Muscle rigidity, increased body temperature, depressed consciousness, and autonomic instability. The first sign of MH may be a sudden and unexpected rise in end-tidal PCO2 (reflecting the underlying hypermetabolism) in the operating room (9,10). This is followed (within minutes to a few hours) by generalized muscle rigidity, which can progress rapidly to widespread myonecrosis (rhabdomyolysis) and subsequent myoglobinuric renal failure. The heat generated by the muscle rigidity is responsible for the marked rise in body temperature (often above 40°C or 104°F) in MH. The altered mental status in MH can range from confusion and agitation to obtundation and coma. Autonomic instability can lead to cardiac arrhythmias, fluctuating blood pressure, or persistent hypotension.

 

 

 

 

The earliest signs of MH during anesthesia are succinylcholine-induced masseter muscle rigidity (MMR) or other muscle rigidity, tachycardia, and hypercarbia (due to increased CO2 production.

Signs of Malignant Hyperthermia.
Markedly increased metabolism
  • Increased CO2 production
  • Increased oxygen consumption
  • Reduced mixed venous oxygen tension
  • Metabolic acidosis
  • Cyanosis
  • Mottling
Increased sympathetic activity
  • Tachycardia
  • Hypertension
  • Arrhythmias
Muscle damage
  • Masseter spasm
  • Generalized rigidity
  • Increased serum creatine kinase
  • Hyperkalemia
  • Hypernatremia
  • Hyperphosphatemia
  • Myoglobinemia
  • Myoglobinuria
Hyperthermia
  • Fever
  • Sweating

 

Two or more of these signs greatly increase the likelihood of MH. Tachypnea is prominent when muscle relaxants are not used. Overactivity of the sympathetic nervous system produces tachycardia, arrhythmias, hypertension, and mottled cyanosis. Hyperthermia may be a late sign, but when it occurs, core temperature can rise as much as 1°C every 5 min. Generalized muscle rigidity is not consistently present. Hypertension may be rapidly followed by hypotension if cardiac depression occurs. Dark-colored urine reflects myoglobinemia and myoglobinuria.

 

Generalized muscle rigidity is not consistently present. Hypertension may be rapidly followed by hypotension if cardiac depression occurs. Dark-colored urine reflects myoglobinemia and myoglobinuria.

Tachypnea is prominent when muscle relaxants are not used. Overactivity of the sympathetic nervous system produces tachycardia, arrhythmias, hypertension, and mottled cyanosis.

Hyperthermia may be a late sign, but when it occurs, core temperature can rise as much as 1°C every 5 min.

 

 

 

Signs of Malignant Hyperthermia.

 
Increased sympathetic activity
  • Tachycardia
  • Hypertension
  • Arrhythmias
Muscle damage
  • Masseter spasm
  • Generalized rigidity
  • Increased serum creatine kinase
  • Hyperkalemia
  • Hypernatremia
  • Hyperphosphatemia
  • Myoglobinemia
  • Myoglobinuria
Hyperthermia
  • Fever
  • Sweating

Laboratory testing typically reveals mixed metabolic and respiratory acidosis with a marked base deficit, hyperkalemia, hypermagnesemia, and reduced mixed-venous oxygen saturation. Some case reports describe isolated respiratory acidosis early in the course of an episode of MH. Serum ionized calcium concentration is variable: it may initially increase before a later decrease. Patients typically have increased serum myoglobin, creatine kinase (CK), lactic dehydrogenase, and aldolase levels. When peak serum CK levels (usually 12-18 h after anesthesia) exceed 20,000 IU/L the diagnosis is strongly suspected. It should be noted that succinylcholine administration to some normal patients without MH may cause serum myoglobin and CK levels to increase markedly.

Much of the problem in diagnosing MH arises from its variable presentation. Fever is an inconsistent and often late-presenting sign. An unanticipated doubling or tripling of end-tidal CO2 (in the absence of a ventilatory change) is one of the earliest and most sensitive indicators of MH. If the patient survives the first few minutes, acute kidney failure and disseminated intravascular coagulation (DIC) can rapidly ensue. Other complications of MH include cerebral edema with seizures and hepatic failure. Most MH deaths are due to DIC and organ failure due to delayed or no treatment with dantrolene.

Image not available. Susceptibility to MH is increased in several musculoskeletal diseases. These include central-core disease, multi-minicore myopathy, and King-Denborough syndrome. The latter syndrome is seen primarily in young boys who exhibit short stature, mental retardation, cryptorchidism, kyphoscoliosis, pectus deformity, slanted eyes, low-set ears, webbed neck, and winged scapulae. Duchenne’s and other muscular dystrophies, nonspecific myopathies, heat stroke, and osteogenesis imperfecta have been associated with MH-like symptoms in some reports; however, their association with MH is controversial. Other possible clues to susceptibility include a family history of anesthetic complications, or a history of unexplained fevers or muscular cramps. There are several reports of MH episodes occurring in patients with a history of exercise-induced rhabdomyolysis. Prior uneventful anesthesia procedures and absence of a positive family history are notoriously unreliable predictors of lack of susceptibility to MH. Any patient who develops MMR during induction of anesthesia should be considered potentially susceptible to MH.

 

 Treatment of an MH episode is directed at terminating the episode and treating complications such as hyperthermia and acidosis. First and most importantly, the triggering agent must be stopped and dantrolene must be given immediately.

Protocol for Immediate Treatment of Malignant Hyperthermia.
  1. Discontinue volatile anesthetic and succinylcholine. Notify the surgeon. Call for help.

  2. Mix dantrolene sodium with sterile distilled water and administer 2.5 mg/kg intravenously as soon as possible.

  3. Administer bicarbonate for metabolic acidosis

  4. Institute cooling measures (lavage, cooling blanket, cold intravenous solutions).

  5. Treat severe hyperkalemia with dextrose, 25-50 g intravenously, and regular insulin, 10-20 units intravenously (adult dose).

  6. Administer antiarrhythmic agents if needed despite correction of hyperkalemia and acidosis

  7. Monitor end-tidal CO2 tension, electrolytes blood gases, creatine kinase, serum myoglobin, core temperature, urinary output, and color, coagulation status

  8. If necessary, consult on-call physicians at the 24-hour MHAUS hotline, 1-800-644-9737.

Data from the MHAUS protocol available at http://www.mhaus.org/nf/Shop/EmergencyTherapyMHPosterSample.png.

 

 

 

Markedly increased metabolism

One early focus of investigations into the mechanisms of MH has been the gene for the ryanodine (Ryr1) receptor, located on chromosome 19. Ryr1 is an ion channel responsible for calcium release from the sarcoplasmic reticulum and it plays an important role in muscle depolarization. Subsequent reports linked MH with mutations involving the sodium channel on chromosome 17. An autosomal recessive form of MH has been associated with the King-Denborough syndrome.

Most patients with an episode of MH have a history of relatives with a similar episode or with an abnormal halothane-caffeine contracture test (see below). The complexity of genetic inheritance patterns in families reflects the fact that MH can be caused by mutations of one or more genes on more than one chromosome. To date genetic studies in humans have revealed at least five different chromosomes and more than 180 individual mutations associated with MH. Genetic testing, although available, currently screens for less than 20% of recognized mutations. A patient with abona fide clinical history of MH has about a 30-50% chance of testing positive.

 

A halogenated anesthetic agent alone may trigger an episode of MH.


Drugs Known to Trigger Malignant Hyperthermia.

Inhaled general anesthetics
  • Ether
  • Halothane
  • Methoxyflurane
  • Enflurane
  • Isoflurane
  • Desflurane
  • Sevoflurane
Depolarizing muscle relaxant
  • Succinylcholine

In many of the early reported cases, both succinylcholine and a halogenated anesthetic agent were used. However, succinylcholine is less frequently used in modern practice, and about half of the cases in the past decade were associated with volatile anesthetics as the only triggering agents. 

 Nearly 50% of patients who experience an episode of MH have had at least one previous uneventful exposure to anesthesia during which they received a recognized triggering agent. Why MH fails to occur after every exposure to a triggering agent is unclear.

Investigations into the biochemical causes of MH reveal an uncontrolled increase in intracellular calcium in skeletal muscle. The sudden release of calcium from sarcoplasmic reticulum removes the inhibition of troponin, resulting in sustained muscle contraction. Markedly increased adenosine triphosphatase activity results in an uncontrolled increase in aerobic and anaerobic metabolism. The hypermetabolic state markedly increases oxygen consumption and CO2 production, producing severe lactic acidosis and hyperthermia.1

Malignant hyperthermia (MH) is a rare (1:15,000 in pediatric patients and 1:40,000 adult patients) genetic hypermetabolic muscle disease.1 Most cases have been reported in young males; almost none have been reported in infants, and few have been reported in the elderly. Nevertheless, all ages and both sexes may be affected.
The upper Midwest appears to have the greatest incidence of MH in the United States.
  • Nearly 50% of patients who experience an episode of malignant hyperthermia (MH) have had at least one previous uneventful exposure to anesthesia during which they received a recognized triggering agent. Why MH fails to occur after every exposure to a triggering agent is unclear.
  • Image not available. Musculoskeletal diseases associated with a relatively high incidence of MH include central-core disease, multi-minicore myopathy, and King-Denborough syndrome. Duchenne’s and other muscular dystrophies, nonspecific myopathies, and osteogenesis imperfecta have been associated with MH-like symptoms in some reports; however, their association with MH is controversial.
  • Image not available. Treatment of an MH episode is directed at terminating the episode and treating complications such as hyperthermia and acidosis. The mortality rate for MH, even with prompt treatment, ranges from 5% to 30%. First and most importantly, the triggering agent must be stopped; second, dantrolene must be given immediately.
  • Image not available. Dantrolene, a hydantoin derivative, directly interferes with muscle contraction by inhibiting calcium ion release from the sarcoplasmic reticulum. The dose is 2.5 mg/kg intravenously every 5 min until the episode is terminated (upper limit, 10 mg/kg). Dantrolene should be continued for 24 h after initial treatment.
  • Image not available. Propofol, thiopental, etomidate, benzodiazepines, ketamine, opiates, droperidol, nitrous oxide, nondepolarizing muscle relaxants, and all local anesthetics are nontriggering agents that are safe for use in MH-susceptible patients.

 

 

 

Complications of Injecting Drug Use

  • Local problems—Abscess (Figures 240-2 
    Image not available.

    A 32-year-old woman with type 1 diabetes developed large abscesses all over her body secondary to injection of cocaine and heroin. Her back shows the large scars remaining after the healing of these abscesses. (Courtesy of ­Richard P. Usatine, MD.)

    and 240-3; Abscess), cellulitis, septic thrombophlebitis, local induration, necrotizing fasciitis, gas gangrene, pyomyositis, mycotic aneurysm, compartmental syndromes, and foreign bodies (e.g., broken needle parts) in local areas.2
    • IDUs are at higher risk of getting methicillin-resistant Staphylococcus aureus(MRSA) skin infections that the patient may think are spider bites (Figure 240-4).
    • Some IDUs give up trying to inject into their veins and put the cocaine directly into the skin. This causes local skin necrosis that produces round atrophic scars (Figure 240-5).
  • IDUs are at risk for contracting systemic infections, including HIV and hepatitis B or hepatitis C.
    • Injecting drug users are at risk of endocarditis, osteomyelitis (Figures 240-6and 240-7), and an abscess of the epidural region. These infections can lead to long hospitalizations for intravenous antibiotics. The endocarditis that occurs in IDUs involves the right-sided heart valves (see Chapter 50, Bacterial Endocarditis).2 They are also at risk of septic emboli to the lungs, group A β-hemolytic streptococcal septicemia, septic arthritis, and candidal and other fungal infections.

 

The mortality rate for MH, even with prompt treatment, ranges from 5% to 30%.

Content 11

_____________________________

most cases of classic hyperthermia are due to diseases causing imbalances in heat production and heat loss, such as malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, anticholinergic drugs, sympathomimetic drugs, thyrotoxicosis, and heat stroke 

 


TABLE 92-2 Common Causes of Hyperthermia: Remember Them by Using the Mnemonic CHASE NMS

Central Nervous System Damage

Mechanism: damage of the hypothalamic regulatory center

Causes: subarachnoid hemorrhage, status epilepticus, hypothalamic injury

When to suspect: hyperthermia (>104°F) with associated head trauma, central nervous system infection, or history of seizures

Heat Stroke

Mechanism: inability to dissipate heat

Causes: exposure to high ambient temperatures, strenuous exercise

When to suspect: hyperthermia, dry skin, delirium in a patient exposed to high temperatures or having undergone severe exercise

Anticholinergic Poisoning/Exposure

Mechanism: central and peripheral muscarinic receptor blockade

Causes: antihistamines, atropine, belladonna alkaloids, carbamazepine, diphenhydramine, meclizine, phenothiazines

When to suspect: hyperthermia, altered mental status, dry mouth, lack of perspiration, flushing, and urinary retention

Serotonin Syndrome

Mechanism: overstimulation of 5-HT1A receptors in the central grey nuclei and the medulla; 5-HT2 receptors may also play a role

Causes and examples:

  1. Excess precursors of serotonin or serotonin agonists—buspirone, L-dopa, lithium, LSD, L-tryptophan, trazodone

  2. Increased release of serotonin—amphetamines, 3,4-methylenedioxymethamphetamine (MDMA), cocaine, reserpine, fenfluramine

  3. Reduced uptake of serotonin—selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), trazodone, venlafaxine, meperidine

  4. Slowing of serotonin metabolism—monoamine oxidase inhibitors

When to suspect: hyperthermia, hyperhidrosis, confusion or agitation with significant autonomic and neurologic derangement

Endocrine

Mechanism: elevated endogenous metabolism

Causes: thyrotoxicosis, pheochromocytoma

When to suspect: hyperthermia, adrenergic symptoms, hypertension, and no associated drug exposures or heat exposures

Neuroleptic Malignant Syndrome (NMS)

Mechanism: unproven, but dopamine receptor blockade is thought to play a key role in precipitating NMS

Causes and examples:

  1. Typical antipsychotic medications—haloperidol, chlorpromazine, loxapine

  2. Atypical antipsychotic medications—aripiprazole, olanzapine, quetiapine, risperidone

  3. Dopamine antagonists—metoclopramide, promethazine

When to suspect: hyperthermia, rigidity, altered mental status in a patient taking any of the classes of medications known to cause NMS

Malignant Hyperthermia

Mechanism: genetic disorder of calcium channels in skeletal muscle that allows an uncontrolled influx of calcium into the cell resulting in sustained muscle contraction and increased metabolism

Causes: inhalational anesthetics—halothane, enflurane, isoflurane; succinylcholine

When to suspect: hyperthermia in anyone receiving inhalational anesthetics or succinylcholine

Sympathomimetic Poisoning/Overdose

Mechanism: central and peripheral disturbances in thermoregulation

Causes: amphetamines, methamphetamines, cocaine, MDMA or ecstasy

When to suspect: recreational drug users and other high-risk populations with hyperthermia, mental status changes, and evidence of adrenergic stimulus

 

 

It is an inherited disorder with an autosomal dominant pattern and it is characterized by excessive release of calcium from the sarcoplasmic reticulum in skeletal muscle in response to halogenated inhalational anesthetic agents (e.g., halothane, isoflurane, servoflurane, and desflurane) and depolarizing neuromuscular blockers (e.g., succinylcholine) (1).The calcium influx into the cell cytoplasm leads to uncoupling of oxidative phosphorylation and a marked rise in metabolic rate.


Table 52-2 Drugs Known to Trigger Malignant Hyperthermia.2

Inhaled general anesthetics
  • Ether
  • Halothane
  • Methoxyflurane
  • Enflurane
  • Isoflurane
  • Desflurane
  • Sevoflurane
Depolarizing muscle relaxant
  • Succinylcholine

One early focus of investigations into the mechanisms of MH has been the gene for the ryanodine (Ryr1) receptor, located on chromosome 19. Ryr1 is an ion channel responsible for calcium release from the sarcoplasmic reticulum and it plays an important role in muscle depolarization. Subsequent reports linked MH with mutations involving the sodium channel on chromosome 17. An autosomal recessive form of MH has been associated with the King-Denborough syndrome. Most patients with an episode of MH have a history of relatives with a similar episode or with an abnormal halothane-caffeine contracture test. The complexity of genetic inheritance patterns in families reflects the fact that MH can be caused by mutations of one or more genes on more than one chromosome.

To date genetic studies in humans have revealed at least five different chromosomes and more than 180 individual mutations associated with MH.

Genetic testing, although available, currently screens for less than 20% of recognized mutations. A patient with a bona fide clinical history of MH has about a 30-50% chance of testing positive.

1

 

 

 

A halogenated anesthetic agent alone may trigger an episode of MH (Table 52-2).

In many of the early reported cases, both succinylcholine and a halogenated anesthetic agent were used. However, succinylcholine is less frequently used in modern practice, and about half of the cases in the past decade were associated with volatile anesthetics as the only triggering agents. Image not available. Nearly 50% of patients who experience an episode of MH have had at least one previous uneventful exposure to anesthesia during which they received a recognized triggering agent. Why MH fails to occur after every exposure to a triggering agent is unclear. Investigations into the biochemical causes of MH reveal an uncontrolled increase in intracellular calcium in skeletal muscle. The sudden release of calcium from sarcoplasmic reticulum removes the inhibition of troponin, resulting in sustained muscle contraction. Markedly increased adenosine triphosphatase activity results in an uncontrolled increase in aerobic and anaerobic metabolism. The hypermetabolic state markedly increases oxygen consumption and CO2 production, producing severe lactic acidosis and hyperthermia.

 

 

 

 

Malignant hyperthermia (MH) is an uncommon disorder that occurs in approximately 1 in 15,000 episodes of general anesthesia.

Malignant hyperthermia (MH) is a rare (1:15,000 in pediatric patients and 1:40,000 adult patients) genetic hypermetabolic muscle disease,

MH may occasionally present more than an hour after emergence from an anesthetic, and rarely may occur without exposure to known triggering agents. Most cases have been reported in young males; almost none have been reported in infants, and few have been reported in the elderly. Nevertheless, all ages and both sexes may be affected. The upper Midwest appears to have the greatest incidence of MH in the United States.1

 

The first suspicion of MH should prompt immediate discontinuation of the offending anesthetic agent.

Content 1

Dantrolene sodium

Dose regimen: 1 to 2 mg/kg as IV bolus, and repeat every 15 minutes if needed to a total dose of 10 mg/kg.

Follow the initial dosing regimen with a dose of 1 mg/kg IV or 2 mg/kg orally four times daily for 3 days to prevent recurrences.

Specific treatment for the muscle rigidity

A muscle relaxant that blocks the release of calcium from the sarcoplasmic reticulum.

Dantrolene and bromocriptine are the main medications for the treatment of NMS. Intravenous clonidine, carbamazepine, amantadine, levodopa, and anticholinergic medications have been used in case reports. Treatment should continue for at least 10 days and then tapered slowly. If the insult is due to depot antipsychotics, treatment should extend for a total of 2 to 3 weeks. In cases refractory to medical treatment, electroconvulsive therapy may be used to improve fever, sweating, and delirium.


When given early in the course of MH, dantrolene can reduce the mortality rate from 70% or higher (in untreated cases) to 10% or less.

The most common side effect of dantrolene is muscle weakness, particularly grip strength, which usually resolves in 2 to 4 days after the drug is discontinued (11). The most troublesome side effect of dantrolene is hepatocellular injury, which is more common when the daily dose exceeds 10 mg/kg (9). Active hepatitis and cirrhosis are considered contraindications to dantrolene therapy (11) but, considering the high mortality in MH if left untreated, these contraindications should not be absolute.

Antipyretics, such as nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen, have no role in hyperthermia because the actions of these medications are distinct from the underlying mechanisms of hyperthermia. Acetaminophen can hasten hepatic damage, and salicylates can worsen existing coagulopathy.

The central core temperature should be monitored continuously by rectal, esophageal, or tympanic probe.

Content 3

Aggressive volume resuscitation is extremely important.

Vital signs should be closely monitored as well.

If rhabdomyolysis is significant, intravenous fluids are essential to avoid the risks of myoglobinuria. Active measures should be taken to lower body temperature (Table 92-13). The best method is debated, but direct application of ice packs to the groin, axilla, and neck can be used. Evaporative cooling may be used, in which the naked patient is sprayed with alcohol and water and cooled with fans. Immersion in cool water is an option but may interfere with resuscitation and lead to complications from vasoconstriction. Other methods include extracorporeal bypass, cooling blankets, and iced peritoneal or gastric lavage. There has been much success with the rapid infusion of 30 mL/kg of iced (4°C) normal saline to induce hypothermia in comatose survivors of cardiac arrest, and this should be considered in patients with hyperthermia. To prevent excessive cooling, these methods should be halted when core body temperature reaches 38.5°C.

 

TABLE 92-13Additional Treatments for Specific Causes of Hyperthermia

Cause of Hyperthermia Specific Additional Treatments
1. Malignant hyperthermia Dantrolene, hyperventilation with 100% oxygen
2. Neuroleptic malignant syndrome Bromocriptine, dantrolene, muscle relaxants
3. Serotonin syndrome Serotonin antagonists, propranolol, benzodiazepines, cyproheptadine
4. Sympathomimetic Sympatholytics, benzodiazepines
5. Anticholinergics Physostigmine (rarely needed), sedatives
6. Endocrine Propranolol, methimazole
7. Heat stroke Supportive care
8. CNS injury/infection Antibiotic

 

 

 

 

 

Most patients with serotonin syndrome will improve within 24 hours after stopping the causative agents and beginning supportive therapy. Besides rapid cooling, benzodiazepines can be used to induce muscle relaxation and decrease associated anxiety. Cyproheptadine and chlorpromazine may be used to combat many of the symptoms associated with serotonin syndrome. Cyproheptadine is considered to be the first line, as chlorpromazine can cause hypotension, which should be avoided in the setting of cardiovascular instability.

 

All patients who survive an episode of MH should be given a medical bracelet that identifies their susceptibility to MH.

Because MH is a genetic disorder with a known inheritance pattern (autosomal dominant), immediate family members should be informed of their possible susceptibility to MH.

A test is available to identify the responsible gene for MH in family members (10).

 

 

Complications of Injecting Drug Use

  • Local problems—Abscess (Figures 240-2 
    Image not available.

    A 32-year-old woman with type 1 diabetes developed large abscesses all over her body secondary to injection of cocaine and heroin. Her back shows the large scars remaining after the healing of these abscesses. (Courtesy of ­Richard P. Usatine, MD.)

    and 240-3; Abscess), cellulitis, septic thrombophlebitis, local induration, necrotizing fasciitis, gas gangrene, pyomyositis, mycotic aneurysm, compartmental syndromes, and foreign bodies (e.g., broken needle parts) in local areas.2
    • IDUs are at higher risk of getting methicillin-resistant Staphylococcus aureus(MRSA) skin infections that the patient may think are spider bites (Figure 240-4).
    • Some IDUs give up trying to inject into their veins and put the cocaine directly into the skin. This causes local skin necrosis that produces round atrophic scars (Figure 240-5).
  • IDUs are at risk for contracting systemic infections, including HIV and hepatitis B or hepatitis C.
    • Injecting drug users are at risk of endocarditis, osteomyelitis (Figures 240-6and 240-7), and an abscess of the epidural region. These infections can lead to long hospitalizations for intravenous antibiotics. The endocarditis that occurs in IDUs involves the right-sided heart valves (see Chapter 50, Bacterial Endocarditis).2 They are also at risk of septic emboli to the lungs, group A β-hemolytic streptococcal septicemia, septic arthritis, and candidal and other fungal infections.

 

Content 3

Content 13

Content 11

 

A

 

 

 


 

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