CC

A 15-year-old male is undergoing an open reduction with internal fixation (ORIF) of a left mandibular angle fracture in the operating room. (The incidence of malignant hyperthermia [MH] is highest in children and is more common in males). He had presented to the emergency department complaining of pain, swelling, and malocclusion. He has previously had ear tubes and a tonsillectomy under general anesthesia without anesthesia complication.

HPI

While playing ball, the patient sustained an accidental blow to the left side of the jaw from an opponent’s elbow. He was diagnosed with a fractured mandible and subsequently was admitted to the hospital for treatment of his injury under general anesthesia. The patient was induced with propofol, given succinylcholine, and nasotracheally intubated without difficulty. He was maintained on sevoflurane (halogenated inhaled anesthetic) and intravenous (IV) agents. The patient had a smooth anesthetic course for the first 20 minutes of the procedure before the onset of unexplained tachycardia and elevation in his end-tidal carbon dioxide (Et co ₂ , the earliest signs of MH). The diagnosis of MH was considered.

PMHX/PDHX/medications/allergies/SH/FH

The patient underwent tonsillectomy and adenoidectomy at 6 years of age under general anesthesia without any surgical or anesthetic complications. (Fifty percent of MH cases occur in patients with two or more prior uneventful experiences with anesthetics.) His family history is negative for MH. (MH is an autosomal dominant inherited disorder. However, many patients present with MH without any prior documented family history.)

Examination

Malignant hyperthermia may present immediately upon induction of anesthesia, especially with inhalation induction or with the use of succinylcholine. Alternatively, it may onset during the procedure. Occasionally, MH may become apparent hours after the operation. In all situations, the progression from onset to full-blown MH is extremely rapid.

The clinical presentation of MH comprises a spectrum of signs, symptoms in an awake patient, and laboratory values. Many of these manifestations (discussed later) are nonspecific, and many conditions in an anesthetized patient can mimic MH ( Box 21.1 ). Therefore, the clinician must constantly reevaluate the clinical situation to determine the likelihood that MH may exist. The presence of only one sign or symptom decreases the likelihood of MH. In general, several coexist in an MH reaction.

Hypermetabolism is the hallmark feature of MH and is caused by disordered calcium homeostasis in skeletal muscle. Because skeletal muscle makes up about 50% of body weight, the changes to the physiological state can be profound.

Changes in Et co ₂ concentration are usually the first sign of MH. However, these changes may vary depending on the mode of ventilation and the stage of the process when the change is observed. In a spontaneously breathing patient under general anesthesia, the first sign may be hypocarbia, or a decrease in expired carbon dioxide concentration. Early in an MH episode, a spontaneously breathing patient will breathe more rapidly and with larger tidal volumes to offset metabolic acidosis and maintain acid–base balance. However, as the patient’s metabolic acidosis worsens and fatigue ensues, they will not be able to compensate fully, and hypercarbia (increased Et co ₂ ) will occur. This leads to a combined metabolic and respiratory acidosis. In a patient who is mechanically ventilated, the carbon dioxide concentration increases much earlier provided the tidal volume and respiratory rate on the ventilator are not altered because the mechanically ventilated patient cannot alter their respiratory pattern on their own.

Although increased Et co ₂ is highly sensitive for MH (its absence basically rules out the diagnosis), the differential diagnosis of this increased sign is extensive. An exhausted soda lime canister, a stuck expiratory valve, light anesthesia, or an increase in surgical stimulation may all cause an increase in Et co ₂ . These and other conditions must be considered during the evaluation of the patient (see Box 21.1 ).

Early in MH, tachycardia and hypertension are common and are caused by sympathetic nervous system activation. The increases in circulating epinephrine and norepinephrine lead to increases in heart rate and vasoconstriction with resultant hypertension. Sympathetic nervous system responses in MH appear to be secondary to hypercarbia and acidosis.

Sweating also results from sympathetic activation and helps to regulate body temperature when hyperthermia begins.

Hyperthermia is caused by increased metabolism with corresponding increases in heat production (because metabolic reactions are exothermic). It must be emphasized that hyperthermia is a late sign, and thus the presence of other signs with a normal temperature does not preclude MH. The rate of rise in core body temperature may be as much as 2°C every 5 minutes.

Hypoxia is attributable to increased oxygen consumption. The practitioner may find that increased inspired oxygen concentrations are required to maintain oxygen saturation despite little change in stimulation or clinical state during the procedure. Hypoxia results in an increase in anaerobic metabolism with the production of lactate, causing lactic acidosis and increased membrane permeability.

Later in the progression of MH, hypertension is replaced by hypotension. This stems partly from increases in serum lactate and carbon dioxide, which cause vascular smooth muscle relaxation and vasodilation. Second, myocardial oxygen consumption increases dramatically because of increases in sympathetic nervous system activity, predisposing to myocardial ischemia and decreased cardiac output. The effects on cardiac muscle are not a direct effect of derangements in calcium metabolism but rather caused by sympathetic overactivity induced by hyperthermia, acidosis, and hyperkalemia.

Arrhythmias in MH begin with sinus tachycardia but can progress to ventricular ectopy, ventricular tachycardia, and ventricular fibrillation.

Muscle rigidity is caused by sustained muscle contraction mediated by unopposed calcium release.

The breakdown of muscle, or rhabdomyolysis, leads to accumulation of myoglobin (the hemoglobin of skeletal muscle), and the resultant myoglobinuria renders the urine cola colored. Myoglobinuria can contribute to renal failure in those with MH. Myoglobin has a direct toxic effect on proximal renal tubules, and it may bind to proteins in the distal tubules (Tamm-Horsfall protein) to form casts.

Cerebral oxygenation may be impaired in an MH episode because of the increased metabolic state, causing hypoxia and anaerobic metabolism. Hyperthermia and acidosis are poorly tolerated by cerebral tissues and may compound the insult, leading to transient or permanent neurologic sequelae.

Masseter muscle rigidity

The use of succinylcholine normally causes a transient increase in tone of the masseter and lateral pterygoid muscles immediately after injection. If prolonged or exaggerated, such increase in jaw muscle tension in the absence of temporomandibular joint dysfunction or myotonia is referred to as masseter muscle rigidity (MMR). The rigidity is so profound that manual mouth opening, direct laryngoscopy, and tracheal intubation are rendered unachievable. This “jaws of steel” phenomenon should alert the clinician to the possibility of MH. Up to 50% of people with MMR have a predisposition to MH. If MMR is accompanied by rigidity of other muscles, then MH is inevitable. However, in patients who have MMR with limb flaccidity, MH may still occur. Current consensus states that if the procedure is elective, it is prudent to cancel the procedure and monitor for signs and symptoms of MH for 24 hours. If the procedure is emergent, then continuation with nontriggering agents is acceptable, with intraoperative and postoperative surveillance for MH evolution.

Masseter muscle rigidity is most common in children, with its highest incidence between 8 and 12 years of age. Because a high percentage of patients with MMR progress to having fulminant MH, it seems prudent to avoid the routine use of succinylcholine in children.

In addition, the use of succinylcholine in pediatric anesthesia is also relatively contraindicated because of the possibility of undiagnosed myopathies. The most common such myopathy is muscular dystrophy. The muscle weakness leads to an upregulation of acetylcholine receptors, which can precipitate massive release of intracellular potassium ions upon administration of succinylcholine. The resulting hyperkalemic arrest may be even more difficult to resuscitate in the pediatric population. It should be noted that the mechanism of hyperkalemia in these myopathies should be distinguished from the hyperkalemia that occurs in MH. The management, however, is the same in all episodes of hyperkalemia.

Labs

Laboratory values in MH may be severely altered. The destruction of muscle cells leads to myoglobinuria, increased creatine kinase levels, and hyperkalemia. Arterial blood gas analysis will show hypoxemia, increased arterial carbon dioxide levels (although this value may be decreased early on in a spontaneously breathing patient), elevated lactate, a decrease in bicarbonate, and an anion gap metabolic acidosis. The pH may be normal early in an MH crisis if respiratory compensation has taken place but will eventually decrease as metabolic exhaustion ensues. The gradient of alveolar to arterial oxygen will increase, reflecting inadequate tissue perfusion. Acute renal failure is reflected by an increased creatinine value and is caused by dehydration combined with the toxic effects of myoglobin on renal tubules.

On diagnosis of MH, a full set of serum electrolytes, liver function tests, urinalysis, and arterial blood gases should be ordered to aid in the correction and diagnosis of electrolyte and acid–base disturbances.

The laboratory findings characteristically reflect the following metabolic conditions:

• •

  Acidemia (elevated P co ₂ and metabolic acidosis). (Of cases seen between 1987 and 2006, 78.6% presented with both muscular abnormalities and respiratory acidosis; only 26% had metabolic acidosis.)

• •

  Hyperkalemia (secondary to acidosis)

• •

  Hypercalcemia (secondary to reduced uptake of calcium from the sarcoplasmic reticulum of skeletal muscles)

• •

  Elevated serum transaminases and creatinine kinase (CK) and subsequent rhabdomyolysis, causing myoglobinuria (secondary to hypermetabolic skeletal muscle activity)

The standard for diagnostic testing for suspected susceptibility to MH is the caffeine-halothane contracture test (CHCT), which is performed on muscle biopsy specimens at specialized centers.

Electrocardiography (ECG) changes and dysrhythmias can occur; these are late findings. They are caused by elevated potassium levels from muscle breakdown. They can occur more rapidly in muscular patients.

The presence of premature ventricular contractions may indicate a life-threatening hyperkalemia and is an ominous sign because this condition may degrade into ventricular tachycardia or ventricular fibrillation.

Biopsy and testing

Testing for MH susceptibility is offered to patients who may display MH signs or symptoms intraoperatively or to first-degree relatives of patients who have known MH susceptibility.

Patient selection is vital to ensure that those who warrant testing receive such testing while avoiding unnecessary intervention. A clinical grading scale has been developed to assess the probability that an MH reaction has occurred and can guide decisions regarding testing. The criteria are as follows:

• 1.

  Generalized or masseter muscle rigidity

• 2.

  CK greater than 20,000 units/L, cola-colored urine, myoglobinuria, or hyperkalemia,

• 3.

  Et co ₂ greater than 55 mm Hg or arterial PCO ₂ greater than 60 mm Hg

• 4.

  Rapidly increasing temperature or temperature greater than 38.8°C

• 5.

  Unexplained sinus tachycardia, ventricular tachycardia, or ventricular fibrillation

• 6.

  Family history of MH

• 7.

  Elevated resting creatine kinase

• 8.

  pH less than 7.25

• 9.

  Rapid reversal of signs of MH with dantrolene

Malignant hyperthermia testing can be achieved, in theory, through either physiological or genetic testing. However, wide genetic heterogeneity exists in expression of MH susceptibility, and this renders genetic testing difficult. One patient may have one mutation, and another member of the same family may have a different mutation. Both patients may possess MH susceptibility. Practically, therefore, physiological testing via muscle biopsy is more definitive.

The demonstration by Kalow and Britt that caffeine accentuated the response of muscles in vitro to halothane formed the basis of the CHCT. Physiological testing involves the exposure of strips of muscle excised from the vastus medialis or vastus lateralis to caffeine and halothane. Because direct infiltration of local anesthetic to the site may interfere with tissue viability, the surgical procedure is performed with a nerve block and sedation. The muscle biopsy must be performed at specialized centers where the analysis of the fibers will take place. There are five centers in the United States and one in Canada. Because the muscle degrades quickly, testing must be performed within 5 hours of biopsy. Failure to do so may render a false-negative test result. To maintain viability, the muscle must not be cauterized or stretched. The viability of the muscle is confirmed by electrical stimulation of the fibers, which should result in muscle contraction. Six muscle fibers are then mounted and attached to a force transducer. They are inserted into a muscle bath and exposed to solutions of caffeine of 0.5, 1, and 2 mM, as well as to 3% halothane. The tension generated within the muscles is measured. Disproportionately high levels of contractile force suggest MH susceptibility. A tension of 0.3 g in a caffeine-exposed muscle strip or of 0.7 g in a halothane-exposed muscle strip deems the patient MH susceptible. For halothane, a result of 0.5 to 0.69 g of muscle tension is classified as MH equivocal. The incorporation of ryanodine or 4-chloro-m-cresol (a ryanodine receptor agonist) can increase the accuracy of the CHCT.

These diagnostic thresholds have been adjusted to maximize sensitivity of the test (i.e., to minimize false-negative results). Obviously, a false-negative result could be detrimental because exposure of a patient who has tested negative for MH susceptibility to halothane or succinylcholine could lead to a catastrophic outcome if the patient is indeed positive. Sensitivity of the CHCT is reported to be 97% to 99%. This high sensitivity sacrifices specificity, and the false-positive rate ranges from 10% to 20%.

Because treatment of MH-susceptible patients can be achieved easily and cost effectively, the lower specificity of the CHCT can be tolerated. The main disadvantage of false-positive test results is the possible labeling of patients and their entire families as MH susceptible. Another drawback to muscle biopsy testing is the invasiveness of the procedure. The CHCT is not performed in children younger than 5 years of age because of the significant loss of muscle that would result. Finally, the test can be restrictive because of its high cost, which is approximately $6000.

Creatine kinase levels may facilitate the diagnosis of MH susceptibility. An elevated resting CK value in a first-degree relative of a patient with known MH susceptibility confers MH susceptibility without the need for further testing. There should be no history of recent trauma before testing because muscle trauma elevates CK. However, a normal CK concentration does not exclude the possibility of MH susceptibility, thereby necessitating a muscle biopsy.

Assessment

Acute onset of MH during ORIF of a mandibular fracture.

Treatment

Discussion

Malignant hyperthermia, also known as malignant hyperpyrexia, is a hypermetabolic disease of skeletal muscle. The basic physiological derangement in MH is a massive and sustained release of intracellular calcium ions, to concentrations that are 500 times the levels seen in the relaxed state. Sustained muscle contraction ensues, leading to supraphysiological increases in metabolism, with resultant hyperthermia, muscle rigidity, acidosis, and cell death.

Skeletal muscle contraction involves a process known as excitation–contraction coupling. This process was first described by Sandow in 1950 and involves a precise series of steps beginning with the generation of an action potential in skeletal muscle fibres and ending in increased muscle tension. A neuronal signal that reaches the neuromuscular junction causes the release of the neurotransmitter acetylcholine into the synaptic cleft. The acetylcholine activates nicotinic receptors on the motor end plate. The opening of sodium channels in the end plate creates an end plate potential, which allows the signal to propagate throughout the muscle membrane. Complex invaginations of the muscle cell membrane known as T-tubules allow the action potential to spread diffusely throughout the muscle cell. The changes in membrane potential are detected by dihydropyridine receptors (DHPRs), which are L-type (L stands for long-lasting) calcium channels. These DHPRs interact with ryanodine receptors (RyRs), which are calcium-release channels located in the sarcoplasmic reticulum (the endoplasmic reticulum of skeletal muscle). Normally, the DHPR keeps the RyR in a closed state. Depolarization of the muscle cell membrane induces a conformational change in the DHPR, thereby mediating the opening of the RyR. The resulting influx of calcium leads to a rise in calcium concentrations in the myoplasm. This initiates a chain of events that lead to activation of the actin–myosin complex, the so-called contractile apparatus, causing muscle contraction. Relaxation of the muscle occurs when specialized pumps transport calcium back into the sarcoplasmic reticulum, and intracellular calcium concentrations fall below threshold values.

In other words, the release of calcium in excitation–contraction coupling is through calcium release channels and is mediated by the RyR. This receptor has three subtypes, and mutations of subtype 1 (RyR ₁ ) confer susceptibility to MH by causing overactivation of the calcium release channel. This prevents calcium concentrations from falling sufficiently, leading to sustained muscle contraction.

More than a dozen mutations of RyR ₁ have been linked to MH susceptibility in humans.

Although rare cases follow an autosomal recessive pattern, MH is mainly inherited in an autosomal dominant pattern. Therefore, 50% of children, parents, and siblings of an MH susceptible patient will possess MH susceptibility.

Malignant hyperthermia has been observed in pigs, rabbits, and humans.

The porcine model of MH has been widely studied to learn about MH in humans. In swine, it can be elicited by a wide range of triggers. Even seemingly minor stressors, such as heat, exercise, environmental stress, and the flight-or-fright response, may cause an MH reaction. This phenomenon is known as awake triggering.

In humans, MH is mostly observed during general anesthesia and is initiated by specific triggering agents. However, evidence does suggest that awake triggering may exist in humans, albeit at a much lower incidence than in swine. Anxiety may precipitate an MH-like response.

It may occur with exercise or exposure to noxious stimuli. Awake triggering may manifest as heat stroke, unusual stress and fatigue, myalgias, or sudden unexpected death.

When MH susceptibility exists, not every anesthetic with triggering agents will produce an MH reaction. This is evidenced by one patient who had multiple uneventful anesthetics before developing an MH crisis. When an MH reaction occurs, it may present on induction of anesthesia, especially with inhalation induction or when succinylcholine is used for intubation. It also may manifest intraoperatively and rarely even postoperatively. Thus, clinicians should always include the possibility of MH in the differential diagnosis when classic signs or symptoms appear. Prompt recognition and treatment are potentially lifesaving.

The incidence of MH is reported to be 1 in 250,000 anesthetics. However, if one only looks at cases in which triggering agents are used, this incidence increases to 1 in 62,000 anesthetics. The suspicion of MH in this study arose in 1 in 16,000 anesthetics and in 1 in 4200 anesthetics in which triggering agents were administered. Therefore, we can extrapolate that if the suspicion of MH arises, there is a 1 in 15, or 7%, chance that fulminant MH will ensue.

The first reports of MH-like reactions were between 1915 and 1925, when one family experienced a cluster of three anesthetic deaths. These deaths were preceded by muscle rigidity and hyperthermia. MH susceptibility was eventually identified several decades later in three descendants in this family. Ombredanne, in 1929, noted postoperative hyperthermia and pallor in children who were given anesthesia. However, he did not recognize familial patterns. In 1960, Denborough and Lovell presented the case of a 21-year-old Australian male with an open femur fracture who was terrified of receiving anesthesia because 10 of his relatives had died in the perioperative period. Lovell, being the anesthetist, commenced the anesthetic with the newfound inhalational agent halothane but aborted and administered a spinal anesthetic when signs of MH appeared.

Other disorders

The muscular dystrophies are a group of muscle diseases that vary in their presentation, disease progression, and inheritance. The most common, Duchenne muscular dystrophy (DMD), is characterized by a deficiency in the muscle protein dystrophin. It is inherited in an X-linked recessive manner, primarily affecting males with an incidence of 1 in 3500 births. Muscle weakness presents early in childhood, with a median age of diagnosis of 5 years. Patients with DMD usually die in their 20s because of respiratory failure and cardiac muscle dysfunction.

Patients with muscular dystrophies are prone to perioperative complications, including hyperthermia, tachycardia, rhabdomyolysis, and hyperkalemic cardiac arrest, on exposure to volatile anaesthetics or succinylcholine. Although the clinical presentation may be indistinguishable from MH, the underlying pathophysiology is seemingly different. One study analyzed the ryanodine receptor gene in 47 patients with DMD. None of these patients had alterations of known gene segments that have conferred MH susceptibility. The mechanism of succinylcholine-induced cardiac arrest was outlined earlier (see the discussion of MMR). The susceptibility of patients with DMD to volatile anaesthetics is more puzzling and may involve disruption of cell membrane integrity caused at least in part by the absence of dystrophin.

Central core disease (CCD) is a congenital myopathy with an autosomal dominant pattern of inheritance. As with MH susceptibility, the defect is in the ryanodine receptor gene RyR ₁ . There is a high association between CCD and MH. In fact, Denborough’s original patient was later found to have CCD. It is characterized by central cores, which are areas of decreased oxidative activity stemming from mitochondrial depletion. Histologically, central cores may not be identified early in the disease even with symptoms. Thus, their absence does not exclude the diagnosis. Clinically, hypotonia and nonprogressive proximal muscle weakness are evident, especially in the hip and trunk muscles. Orthopedic complications include hip dislocation, scoliosis, and foot deformities. Most patients with CCD are able to walk independently. Respiratory and cardiac involvement are rare. Extreme caution should be taken in anesthetizing patients with CCD because of the high likelihood of MH susceptibility.

King-Denborough syndrome (KDS) is a rare disease with an unclarified mode of genetic transmission characterized by myopathy, dysmorphic features, short stature, musculoskeletal abnormalities, delay in motor development, and MH susceptibility. Dysmorphic features include downslanting palpebral fissures, malar hypoplasia, a high-arched palate, dental malocclusion, micrognathia, low-set ears, and a webbed neck. Musculoskeletal changes include kyphosis, lumbar lordosis, and pectus excavatum. The RyR ₁ locus appears to play a key role in KDS, thereby explaining the link between KDS and MH susceptibility.

Neuroleptic malignant syndrome (NMS) is a life-threatening condition that may occur with the use of dopamine antagonists or with the abrupt discontinuation of dopamine receptor agonists. The former situation may be encountered with all classes of neuroleptic medications, which inhibit dopaminergic transmission to varying extents. The latter scenario may occur if Parkinson’s disease medications are suddenly stopped. The typical presentation is one of mental status changes, rigidity, fever, and autonomic instability developing in that order, over 1 to 3 days. With the antipsychotic medications, it classically presents after about 2 weeks of use, although it may occur after a single dose or after years of chronic therapy. Mental status changes include stupor and coma. Extreme muscle rigidity and intense muscle contractions are the effect of a deficit in dopamine in the extrapyramidal system of the brain. This results in a hypermetabolic state resembling MH. Increased muscle metabolism leads to hyperpyrexia. Last, autonomic instability may manifest, with tachycardia, diaphoresis, tachypnea, and elevated or labile blood pressure. Respiratory muscle rigidity leads to decreased chest wall compliance and predisposes to hypoventilation and aspiration pneumonia. Muscle breakdown eventually ensues, resulting in rhabdomyolysis, myoglobinuria, acute tubular necrosis, and acute renal failure.

Neuroleptic malignant syndrome may mimic MH, but the diagnoses differ in several ways. The patient with NMS may have recently started or had an increase in dosage of a neuroleptic medication. In NMS, autonomic instability is a late sign, but this feature typically presents earlier in MH.

Treatment of NMS begins with discontinuation of the offending drug and treatment with dopamine receptor agonists such as bromocriptine or amantadine. Many of the treatment modalities used in MH, such as rehydration, cooling, and hyperventilation, are effective in the management of NMS. Dantrolene, although not the mainstay of treatment, is useful because it decreases body temperature by reducing muscle contraction. Because dantrolene also relaxes skeletal muscle while preserving the ability to breathe deeply and cough, it may improve chest wall compliance and help avoid the need for intubation. In contrast with the more rapid response to treatment in MH, improvement of NMS requires several days.

In summary, MH is a hypermetabolic disorder of skeletal muscle that mainly manifests under anesthesia with specific triggers. The anesthesiologist should always have a high index of suspicion as to its possibility because prompt recognition and treatment are usually lifesaving. A thorough personal and family history of anesthesia-related problems can lead the clinician to suspect an increased likelihood. Although much is already known about MH, further research will make the diagnosis and treatment of patients with this disorder easier in the future.