MH related to exposure to anesthesia was stratified by patient characteristics such as age, race, sex, and Charlson-Deyo Comorbidity Score ≥1, and by hospitalization circumstances, such as scheduled admission. The Charlson Comorbidity Score is a summary measure used to classify comorbidities that may affect mortality.22 The Deyo translation allows Charlson Comorbidity Scores to be applied to administrative data using ICD-9-CM codes.23,24 New York defined a scheduled admission as one that was arranged through the hospital at least 24 h before the admission. χ2 tests were used to assess the statistical significance in differences in prevalence rates among different patient groups.
Of 12,749,125 discharges from New York State hospitals during 2001 through 2005, 73 patients had a diagnosis of MH due to anesthesia. For 38 of the 73 cases, the MH diagnosis was marked as the condition being present at admission. For the remaining 35 cases, the diagnosis referred to events that occurred during the index hospitalization. The overall prevalence of MH related to exposure to anesthesia was 0.57 per 100,000 hospitalizations, 0.96 per 100,000 surgical discharges, 1.08 per 100,000 discharges in which there was any indication of anesthesia, and 4.39 per 100,000 nonsurgical therapeutic procedures requiring anesthesia (Table 1).
Although MH prevalence rates varied by the denominator type, higher rates for males were seen across risk groups (Fig. 1). The estimated prevalence of MH for males was 2.5–4.5 times the rate for females depending on the denominator used. The difference in MH prevalence between sexes was statistically significant at P < 0.05 level for all risk groups.
There was no apparent association between patient age and the prevalence of MH. The prevalence rate of MH per 100,000 surgical discharges was similar across racial groups (1.09 for Caucasians, 1.12 for African Americans, and 0.95 for Hispanics; P = 0.96).
The 73 MH cases were reported by 49 hospitals scattered across the state. Of them, nearly one half (49%) were aged 45 years and older, 66% were Caucasian and 73% were men (Table 2). The majority of the MH cases were from unscheduled admissions and emergency/urgent admissions (Table 2). About 47% of the MH patients had at least one significant preexisting medical condition as indicated by the Charlson-Deyo Comorbidity Score ≥1. The prevalence rates of MH based on all hospitalizations did not differ significantly by patient age, race, admission type, and the Charlson-Deyo Comorbidity Index (Table 2). Of the 73 patients with a diagnosis of MH, 16 (22%) were dead on discharge.
When the analysis was restricted to the 35 incident MH cases, the estimated incidence rates were approximately 50% less than the overall prevalence presented in Table 1. The epidemiologic patterns, however, remained virtually unchanged. For instance, the incidence rate of MH showed a statistically significant difference between sexes (0.46 per 100,000 for males vs 0.14 for females), but did not differ by other variables, such as age, race, admission type, and the Charlson-Deyo Comorbidity Index.
Our study indicates that the prevalence rates of MH related to exposure to anesthesia are approximately 1 per 100,000 surgical patients and 4.4 per 100,000 nonsurgical patients who receive therapeutic procedures requiring anesthesia. The wide-ranging estimates in MH risk are due, in part, to the different methods for defining at-risk patients. Unfortunately, information on exposure to anesthesia in hospital discharge records is often incomplete. The first denominator used in this study, all hospitalizations, is an overall estimate of MH risk (including both prevalent and incident cases) for the general inpatient population.
The second denominator, hospitalizations with any noted surgical DRG or procedure, only captures the risk of MH associated with inpatient surgery. Ambulatory outpatient surgeries would not be captured in this risk grouping unless the patient was transferred to the hospital. Hospitalizations in which the patient receives anesthesia, but does not have surgery, would also not be included in this risk grouping. Therefore, the estimated prevalence of MH related to exposure to anesthesia of 0.96 per 100,000 hospitalizations with an indication of surgery is only relevant to inpatients undergoing surgery.
The third denominator is constructed using an anesthesia variable and billing charges for anesthesia. Reflecting the interrelationship between anesthesia and surgery, 79% of the patients with any indication of anesthesia exposure were also included in the surgical DRG or procedure group. The estimated prevalence rate of MH based on anesthesia exposure, 1.08 per 100,000 patients, was very similar to the estimated rate based on surgical DRG or procedure data, 0.96 per 100,000 patients. The consistency in the findings based on these two methods provides supportive evidence for the reliability of the study results.
The fourth denominator, nonsurgical therapeutic procedures, only includes a few therapeutic procedures thought likely to include exposure to anesthesia for the majority of MH patients who did not receive any surgical procedure. The nonsurgical therapeutic procedures risk group does not represent the risk of MH for all nonsurgical therapeutic procedures, but just for those selected procedures. Consequently, the incidence rate of 4.4 events of MH per 100,000 is likely an overestimation of risk of MH.
Apart from using different denominators, there are additional reasons for the variation in estimated MH risks across studies. Discrepancies in MH prevalence and incidence between this study and other reports may result from the temporal bias. A study performed before the development of the MH susceptibility clinical grading scale, and before widespread awareness of MH, which resulted in the discontinuation of anesthetics with early MH signs, or the development of ICD-9 code 995.86 in 1998, may yield different results than a study after this time. Other causes of the variation in estimated MH prevalence and incidence among studies have been attributed to the “founder effect” in isolated geographic locations, changes and regional differences in anesthetic practice, lack of reporting of MH cases, the practice of using different diagnostic testing protocols in the US and Europe, the use of multiple clinical MH case definitions over time, and differences in the severity of MH reactions.2,8–10,12,13,16,25
Consistent with prior reports,3,4,10,17,19,20 our study shows the prevalence of MH related to exposure to anesthesia is significantly higher in males than in females. It is noteworthy that the in-hospital mortality rate for patients with a diagnosis of MH (22%) reported in our study is much higher than in other studies.2,3,17–20 The higher mortality rate reported in our study is likely due to the fact that it included both prevalent and incident MH cases and that most of the deaths may have been caused by medical conditions other than MH. Therefore, the in-hospital mortality rate reported in our study cannot be regarded as the case fatality rate for MH and thus should not be directly compared with other studies.
Our study is subject to several limitations. First, the prevalence rates reported are subject to misclassification due to lack of reporting or miscoding. Although the hospital discharge data are collected and recorded using standardized protocols, coding accuracy remains a concern. Clearly, some clinicians may ascribe a diagnosis of MH to any situation in which body temperature is exceedingly elevated.∥ Second, because the agreement on HCUP SID data use prohibited the release of data for any group with 10 or fewer patients, it was impossible for us to perform a more detailed analysis according to patient characteristics and diagnosis type. Finally, our study unit was the hospitalization, not individual patients. Some patients may have been hospitalized multiple times during the 5-year study period. Each hospitalization was treated as an independent event in our analysis. Because the HCUP SID data do not allow us to link individual records over time, our analysis did not consider that each hospitalization may not represent a unique person. Because an MH event may not occur with the first administration of anesthesia, patients previously receiving anesthesia are still at risk for MH.
Despite these limitations, our study provides valuable data for understanding the prevalence and incidence of MH related to anesthesia. Moreover, this study suggests that the epidemiology of rare medical conditions, such as MH related to exposure to anesthesia, may be examined using readily available administrative data systems. However, the study also demonstrates the need for further work to refine the clinical diagnosis of MH and to define the incidence and prevalence of this potentially life-threatening disorder.
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*www.hcup-us.ahrq.gov/sidoverview.jsp, last accessed September 8, 2008.
†http://www.qualityindicators.ahrq.gov/downloads/psi/psi_guide_v31.pdf, last accessed September 8, 2008.
‡http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=aps.section. 1514, last accessed September 8, 2008.
§Appendices A and B: http://www.qualityindicators.ahrq.gov/downloads/psi/psi_technical_specs_v32.pdf, last accessed September 8, 2008.
∥Quality control efforts at Columbia University Medical Center ascertained 13 coded MH diagnoses since 1998. Some evidence suggestive of MH (a previous episode, acute MH event, dantrolene sodium administration, or idiopathic raises in temperature) was found in 10 (77%) of these cases.