Myoglobinuric Syndromes Including Malignant Hyperthermia

Myoglobinuria—the presence in urine of a 17.8-kDa, red pigment, iron-protein compound called myoglobin—results from rhabdomyolysis, which is the acute breakdown or necrosis of skeletal muscle fibers whose contents (among them myoglobin) subsequently leak into the circulation. Rhabdomyolysis reflects a fundamental problem involving disturbed muscle metabolism. The disorder is not uncommon; a recent study reported 26,000 cases per year annually from patient discharge databases. There tends to be a male predominance with a male to female ratio of 2 : 1.

The most common cause of rhabdomyolysis, amounting to 46% of cases, is exposure to exogenous myotoxic agents, such as illicit drugs, alcohol, and prescribed medications, including antipsychotics (the most common), statins, colchicines (in the setting of renal insufficiency), selective serotonin reuptake inhibitors (SSRIs), and lithium. Statins are commonly associated with myalgia and sometimes modest increases in creatine kinase (CK) but uncommonly with frank rhabdomyolysis; yet they are still the second largest group of drugs associated with rhabdomyolysis. When myoglobinuria does occur with a statin, the subject is more likely to have received a synthetic statin, such as atorvastatin, than a first-generation agent, such as pravastatin, and to be using other medications, such as gemfibrozil, that interfere with the statin’s metabolic (CYP3A4) pathway.

Underlying muscle disease, including metabolic myopathies and inflammatory myopathy, are other rhabdomyolysis etiologies. Recurrent rhabdomyolysis occurs in 10% of patients with metabolic myopathies due to impaired glycogen metabolism or fatty acid oxidation, usually triggered by prolonged fasting or strenuous exertion. Defects in the mitochondrial respiratory chain, where adenosine triphosphate (ATP) is produced, also need consideration. These are ultimately caused by mutations or microdeletions in the cytochrome b oxidase gene or in genes encoding cytochrome oxidase (COX) subunits. Rarely, recurrent myoglobinuria may be caused by mitochondrial transfer ribonucleic acid (tRNA) mutations.

The clinical manifestations of rhabdomyolysis are muscle weakness, pain, tenderness and swelling, severely elevated serum levels of creatine kinase (CK), and tea- or cola-colored urine caused by the presence of myoglobin. This pigment is grossly visible as tea-colored when serum concentration surpasses 100 mg/dL. Weakness may be profound and generalized, but respiratory and bulbar muscles are not affected. Between attacks, strength is typically normal, but in the case of alcohol-induced rhabdomyolysis, a chronic myopathy may emerge after repeated attacks. Patients often have a low-grade fever and leukocytosis. Myoglobin is detected in the urine by dipstick and ultrafiltration and is probably found in only 20% of cases.

Acute renal failure complicates almost 15% to 30% of cases of rhabdomyolysis, and among patients with rhabdomyolysis, there is a fatality rate of 3%. However, most patients respond to hydration, sodium bicarbonate and mannitol, or furosemide diuresis.

Malignant hyperthermia (MH) is an autosomal dominant disorder caused by a ryanodine receptor gene defect on the long arm of chromosome 19. Occasionally, patients with MH have mild subclinical weakness, CK elevation, and nonspecific muscle biopsy changes. MH is associated with several well-characterized myopathies, including Duchenne muscular dystrophy, central core disease, myotonic dystrophy, and idiopathic hyper-CKemia. The pathophysiology involves an abnormality in the sarcoplasmic reticulum’s ability to regulate intracellular calcium.

Succinylcholine or inhalational anesthetics lead to a rapid rise in intracellular calcium. Within minutes, an alarming clinical syndrome of increased muscle metabolism unfolds, characterized by rigidity secondary to muscle contracture, hyperthermia (temperature may soar, rising at a rate of l degree every 5 minutes, to as high as 43° C), metabolic acidosis, cardiovascular instability, and myoglobinuria. Urgent treatment consists of immediately stopping anesthesia, uncoupling excitation and contraction with dantrolene, reducing body temperature, intravenous fluids and diuresis, and correcting metabolic acidosis with bicarbonate. Certain anesthetics, including nitrous oxide, opiates, barbiturates, droperidol are considered safe to use in patients at risk of malignant hyperthermia.

Malignant hyperthermia bears some resemblance to neuroleptic malignant syndrome (NMS) because both share features of hyperthermia, rigidity, and myoglobinuria. NMS is triggered by a variety of neuroleptic agents, including phenothiazines and haloperidol, or by the withdrawal of dopaminergic drugs. It has additional clinical characteristics, including extrapyramidal and autonomic dysregulation. The primary pathophysiology is inhibition of central dopaminergic receptors so that heat generation is increased and heat dissipation is attenuated. Treatment requires dantrolene and dopamine agonists.

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