Malignant Hyperthermia



Malignant Hyperthermia


Robert Brislin

Mary Theroux

Henry Rosenberg

Vinod Malhotra





A. Medical Disease and Differential Diagnosis



  • What was the problem of concern in this case?


  • What is malignant hyperthermia (MH)?


  • What are the clinical features of a susceptible patient?


  • Does the history of previous uneventful sevoflurane anesthesia reasonably exclude the patient’s susceptibility to MH?


  • What are the clinical features of the syndrome?


  • What are the laboratory findings during an acute crisis of MH?


  • What is the incidence of this syndrome?


  • What is the mode of inheritance of the disease? Does MH skip generations?


  • What genetic disorder results in MH susceptibility?


  • What is the pathophysiology of the syndrome?


  • What laboratory tests can further substantiate the susceptibility of the patient to MH?


  • What is neuroleptic malignant syndrome?


B. Preoperative Evaluation and Preparation



  • How would you prepare this patient for anesthesia and surgery?


  • Is dantrolene prophylaxis indicated?


  • What laboratory tests would you obtain before surgery?


  • Is outpatient surgery appropriate for this patient?


  • In anticipation of general anesthesia, what preparations would you make?


C. Intraoperative Management



  • What anesthetic techniques and agents would you employ?


  • Should body (core) temperature be monitored during general anesthesia lasting more than a short time?


  • What anesthetic agents are contraindicated?


  • If the surgeon wants to use local anesthesia for a procedure, what agents will you recommend?


  • What is the significance of masseter muscle spasm occurring after succinylcholine administration?



  • Twenty minutes into the procedure with sevoflurane anesthesia, the patient developed increasing tachycardia with ventricular premature beats and mottled skin. What emergency measures would you take?


  • What modalities would you monitor closely during management of the crisis?


  • What steps should be taken to avoid major morbidity from MH?


  • How does the new formulation of dantrolene (Ryanodex) compare with the existing formulation of dantrolene (Dantrium or Revonto)?


D. Postoperative Management



  • What complications may follow this syndrome?


  • What would be your follow-up in this case?


  • What would you advise the patient and the family?


  • What precautions should an MH-susceptible patient take out of the operating room (OR)?


A. Medical Disease and Differential Diagnosis


A.1. What was the problem of concern in this case?

The patient was a 7-year-old boy with kyphoscoliosis and strabismus and a history of an anesthetic-related death in the family in Wisconsin. Therefore, in addition to the respiratory problems associated with kyphoscoliosis, he presented a likelihood of susceptibility to MH syndrome. The supporting factors for strong suspicion were the family history, kyphoscoliosis, and geographic location. There is a high density of MH-susceptible families in the state of Wisconsin.



Li G, Brady JE, Rosenberg H, et al. Excess comorbidities associated with malignant hyperthermia diagnosis in pediatric hospital discharge records. Paediatr Anaesth. 2011;21(9):958-963.

Rosenberg H, Sambuughin N, Riazi S, et al. Malignant hyperthermia susceptibility. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993. www-ncbi-nlm-nih-gov.proxy1.lib.tju.edu/books/NBK1146/. Accessed September 9, 2015.


A.2. What is malignant hyperthermia (MH)?

MH, first described by Denborough and Lovell in 1960, is an inherited clinical syndrome characterized by elevated core temperature, tachycardia, tachypnea, hypercarbia, muscle rigidity and rhabdomyolysis, acidosis, and hyperkalemia. The underlying abnormality relates to an uncontrolled elevation of intracellular calcium in skeletal muscle cells leading to activation of muscle contractile elements and hypermetabolism. These changes are reversed with the administration of dantrolene, but in the absence of timely treatment, death is likely. In almost every instance, the clinical syndrome occurs in a susceptible patient when a “triggering” anesthetic agent is employed. There are several documented instances where an apparent MH crisis has occurred in humans in the absence of anesthetic drugs.



Denborough MA, Lovell RRH. Anaesthetic deaths in a family [letter]. Lancet. 1960;2:45.

Groom L, Muldoon SM, Tang ZZ, et al. 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(5):938-945.

Lavezzi WA, Capacchione JF, Muldoon SM, et al. Case report: death in the emergency department: an unrecognized awake malignant hyperthermia-like reaction in a six-year-old. Anesth Analg. 2013;116(2):420-423.

Miller RD, ed. Miller’s Anesthesia. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015:1287-1300.


A.3. What are the clinical features of a susceptible patient?

A family history, if present, particularly in a first-degree relative, is a strong indicator of MH susceptibility. Epidemiologic studies have demonstrated that certain comorbidities such as scoliosis and muscle disorders are more frequent in MH-susceptible individuals. However, only a few diseases involving skeletal muscle are known to be associated with MH susceptibility. They include central core disease, King-Denborough syndrome, multiminicore
disease, centronuclear myopathy, congenital fiber-type disproportion, and Native American myopathy (Table 54.1). Nevertheless, many patients susceptible to MH do not have obvious musculoskeletal disorders or a positive family history.








TABLE 54.1 Associated Musculoskeletal Disorders/Signs in Patients Susceptible to Malignant Hyperthermia

















Central core disease


Multiminicore disease


King-Denborough syndrome


Native American myopathy


Centronuclear myopathy


Congenital fiber type disproportion


Exercise-induced rhabdomyolysis


Confusion often exists among some anesthesia providers regarding Duchenne or Becker muscular dystrophy and whether such patients need a nontriggering anesthetics. The concern about Duchenne or Becker dystrophy is related to the use of volatile anesthetics resulting in rhabdomyolysis and hyperkalemia due to the direct damage to the muscle cells. However, the pathophysiology of this adverse reaction is apparently not similar to that of MH. MH triggers, especially succinylcholine, should be avoided.



Brislin RP, Theroux MC. Core myopathies and malignant hyperthermia susceptibility: a review. Paediatr Anaesth. 2013;23(9):834-841.

Larach MG, Gronert GA, Allen GC, et al. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg. 2010;110:498-507.

Larach MG, Rosenberg H, Gronert GA, et al. Hyperkalemic cardiac arrest during anesthesia in infants and children with occult myopathies. Clin Pediatr (Phila). 1997;36(1):9-16.

McCarthy TV, Quane KA, Lynch PJ. Ryanodine receptor mutations in malignant hyperthermia and central core disease. Hum Mutat. 2000;15:410-417.

Rosenberg H, Pollock N, Schiemann A, et al. Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015;10:93.


A.4. Does the history of previous uneventful sevoflurane anesthesia reasonably exclude the patient’s susceptibility to MH?

No, it does not. Cases may occur during a second or subsequent anesthetic course. A notable case is one described in the case report, of an 8-month-old infant born at 24 weeks of gestation who died unexpectedly 12 hours after his ninth uneventful general anesthetic. The authors have personal experience with similar cases where uneventful anesthetics with triggering agents preceded fulminant episode of MH at a later anesthetic exposure.



Bendixen D, Skovgaard LT, Ording H. Analysis of anaesthesia in patients suspected to be susceptible to malignant hyperthermia before diagnostic in vitro contracture test. Acta Anaesthesiol Scand. 1997;41:480-484.

Newmark JL, Voelkel M, Brandom BW, et al. Delayed onset of malignant hyperthermia without creatine kinase elevation in a geriatric, ryanodine receptor type 1 gene compound heterozygous patient. Anesthesiology. 2007;107(2):350-353.


A.5. What are the clinical features of the syndrome?

The clinical features of MH are the result of an uncontrolled, exaggerated, hypermetabolic state triggered by the use of potent inhalation anesthetic agents and/or succinylcholine. In humans, MH-like events have occurred in association with heat and exercise. Some of those patients harbor MH causative mutations in the ryanodine receptor 1 (RYR1) gene. Common manifestations of MH include the following:


Specific for malignant hyperthermia



  • Increase in end-tidal carbon dioxide during constant ventilation (the most sensitive and specific sign)



  • Generalized rigidity (extremely high specificity)


  • Masseter muscle rigidity (not as specific as generalized rigidity and also sometimes difficult to distinguish from tight jaw due to “light anesthesia” and a normal increase in masseter muscle tension when succinylcholine is used.)


  • Increased temperature (not uncommonly higher than 40°C); formerly considered a late sign of MH but now recognized as a sign often occurring early during the course of MH


Nonspecific



  • Tachycardia (the earliest and most consistent clinical sign, although not specific)


  • Tachypnea


  • Arrhythmias


  • Skin mottling


  • Profuse sweating


  • Altered blood pressure


Hyperkalemic Cardiac Arrest

Sudden hyperkalemic cardiac arrest has been reported after the administration of MH trigger agents in children with undiagnosed myopathy, especially the dystrophinopathies, Duchenne or Becker muscular dystrophy. This response is not a result of pathophysiologic changes typical for MH but rather muscle membrane destruction leading to hyperkalemia. The pathways leading to the abnormal response is not clear.

The treatment is similar to treatment for hyperkalemia, that is, glucose and insulin, calcium chloride or gluconate, and hyperventilation.



Gurnaney H, Brown A, Litman RS. Malignant hyperthermia and muscular dystrophies. Anesth Analg. 2009;109:1043-1048.

Larach MG, Gronert GA, Allen GC, et al. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg. 2010;110:498-507.

Larach MG, Localio AR, Allen GC, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology. 1994;80:771-779.

Larach MG, Rosenberg H, Gronert GA, et al. Hyperkalemic cardiac arrest during anesthesia in infants and children with occult myopathies. Clin Pediatr (Phila). 1997;36(1):9-16.

Van der Spek AF, Fang WB, Ashton-Miller JA, et al. The effects of succinylcholine on mouth opening. Anesthesiology. 1987;67(4):459-465.


A.6. What are the laboratory findings during an acute crisis of MH?

The laboratory values reflect changes of a hypermetabolic state and muscle tissue damage (Table 54.2). Hence, hypercarbia, respiratory and metabolic acidosis, hyperkalemia, elevated creatine kinase, myoglobinemia, and coagulopathy are common findings. Disseminated intravascular coagulation syndrome may result in cases of extreme (>105°F) hyperthermia.



Larach MG, Gronert GA, Allen GC, et al. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg. 2010;110:498-507.

Litman RS, Rosenberg H. Malignant hyperthermia: update on susceptibility testing. JAMA. 2005;293:2918-2924.


A.7. What is the incidence of this syndrome?

The incidence of clinical MH is difficult to measure because many clinical syndromes resemble MH, and often, the anesthetic management is altered when initial signs suggesting MH are detected. The incidence also depends on the prevalence in a population of genetic mutations causal for MH as well as the prevalence of use of MH trigger agents.

One of the earliest epidemiologic studies of MH was conducted in Denmark, where an estimate of the incidence of fulminant MH was noted to be 1 in 260,000 general anesthetics and 1 in 60,000 anesthetics where succinylcholine was used. The incidence was even higher, that is, 1 in 5,000 anesthetics, when such signs as masseter muscle rigidity, unexplained tachycardia, and unexplained fever were included.

Genetic studies as well as studies of discharge diagnoses after surgery have suggested that the prevalence as opposed to incidence of MH is much higher. Mutations causal for MH have
been found in 1 in 3,000 people in France and in Japan. A recent study in the United States documented a prevalence of genetic changes associated with MH close to 1 in 500 people.








TABLE 54.2 The Laboratory Findings of Acute Malignant Hyperthermia

















































METABOLIC AND RESPIRATORY ACIDOSIS


Arterial blood gases



↓↓ pH



↑↑↑ PCO2



Mild decreases in PO2


Electrolytes



↑ K



↑ Ca or decreased



↑ Mg


Serum



↑ Lactate



↑ Pyruvate



↑ Creatine kinase



↑ Lactate dehydrogenase



↑ Aldolase



↑ Myoglobin


Increased international normalized ratio, increased fibrin split products increased prothrombin time, increased partial thromboplastin time.


It is generally acknowledged that MH is more common in children than adults. In addition, the incidence in males is higher than in females. Two recent studies of coded hospital discharge data showed that the prevalence of MH is 1 in 100,000 hospital discharges for adults and 4 per 100,000 discharges for children.



Brady JE, Sun LS, Rosenberg H, et al. Prevalence of malignant hyperthermia due to anesthesia in New York State, 2001-2005. Anesth Analg. 2009;109:1162-1166.

Gonsalves SG, Ng D, Johnston JJ, et al. Using exome data to identify malignant hyperthermia susceptibility mutations. Anesthesiology. 2013;119(5):1043-1053.

Li G, Brady JE, Rosenberg H, et al. Excess comorbidities associated with malignant hyperthermia diagnosis in pediatric hospital discharge records. Paediatr Anaesth. 2011;21(9):958-963.

Monnier N, Krivosic-Horber R, Payen JF, et al. Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology. 2002;97(5):1067-1074.

Rosero EB, Adesanya AO, Timaran CH, et al. Trends and outcomes of malignant hyperthermia in the United States, 2000 to 2005. Anesthesiology. 2009;110:89-94.


A.8. What is the mode of inheritance of the disease? Does MH skip generations?

MH is inherited in humans in an autosomal dominant fashion with reduced penetrance and variable expressivity. It is heterogenetic with up to seven gene loci implicated, but only three are confirmed to be causal for MH.

More than 70% of MH cases are linked to the RYR1 located on chromosome 19. Less than 2% are related to mutations in the gene coding for dihydropyridine receptor (DHPR) known as CACNA1s. Over 300 mutations have been found in the RYR1 gene with at least 35 mutations documented to be causal for the syndrome by the European Malignant Hyperthermia Group (EMHG.org).

Because MH is inherited in an autosomal dominant manner, the susceptibility to it does not “skip” generations. Nevertheless, because of the low penetrance, not all of those with MH mutations display the syndrome on exposure to trigger agents.

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Mar 18, 2021 | Posted by in ANESTHESIA | Comments Off on Malignant Hyperthermia
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