Human Malignant Hyperthermia Associated with Desflurane Anesthesia

Desflurane was released for clinical use in the United States in 1992. Before its release, desflurane was known to trigger malignant hyperthermia (MH) in susceptible swine [1]. However, it seems to be a less potent trigger than halothane [2]. Of six MH-susceptible swine, four did not develop MH when they were exposed to desflurane until they also received succinylcholine [1]. Two case reports have documented MH in humans exposed to desflurane. In one case, desflurane was the only MH trigger used; the patient received desflurane for 90 min before severe hypercarbia developed [3]. In the other case, the patient received both succinylcholine and desflurane, and hypercarbia developed after only 15 min [4]. We reviewed the database of the North American MH Registry for cases of presumed MH triggered by desflurane. We sought evidence to support the premise that although desflurane may be a weaker MH trigger, the onset of MH is shortened by the administration of succinylcholine. Methods The North American MH Registry has been described previously [5,6]. Its database holds information on 365 patients who have had adverse reactions under anesthesia from 1992 to January 1998. Clinicians report information to the Registry using a standardized form (Adverse Metabolic Response to Anesthesia; AMRA) that is provided by the Registry at no charge. Information noted on the AMRA form includes patient demographics, details about the adverse reaction, its treatment, and patient outcome. Patient identity is not reported to the Registry without the patient's written, informed consent. Using this information, the database calculates a score according to the Clinical Grading Scale (CGS) [7]. This score qualitatively estimates the likelihood that the patient suffered an MH episode. The grading scale does not rely on results of the caffeine halothane muscle contracture test to estimate MH susceptibility. By definition, grades D5 (very likely) and D6 (almost certain MH) require scores on the grading scale of 35-49 and >or=to50, respectively. After institutional review board approval, we searched for any patient reported to have had an adverse response associated with desflurane, then excluded any patient who did not have a D5 or D6 grade. We reviewed age, gender, race, exposure to other triggers, time to onset of signs and to MH diagnosis, maximal end-tidal CO2, peak serum creatine kinase (CK) level, peak body temperature, presence of muscle rigidity, and patient outcome. To test the hypothesis that desflurane may be a less potent MH trigger, we compared the time of onset of MH among desflurane, halothane, and isoflurane, in the presence and absence of succinylcholine, in patients with CGS grades of D5 or D6. Multiple group comparisons were made using the Kruskal-Wallis test for nonparametric data with Bonferroni's corrections. A P value of <0.05 was considered significant. Results From the Registry database of 365 AMRA reports, we found 14 reporting adverse responses associated with desflurane administration. Of the 14 reports, 12 scored a D5 or D6 on the CGS. This represents 6% of all D5 or D6 reports in the Registry database. One patient's experience had been published as a case report [4], leaving 11 previously unreported cases (Table 1). One patient had positive blood cultures, and a diagnosis of septicemia was reported on the AMRA. This patient had been treated with IV dantrolene as well as antibiotics. The other 10 patients also received IV dantrolene, and all survived the presumed MH episode. Three patients developed recrudescence reactions that were successfully treated with additional dantrolene. None of the patients had undergone muscle biopsy for caffeine halothane muscle contracture testing.Table 1: Malignant Hyperthermia Associated with DesfluraneIn four of five patients who received both succinylcholine and desflurane, the onset of MH was earlier than in patients exposed to only desflurane (Table 1 and Table 2). Four patients who received succinylcholine and desflurane presented with generalized muscle rigidity and/or masseter muscle rigidity (MMR); in one case, MMR was observed at 10 min, but other signs of MH (hypercarbia, tachycardia, muscle rigidity, hyperthermia) were noted at 80 min, and dantrolene was given at 85 min. In one other patient who received succinylcholine and desflurane, the presenting sign was tachycardia. The patient also developed "decreased pulmonary compliance" at some time during the procedure.Table 2: Time to Onset of Malignant HyperthermiaIn the five patients exposed to desflurane only, none presented with generalized rigidity or MMR; in three cases, hypercarbia was the presenting sign. However, two of five patients developed muscle rigidity during the MH episode. In one case in which the presenting sign was hypercarbia, the clinician noted that MMR had occurred earlier in the procedure before the diagnosis of MH had been made. We compared the median onset time of MH associated with desflurane, halothane, and isoflurane (Table 2). The onset of MH occurred more rapidly with desflurane or isoflurane in the presence of succinylcholine than with either drug alone. Halothane triggered MH more rapidly than isoflurane, with or without succinylcholine, but its onset times were not significantly different from those for desflurane. Discussion This case series adds support to published reports of MH associated with desflurane. In particular, it confirms observations made about the onset of MH with desflurane [2]. The time to diagnosis was relatively long (53-380 min) in the five patients exposed only to desflurane. This is in keeping with the observations of Wedel et al. [2] that desflurane is a less potent MH trigger than halothane (but not isoflurane). Our results found halothane to be a more potent trigger than isoflurane, but the results comparing halothane alone with desflurane alone did not reach statistical significance (P = 0.066). This may be due to the difference in sample size of the two groups and the corrections made when multiple statistical comparisons are performed (unadjusted P value = 0.007). These results are also in agreement with a recent case report of human MH [3]. A 13-yr-old boy was exposed to desflurane for 90 min before the diagnosis of MH was made. The patient had also received IV propofol and vecuronium, neither of which is an MH trigger. Nondepolarizing muscle relaxants may actually delay the onset of MH [8]. Although desflurane may be a less potent MH trigger, 3 of 10 patients suffered recrudescence reactions that required additional dantrolene therapy. Recrudescence occurs in up to 25% of all MH episodes [6], more often after fulminant episodes. Signs of recrudescence include evidence of hypermetabolism (increased CO2 production, tachycardia, temperature increase) or rhabdomyolysis (hyperkalemia, oliguria, and muscle edema) [9]. In addition, muscle edema may lead to the development of compartment syndromes [10], requiring surgical intervention. Patient 4 required an above-knee amputation after developing a compartment syndrome. Our observation that four of five patients exposed to both desflurane and succinylcholine rapidly developed MH is in agreement with studies of MH-susceptible swine [1]. Wedel et al. [1] reported that four of six swine developed fulminant MH on exposure to desflurane only after they also received IV succinylcholine. The potentiating effect of succinyl-choline in the development of MH, presumably due to its adverse effect on skeletal muscle, has already been reported [11]. This observation is supported by the case of a 10-yr-old boy who developed MH 15 min after receiving IV thiopental and succinylcholine followed by desflurane [4]. Fu et al. [4] questioned whether the sympathetic activation induced by desflurane could be mistaken for MH or might lead to a delay in its diagnosis. Although desflurane-induced sympathetic activation causes tachycardia, a nonspecific sign of MH, it does not produce hypercarbia [12]. Tachycardia produced by desflurane's effect on the sympathetic nervous system is transient; in MH, tachycardia tends to persist and progress in the untreated episode. Although hypercarbia is nonspecific, it is a very sensitive sign of the hypermetabolic MH state. Its detection is now hastened by the routine use of capnography, and MH is diagnosed earlier in its course. However, the lack of specificity of hypercarbia is exemplified by Patient 3, in whom the maximal recorded end-tidal CO2 value occurred 75 min before the diagnosis of MH was made; and by the patient with septicemia, whose endtidal CO2 value reached 70 mm Hg. It is interesting that all four patients who developed MH after exposure to desflurane and succinylcholine presented with generalized muscle rigidity and/or MMR. Muscle rigidity seems to occur more frequently when patients received succinylcholine [13]. This difference in the presentation of MH associated with succinylcholine is important because anesthesiologists do not routinely monitor for muscle rigidity as they do for hypercarbia. In four of five patients, the maximal reported end-tidal CO2 level occurred after the onset of muscle rigidity and the diagnosis of MH. Of the 10 patients exposed to desflurane, 6 developed skeletal muscle rigidity, although it was the presenting sign in only 4 of 6 cases. We could not compare the degree of postoperative serum CK increase with the presence of muscle rigidity because of incomplete data reporting. This was usually because laboratory tests, including arterial and/or venous blood gas, serum CK, and potassium determinations, were not performed during the MH episode. These data are necessary to make an adequate clinical assessment of the episode, as well as for the accurate use of the CGS [7]. Clinicians are encouraged to perform serial arterial and/or venous blood gas, serum potassium, and CK measurements when MH occurs and to report these cases to the North American MH Registry (717-531-6936). Many centers have begun to stock AMRA forms on their MH carts in the operating room. The CGS was designed so that the treating physician would have some latitude in deciding whether observed signs are inappropriate for that patient [7]. In the case of Patient 7, other than generalized muscle rigidity and reversal with dantrolene, the observations seem unimpressive (Table 1). However, changes in body temperature and end-tidal CO2 were considered inappropriate by the reporting physician. This combination of signs produced a CGS score of 50 [7]. In the patient with septicemia, the increase in body temperature, heart rate, and end-tidal CO2 were considered inappropriate; this produced a CGS score of 38. Sepsis or bacteremia may be difficult to differentiate from MH. The results of blood cultures confirmed the diagnosis of urosepsis. Muscle rigidity was absent in this patient, as was an increase of serum CK. Muscle rigidity is considered very specific for MH, but it may be absent in up to 25% of MH episodes [14]. In conclusion, these observations support others that suggest that desflurane is a weak MH trigger; the onset of MH seems more rapid when succinylcholine is also administered. When MH is triggered by desflurane alone, it presents with hypercarbia, tachycardia, or temperature increase. Muscle rigidity is the most common presenting sign when succinylcholine is also administered. Recrudescence may occur after MH episodes triggered by desflurane. Our thanks for statistical support to Allen R. Kunselman, MA, Research Assistant in Biostatistics, Department of Health Evaluation Sciences, College of Medicine, The Pennsylvania State University.