MH is a rare, pharmacogenetic disorder which manifests itself during general anesthesia after using triggering drugs, such as the depolarising muscle relaxant, succinylcholine and/or halogenated inhalational anesthetics (Halothane, Enflurane, Isoflurane, Sevoflurane, and Desflurane).
MH has an incidence that varies between 1/15000 and 1/50000 anesthetics.
Pathogenesis: In the normal state, intracellular calcium is lower than the extracellular calcium. During muscle contracture intracellular calcium increases, (sarcoplasmic reticulum binds and releases calcium). In MH there is a positive feedback in calcium metabolism, whereby calcium control is lost. There is an increase in the intracellular calcium level as a result of decreased calcium re-uptake by the sarcoplastic reticulum. Energy demand increases but ATP production falls. This process creates an increase in heat production, lactate, and carbon dioxide resulting from the increase in intracellular metabolism. Increased cellular permeability results in potassium, myoglobin, and creatinine kinase release into the blood.
MH is inherited as an autosomal dominant trait. The gene responsible for this hereditary deficiency causes a mutation in the Ryantodine receptor, and is situated on Chromosome 19. This means that both sexes are affected and only one pair of the gene need be present for the condition to be expressed in an individual, therefore each child of a MH patient has a 50% chance of being affected.
In 1960, the first case of MH was reported by Denborough and Lovell in Australia; in 1967 Dantrolene was discovered by Sneider in U.S.A; in 1971 the first International Symposium on MH was held in Canada; in 1979 the first clinical application of Dantrolene in pigs by Gronert and Harrison in the U.S.A; and finally in 1981 Dantrolene was applied to human clinical practice in Germany.
In 1960 the mortality was 80%, after treatment with Dantrolene the mortality decreased to less than 5%. Since the discovery of MH, the diagnosis still remains difficult even after 40 years of research. The diagnosis of a fulminant case of MH, by clinical criteria can be difficult because of the non specific nature and variable incidence of clinical signs and laboratory findings. Development of a standardized means of estimating the qualitative likelihood of MH in a given patient without the use of specific diagnostic testing was the next step for patient assessment. In 1994 an article published in "Anesthesiology" referred to a "Clinical Grading Scale to predict MH susceptibility". This scale was elaborated by the contribution of 11 experts in MH throughout the world, during 18 months of intensive work. The classical clinical signs and symptoms were grouped into the processes as indicators. These indicators were scored with points concerning the importance that they played in each process. The seven processes included:rigidity, muscle breakdown, respiratory acidosis, temperature increase, cardiac involvement, family history and other indicators that were not part of a single process. In each process the indicator with the highest score is selected. These selected indicators are added and the final sum interpreted according to the "Raw Score Range" elaborated by the experts. More than 20 points as a total sum of pathological indicators is indicative of a greater likelyhood of MH and practically the patient must be treated. There is no recommendation for a certain score demanding treatment with Dantrolene, and likewise Dantrolene may be given to a patient that will be later classified as MH negative by the IVCT. Once the diagnosis is established, treatment must be applied as soon as possible.
Dantrolene inhibits the release of calcium by the sarcoplasmic reticulum and directly or indirectly prevents the increase of myoplasmic calcium, thus the pathological process associated with the crisis is reversed or attenuated.
All patients that have suffered a fulminant episode of MH must be referred to a specialized center for diagnosis of MH and tested with an In-Vitro Contracture Test (IVCT). This is the only officially accepted test for the diagnosis of MH throughout the world. A recent study of the European Malignant Hyperpyrexia Group found that the IVCT test had a 100% sensitivity and 97% specificity if the patients with equivical responses were considered positives too.The future diagnosis of MH will be non-invasive involving genetic testing.
Although recent investigations have shed much light on the pathophysiology and etiology of MH, the varied clinical presentations are still perplexing and controversial for the clinician. MH has many clinical presentations including:
Masseter Muscle Rigidity is a clinical sign that is characterized by intense spasm of the jaw after succinylcholine administration. It may last for one or two minutes or persist, being accompanied by fasciculations, general rigidity and failure in performing tracheal intubation. Van Der Spek et al found that in children, following induction of anesthesia with halogenated agents and succinylcholine there is normally an increase in jaw muscle tone for several minutes without evidence of hypermetabolism (Anesthesiology 1988). Rosenberg et al published in Anesthesia and Analgesia a study of the relation between trismus and MH susceptibility, where 50% of the patients presenting with masseter spasm were MH positives.
In the following disorders anesthetic triggering agents should be avoided:
Duchenne Muscular Dystrophy is associated with MH in 50% of patients after IVCT.
Central Core Disease.
Neuroleptic Malignant Syndrome is precipitated by phenothiazine and haloperidol and is manifested by fever, rhabdomyolysis and acidosis. NMS is not hereditary. The treatment of NMS is with Dantrolene, after the interruption of triggering drugs.
Dramatic elevations of body temperature outside of the operating room may occur secondary to the use of sympathetic stimulants such as amphetamine and MAO inhibitors.
There are some conditions/syndromes that may be confused
Finally, MH is a syndrome that can present in many different ways. One diagnosed, if the correct treatment is rapidly instituted the pathophysiological process is completely reversible. Where there is doubt about the diagnosis, use the CLINICAL GRADING SCORE, phone the nearest MH Center for advise, treat with Dantrolene, and observe the patient for 24 hours. All patients should be referred to an MH Center following an episode of MH.
In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: Results of testing patients surviving fulminant MH and unrelated low-risk subjects.
H. Ørding, V. Brancadoro, S. Cozzolino, F.R. Ellis, V. Glauber et al.
Acta Anaesthesiol Scand 1997; 41: 955-966
The Israeli Diagnostic Center for Malignant Hyperthermia:7-Years Accumulated Experience
Violeta Glauber, Ron Ben Abraham, Ami Zweig and Azriel Perel
Isr J Med Sci 1997:33:643-648
Ron Ben Abraham, Pascal Adnet, Violeta Glauber, Azriel Perel
Postgraduate Medical Journal
January 1998, Vol 74, No 867, p11-17
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