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doi: 10.1097/01.anes.0000265144.63696.af
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Recrudescence of Malignant Hyperthermia

Hopkins, Philip M. M.B., B.S., M.D., F.R.C.A.

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RECRUDESCENCE of a malignant hyperthermia (MH) reaction has previously been reported anecdotally, but in this month’s issue of Anesthesiology, Burkman et al.1 present the first detailed evaluation of its incidence and associated factors. Appreciation of the potential for recrudescence of MH reactions is important for the anesthesiologist managing a suspected case because it informs decisions regarding the level of care required after treatment of the acute event. If we accept the data provided by Burkman et al. to be reliable, the 20% incidence of recrudescence supports current advice that patients should be monitored for at least 24 h in a critical care environment after resolution of the signs of the acute MH reaction. Furthermore, the presence of certain characteristics might suggest an even longer period of close observation.
Because the study of Burkman et al. may impact on postreaction management of possible MH cases, it is appropriate to examine how reliable the data are and how applicable they are to practice outside North America. The study was a retrospective cohort study, and the authors discuss its limitations. The most obvious of these is the subjectivity of the key diagnoses, first the diagnosis of the initial episode as MH and second that of recrudescence. The clinical diagnosis of MH is difficult because there is no single pathognomonic feature and there are multiple differential diagnoses.2 Without a definitive laboratory diagnosis, the cohort of Burkman et al. will include some non-MH cases, which may have reduced the apparent incidence of recrudescence. On the other hand, the diagnosis of recrudescence is subject to the same vagaries with the additional differential of an inflammatory response in a critically ill patient. It may well be that these presumed overdiagnoses on both numerator and denominator of the recrudescence incidence ratio have a net neutral effect.
In some senses though, this is academic. Until we have a point-of-care diagnostic test for MH susceptibility, management decisions must be based on the presumed diagnosis of MH and, indeed, recrudescence. By restricting their analyses to cases deemed retrospectively to be “likely MH” on the basis of the MH clinical grading score,3 Burkman et al. acknowledge the introduction of selection bias. Inclusion of only 308 of 528 reports to the North American MH Registry may have resulted in underestimation of the true incidence of recrudescence. Even if there were no further cases from the 220 reports not included, however, the 95% confidence interval would be approximately 10–15%. Such an incidence, considering the consequences of not identifying recrudescence and managing it appropriately, would still warrant high dependency care of all patients after an MH reaction.
Having estimated the incidence of recrudescence, Burkman et al. next sought to determine which, if any, clinical variables were associated with its development. Considerable caution must be exercised in the interpretation of such data, and the authors of this article are right to stress the difference between association and causation. Significant univariate associations with the occurrence of recrudescence were found for muscular (vs. normal/lean) body habitus, increasing duration of the interval between induction of anesthesia and onset of the MH reaction, and the development of a temperature increase (inappropriate rate of temperature rise or temperature ≥ 38.8°C) as part of the reaction. Examination of the data indicates, however, that the predictive value for recrudescence will be low for each of the identified variables. A multivariate logistic regression model for prediction of recrudescence using the same variables was also generated. Such analyses can moderate the influence of interdependent covariates, but in doing so, they may exclude the real predictor at the expense of a confounding factor. The model-generating capabilities of the statistical software packages, furthermore, are so powerful at fitting the data that a statistically significant model can be produced even though the contribution to the outcome variable of the selected predictor variables is small. This can be examined using the r2 value for the model, which estimates the proportion of the variance of the outcome variable that the model explains. The r2 value of 0.102 for the model of Burkman et al. suggests that the identified variables are unlikely to be useful predictors of recrudescence.
I do not think we should ignore the associations identified by Burkman et al. altogether, however, because they perhaps point to something interesting even if it may seem intuitively obvious: The more severe the MH reaction, the more likely is recrudescence. It is now recognized that a temperature increase is a relatively late manifestation of MH.2 There is no evidence that delay in onset of an MH reaction determines its severity, but in my experience, the attending anesthetist often defines the onset of the MH reaction as the time that he or she started treatment, rather than when signs became apparent. In the study of Burkman et al., the interval between induction of anesthesia and onset of the MH reaction may well be a composite of delay in onset and delay in diagnosis. The latter component would be a major determinant of the severity of the reaction. Finally, anthropometric studies have revealed MH-susceptible patients to be more muscular than normal,4 whereas the mass of affected muscle during an MH reaction will determine the amount of heat, lactate, and carbon dioxide generated, the oxygen consumption, and the amount of potassium and myoglobin liberated from the muscle.
Support for an association between severity of reaction and recrudescence is, in fact, provided by Burkman et al.1 In a post hoc analysis, they found a greater proportion of patients with high MH clinical grading scores in the recrudescence group. It would have been interesting to know the impact of including the clinical grading score on the multivariate logistic regression analysis. Meanwhile, such an association would support a previously hypothesized mechanism for recrudescence.2 This mechanism is dependent on the reaction being severe enough to increase the myoplasmic Ca2+ concentration sufficiently to cause Ca2+-induced Ca2+ release5 from the sarcoplasmic reticulum, thereby maintaining increased Ca2+ cycling after elimination of the trigger drug. Clinical features may then reappear if, for example, muscle activity is further increased,6 if Ca2+ sequestration is compromised by an exhausted capacity for adenosine triphosphate production, or indeed if falling dantrolene concentrations cease to oppose the sensitized Ca2+ release mechanism.1 However, it should be noted that the first reported cases of recrudescence occurred before the availability of dantrolene.7
Burkman et al.1 propose that the specific genetic defect predisposing to MH may influence the likelihood of recrudescence. This also is consistent with the association between recrudescence and severity of the initial reaction, as we have previously demonstrated the influence of specific RYR1 mutations on “severity” of MH phenotype.8 Furthermore, this genetic predisposition to recrudescence has implications for the applicability of findings based on North American patients to other parts of the world because RYR1 mutations are clustered geographically.9 For example, the most prevalent RYR1 mutation reported in North American and United Kingdom families is p.G2434R,9,10,11 but this has a relatively weak phenotype8 and might therefore be expected, on the basis of Burkman et al.’s data, to be associated with a relatively low incidence of recrudescence. Different RYR1 mutations predominate in other countries (p.R614C in France and Italy, p.V2168M and p.I2336H in Switzerland, p.G341R in Belgium).9 There are insufficient published data to compare strength of phenotype of most of these mutations with p.G2434R (other than for p.G341R, which is similar8). However, should any of these mutations be associated with a stronger phenotype, the work of Burkman et al.1 suggests that the incidence of recrudescence may be higher in the relevant country than in North America. RYR1 mutations private to individual families predominate in Asia and Australasia,9 and so it is difficult to comment on possible differences in the incidence of recrudescence in these parts of the world.
In summary, Burkman et al. have provided clinically useful data to strengthen the evidence base for patient treatment after an MH reaction. The methodology used may slightly exaggerate the incidence of recrudescence, which may further vary outside North America depending on the prevalence of individual mutations predisposing to MH. Credit must be given to the North American MH Registry for their dedication to systematic collection of clinical data, which on this scale is unique.
Philip M. Hopkins, M.B., B.S., M.D., F.R.C.A.
University of Leeds, Leeds, United Kingdom. p.m.hopkins@leeds.ac.uk
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References

1. Burkman JM, Posner KL, Domino KB: Analysis of the clinical variables associated with recrudescence after malignant hyperthermia reactions. Anesthesiology 2007; 106:901–6

2. Hopkins PM: Malignant hyperthermia: Advances in clinical management and diagnosis. Br J Anaesth 2000; 85:118–28

3. Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, Kaplan RF, Muldoon SM, Nelson TE, Ording H, Rosenberg H, Waud BE, Wedel DJ: A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994; 80:771–9

4. Campbell IT, Ellis FR, Halsall PJ, Hogge MS: Anthropometric studies of human subjects susceptible to malignant hyperpyrexia. Acta Anaesthesiol Scand 1982; 36:363–7

5. Yamazawa T, Takeshima H, Sakurai T, Endo M, Iino M: Subtype specificity of the ryanodine receptor for Ca2+ signal amplification in excitation-contraction coupling. EMBO J 1996; 15:6172–7

6. Short JA, Cooper CM: Suspected recurrence of malignant hyperthermia after postextubation shivering in the intensive care unit, 18 h after tonsillectomy. Br J Anaesth 1999; 82:945–7

7. Mathieu A, Bogosian AJ, Ryan JF, Crone RK, Crocker D: Recrudescence after survival of an initial episode of malignant hyperthermia. Anesthesiology 1979; 51:454–5

8. Robinson RL, Brooks C, Brown SL, Ellis FR, Halsall PJ, Quinnell RJ, Shaw M-A, Hopkins PM: RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes. Hum Mut 2002; 20:88–97

9. Robinson RL, Carpenter D, Shaw M-A, Halsall PJ, Hopkins PM: Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mut 2006; 27:977–89

10. Sei Y, Sambuughin N, Davis E, Sachs D, Cuenca P, Brandom B, Tautz T, Rosenberg H, Nelson TE, Muldoon SM: Malignant hyperthermia in North America: Genetic screening of the three hot spots in the type I ryanodine receptor gene. Anesthesiology 2004; 101:824–30

11. Sambuughin N, Holley H, Muldoon S, Brandom BW, Bantel AM, Tobin JR, Nelson TE, Goldfarb LG: Screening the entire ryanodine receptor type 1 coding region for sequence variants associated with malignant hyperthermia susceptibility in the North American population. Anesthesiology 2005; 102:515–21

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