Malignant Hyperthermia

An important complication of anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts is malignant hyperthermia, an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance disorder of the regulation of calcium transport in the skeletal muscles resulting in a hypermetabolic crisis. Malignant hyperthermia is marked by high fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, muscle rigidity, rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis, and respiratory and metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis. The mortality rate reaches 90% if not quickly identified and treated. Management involves stopping the offending agent and administering dantrolene.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Malignant hyperthermia (MH) is a hypermetabolic response in a patient exposed to a volatile anesthetic or succinylcholine resulting in fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, muscle rigidity, rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis, and pulmonary and cerebral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema.

Epidemiology

  • Anesthesia-induced condition
  • Rare (< 1:100,000)
  • Very dangerous → 80%–90% mortality without proper treatment
  • 90% cure rate when treated appropriately
  • Seen in patients of all ethnicities and geographic distributions
  • Twice as common in males
  • Up to 50% of cases occur in patients < 19 years of age.

Etiology

Triggering substances:

  • Inhalation anesthetics (e.g., halothane, enflurane, and isoflurane) 
  • Succinylcholine (muscle relaxant)

“Safe” anesthetics for patients with previously diagnosed malignant hyperthermia:

  • “Laughing gas” (nitrous oxide)
  • Barbiturates
  • Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines
  • Etomidate
  • Propofol
  • Ketamine
  • Opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
  • Non-depolarizing muscle relaxants

Pathophysiology

  • Autosomal dominant genetic disorder of hypermetabolism of skeletal muscle after exposure to certain anesthetics
  • Due to mutations encoding for:
    • Dihydropyridine (DHP) receptors → sense action potential in T tubules
    • Ryanodine (RYR1) receptors → release calcium from sarcoplasmic reticulum into intracellular space
  • Defects lead to continuous muscle contraction, causing:
    • Cellular metabolism (hypermetabolism) 
    • ↓ ATP
    • O₂ consumption and CO₂ production
    • Tissue hypoxia and lactic acidosis
    • Heat production
    • Cell destruction causing CK release and myoglobinuria

Diagnosis

Clinical features

Symptoms may appear at any point during anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts (induction, maintenance, rarely after discontinuation). Symptoms follow a regular pattern; the speed of progression through symptoms varies, however.

Early signs:

  • Rapid rise in end-tidal carbon dioxide (ETCO₂): earliest symptom
  • Arrhythmias:
    • Tachycardia 
    • Peaked T waves
    • Due to hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia
    • Often misinterpreted as too low a depth of anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts
  • Muscular rigor (masseter spasms specific for succinylcholine-induced MH): blood pressure is initially (decreased blood pressure is sign of circulatory failure)

Late signs:

  • Fever (not required for diagnosis)
  • Rhabdomyolysis
  • Myoglobinuria
  • Renal failure
  • Cerebral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema

Laboratory findings

  • Metabolic/ respiratory acidosis Respiratory acidosis The respiratory system is responsible for eliminating the volatile acid carbon dioxide (CO2), which is produced via aerobic metabolism. In the setting of hypoventilation, this acid load is not adequately blown off, and respiratory acidosis occurs. Renal compensation occurs after 3-5 days, as the kidneys attempt to increase the serum bicarbonate levels. Respiratory Acidosis:
    • Respiratory acidosis: caused by in CO₂ due to hypoventilation
    • Metabolic acidosis: due to lactic acid production
  • Hyperkalemia: due to potassium released from damaged cells
  • CK: released by muscle breakdown
  • Myoglobinuria:
    • Smooth muscle cell breakdown releases myoglobin.
    • Myoglobin spills into urine.

Management

Care in the ICU is necessary as the condition can reactivate after apparent improvement.

Immediate actions

  • Termination of triggering substances
  • Hyperventilation with 100% oxygen
  • Terminating surgery as soon as possible
  • If necessary, change to safer anesthetics (IV agents).

Dantrolene

  • Inhibits ryanodine receptor
  • Prevents release of Ca2+ from sarcoplasmic reticulum of skeletal muscle
  • Leads to muscle relaxation
  • Has no negative effects if patient not in HM

Symptomatic treatment

  • Active cooling: 
    • Ice packs to groin
    • Cooled IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids
    • Flushing bladder with cold fluid
  • Balance acidosis with sodium bicarbonate.
  • Treat electrolyte abnormalities.
  • Treat hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia in patients with arrhythmias.

Potential complications

  • Severe metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis
  • Hyperkalemia
  • Renal failure
  • Cerebral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema

Clinical Relevance

Related conditions

  • Serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. Serotonin Syndrome: fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, autonomic dysfunction, rigidity/spasticity related to overdoses of selective serotonin reuptake inhibitors Serotonin Reuptake Inhibitors Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications (SSRIs) or other antidepressants Other antidepressants Antidepressants encompass several classes of medications and are used to treat individuals with depression, anxiety, and other psychiatric conditions, as well as to manage chronic pain and menopausal symptoms. Other Antidepressants. Presents with more GI symptoms (nausea, vomiting) than in MH.
  • Neuroleptic malignant syndrome Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially life-threatening reaction to antipsychotic drugs. Neuroleptic malignant syndrome presents with ≥ 2 of the following cardinal symptoms: fever, altered mental status, muscle rigidity, and autonomic dysfunction. Neuroleptic Malignant Syndrome (NMS): rare, idiosyncratic, and potentially life-threatening reaction to neuroleptic (e.g., antipsychotic Antipsychotic Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics) drug. Very similar to serotonin syndrome, but without the GI symptoms and more muscle rigidity. Treated similarly to serotonin syndrome, by discontinuing causative drugs and offering supportive care.

Differential diagnosis

Presentations with altered mental status, autonomic dysfunction, and fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever:

  • Meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis/ encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis
  • Toxic encephalopathy
  • Excited delirium Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium
  • Heatstroke Heatstroke Heatstroke is an illness characterized as a core body temperature exceeding 40°C (104°F) with accompanying neurological symptoms including ataxia, seizures, and/or delirium. Heatstroke is usually due to the body's inability to regulate its temperature when challenged with an elevated heat load. Heatstroke
  • Status epilepticus
  • Alcohol or sedative withdrawal
  • Hypertensive crisis
  • Thyrotoxicosis Thyrotoxicosis Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism

References

  1. Litman, R. S. (2019). Malignant Hyperthermia: Diagnosis and management of acute crisis. In M. Crowly (Ed), UpToDate. Retrieved February 2, 2021, from https://www.uptodate.com/contents/malignant-hyperthermia-diagnosis-and-management-of-acute-crisis
  2. Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K. (2015). Malignant hyperthermia: a review. Orphanet J Rare Dis. https://pubmed.ncbi.nlm.nih.gov/26238698/ 
  3. Larach MG, Gronert GA, Allen GC, Brandom BW, Lehman EB. (2010). Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg. https://pubmed.ncbi.nlm.nih.gov/20081135/ 
  4. Malignant Hyperthermia Association of the United States. Retrieved February 15, 2021, from https://www.mhaus.org/

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