What you must know about malignant hyperthermia.
Everything That You Must Know About Malignant Hyperthermia
Rae Brown, M.D.
Malignant hyperthermia is a pharmacogenetic disease process. The manifestations of the disease occur when predisposed individuals are exposed to a small number of drugs. Most of these “triggering agents” are general anesthetics. Succinylcholine and all of the potent inhalational agents have been implicated – including xenon.
MH occurs because of a defect in the calcium sensitive ryanidine receptor - RYR1. This receptor is found in all skeletal muscle, smooth muscle, neurons, and in B-lymphocytes. In skeletal muscle, the RYR forms the footplate between the transverse tubules and the sarcoplasmic reticulum. Calcium homeostasis is mediated through these receptors and defects can produce massive outpouring of calcium during excitation contraction coupling. Because skeletal muscle contains a large percentage of the intracellular calcium in the body, failure of regulation creates exaggerated contraction, a hypermetabolic state, with an elevated temperature and subsequent severe acidosis. This is the clinical picture that is called malignant hyperthermia.
A specific point mutation in the RYR1 has been associated with MH. However, only about a third of the patients with MH will demonstrate this specific point mutation. RYR1 is a very large protein, the largest known receptor in the body. It is likely that other point mutations will be found that produce the same clinical effect.
There is one very sensitive test for malignant hyperthermia – the caffeine halothane contraction test. This test will be positive in more that 97% of patients that have true MH and is 78% specific. This includes patients with known point mutations in the RYR1 protein that are known to be associated with MH as well as those that do not. For this reason, the CHCT is the only test that is available that is reliable/specific/sensitive. Molecular genetics testing will demonstrate the point mutation that is known in the RYR1, but will miss the other 65% of patients. Molecular testing is appropriate for relatives of a proband that has had molecular genetic testing that is positive. Otherwise, it should not be used as a screening test.
The CHCT is difficult to perform and can only be performed on fresh muscle. There are currently only five centers in North America that are certified to do this test. The number of centers is kept to a minimum in order to improve the specificity of the test. The center that is closest to Lexington is in Winston-Salem, NC. Because the multiple fascicles that are required to perform the test, it would be uncommon for a child under 40 kg/ten years old to present for testing.
MH may randomly present associated with any disease process. In the past, an association between strabismus and MH was shown to represent a statistical error caused by the increased likelihood that these patients would present for surgery. There are very few disease processes that are now recognized as being tightly linked to MH. In the future, this number may decrease further as we understand more about the genetic basis for the disease. Presently central core disease, hypokalemic periodic paralysis, and King-Denborough Syndrome, a combination of facial dysmorphic features with MH, are the only disease processes that seem to manifest the hypermetabolic state with exposure to anesthetics. For these patients, at present, all should be managed with nontriggering techniques.
The association between muscular dystrophy and the hyperkalemic cardiac arrests associated with the administration of succinylcholine represent an entirely separate pathophysiology, but can be equally as deadly. The presence of a large number of cases of cardiac arrest in infant boys, later found to have muscular dystrophy, is the primary reason that succinylcoline is not routinely used in the United States.
Malignant hyperthermia presents as a profound hypermetabolic response. Early indicators include tachycardia, rapid increases in end tidal carbon dioxide despite seemingly adequate ventilation, and rigidity. Despite its name MH rarely presents with an elevation in temperature as the first and/or only manifestation of a crisis. Continued exposure to the causative agent, however, will accelerate the disease process and early reversion to nontriggers as the primary anesthetic is a key to the resuscitation of the patient.
Immediate treatment with dantrolene can be life saving. This medication should be prepared and given quickly after a presumptive diagnosis is made. Dantrolene inhibits the release of calcium from the sarcoplasmic reticulum of skeletal muscle. This is accomplished by limiting the activation of the RYR. Though dantrolene does not act at the neuromuscular junction it will produce profound muscle weakness. Patients treated during the preoperative period with prophylactic dantrolene have aspirated because of this effect and there is no evidence that use of the drug prior to an exposure to a triggering agent is better than after exposure.
There are several keys to successful resuscitation of patients with MH:
1. Vigilance allows the savvy clinician to recognize the clinical scenario early in its course. Good anesthesiologists are suspicious and will note the association of tachycardia, increasing carbon dioxide, and possibly rigidity for what it is.
2. Early elimination of triggers and administration of dantrolene is very important. Dantrolene is difficult to prepare and extra hands are always necessary. It will require more than one person to prepare dantrolene alone. Currently, a bolus of 2.5 mg/kg as a first dose is recommended, with subsequent boluses of 2.5 mg/kg, administered until the patient is stabilized.
3. Secondary cooling of the patient is important, but should not prevent or slow the preparation and administration of dantrolene. Time and resources are often wasted running for ice and getting rafts, when the primary drug for resuscitation sits unopened.
4. If there are sufficient resources to prepare dantrolene and provide the resources to cool the patient, then this can be done with cool IV fluids or saline lavage of the bladder or stomach.
5. Further treatment is symptomatic and includes response to acidosis, arrhythmias, electrolyte disturbances, and excess myoglobin production caused by muscle destruction with subsequent acute renal failure.
6. Patients that manifest and are treated for MH should be monitored and treated in an intensive care setting postoperatively. It is recommended that patients be treated with dantrolene for 24 hours after metabolic stability returns. The MHAUS recommends a dose of 1 mg/kg every 4 to 6 hours. In addition, because of the risk of recrudescence of MH, patients should be monitored for at least 24 hours after the last dose of dantrolene is given.
Patients that have had an episode of MH, with first degree relatives that have had a clinical incident strongly suggestive of MH, those with a positive CHCT, or who have had molecular genetic testing demonstrating the point defect in RYR1 that has been tied to MH, should subsequently have nontriggering anesthetics. This can be accomplished with virtually any agent normally used by the anesthetist, with the exception of succinylcholine and potent inhalational agents. Patients have been successfully anesthetized as out patients, for labor and delivery, and with regional anesthesia.
Neuroleptic malignant syndrome is a rare, but life threatening idiosyncratic response to a neuroleptic medication. Though the clinical picture emulates MH with rigidity, fever, and autonomic dysfunction, NMS is mediated through the blockade of dopaminergic pathways within the central nervous system. Drugs such as haloperidol, thorazine and resperidone can produce the picture of NMS as well as phenergan, droperidol, and metaclopramide. Treatment with dantrolene is not specifically indicated, but withdrawal of neuroleptics and symptomatic management of rigidity (levodopa/carbodopa), respiratory failure or renal failure is necessary.
Masseter muscle rigidity, also called masseter spasm, is usually associated with the administration of succinylcholine. It has been suggested that this may be an early sign of MH. Masseter spasm with associated elevations in carbon dioxide or fever should be treated as MH
MHAUS, The Malignant Hyperthermia Society of the United States, has an excellent web site, which provides up to date information about testing, diagnosis and treatment.
Rae Brown, MD
Department of Anesthesiology
University of Kentucky Medical Center
Kentucky Children’s Hospital
Rae Brown, M.D.
Malignant hyperthermia is a pharmacogenetic disease process. The manifestations of the disease occur when predisposed individuals are exposed to a small number of drugs. Most of these “triggering agents” are general anesthetics. Succinylcholine and all of the potent inhalational agents have been implicated – including xenon.
MH occurs because of a defect in the calcium sensitive ryanidine receptor - RYR1. This receptor is found in all skeletal muscle, smooth muscle, neurons, and in B-lymphocytes. In skeletal muscle, the RYR forms the footplate between the transverse tubules and the sarcoplasmic reticulum. Calcium homeostasis is mediated through these receptors and defects can produce massive outpouring of calcium during excitation contraction coupling. Because skeletal muscle contains a large percentage of the intracellular calcium in the body, failure of regulation creates exaggerated contraction, a hypermetabolic state, with an elevated temperature and subsequent severe acidosis. This is the clinical picture that is called malignant hyperthermia.
A specific point mutation in the RYR1 has been associated with MH. However, only about a third of the patients with MH will demonstrate this specific point mutation. RYR1 is a very large protein, the largest known receptor in the body. It is likely that other point mutations will be found that produce the same clinical effect.
There is one very sensitive test for malignant hyperthermia – the caffeine halothane contraction test. This test will be positive in more that 97% of patients that have true MH and is 78% specific. This includes patients with known point mutations in the RYR1 protein that are known to be associated with MH as well as those that do not. For this reason, the CHCT is the only test that is available that is reliable/specific/sensitive. Molecular genetics testing will demonstrate the point mutation that is known in the RYR1, but will miss the other 65% of patients. Molecular testing is appropriate for relatives of a proband that has had molecular genetic testing that is positive. Otherwise, it should not be used as a screening test.
The CHCT is difficult to perform and can only be performed on fresh muscle. There are currently only five centers in North America that are certified to do this test. The number of centers is kept to a minimum in order to improve the specificity of the test. The center that is closest to Lexington is in Winston-Salem, NC. Because the multiple fascicles that are required to perform the test, it would be uncommon for a child under 40 kg/ten years old to present for testing.
MH may randomly present associated with any disease process. In the past, an association between strabismus and MH was shown to represent a statistical error caused by the increased likelihood that these patients would present for surgery. There are very few disease processes that are now recognized as being tightly linked to MH. In the future, this number may decrease further as we understand more about the genetic basis for the disease. Presently central core disease, hypokalemic periodic paralysis, and King-Denborough Syndrome, a combination of facial dysmorphic features with MH, are the only disease processes that seem to manifest the hypermetabolic state with exposure to anesthetics. For these patients, at present, all should be managed with nontriggering techniques.
The association between muscular dystrophy and the hyperkalemic cardiac arrests associated with the administration of succinylcholine represent an entirely separate pathophysiology, but can be equally as deadly. The presence of a large number of cases of cardiac arrest in infant boys, later found to have muscular dystrophy, is the primary reason that succinylcoline is not routinely used in the United States.
Malignant hyperthermia presents as a profound hypermetabolic response. Early indicators include tachycardia, rapid increases in end tidal carbon dioxide despite seemingly adequate ventilation, and rigidity. Despite its name MH rarely presents with an elevation in temperature as the first and/or only manifestation of a crisis. Continued exposure to the causative agent, however, will accelerate the disease process and early reversion to nontriggers as the primary anesthetic is a key to the resuscitation of the patient.
Immediate treatment with dantrolene can be life saving. This medication should be prepared and given quickly after a presumptive diagnosis is made. Dantrolene inhibits the release of calcium from the sarcoplasmic reticulum of skeletal muscle. This is accomplished by limiting the activation of the RYR. Though dantrolene does not act at the neuromuscular junction it will produce profound muscle weakness. Patients treated during the preoperative period with prophylactic dantrolene have aspirated because of this effect and there is no evidence that use of the drug prior to an exposure to a triggering agent is better than after exposure.
There are several keys to successful resuscitation of patients with MH:
1. Vigilance allows the savvy clinician to recognize the clinical scenario early in its course. Good anesthesiologists are suspicious and will note the association of tachycardia, increasing carbon dioxide, and possibly rigidity for what it is.
2. Early elimination of triggers and administration of dantrolene is very important. Dantrolene is difficult to prepare and extra hands are always necessary. It will require more than one person to prepare dantrolene alone. Currently, a bolus of 2.5 mg/kg as a first dose is recommended, with subsequent boluses of 2.5 mg/kg, administered until the patient is stabilized.
3. Secondary cooling of the patient is important, but should not prevent or slow the preparation and administration of dantrolene. Time and resources are often wasted running for ice and getting rafts, when the primary drug for resuscitation sits unopened.
4. If there are sufficient resources to prepare dantrolene and provide the resources to cool the patient, then this can be done with cool IV fluids or saline lavage of the bladder or stomach.
5. Further treatment is symptomatic and includes response to acidosis, arrhythmias, electrolyte disturbances, and excess myoglobin production caused by muscle destruction with subsequent acute renal failure.
6. Patients that manifest and are treated for MH should be monitored and treated in an intensive care setting postoperatively. It is recommended that patients be treated with dantrolene for 24 hours after metabolic stability returns. The MHAUS recommends a dose of 1 mg/kg every 4 to 6 hours. In addition, because of the risk of recrudescence of MH, patients should be monitored for at least 24 hours after the last dose of dantrolene is given.
Patients that have had an episode of MH, with first degree relatives that have had a clinical incident strongly suggestive of MH, those with a positive CHCT, or who have had molecular genetic testing demonstrating the point defect in RYR1 that has been tied to MH, should subsequently have nontriggering anesthetics. This can be accomplished with virtually any agent normally used by the anesthetist, with the exception of succinylcholine and potent inhalational agents. Patients have been successfully anesthetized as out patients, for labor and delivery, and with regional anesthesia.
Neuroleptic malignant syndrome is a rare, but life threatening idiosyncratic response to a neuroleptic medication. Though the clinical picture emulates MH with rigidity, fever, and autonomic dysfunction, NMS is mediated through the blockade of dopaminergic pathways within the central nervous system. Drugs such as haloperidol, thorazine and resperidone can produce the picture of NMS as well as phenergan, droperidol, and metaclopramide. Treatment with dantrolene is not specifically indicated, but withdrawal of neuroleptics and symptomatic management of rigidity (levodopa/carbodopa), respiratory failure or renal failure is necessary.
Masseter muscle rigidity, also called masseter spasm, is usually associated with the administration of succinylcholine. It has been suggested that this may be an early sign of MH. Masseter spasm with associated elevations in carbon dioxide or fever should be treated as MH
MHAUS, The Malignant Hyperthermia Society of the United States, has an excellent web site, which provides up to date information about testing, diagnosis and treatment.
Rae Brown, MD
Department of Anesthesiology
University of Kentucky Medical Center
Kentucky Children’s Hospital
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