Malignant hyperthermia

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Malignant hyperthermia
PBB Protein RYR1 image.jpg
Abnormalities in the Ryanodine receptor 1 gene are commonly detected in malignant hyperthermia
ICD-10 T88.3
ICD-9 995.89
OMIM 145600 154275 154276 600467 601887 601888
DiseasesDB 7776
MeSH D008305

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nima Nasiri, M.D.[2]

Overview

Malignant hyperthermia (MH or MHS for "malignant hyperthermia syndrome", or "malignant hyperpyrexia due to anaesthesia") is a rare life-threatening condition that is triggered by exposure to certain drugs used for general anesthesia (specifically all volatile anesthetics), nearly all gas anesthetics, and the neuromuscular blocking agent succinylcholine. In susceptible individuals, these drugs can induce a drastic and uncontrolled 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 collapse and death if not treated quickly. MH susceptibility is phenotypically and genetically related to central core disease (CCD), an autosomal dominant disorder characterized both by MH symptoms and myopathy. When MH develops during a procedure, treatment with dantrolene sodium is usually initiated; dantrolene and the avoidance of anesthesia in susceptible people have markedly reduced the mortality from this condition.

Signs and symptoms

  • Malignant hyperthermia develops during or after receiving a general anaesthetic, and symptoms are generally identified by operating department staff.
  • Characteristic signs are muscular rigidity, followed by a hypermetabolic state with increased oxygen consumption, increased carbon dioxide production (hypercapnia, usually measured by capnography), tachycardia (fast heart rate), and an increase in body temperature (hyperthermia) at a rate of up to ~2°C per hour; temperatures up to 42°C are not uncommon.
  • Halothane, a once popular but now rarely used volatile anaesthetic, has been linked to a large proportion of cases, however, all halogenated volatile anaesthetics are potential triggers of malignant hyperthermia. Succinylcholine, a neuromuscular blocking agent, is also a trigger for MH.
  • MH does not occur with every exposure to triggering agents, and susceptible patients may undergo multiple uneventful episodes of anesthesia before developing an episode of MH. The symptoms usually develop within one hour after exposure to trigger substances, but may even occur several hours later in rare instances.
  • A proportion of people susceptible to malignant hyperthermia may have particular characteristics. A 1972 report on a family with MH also described myopathy (muscle weakness due to muscle cell abnormality), short stature, cryptorchidism (undescended testicles), pectus carinatum (a chest wall deformity), lumbar lordosis and thoracic kyphosis (reversed curvature of the spine), and unusual facial characteristics. Later reports have termed this combinations the King-Denborough syndrome, after the authors of the report.[1]

Diagnosis

Susceptibility testing

In patients who have suffered an episode of MH, further tests are usually not performed as even a normal test would not mean that the patient is not at further risk of further episodes on future occasions. The exception would be if it is unclear whether the initial attack was due to a different medical problem, such as sepsis (severe infection).[2][3]

  • The main candidates for testing are those with a close relative who has suffered an episode of MH or has been shown to be susceptible. The standard procedure is the "caffeine-halothane contracture test", CHCT.
  • A muscle biopsy is carried out at an approved research center, under local anesthesia. The fresh biopsy is bathed in solutions containing caffeine or halothane and observed for contraction; under good conditions, the sensitivity is 97% and the specificity 78%.[4]
  • Any patient who is suspected of MH by their medical history or that of blood relatives is generally treated with non-triggering anesthetics even if the biopsy was negative. Some researchers advocate the use of the "calcium-induced calcium release" test in addition to the CHCT to make the test more specific.
  • Less invasive diagnostic techniques have been proposed, intramuscular injection of halothane 6 vol% has been shown to result in higher than normal increases in local pCO2 among patients with known malignant hyperthermia susceptibility. The sensitivity was 100% and specificity was 75%. For patients at similar risk to those in this study, this leads to a positive predictive value of 80% and negative predictive value of 100%. This method may provide a suitable alternative to more invasive techniques.[3]
  • Based on the studies done, there is another possible metabolic test for diagnosing MH. In this test, intramuscular injection of caffeine was followed by local measurement of the pCO2; those with known MH susceptibility had a significantly higher pCO2 (63 versus 44 mmHg). The authors propose larger studies to assess the test's suitability for determining MH risk.[5]
  • A 2005 paper proposes a protocol for investigating people with a family history of MH, where first-line genetic screening of RYR1 mutations is one of the options.[6]

Diagnostic criteria

Diagnosis of malignant hyperhtermia is vased on clinical manifestation or laboratory testing. In 1994, a clinical grading scale was developed by Larach and colleagues in order to predict malignant hyperthermia susceptibility. The elements of this grading scales include:[7]

  • Respiratory acidosis (end-tidal CO2 above 55 mmHg or arterial pCO2 above 60 mgHg)
  • 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 6 mmol/l)
  • Temperature increase (rapidly increasing temperature, T >38.8°C)
  • Other (rapid reversal of MH signs with dantrolene, elevated resting serum CK levels)
  • Family history (autosomal dominant pattern)

Pathophysiology

Disease mechanism

  • The potential for malignant hyperthermia is caused in a large proportion (50-70%) of cases by a mutation of the ryanodine receptor (type 1), located on the sarcoplasmic reticulum (SR), the organelle within skeletal muscle cells that stores calcium.[8][9]
  • 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.
  • Mg2+ also affect 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.[10][11]
  • The excess Ca2+ must be reabsorbed and this process utilize large amounts of ATP (adenosine triphosphate), this leads to generation of 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, creatine, phosphate and creatine kinase.
  • The other known causative gene for MH is CACNA1S, which encodes and L-type voltage-gated calcium channel α-subunit. There are two known mutations in this protein, both affecting the same residue, R1086.[12][13]
  • 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 HEK 293 (human embryonic kidney) 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.[14]
  • Other mutations causing MH have been identified, although in most cases the relevant gene remains to be identified.[6]

Animal model

  • Research into malignant hyperthermia was limited until the discovery of "porcine stress syndrome" in Landrace pigs, a condition in which stressed pigs develop "pale, soft, exudative" flesh (a manifestation of the effects of malignant hyperthermia) rendering their meat unmarketable at slaughter.
  • This "awake triggering" was not observed in humans, and initially cast doubts on the value of the animal model, but subsequently susceptible humans were discovered to "awake trigger" (develop malignant hyperthermia) in stressful situations.
  • This supported the use of the pig model for research. Pig farmers use halothane cones in swine yards to expose piglets to halothane. Those that die were MH-susceptible, thus saving the farmer the expense of raising a pig whose meat he would not be able to market.
  • Gillard et al discovered the causative mutation in humans only after similar mutations had first been described in pigs.[8]
  • Horses also suffer from malignant hyperthermia. It is the Thoroughbred breed that was found to have susceptibility. It can be caused by overwork, anesthesia, or stress. An inheritable genetic mutation is found in susceptible animals. [15]
  • An MH mouse has been constructed, bearing the R163C mutation prevalent in humans. These mice display symptoms similar to human MH patients, including sensitivity to halothane (increased respiration, body temperature, and death). Blockade of RYR1 by dantrolene prevents adverse reaction to halothane in these mice, as with humans. Muscle from these mice also shows increased K+-induced depolarization and an increased caffeine sensitivity.[16]

Genetics

  • At least 70 mutations in the ryanodine receptor have been described, which are transmitted in an autosomal dominant fashion.
  • The gene is located on the long arm of the nineteenth chromosome (19q13.1).
  • These mutations tend to cluster in one of three domains within the protein, designated MH1-3. MH1 and MH2 are located in the N-terminus of the protein, which interacts with L-type calcium channels and Ca2+. MH3 is located in the transmembrane forming C-terminus.
  • This region is important for allowing Ca2+ passage through the protein following opening.

Differential diagnosis of malignant hyperthermia

A number of conditions may present with clinical manifestation similar to those of acute malignant hyperthermia. Although treatment for malignant hyperthermia should be initiated during an acute attack, it is important to consider other causes as an alternative diagnosis. [17]

Disease/Condition Differentiating Signs/Symptoms Differentiating Tests Non-MH rhabdomyolysis

Electrocardiographic abnormality (peaked T waves and/or bradycardia) evolves into ventricular fibrillation prior to the elevation of carbon dioxide tension in blood or end-expiratory gas. With decreasing cardiac output, carbon dioxide tension will decrease in expiratory gas. [52]

Blood gas and electrolyte measurement shows acidemia and hyperkalemia.

Resolves with treatment of hyperkalemia with calcium.

Muscle histopathology reveals primary muscle pathology.

Genetic diagnosis of muscle disease, such as dystrophinopathy.

Muscle disuse atrophy

A history of immobility or neuromuscular injury and exposure to succinylcholine is usually present. [76]

Electrocardiographic abnormality (peaked T waves and/or bradycardia) evolves into ventricular fibrillation prior to elevation of carbon dioxide tension in blood or end-expiratory gas.

Extreme hyperkalemia can occur after the administration of succinylcholine to a patient with muscle disuse atrophy.

Respiratory and metabolic acidosis are usually more marked than hyperkalemia in a patient experiencing an early MH crisis.

Resolves with treatment of hyperkalemia with calcium.

Muscle histopathology may have signs of denervation or necrosis.

Myotonia

Muscle stiffness occurs without a markedly increased metabolism.

Electromyography shows characteristic changes.

In some cases genetic testing can be used to diagnose myotonia.

Sepsis

Sepsis-induced hyperpyrexia may be suppressed by volatile anesthetics, and present more profoundly in the post-anesthetic period. However, unlike MH, it does respond to antipyretic therapy such as acetaminophen. [6]

Responds to antipyretic drugs. The temperature often decreases after acetaminophen in the presence of infection.

Culture of blood, urine, or other material reveals a source of infection.

White cell count is elevated.

Complications of laparoscopic surgery

Increased airway pressure is required to maintain minute ventilation but muscle tone is normal.

Breath sounds are normal.

Crepitus may be present if carbon dioxide has escaped from the body cavity into the skin. This increases carbon dioxide absorption and apparent carbon dioxide production, but is not associated with increased temperature, heart rate, or higher oxygen consumption.

No differentiating tests.

Allergic reaction

Airway edema, wheezing, and urticaria may be present.

Responds to epinephrine, antihistamines, and corticosteroids.

No response to dantrolene.

Tryptase and immunoglobulins elevated in blood.

Skin testing or blood testing identifies allergen.

Serotonin syndrome

Progression to critical temperature and multiorgan system failure may be slower than during MH.

Triggered by serotonergic drugs rather than inhalation anesthetics. [60] [77] [78] [79]

Absence of other causes of temperature elevation and rigidity and presence of the drug in the plasma.

Neuroleptic malignant syndrome

Progression to critical temperature and multiorgan system failure may be slower than during MH.

Triggered by dopamine receptor antagonists rather than inhalation anesthetics. [79] [80]

Absence of other causes of temperature elevation and rigidity and presence of the drug in the plasma.

Baclofen withdrawal syndrome

Chronic exposure to baclofen and sudden termination of administration may be followed after several hours with severe dystonia, critical temperature, and multiorgan system failure. [60]

A low plasma or cerebrospinal fluid concentration of baclofen.

Thyrotoxicosis

Muscle tone is normal.

Increases in metabolism are less marked. [81]

Pseudohyperthyroidism can be induced by some weight loss dietary supplements.

Blood gas to assess pCO2 and pH is normal.

Triiodothyronine (T3) is elevated.

Pheochromocytoma

Headache and weight loss may be present.

Extremities may be cool.

Plasma or urinary catecholamines are elevated.

PET scanning of the abdomen and/or thorax reveals the pheochromocytoma.

Drug-induced muscle injury

A history of the use of known drug triggers (usually statins) is present.

Muscle pain and sometimes muscle edema precede temperature elevation.

No differentiating tests.

MDMA overdose

Volume depletion is also present.

History of recent attendance at a "rave" or MDMA (methylenedioxymethamphetamine) use is present. [79]

Temperature may decrease after carvedilol or dantrolene administration. [82]

Use of designer drugs or new psychoactive substances (e.g., alpha-PVP or flakka)

Rhabdomyolysis, profound acute kidney injury, increased psychomotor activity, and hyperthermia are present. [83]

Urine and serum toxic screening for metabolites of drugs. [51]

Exertional heat stroke

Hyperventilation and dehydration are present.

Blood gas shows a low pCO2.

Thermal dysregulation

A history of recent exposure to a pyrogen is usually present.

No differentiating tests.

Iatrogenic overheating

Usually occurs during surgery at small, superficial surgical sites such as the ear when the rest of the patient is covered by occlusive drapes.

Administration of heat during anesthesia.

No differentiating tests.

Meperidine/MAOI/cocaine abuse

History of antidepressant use, chronic pain, drug seeking behavior.

Monoamine oxidase inhibitors (MAOIs) may enhance the serotonergic effect of meperidine, resulting in serotonin syndrome (triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities). [60] [79]

Epidemiology

  • The incidence has been reported to be between 1:4,500 to 1:60,000 procedures involving general anaesthesia.
  • This disorder occurs worldwide and affects all racial groups.
  • Most cases however occur in children and young adults, which might be related to the fact that many older people will have already had surgeries and thus would know about and be able to avoid this condition.

History

  • The syndrome was first recognized in Australia in an affected family by Denborough et al in 1962.[18]
  • Similar reactions were found in pigs.[19]
  • The efficacy of dantrolene as a treatment was discovered by South African anesthesiologist Gaisford Harrison and reported in a 1975 article published in the British Journal of Anaesthesia.[20]
  • After further animal studies corroborated the possible benefit from dantrolene, a 1982 study confirmed its usefulness in humans.[21]

Treatment

  • The current treatment of choice is the intravenous administration of dantrolene.
  • Treatment must be initiated emergently as soon as malignant hyperthermia diagnosed based on clinical suspicion of the onset of symptoms.
  • Dantrolene is a post-synaptic muscle relaxant which inhibits Ca2+ ions release from sarcoplasmic reticulum stores by antagonizing ryanodine receptors directly on the ryanodine receptor to prevent the release of calcium that leads to lesser excitation-contraction of muscle cells.
  • After the widespread introduction of treatment with dantrolene the mortality of malignant hyperthermia fell from 80% in the 1960s to less than 10%.[22]
  • Its clinical use has been limited by its low water solubility, leading to requirements of large fluid volumes which may complicate clinical management.
  • In MH susceptible swine, azumolene was as potent as dantrolene. It has yet to be studied in vivo in humans, but may present a suitable alternative to dantrolene in the treatment of MH.[23]

Prevention

  • In the past, the prophylactic use of dantrolene was recommended for MH susceptible patients undergoing general anesthesia. However, multiple retrospective studies, have demonstrated the safety of trigger-free general anesthesia in these patients in the absence of prophylactic dantrolene administration. [22]
  • The largest of these studies looked at the charts of 2214 patients who underwent general or regional anesthesia for an elective muscle biopsy. 1082 of the patients were muscle biopsy positive for MH. Only five of these patients exhibited symptoms consistent with MH, four of which were treated successfully with parenteral dantrolene, and the remaining one recovered with only symptomatic therapy.[24]
  • The only sure way to prevent MH is to avoid the use of triggering agents in patients known or suspected of being susceptible to MH.

References

  1. King JO, Denborough MA, Zapf PW (1972). "Inheritance of malignant hyperpyrexia". Lancet. 1 (7746): 365–70. doi:10.1016/S0140-6736(72)92854-1. PMID 4109748.
  2. Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K (August 2015). "Malignant hyperthermia: a review". Orphanet J Rare Dis. 10: 93. doi:10.1186/s13023-015-0310-1. PMC 4524368. PMID 26238698.
  3. 3.0 3.1 Schuster F, Gardill A, Metterlein T, Kranke P, Roewer N, Anetseder M (September 2007). "A minimally invasive metabolic test with intramuscular injection of halothane 5 and 6 vol% to detect probands at risk for malignant hyperthermia". Anaesthesia. 62 (9): 882–7. doi:10.1111/j.1365-2044.2007.05173.x. PMID 17697213.
  4. Allen G, Larach M, Kunselman A (1998). "The sensitivity and specificity of the caffeine-halothane contracture test: a report from the North American Malignant Hyperthermia Registry". Anesthesiology. 88 (3): 579–88. doi:10.1097/00000542-199803000-00006. PMID 9523799.
  5. Anetseder M, Hager M, Müller CR, Roewer N (2002). "Diagnosis of susceptibility to malignant hyperthermia by use of a metabolic test". Lancet. 359 (9317): 1579–80. doi:10.1016/S0140-6736(02)08506-9. PMID 12047971.
  6. 6.0 6.1 Litman R, Rosenberg H (2005). "Malignant hyperthermia: update on susceptibility testing". JAMA. 293 (23): 2918–24. doi:10.1001/jama.293.23.2918. PMID 15956637.
  7. Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, Kaplan RF, Muldoon SM, Nelson TE, Ording H (April 1994). "A clinical grading scale to predict malignant hyperthermia susceptibility". Anesthesiology. 80 (4): 771–9. PMID 8024130.
  8. 8.0 8.1 Gillard E, Otsu K, Fujii J, Khanna V, de Leon S, Derdemezi J, Britt B, Duff C, Worton R, MacLennan D (1991). "A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia". Genomics. 11 (3): 751–5. doi:10.1016/0888-7543(91)90084-R. PMID 1774074.
  9. Galli L, Orrico A, Lorenzini S, Censini S, Falciani M, Covacci A, Tegazzin V, Sorrentino V (2006). "Frequency and localization of mutations in the 106 exons of the RYR1 gene in 50 individuals with malignant hyperthermia". Hum Mutat. 27 (8): 830. doi:10.1002/humu.9442. PMID 16835904.
  10. Balog E, Fruen B, Shomer N, Louis C (2001). "Divergent effects of the malignant hyperthermia-susceptible Arg(615)->Cys mutation on the Ca(2+) and Mg(2+) dependence of the RyR1". Biophys J. 81 (4): 2050–8. PMID 11566777. PMC 1301678
  11. Yang T, Ta T, Pessah I, Allen P (2003). "Functional defects in six ryanodine receptor isoform-1 (RyR1) mutations associated with malignant hyperthermia and their impact on skeletal excitation-contraction coupling". J Biol Chem. 278 (28): 25722–30. doi:10.1074/jbc.M302165200. PMID 12732639.
  12. Monnier N, Procaccio V, Stieglitz P, Lunardi J (1997). "Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle". Am J Hum Genet. 60 (6): 1316–25. doi:10.1086/515454. PMID 9199552. PMC 1716149
  13. The R1086C mutant has never been published, but has nevertheless been referenced multiple times in the literature, e.g. Jurkat-Rott K, McCarthy T, Lehmann-Horn F (2000). "Genetics and pathogenesis of malignant hyperthermia". Muscle Nerve. 23 (1): 4–17. doi:10.1002/(SICI)1097-4598(200001)23:1<4::AID-MUS3>3.0.CO;2-D. PMID 10590402.
  14. Weiss R, O'Connell K, Flucher B, Allen P, Grabner M, Dirksen R (2004). "Functional analysis of the R1086H malignant hyperthermia mutation in the DHPR reveals an unexpected influence of the III-IV loop on skeletal muscle EC coupling". Am J Physiol Cell Physiol. 287 (4): C1094–102. doi:10.1152/ajpcell.00173.2004. PMID 15201141.
  15. Valberg SJ, Mickelson JR, Gallant EM, MacLeay JM, Lentz L, de la Corte F (1999). "Exertional rhabdomyolysis in quarter horses and thoroughbreds: one syndrome, multiple aetiologies". Equine Vet J Suppl. 30: 533–8. PMID 10659313.
  16. Yang T, Riehl J, Esteve E; et al. (2006). "Pharmacologic and functional characterization of malignant hyperthermia in the R163C RyR1 knock-in mouse". Anesthesiology. 105 (6): 1164–75. doi:10.1097/00000542-200612000-00016. PMID 17122579.
  17. Rosenberg H, Davis M, James D, Pollock N, Stowell K (April 2007). "Malignant hyperthermia". Orphanet J Rare Dis. 2: 21. doi:10.1186/1750-1172-2-21. PMC 1867813. PMID 17456235.
  18. Denborough MA, Forster JF, Lovell RR, Maplestone PA, Villiers JD (1962). "Anaesthetic deaths in a family". British Journal of Anaesthesia. 34: 395–6. doi:10.1093/bja/34.6.395. PMID 13885389. Historical account in Denborough MA (2008). "Malignant hyperthermia. 1962". Anesthesiology. 108 (1): 156–7. doi:10.1097/01.anes.0000296107.23210.dd. PMID 18156894. Unknown parameter |doi_brokendate= ignored (help)
  19. Hall LW, Woolf N, Bradley JW, Jolly DW (1966). "Unusual reaction to suxamethonium chloride". Br Med J. 2 (5525): 1305. PMID 5924819. PMC 1944316
  20. Harrison GG (1975). "Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium". British Journal of Anaesthesia. 47 (1): 62–5. PMID 1148076. Unknown parameter |month= ignored (help) A reprint of the article, which became a "Citation Classic", is available in Br J Anaesth81 (4): 626–9. PMID 9924249 (free full text).
  21. Kolb ME, Horne ML, Martz R (1982). "Dantrolene in human malignant hyperthermia". Anesthesiology. 56 (4): 254–62. doi:10.1097/00000542-198204000-00005. PMID 7039419.
  22. 22.0 22.1 Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F (2004). "Dantrolene--a review of its pharmacology, therapeutic use and new developments". Anaesthesia. 59 (4): 364–73. doi:10.1111/j.1365-2044.2004.03658.x. PMID 15023108.
  23. Dershwitz M, Sréter FA (1990). "Azumolene reverses episodes of malignant hyperthermia in susceptible swine". Anesth. Analg. 70 (3): 253–5. doi:10.1213/00000539-199003000-00004. PMID 2305975.
  24. Carr AS, Lerman J, Cunliffe M, McLeod ME, Britt BA (1995). "Incidence of malignant hyperthermia reactions in 2,214 patients undergoing muscle biopsy". Can J Anaesth. 42 (4): 281–6. PMID 7788824.

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