Keywords

Malignant hyperthermia (MH) is an uncommon, life-threatening pharmacogenetic disease, triggered by halogenated volatile anesthetics and the depolarizing muscle relaxant succinylcholine. The first description of MH was published 1960 by Denborough and Lovell, which suggested MH to be an inherited disorder [1]. Indeed, subsequent investigation of the family tree by these same authors showed a dominantly inherited genetic disorder published in a second paper with the full description of the case and the family history [2]. The observation that freshly biopsied muscle strips from patients having survived MH were more sensitive to caffeine and halothane in vitro compared to muscle strips from individuals with no history of MH, allowed the development of diagnostic protocols for the investigation of MH susceptibility [3–5]. Screening of suspected MH susceptible individuals and their family members led to the identification of MH causative genetic mutations and non-invasive genetic screening of families with identified MH mutations.

In 1990, the genetic locus for MH susceptibility was identified on human chromosome 19 (RYR1-gene encoding the ryanodine receptor protein or calcium channel of the sarcoplasmic reticulum in skeletal muscle) [6, 7]. However, several researchers demonstrated heterogeneity of MH susceptibility [8]. Thus, it became clear that MH is not a monogenic disorder, even if one single point mutation in many families may be identified and then be used for the non-invasive diagnosis in these MH families [9, 10]. Evidence for alternative genetic loci in addition to RYR1 in humans was demonstrated on chromosomes 3, 7 and 17, whereas causative mutations were localized in the alpha 1-subunit of the human dihydropyridine-sensitive L-type calcium-channel receptor in skeletal muscle on chromosome 7q [11–13]. An actual list of causative mutations for MH is available on the website of the European Malignant Hyperthermia Group [14].

The pathophysiology of MH is explained by the loss of myoplasmic calcium control in skeletal muscle of MH susceptible individuals. Trigger agents (all halogenated volatile anesthetics and the depolarizing muscle relaxant succinylcholine) may increase the myoplasmic calcium concentration in MH susceptible individuals causing an increase of skeletal muscle metabolism [15]. MH may be life threatening if not immediately diagnosed and correctly treated. The most important components of a successful treatment include [16] early diagnosis (unexplained increase of endtidal CO2, metabolic acidosis), immediate cessation of trigger agents, and dantrolene treatment (Fig. 8.1).

Fig. 8.1
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Treatement screen of iPhone application MHApp. This application might be used for training, teaching and treatment of MH episodes

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Pediatric intensive care specialists may be confronted with MH in various circumstances. For example, pediatric intensive care specialists may be called upon to provide intensive care treatment of a patient presenting with an acute episode of MH, e.g. after MH is diagnosed during or after induction of anesthesia using trigger agents. Anesthesiologists should alert the intensive care team and be available for assistance with ongoing treatment in the ICU. Tables 8.1, 8.2, and 8.3 present detailed information on the early and late clinical symptoms of MH, differential diagnosis, and concepts for appropriate treatment [16]. Modern digital electronic devices, such as iPhone or iPad applications are now available, which may be helpful for a systematic approach [17, 18]. Following a suspected MH episode, the patient should be referred to a MH diagnostic center for a diagnostic workup. A list of centers in Europe is presented on the website of the European Malignant Hyperthermia Group (www.emhg.org). Similarly, a list of centers in the United States is presented on the website of the Malignant Hyperthermia Association of the United States (www.mhaus.org). The patient and his family should get appropriate genetic counseling and a warning card about MH.

Table 8.1 Clinical signs of MH
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Table 8.2 Differential diagnosis of MH
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Table 8.3 MH Treatment
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Alternatively, if a patient with known or suspected MH susceptibility is treated for any reason in the ICU, trigger agents (all volatile anesthetics and succinylcholine) must be strictly avoided. Whether some patients without MH susceptibility may develop an MH-like hypermetabolic syndrome has not been systematically proved. However, it may be speculated, that a genetic predisposition with minor degree of abnormal myoplasmic calcium regulation may develop an MH-like syndrome, which may be treated according to effective MH therapy. Selected myopathies, i.e. central core disease (CCD), multi minicore disease (mMD), nemaline myopathy and King-Denborough myopathies are associated with malignant hyperthermia [19]. Triggering agents must be avoided in these patients. Other myopathies, such as muscular dystrophies and mitochondrial myopathy seem not to be associated with MH [19], although succinylcholine should be avoided in all myopathic patients.

Finally, there are several disorders mimicking MH-like symptoms (see Table 8.2). The differential diagnosis can be quite challenging. With the exception of a fulminant MH episode, diagnosis of MH is frequently difficult. Treatment with dantrolene should be initiated even if there is no clear MH diagnosis, as delayed treatment can be deleterious. Due to the mode of action dantrolene can lead to muscle weakness. The drug is hyperosmotic and can provoke phlebitis.