Correspondence  |   June 2012
In Reply
Author Affiliations & Notes
  • Frank Lehmann-Horn, M.D., Ph.D.
  • *Ulm University, Ulm, Germany.
Article Information
Correspondence   |   June 2012
In Reply
Anesthesiology 6 2012, Vol.116, 1399-1400. doi:10.1097/ALN.0b013e318253a6b1
Anesthesiology 6 2012, Vol.116, 1399-1400. doi:10.1097/ALN.0b013e318253a6b1
We are happy to see that our editorial1 prompts discussion, even though the points raised by Larach et al.  result mainly from the removal of the designated statement of the global context of the editorial. Three points of criticism were made: (1) the interpretation of the in vitro  contracture test result of the boy (Groom et al.  2), (2) possible indicators for individuals at risk for nonanesthetic malignant hyperthermia (MH), and (3) the alleged blaming of the parents.
Regarding item 1: As Larach et al.  correctly noted, the American and European protocols have been compared and found to be mostly concordant. However, Islander and Twetman differentiate between inclusion and exclusion of the MH equivocal results.3 Simply put, 9 of 74 MH-susceptible results according to the North American protocol using 3% halothane were MH equivocal according to the European protocol using 2% halothane as trigger; that is 12%. Therefore, the in vitro  contracture test of the boy could very well be considered MH equivocal by European standards. But more importantly, the message of the editorial was that the in vitro  contracture test may not reliably identify persons at risk. This message becomes clear in the editorial by the statement: “In addition positive In Vitro  Contracture Test results were found in only 24% of 45 individuals with exertional heat stroke,4 and in 83% of 12 patients with exercise-induced rhabdomyolysis.5 Therefore more appropriate test protocols in vitro  (heat, oxidative stress, and nitrogen species as triggers) or in vivo  (using 31P MRI)6 need to be developed.”
Regarding item 2: Again, the statement about possible indicators for individuals at risk for nonanesthetic MH was taken from the original context. It is very clear from the whole paragraph and the statements made immediately preceding the statement in question that we are stating our opinion—in accordance with the purpose of an editorial—and drawing our own conclusions from the cases reported by Groom et al.  2 “Alternatively only one RyR1 mutation (i.e.  , in only 16% of the tetrameric RyR1 complexes, all four RyR1 subunits are impaired) might be sufficient if combined with a second mutation that is associated with a congenital myopathy. Therefore MH susceptible individuals presenting with ophthalmoplegia and muscle hypotonia, hypertrophy, or spasms will be at risk for nonanesthetic MH.” Therefore, it is evident that we are not citing a large-scale human study but rather identifying ophthalmoplegia, muscle hypotonia, hypertrophy, and spasms as possible indicators of an undetected, underlying myopathy.
Regarding item 3: Nowhere in the text do we assign any blame to the parents. We state, “As children have less developed compensation mechanisms for increased body heat and a higher incidence of MH events than adults (1:15,000 vs.  1:100,000),7 their parents should be particularly careful.” Obviously, the parents must be more careful with any temperature elevation in children at risk than are parents of unaffected children. A personal or family history of heat intolerance  should cause avoidance of hot environments, exhausting physical exertion, high fever, and all drugs that increase heat production and reduce heat dissipation. During an episode, cooling should be started immediately until dantrolene can be infused, as in a typical MH crisis. In the meantime, the recommendations given in our editorial have been supported by authorities in the field.8,9 To avoid secondary organ damage, treatment in an intensive care unit is mandatory. The protection offered by various drugs against oxidative muscle damage should be tested as second-line therapy in MH animals, such as the naturally occurring MH-susceptible swine and transgenic mouse. The induction of MH by heat and the protection of MH by hypothermia have been described for these animals.10,11 
Lehmann-Horn F, Klingler W, Jurkat-Rott K: Nonanesthetic malignant hyperthermia. ANESTHESIOLOGY 2011; 115:915–7
Groom L, Muldoon SM, Tang ZZ, Brandom BW, Bayarsaikhan M, Bina S, Lee HS, Qiu X, Sambuughin N, Dirksen RT: Identical de novo  mutation in the type 1 ryanodine receptor gene associated with fatal, stress-induced malignant hyperthermia in two unrelated families. ANESTHESIOLOGY 2011; 115:938–45
Islander G, Twetman ER: Comparison between the European and North American protocols for diagnosis of malignant hyperthermia susceptibility in humans. Anesth Analg 1999; 88:1155–60
Figarella-Branger D, Kozak-Ribbens G, Rodet L, Aubert M, Borsarelli J, Cozzone PJ, Pellissier JF: Pathological findings in 165 patients explored for malignant hyperthermia susceptibility. Neuromuscul Disord 1993; 3:553–6
Wappler F, Fiege M, Steinfath M, Agarwal K, Scholz J, Singh S, Matschke J, Schulte Am Esch J: Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis. ANESTHESIOLOGY 2001; 94:95–100
Bendahan D, Kozak-Ribbens G, Confort-Gouny S, Ghattas B, Figarella-Branger D, Aubert M, Cozzone PJ: A noninvasive investigation of muscle energetics supports similarities between exertional heat stroke and malignant hyperthermia. Anesth Analg 2001; 93:683–9
Jurkat-Rott K, McCarthy T, Lehmann-Horn F: Genetics and pathogenesis of malignant hyperthermia. Muscle Nerve 2000; 23:4–17
Gronert GA, Tobin JR, Muldoon S: Malignant hyperthermia: Human stress triggering. Biochim Biophys Acta 2011; 1813:2191–2
Maclennan DH, Zvaritch E: Response to “Malignant Hyperthermia: Human stress triggering” in reference to original article “Mechanistic models for muscle diseases and disorders originating in the sarcoplasmic reticulum.” Biochim Biophys Acta 2011; 1813:2193–4
Iaizzo PA, Kehler CH, Carr RJ, Sessler DI, Belani KG: Prior hypothermia attenuates malignant hyperthermia in susceptible swine. Anesth Analg 1996; 82:803–9
Chelu MG, Goonasekera SA, Durham WJ, Tang W, Lueck JD, Riehl J, Pessah IN, Zhang P, Bhattacharjee MB, Dirksen RT, Hamilton SL: Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse. FASEB J 2006; 20:329–30