Handbook of Clinical Anesthesia

Chapter 24

Malignant Hyperthermia and Other Inherited Disorders

Malignant hyperthermia (MH) or malignant hyperpyrexia is perhaps the most significant inherited disorder triggered by exposure to anesthetic drugs (Rosenberg H, Brandom BWD, Sambuughin S: Malignant hyperthermia and other inherited disorders. In Clinical Anesthesia. Edited by Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC. Philadelphia: Lippincott Williams & Wilkins, 2009, pp 598–621).

  1. Malignant Hyperthermia
  2. Historical Aspects.MH was first formally described in 1960, and a clinically useful test for MH with limited sensitivity was introduced in 2003. Some deaths formerly attributed to MH were actually the result of destruction of muscle cells that occurred during anesthesia with volatile anesthetics and succinylcholine (Sch) in patients with unrecognized dystrophinopathies (Duchenne and Becker muscular dystrophy).
  3. Clinical Presentation
  4. MH is a hypermetabolic disorder of skeletal muscle that may or may not have a heritable component.
  5. An important pathophysiologic process in this disorder is intracellular hypercalcemia, which activates metabolic pathways, resulting in adenosine triphosphate depletion, acidosis, membrane destruction, and cell death.
  6. Classic Malignant Hyperthermia
  7. The first manifestations of this syndrome most often occur in the operating room but may also occur within the first few hours of recovery from anesthesia (Table 24-1).
  8. Sch may accelerate the onset of MH (entire course over 5–10 minutes) in some patients; in others, a

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volatile anesthetic plus Sch is necessary to trigger the response. Some susceptible patients may develop MH despite multiple prior uneventful exposures to triggering drugs.

Table 24-1 Manifestations of Malignant Hyperthermia

Hypercarbia (reflects hypermetabolism and is responsible for many of the signs of sympathetic nervous system stimulation; this may be masked by hyperventilation of the patient's lungs)
Tachycardia
Tachypnea
Temperature increase (1°–2°C increase every 5 minutes)
Hypertension
Cardiac dysrhythmias
Acidosis
Arterial hypoxemia
Hyperkalemia
Skeletal muscle activity
Myoglobinuria

  1. Even with successful treatment, patients with MH are at risk for myoglobinuric renal failure and disseminated intravascular coagulation. Creatine kinase (CK) levels may exceed 20,000 U in the first 12 to 24 hours. Increased CK may not be present if the syndrome is detected promptly and treatment instituted. Recrudescence of the syndrome may occur in the first 24 to 36 hours.
  2. Masseter Muscle Rigidity(Table 24-2)
  3. Rigidity of the jaw muscles after administration of Sch is referred to as masseter muscle rigidity (MMR) or masseter spasm. Although MMR probably occurs in patients of all ages, it is more common in children and young adults. Repeat doses of Sch or nondepolarizing relaxants do not relieve MMR (peripheral nerve stimulator reveals flaccid paralysis).

Table 24-2 Events That Mimic Masseter Spasm

Inadequate dose of succinylcholine
Inadequate time for onset of action of succinylcholine
Temporomandibular joint dysfunction
Myotonic syndrome

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Table 24-3 Recommendations for Management of Masseter Muscle Rigidity

Discontinue the anesthetic and postpone surgery or continue with a nontriggering anesthetic using end-tidal CO2 monitoring with the availability of dantrolene.
Give dantrolene if generalized rigidity and signs of hypermetabolism.
After event, admit the patient for 12 to 24 hours and monitor for myoglobinuria. Consider administration of dantrolene 1 to 2 mg/kg.
Inform the patient's family of the event and its potential implication.
Monitor CK levels at 6, 12, and 24 hours.
If CK is above 20,000 IU and a concomitant myopathy is not present, the diagnosis of MH is likely.
If contracture test results are normal, it is not recommended that family members be tested, but succinylcholine should be avoided.

CK = creatine kinase.

  1. If the anesthetic is continued with a triggering agent, the initial signs of MH most commonly appear in 20 minutes or more. Conversely, if the anesthetic is discontinued, the patient appears to recover uneventfully.
  2. Recommendations for Management of MMR(Table 24-3)
  3. Variations in Presentation of Malignant Hyperthermia(Table 24-4)

Table 24-4 Variations in the Presentation of Malignant Hyperthermia

Multiple prior uneventful anesthetics
Present several hours postoperatively
Rigidity may not be present
Temperature increase may be unimpressive
Postoperative myoglobinuria may be the only sign (succinylcholine-induced rhabdomyolysis should be ruled out in patients with skeletal muscle disorders and patients taking cholesterol inhibitors)

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  1. Myodystrophies Exacerbated by Anesthesia
  2. Duchene muscular dystrophyoccurs in one in 3000 males. Boys are usually asymptomatic until the age of 4 or 5 years, but elevated CK is present from birth. Hyperkalemia and cardiac arrest may occur after the administration of Sch. Because of potentially fatal hyperkalemia in patients with undiagnosed myopathy, Sch should not be used routinely in children and young adolescents (patients with airway emergencies and full stomachs are exceptions).
  3. Congenital myopathies(central core disease) is often characterized by weakness of the spine and pelvis and may include foot deformities. There is a risk of MH in these patients.
  4. Myotonias and periodic paralysesare caused by point mutations in an ion channel. Muscle contractures occur in response to the administration of Sch.
  5. Syndromes with a Clinical Resemblance to Malignant Hyperthermia(Table 24-5)
  6. Malignant Hyperthermia Outside the Operating Room.Exercise-induced rhabdomyolysis may occur in patients with myopathies with or without exposure to myotoxic drugs (cholesterol-lowering drugs).
  7. Neuroleptic Malignant Syndrome and Other Drug-Induced Hyperthermic Reactions
  8. Neuroleptic malignant syndrome may mimic MH (dantrolene may be effective). Unlike MH, this syndrome is associated with prolonged drug therapy with psychoactive drugs (phenothiazines or haloperidol) or sudden withdrawal of drugs used to treat Parkinson's disease. Bromocriptine (a dopamine agonist) is useful in treatment, suggesting that this syndrome may reflect depletion of central nervous system dopamine stores by psychoactive drugs.

Table 24-5 Syndromes with a Clinical Resemblance to Malignant Hyperthermia

Pheochromocytoma
Thyrotoxicosis
Sepsis
Hypoxic encephalopathy
Mitochondrial myopathies (avoid succinylcholine)

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Table 24-6 Drugs That May or May Not Trigger Malignant Hyperthermia

Unsafe Drugs

Succinylcholine

Volatile anesthetics

Safe Drugs

Antibiotics

Antihistamines

Antipyretics

Vasoactive drugs

Barbiturates

Benzodiazepines

Droperidol

Ketamine (inherent circulatory effects may mimic malignant hyperthermia)

Propofol

Nitrous oxide

Local anesthetics

Propranolol

Opioids

Nondepolarizing neuromuscular blocking drugs

  1. From an anesthesiologist's point of view, it is best to treat patients with neuroleptic malignant syndrome as though they are susceptible to MH.
  2. The recommendation is to conduct electroconvulsive therapy without the use of Sch or other triggering drugs.
  3. Similar signs have been observed in some patients taking serotonin uptake inhibitors.
  4. Drugs That Trigger Malignant Hyperthermia(Table 24-6)
  5. Incidence and Epidemiology
  6. A better understanding of the prevalence of MH is being provided by use of molecular genetics for the diagnosis of MH susceptibility.
  7. Although the incidence of reported cases of MH has increased, the mortality rate from MH has declined (<5%), reflecting both a greater awareness of the syndrome and earlier diagnosis followed by better treatment.
  8. Diagnostic Tests for Malignant Hyperthermia
  9. Halothane–Caffeine Contracture Test
  10. Although several tests have been described, this test remains the standard (100% sensitivity).
  11. Skeletal muscle biopsy specimens (usually vastus lateralis) are bathed in a solution containing 1.5% to 3% halothane plus caffeine or either drug alone. A response indicative of MH susceptibility is based on a previously established contracture threshold.

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  1. Other Agents Used in Contracture Tests
  2. Ryanodine.This test was based on the premise that a defect in the ryanodine receptor (calcium release channel of skeletal muscle) was the only cause of MH that would afford maximum specificity (premise no longer valid).
  3. 4-Chloro-m-cresolis a potent activator of ryanodine receptor-mediated calcium release. Contractures occur in 100% of skeletal muscles from patients who are MH susceptible.
  4. Pitfalls of the Contracture Test
  5. Because of the variation in the presentation of MH, it may not be possible to achieve agreement on the status of a patient based on clinical history.
  6. MH trigger agents should be avoided if a patient has a positive contracture test result.
  7. Tests with More Limited Usefulness in Malignant Hyperthermia Diagnosis
  8. Use of resting CK levels for screening for MH is neither sensitive nor specific, but a relationship exists between postoperative CK levels associated with MMR and the probability of a positive contracture test result.
  9. Elevated CK levels may be useful in identifying family members to be referred for contracture testing and in identifying MH in children who are too young to undergo contracture testing.
  10. Clinical Diagnosis of Malignant Hyperthermia: The Grading Scale(Table 24-7).
  11. Molecular Genetic Testing for Malignant Hyperthermia Susceptibility
  12. Multiple mutations on the RYR1gene and mutations in other genes have been shown to be causal for MH.
  13. Ultimately, genetic testing is likely to replace more invasive diagnostic tests.
  14. The presence of a ryanodine mutation predicts MH susceptibility.
  15. Treatment of Malignant Hyperthermia.MH is a treatable disorder that should have a mortality near zero when recognized early and treated promptly. All institutions in which anesthetic drugs are administered (hospitals, ambulatory surgery facilities, doctors' offices) should have dantrolene available (36 ampoules [720 mg])

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and an established management plan in place (see inside back cover for a malignant hyperthermia protocol).

Table 24-7 Criteria Used in the Malignant Hyperthermia Clinical Grading Scale*

Process 1: Muscle Rigidity

Generalized rigidity

15

Masseter rigidity

15

Process II: Myonecrosis

Elevated CK >20,000 (after succinylcholine administration)

15

Elevated CK >10,000 (without succinylcholine)

15

Cola-colored urine

10

Myoglobin in urine >60 µg/mL

5

Serum potassium >6 mEq/L

3

Process III: Respiratory Acidosis

End-tidal CO2 >55 mm Hg with controlled ventilation

15

PaCO2 >60 mm Hg with controlled ventilation

15

End-tidal CO2 >60 mm Hg with spontaneous ventilation

15

Inappropriate hypercarbia

15

Inappropriate tachypnea

10

Process IV: Temperature Increase

Rapid increase in temperature

15

Inappropriate temperature (>38°C) in perioperative period

10

Process V: Cardiac Involvement

Inappropriate tachycardia

3

Ventricular tachycardia or fibrillation

3

*A total of 50 points (termed “D6”) is almost certainly a case of MH.
A total of 35 to 49 points (termed “D5”) is very likely a case of MH.
CK = creatine kinase.

  1. Acute Episode(Table 24-8)
  2. Management After an Acute Episode(Table 24-9)
  3. Dantrolene
  4. This drug acts in skeletal muscle cells to decrease intracellular levels of calcium, most likely by decreasing sarcoplasmic reticulum release or inhibiting excitation–contracture coupling at the transverse tubular level.
  5. Therapeutic levelsof dantrolene (2.5 mg/mL) usually persist for 4 to 6 hours after an intravenous (IV) dose of 2.5 mg/kg. (This is a reason to supplement every 4 hours.)

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Table 24-8 Management of the Acute Episode of Malignant Hyperthermia

Discontinue inhaled anesthetics and succinylcholine.
Hyperventilate the lungs with oxygen at 10 L/min (this hastens purging of residual anesthetic gases).
Use an Ambu bag and E cylinder (do not spend time replacing anesthesia machine).
Administer dantrolene (2.5 mg/kg IV) with repeated doses (2–3 mg/kg is often sufficient but may require >10 mg/kg) based on PaCO2, heart rate, and body temperature.
Place a bladder catheter (each 20 mg of dantrolene contains 300 mg of mannitol).
Treat persistent acidosis with sodium bicarbonate (1–2 mEq/kg IV).
Control body temperature (gastric lavage, external ice packs until the patient's temperature is 38°C).
Monitor with capnography (best clinical measurement to guide therapy) and arterial blood gases.
Be prepared to treat hyperkalemia (glucose, insulin, hyperventilation, calcium) and cardiac dysrhythmias (avoid verapamil; lidocaine is acceptable).
Obtain baseline laboratory tests (creatinine, coagulation studies, CK [increases may not occur for 6 to 12 hours], liver function tests, myoglobin levels).

CK = creatine kinase.

  1. Prophylaxisfor MH should be carried out with IV or oral dantrolene (5 mg/kg).
  2. Management of Patients Susceptible to Malignant Hyperthermia(Table 24-10)
  3. There have been no deaths from MH in previously diagnosed MH-susceptible patients when the anesthesiologist was prospectively aware of the problem. This information is useful to allay the patient's preoperative anxiety.

Table 24-9 Management of Malignant Hyperthermia After an Acute Episode

Continue dantrolene (1–2 mg/kg IV) every 6 hours for at least 24 to 36 hours.
Anticipate complications.
   Recrudescence
   Disseminated intravascular coagulation
   Myoglobinuric renal failure (alkalinize urine if acidic and administer mannitol to facilitate excretion of myoglobin)
   Skeletal muscle weakness
   Electrolyte abnormalities

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Table 24-10 Management of Malignant Hyperthermia-Susceptible Patients

Administer the standard preoperative medication.
Administer dantrolene (2.5 mg/kg IV) 15–30 minutes before induction of anesthesia.
Clean the anesthesia machine (disposable circuit, new soda lime, drain vaporizers, oxygen flow 10 L/min for 10 minutes or longer to flush the system).
Modern anesthesia workstations are larger than traditional anesthesia machines (it may require more than 10 minutes to purge inhalational agents).
Capnography (increased end-tidal CO2 concentration is the earliest sign of malignant hyperthermia).
Monitor body temperature.
Use nontriggering drugs and techniques (regional if possible).
Closely observe the patient after surgery (routine administration of dantrolene is not indicated in the absence of signs of malignant hyperthermia).
Rehydration (decreases chance that fever caused by dehydration will occur).

  1. Dantrolene need not be repeated after the anesthetic is terminated if there were no signs of MH during surgery.
  2. In MH-susceptible parturients, an acceptable approach to management of routine labor is epidural analgesia without dantrolene pretreatment and close monitoring of vital signs. If general anesthesia is necessary for delivery, an acceptable approach is to administer dantrolene IV and use nontriggering drugs. No adverse fetal effects of dantrolene have been observed.
  3. Disorders of Plasma Cholinesterase
  4. Succinylcholine-Related Apnea
  5. Hydrolysis of Sch by plasma cholinesterase is slowed to absent in patients with inherited alterations on the gene locus responsible for production of this enzyme by the liver (Table 24-11).

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Table 24-11 Genotypes for Plasma Cholinesterase Enzyme

Genotype

Dibucaine Number

Fluoride Number

Cholinesterase Activity

Response to Succinylcholine

Incidence

EuEu

78–86

55–65

Normal

Normal

96%

EaEa

18–26

16–32

Decreased

Greatly prolonged

1 in 2000

EuEa

51–70

38–55

Intermediate

Slightly prolonged

1in 25

EuEf

74–80

47–48

Intermediate

Slightly prolonged

1 in 200

EfEa

49–59

25–33

Intermediate

Greatly prolonged

1 in 20,000

EfEs

63

26

Decreased

Moderately prolonged

1 in 150,000

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  1. When there is a question about the rate of hydrolysis of Sch, the plasma cholinesterase activity as well as dibucaine and fluoride numbers should be measured.
  2. Patients who are homozygous for atypical cholinesterase enzyme should wear Medic-Alert bracelets indicating that Sch will result in prolonged apnea (often longer than 2 hours).
  3. Depression of plasma cholinesterase activity in the absence of atypical genotypes can be seen after administration of anticholinesterase drugs or plasmapheresis and in the presence of advanced liver disease (Table 24-12). This usually results in only moderate prolongation of Sch-induced skeletal muscle paralysis (rarely longer than 30 minutes).
  4. Treatment of Succinylcholine Apnea
  5. The safest course of treatment after a patient fails to breathe spontaneously within 10 to 15 minutes after Sch administration is to continue mechanical ventilation of the patient's lungs until adequate skeletal muscle strength has returned.
  6. The use of anticholinesterase drugs in treating patients with Sch apnea is controversial.
  7. Plasma Cholinesterase Abnormalities and the Metabolism of Local Anesthetics
  8. Ester local anesthetics are metabolized by plasma cholinesterase.
  9. Despite the theoretical argument that the action of these drugs might be prolonged, there is evidence that the response of homozygous atypical patients is usually normal.

III. Porphyrias

  1. These inherited defects of heme synthesis can mimic surgical diseases and may be provoked by administration of certain drugs (Table 24-13).
  2. Management of Patients with Porphyria
  3. Triggering drugs (barbiturates, perhaps benzodiazepines and ketamine) should be avoided. Nontriggering drugs include propofol, nitrous oxide, volatile anesthetics, opioids, and muscle relaxants. Regional anesthesia may be avoided to prevent confusion if neurologic changes occur postoperatively.

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Table 24-12 Causes of Changes in Cholinesterase Activity

Inherited
Cholinesterase variants (silent gene, C5 variant)
Physiologic
Decreases in last trimester of pregnancy
Decreases in newborn
Acquired Decreases
Liver disease
Cancer
Debilitating diseases
Collagen diseases
Uremia
Malnutrition
Myxedema
Acquired Increases
Obesity
Alcoholism
Thyrotoxicosis
Nephrosis
Psoriasis
Electroshock therapy
Drug-Related Decreases
Echothiophate iodide
Anticholinesterases
Chlorpromazine
Cyclophosphamide
Monoamine oxidase inhibitors
Pancuronium
Contraceptives
Organophosphate insecticides
Hexafluorenium
Other Causes of Decreased Activity
Plasmapheresis
Extracorporeal circulation
Tetanus
Radiation therapy
Burns

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Table 24-13 Manifestations of Porphyria

Abdominal pain
Fever
Vomiting
Confusion
Tachycardia
Seizures
Hypertension
Somnolence
Neuropathy

  1. Glucose infusions are important in prevention (starvation can induce an attack) and treatment of porphyria.
  2. Glycogen Storage Diseases
  3. These inherited diseases are characterized by dysfunction of one of the many enzymes involved in glucose metabolism.
  4. Associated problems that may influence anesthetic management include hypoglycemia, acidosis, and cardiac and hepatic dysfunction.
  5. Osteogenesis Imperfecta

Osteogenesis Imperfecta occurs in approximately one in 50,000 births. Minor trauma can lead to fractures, and airway management may be difficult because of cervical spine involvement. Inhalation anesthetics have been administered to many of these patients without complications of MH.

Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.; Cahalan, Michael K.; Stock, M. Christine

Title: Handbook of Clinical Anesthesia, 6th Edition

Copyright ©2009 Lippincott Williams & Wilkins

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