It is a life threatening condition that is triggered by exposure to certain drugs used in general anesthesia, specifically volatile anesthetic agents and neuromuscular blocking agent, succinylcholine. These drug induce a drastic increase in skeletal muscle oxidative metabolism, which overwhelms the body’s capacity to supply oxygen, remove carbon dioxide and regulate body temperature, eventually leading to circulatory failure and death.
It is most commonly inherited as autosomal dominant disorder with 6 genetic loci of interest, most predominantly the ryanodine receptor gene (RYR1). Certain inherited muscle disease (central core disease and multiminicore disease) are associated with malignant hyperthermia.
The reported frequency of malignant hyperthermia (MH) in the United States ranges from 1 in 10,000 patients receiving anesthetics to 1 in 50,000; the reported frequency in children is higher. The annual number of suspected MH cases per year in the United States is around 700.
Pathophysiology of malignant hyperthermia
In a large proportion (50–70%) of cases, the propensity for malignant hyperthermia is due to a mutation of the ryanodine receptor (type 1), located on the sarcoplasmic reticulum (SR), the organelle within skeletal muscle cells that stores calcium. RYR1 opens in response to increases in intracellular Ca2+ level mediated by L-type calcium channels, thereby resulting in a drastic increase in intracellular calcium levels and muscle contraction. RYR1 has two sites believed to be important for reacting to changing Ca2+ concentrations: the A-site and the I-site. The A-site is a high affinity Ca2+
binding site that mediates RYR1 opening. The I-site is a lower affinity site that mediates the protein's closing. Caffeine, halothane, and other triggering agents act by drastically increasing the affinity of the A-site for Ca2+ and concomitantly decreasing the affinity of the I-site in mutant proteins. Mg2+ also affects RYR1 activity, causing the protein to close by acting at either the A- or I-sites. In MH mutant proteins, the affinity for Mg2+ at either one of these sites is greatly reduced. The end result of these alterations is greatly increased Ca2+ release due to a lowered activation and heightened deactivation threshold. The process of sequestering this excess Ca2+ consumes large amounts of adenosine triphosphate (ATP), the main cellular energy carrier, and generates the excessive heat (hyperthermia) that is the hallmark of the disease. The muscle cell is damaged by the depletion of ATP and possibly the high temperatures, and cellular constituents "leak" into the circulation, including potassium, myoglobin, creatinine, phosphate and creatinine kinase.
The other known causative gene for MH is CACNA1S, which encodes an L-type voltage-gated calcium channel α-subunit. There are two known mutations in this protein, both affecting the same residue, R1086. This residue is located in the large intracellular loop connecting domains 3 and 4, a domain possibly involved in negatively regulating RYR1 activity. When these mutant channels are expressed in human embryonic kidney (HEK 293) cells, the resulting channels are five times more sensitive to activation by caffeine (and presumably halothane) and activate at 5–10mV more hyperpolarized. Furthermore, cells expressing these channels have an increased basal cytosolic Ca2+ concentration. As these channels interact with and activate RYR1, these alterations result in a drastic increase of intracellular Ca2+, and, thereby, muscle excitability.
It is an autosomal dominant inherited disorder. The defect is located on the long arm of chromosome 19 (19q13.1) involving the ryanodine receptor.
The most common trigger agents include:
• Other agents like
o Monoamine oxidase inhibitors
The signs and symptoms are developed due to hypercatabolic state. The symptoms develop within an hour after exposure to trigger substance, but may even occur after several hours. The symptoms are:
• Very high temperature
• Increased heart rate
• Increased respiration
• Increased carbon dioxide production
• Increased oxygen consumption
• Rigid muscles
Clinical conditions associated with susceptibility to MH include King-Denborough syndrome, central core disease, and minicore myopathy. Individuals with these disorders have RyR1 mutations and should be considered at risk for MH.
King-Denborough syndrome is characterized by short stature, musculoskeletal abnormalities, and mental retardation. Some individuals with this syndrome also have central core disease. Central core disease is characterized by hypotonia, muscle weakness, and central cores on muscle biopsy. Minicore myopathy is a group of disorders characterized by severe hypotonia and generalized weakness.
During an attack
Clinical diagnosis is made by presence of following signs:
• Early masseter muscle contracture
• A rise in end tidal carbon dioxide concentration (despite increased minute ventilation)
• Unexplained tachycardia
• Muscle rigidity
• Cardiac dysrhythmias
Blood tests done shows:
• Raised creatinine kinase level
• Elevated potassium
• Increased phosphate
• Decreased calcium
• Raised myoglobin
• Metabolic and respiratory acidosis
• Severe rhabdomyolysis may lead to acute renal failure
1. Caffeine-halothane contracture test
A muscle biopsy is done under local anesthesia. The fresh biopsy is bathed in solutions containing caffeine or halothane and is observed for contraction.
The sensitivity if the test is 97% and the specificity is 78%.
The test is performed on freshly biopsied muscle tissue at 30 centers worldwide; 1 of these centers is located in Canada, and 4 are located in the United States.
The CHCT testing centers in North America are located at the following sites:
• The Ottawa Hospital, Civic Campus, Ottawa, Ontario; Kevin Nolan, MD, FRCPC; (613) 761-4169; firstname.lastname@example.org email@example.com
• Uniformed Services University of the Health Sciences, Bethesda, MD (Military & Civilian); Sheila M. Muldoon, MD; (301) 295-3532; firstname.lastname@example.org
• University of California, Davis; Timothy Tautz, MD; (530) 752-7805; email@example.com
• University of Minnesota, Minneapolis; Paul A. Iaizzo, PhD; (612) 624-7912 or (612) 624-3959; firstname.lastname@example.org (for more information on this center: www.vhlab.umn.edu/mh/index.html)
• Wake Forest University, Winston-Salem, NC; Joseph R. Tobin, MD; (336) 716-4498; email@example.com
2. Intramuscular injection of halothane 6 vol% results in higher increase in local pCO2 among patients with known malignant hyperthermia susceptibility. The sensitivity of the test is 100% and specificity is 75%.
Diagnostic criteria of malignant hyperthermia
• Respiratory acidosis (end tidal CO2 bove 55 mm Hg/ 7.32 kPa or arterial pCO2 above 60 mmHg/ 7.98kPa)
• Heart involvement (unexplained sinus tachycardia, ventricular tachycardia or ventricular fibrillation)
• Metabolic acidosis (base excess lower than -8, pH <7.25)
• Muscle rigidity (generalized rigidity including severe masseter muscle rigidity)
• Muscle breakdown (CK > 20,000/L units, cola colored urine or excess myoglobin in urine or serum, potassium above 6mmol/l)
• Temperature increase (rapidly increasing temperature, T > 38.8 degC)
• Other (rapid reversal of MH signs with dantrolene, elevated resting serum CK levels)
• Family history (autosomal dominant pattern)
The current treatment of choice is intravenous administration of dantrolene, discontinuation of triggering agents and supportive treatment directed at correcting hyperthermia, acidosis and organ dysfunction.
Dantrolene is a muscle relaxant that works directly on the ryanodine receptor to prevent the release of calcium. Its clinical use has been limited by its low water solubility, leading to requirements of large fluid volumes, which may complicate the clinical management.
The initial dose is 2.5 mg/kg, repeated every 5 minutes until reversal of the reaction occurs or a total dose of 10 mg/kg (or 20 mg/kg, according to some practitioners) is reached. If there is no clinical response, another diagnosis should be considered. Dantrolene will also lower an elevated temperature in disorders other than MH, such as thyroid storm, neuroleptic malignant syndrome, and sepsis. Each 20-mg vial of lyophilized powder contains sodium hydroxide for a pH of 9-10 and mannitol, which makes the solution isotonic. The half-life is 6-10 hours.
Once the initial reaction is controlled, continued monitoring in the ICU for 24-48 hours is recommended, along with administration of dantrolene (1 mg/kg every 4-6 hours, or an equivalent amount given as a continuous infusion). Myoglobinuria should be watched for and treated with fluids and diuretics if it occurs. The creatine kinase level will peak about 8-10 hours after the event and should be followed until it returns to near normal.
A new version of dantrolene dissolves in 15 seconds and thereby improves the rapidity of treatment. Another improvement is the addition of charcoal filters that can be placed in the anesthesia machine circuit. These filters can remove the inhalation agent in 1-2 minutes and help quickly reverse the effects of the MH reaction.
Additional treatment can include:
• Lowering body temperature with:
o Cool mist and fans
o Cooling blankets
o Cooled intravenous fluids
• Administering oxygen
• Dextrose, insulin, calcium chloride and possibly dialysis for correction of hyperkalemia
• Hyperventilation and possibly sodium bicarbonate for management of acidosis
• Using medications to:
o Control the heartbeat
o Stabilize blood pressure
• Monitoring in an intensive care unit
Azumolene is a 30 fold more water soluble analogue of dantrolene that decrease the release of intracellular calcium by its action on ryanodine receptor.
Various conditions and circumstances may mimic MH, including the following:
• Contrast dye
• Diabetic coma
• Drug toxicity
• Environmental heat gain
• Equipment malfunction, increased carbon dioxide, rebreathing, soda lime exhaustion
• Exercise hyperthermia
• Freeman-Sheldon syndrome
• Heat stroke
• Hypokalemic periodic paralysis
• Intracranial free blood
• Muscular dystrophies (eg, Duchenne, Becker)
• Neuroleptic malignant syndrome
• Osteogenesis imperfecta
• Prader-Willi syndrome
• Ventilation problems
• Wolf-Hirschhorn syndrome
Cancellation of a surgical procedure
A diagnosis of trismus after giving succinylcholine with induction raises the question of whether the surgical procedure should be canceled; a clinical episode will follow the trismus 20% of the time. When the anesthesia provider first suspects that an MH reaction may be occurring, the surgeon should be notified promptly, and a decision should be made about whether the procedure is to be continued or canceled. If the procedure is canceled, the patient should be observed in the hospital for 24 hours for signs of MH.
Modification in anesethesia approach
The following considerations should be kept in mind in planning anesthesia for an MH-susceptible patient:
• Avoid triggering agents (eg, major inhalational agents and succinylcholine)
• Use nontriggering general, regional, spinal, epidural, local, or MAC
• Watch for signs of MH
• Use a clean anesthesia machine; remove vaporizers or tape them in the off position, change soda lime and baralyme, replace the circuits, replace the fresh gas tubing if possible, and run oxygen through the machine at 10 L/min for 20 minutes (10 minutes if the fresh gas tubing was replaced)
• The procedure can be done on an outpatient basis; if all goes well, the patient can be dismissed safely after 2-3 hours
The prognosis is poor if the condition is not treated aggressively. With current management, the mortality is less than 5%.
Malignant hyperthermia association of the United States (MHAUS) has been established since 1981 with the mission to promote optimum care and scientific understanding of malignant hyperthermia and related disorders.