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Review Article From the Departments of Internal Medicine and Pharmacology, King Faisal University, College of Medicine, Dammam, Saudi Arabia. Dr. Larbi: Departments of Medicine and Pharmacology, King Faisal University, College of Medicine, P.O. Box 2114, Dammam, Saudi Arabia. Accepted for publication 20 July 1998. Received 22 March 1998. DRUG-INDUCED RHABDOMYOLYSIS E.B. Larbi, MB, PhD, FRCP The syndrome of rhabdomyolysis is the result of skeletal muscle injury that alters the integrity of the sarcolemma and leads to the eventual release of intracellular contents into the plasma. The causes are diverse, and include muscle trauma (for instance, from vigorous exercise, crush injuries, battering, or seizures), inadequate blood perfusion, heat stroke, electrolyte imbalance, hereditary enzyme deficiencies, infections and ingestion of drugs and toxins. Various serious medical disorders, particularly those resulting in states of disordered energy production, are also associated with rhabdomyolysis. In general, drug toxicity involves organs, such as the kidney, liver, gastrointestinal tract and the central nervous system, with skeletal muscle being usually less readily affected. Although drug-induced rhabdomyolysis was uncommon in the past, it is no longer rare, due to the introduction of more and increasingly potent drugs into clinical practice. The incidence of drug-induced rhabdomyolysis is uncertain, largely because most of it is unreported. Similarly, the mortality rates are unknown. However, it has been suggested that rhabdomyolysis from all causes leads to 5%-25% of cases of acute renal failure. Furthermore, about 10%-40% of patients with rhabdomyolysis develop acute renal failure. Rhabdomyolysis can result from direct muscle injury by myotoxic drugs, such as cocaine and alcohol. This mechanism must be distinguished from rhabdomyolysis that develops secondarily from muscle ischemia due to prolonged seizures or local muscle compression in comatose states following drug overdosage. Mechanisms A large number of drugs can cause rhabdomyolysis through various mechanisms, which are probably multifactorial (Table 1). Any drug which directly or indirectly impairs the production or use of adenosine triphosphate (ATP) by skeletal muscle, or increases energy requirements so as to exceed ATP production, can cause rhabdomyolysis. The processes include ischemia as a result of prolonged immobilization from drug overdosage with CNS depressants, thus impairing the delivery of oxygen and nutrients, drug-induced delirium, choreoathetosis, dystonic reactions and seizures (which increase muscle activity and the demand for ATP). Drugs can also be directly toxic to muscle cells, interfering with the production or use of ATP. The potential mechanisms of drug-induced sarcolemmal injury, as reviewed by Knochel and Armstrong et al., are as follows. A change in the viscosity of sarcolemma is caused by activation of phospholipase A. It results in increased permeability of the sarcolemma, permitting leakage of intracellular contents, as well as an increase in the entry of sodium ions into the cell. The increased intracellular sodium ion concentration activates Na+,K+-ATPase, a process which requires energy. This eventually exhausts the supplies of ATP and thus impairs cellular transport. The increase in cellular sodium ion concentration also leads to an accumulation of intracellular calcium ion concentration, which activates neutral proteases within the cell, causing further cellular injury. However, it has been suggested that, irrespective of the mechanisms involved, there is a final common pathway, namely, there is an increase in the intracellular concentration of sodium ion, which in turn leads to an increase in the concentration of intracellular calcium ion. This enhances the activity of the intracellular proteolytic enzymes, leading to further destruction of intracellular structures. There is another mechanism peculiar to the 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-Co A) reductase inhibitors, which inhibit cholesterol synthesis. They reduce serum levels of coenzyme Q, a component of the electron transport chain. This affects oxidative phosphorylation. The HMG-Co A reductase inhibitors inhibit the synthesis of mevalonate, the reduced supplies of which inhibit the formation of coenzyme Q. Severe hypokalemia, especially that associated with significant reduction in intracellular muscle potassium content, has also been implicated in the pathogenesis of rhabdomyolysis. Glycogen synthesis is impaired in hypokalemic states, leading to a reduction in energy production during sustained muscle contraction. Hypokalemia has been shown experimentally to reduce muscle cell transmembrane voltage and to cause muscle damage. Contraction of muscle leads to the release of potassium ions into intracellular space. Concentrations as high as 15 mEq/L can be attained. This has a vasodilator effect, which thus enhances the increase in muscle blood flow during exercise. In hypokalemic states there is no release of potassium from the contracting muscles, and so blood flow is not increased. Continued muscle contraction, therefore, leads to ischemia and muscle necrosis. Alcohol directly injures the sarcolemma and increases sodium permeability. This in turn increases the activity of the Na+,K+-ATPase pump, with the eventual exhaustion of energy stores. Increased cytosolic Na+ enhances the accumulation of cytosolic Ca++, which in addition to increased mitochondrial Ca++ causes cellular injury. Analysis of skeletal muscle from chronic alcoholics and experimental animals fed ethanol shows a marked depletion of potassium, phosphorus, and magnesium, and elevated sodium, chloride, calcium and water content. Acute hypophosphatemia would shut off ATP synthesis. Uniform muscle necrosis, leukocyte and macrophage invasion of degenerated muscle fibers are observed with light microscopy, and ultrastructural changes include the separation of myofibrils and other cellular elements by clear spaces. Acute alcohol-induced rhabdomyolysis can occur after binge drinking or a sustained period of alcohol abuse, and is associated with pain and swelling of muscles, particularly the quadriceps. Symptoms resolve if the patient abstains from alcohol use. Serious drug poisoning is frequently associated with rhabdomyolysis, although the incidence is uncertain. The mechanisms involved vary with the drug. General anesthetic agents and overdosage with central nervous system drugs, such as narcotics, cyclic antidepressants, benzodiazepines, antihistamines and barbiturates, cause rhabdomyolysis by pressure-induced ischemia due to prolonged immobilization. Drugs such as LSD, sympathomimetics and phencyclidine, which induce delirium or agitation, and those which cause prolonged involuntary muscle contraction (e.g., phenothiazines and butyrophenones), lead to increased ATP demand and eventual exhaustion of its stores. Hyperthermia also increases the energy requirements of muscle and contributes to its damage. Cocaine and salicylate intoxication-induced rhabdomyolysis is due partly to the associated hyperthermia. Cocaine, in addition, produces a syndrome similar to neuroleptic malignant syndrome associated with intermittent dystonia, alternating with substantial agitation, thus further increasing the ATP requirement. Halothane-induced rhabdomyolysis results from the production of malignant hyperthermia (in predisposed patients) and a resultant increase in ATP requirement. The frequent causative agents include psychotropic and central nervous system depressant drugs, as well as alcohol. The occurrence of rhabdomyolysis is further enhanced in the presence of predisposing factors, namely, hypokalemia, hyponatremia, hypernatremia, magnesium and phosphorus depletion, hypothermia or hyperthermia, diabetic ketoacidosis or hypertonic states. TABLE 1. Drugs which can cause rhabdomyolisis. Antipsychotics and antidepressants Amitriptyline Amoxapine Doxepine Fluoxetine Fluphenazine Haloperidol Lithium Protriptyline Phenelzine Perphenazine Promethazine Chlorpromazine Loxapine Promazine Trifluoperazine Sedative hypnotics Benzodiazepines: -Diazepam -Nitrazepam -Flunitrazepam -Lorazepam -Triazolam Barbiturates Gluthetimide Antilipemic agents Lovastatin Pravastatin Simvastatin Bezafibrate Clozafibrate Ciprofibrate Clofibrate Drugs of addiction Heroin Cocaine Amphetamine Methadone Antihistamines Diphenhydramine Doxylamine Others Alcohol Amphotericin B Azathioprine Butyrophenones Emetics Epsilon-aminocaproic acid Halothane Laxatives Moxalactam Narcotics Oxprenolol Paracetamol Penicillamine Pentamidine Phencyclidine Phenytoin Phenylpropanolamine Quinidine Salicylates Strychnine Succinylcholine Theophyline Terbutaline Thiazides Vasopressin Biochemical Features and Basis for Diagnosis Injury to the sarcolemma and skeletal muscle cell results in the release of myoglobin, creatinine phosphokinase (CK), as well as other protein and nonprotein cellular contents into plasma. Among others, there occurs an increase of serum myoglobin, CK, aldolase, lactic dehydrogenase, potassium, phosphates, purines, uric acid, aspartate aminotransferase (AST), carbonic anhydrase III, as well as myosin heavy-chain fragments. Estimation of myoglobin in the serum and urine is useful for the diagnosis of rhabdomyolysis, particularly in the early phases of the disease. Myoglobin is filtered by the kidney and appears in the urine when the plasma concentration exceeds 1.5 mg/dl. It imparts a dark red brown color to urine when urine concentration exceeds 100 mg/dl. Myoglobin has a short half-life (2-3 hours), and is rapidly cleared by both renal excretion and metabolism to bilirubin. Serum myoglobin levels, therefore, return to normal in about 6-8 hours, following cessation of muscle injury. Owing to its rapid clearance from plasma, its absence does not exclude the diagnosis of rhabdomyolysis. Elevated creatinine phosphokinase is the hallmark of rhabdomyolysis. It rises within 12 hours of the onset of muscle injury, peaks in 1-3 days, and declines 3-5 days after cessation of muscle injury. The half-life of CK is 1.5 days and so it remains elevated longer than serum myoglobin levels. Hyperkalemia increases the risk of cardiac dysrrhythmia. The release of organic and inorganic phosphates from the injured muscles causes an increase in serum phosphate levels, which may elevate calcium phosphate product resulting in deposition of calcium salts in muscle and other tissues. Hypocalcemia then ensues. However, in late stages of the disease, mobilization of calcium from damaged muscle results in hypercalcemia. The released purine precursors are converted to uric acid, thus increasing its levels. Carbonic anhydrase III is present in skeletal muscles but not in myocardium. An increase in its levels is thus more specific for skeletal muscle injury than CK. Increase in myosin heavy-chain fragments is also more specific in skeletal than myocardial muscle injury. The levels increase in about 4 to 7 days after muscle injury, and remain so even until after day 12. Measurement of myosin heavy-chain fragments is particularly useful for the late diagnosis of rhabdomyolysis. Unfortunately, these tests are not readily available. Other biochemical abnormalities include increased serum levels of creatinine, hydroxybutyrate and lactic acid, thrombocytopenia, increased fibrinogen degradation products, prolonged prothrombin time and proteinuria. Clinical Manifestations There is wide variation in the clinical presentation of rhabdomyolysis. The classical triad of symptoms are muscle pain, weakness and dark urine. The muscles can be tender and swollen, and there can be skin changes indicating pressure necrosis. However, these classical features are seen in less than 10% of patients. Over 50% of patients may not complain of muscle pain or weakness. Diagnosis becomes even more difficult in patients with altered mental state or levels of consciousness, who are unable to give a coherent history. Features related to the effects of drug poisoning can also predominate and the possibility of rhabdomyolysis can be missed. A high index of suspicion of rhabdomyolysis is thus necessary for early diagnosis. Rhabdomyolysis should be suspected in patients presenting with drug poisoning, altered levels of consciousness, severe fluid and electrolyte abnormality, hyperthermia, hypotension, hypoxia, and states of increased muscular activity, such as seizures, agitation, strenuous muscle exercise or dystonia, particularly in patients with alcohol or substance abuse. Patients who have ingested neuroleptic drugs can present initially with dystonia, hyperthermia, or neuroleptic malignant syndrome characterized by fever, muscle rigidity, autonomic dysfunction and altered consciousness. Acute Renal Failure Acute renal failure, oliguric or nonoliguric, is the most common complication of rhabdomyolysis. It occurs in 10%-40% of patients. Rhabdomyolysis also accounts for 5%-25% of all cases of acute renal failure. The causes of the renal injury include direct nephrotoxicity of ferrihemate produced by the dissociation of myoglobin at pH 5.6 or less, tubular obstruction due to protein, uric acid crystals and precipitates of myoglobin (myoglobin casts), and reduction in renal blood flow as a result of renal vasoconstriction. Intracellular iron is an important mediator of tissue damage. As a transition metal it can donate and accept electrons, and its toxicity is due to its ability to catalyze oxygen- and non-oxygen-based free radical reactions. In rhabdomyolysis, the cytotoxic iron moiety is derived from heme, a product of myoglobin metabolism. In the renal tubules the iron so derived catalyzes free radical reactions, which are associated with lipid peroxidation. The major mechanism of renal tubular damage in rhabdomyolysis is the mitochondrial free radical production which induces lipid peroxidation. Procedures which chelate iron, or prevent or reduce the release of free iron, have been shown to have a protective effect, thus demonstrating the important role of iron in tubular damage in rhabdomyolysis. Acute renal failure is associated in the early phases with a marked rise in uric acid and hypocalcemia. The raised uric acid is due to rapid metabolism of muscle purines. Binding of calcium by damaged muscle and decreased levels of serum dihydroxycholecalciferol account for the observed hypocalcemia. The combination of hypocalcemia and hyperkalemia can result in ventricular dysrrhythmia and possible cardiac arrest. Acute renal failure is also associated with a disproportionate increase in serum creatinine levels as a result of the release of preformed creatinine from the damaged muscle into plasma. Currently there is no reliable factor of predictive value in those likely to develop acute renal failure. Involvement of myocardium and intercostal muscles and diaphragm can lead to acute cardiomyopathy and acute respiratory failure. Compartment syndrome is not unusual in drug-induced rhabdomyolysis. The compartments containing anterior tibial, peroneal, lateral thigh, soleus, gluteal, deltoid and forearm muscles may be affected. There is increased swelling and tenderness of the involved muscle, and the increased pressure in the compartment can be associated with decreased pulse and neuropathy in the affected limb. Re-elevation of CK levels can herald the onset of compartment syndrome. Immediate fasciotomy is required if intracompartment pressure exceeds 30-50 mm Hg, in order to prevent the sequelae of limb contracture, ischemia and possible amputation. Management The treatment of rhabdomyolysis consists of: 1) general measures; 2) attempts to prevent acute renal failure; 3) hemodialysis; and 4) other measures. General measures General management of drug overdosage includes termination of further exposure, reduction of absorption, enhancement of metabolism and excretion of the offending drug as appropriate. Features of drug overdosage, particularly in comatose patients, namely, hypothermia, hyperthermia, hypoxia, hypovolemia and hypotension, should be identified and treated. Measures should also be taken to stop further muscle damage. These include control of excessive muscle activity, such as in severe agitation and convulsions and abnormal posturing in unconscious patients. Sedatives, or in some cases anticonvulsants, may be required to control convulsions. Overdosage with phenothiazines may require the administration of anticholinergic agents to control dystonic reactions. Attempts to prevent acute Renal failure Early correction of hypovolemia reduces the incidence of renal failure. Various types of fluid composition and infusion regimes have been suggested. Other additional measures include continued infusion of 0.9% saline and the administration of mannitol following correction of hypovolemia in order to induce diuresis. Although it may be difficult, it is essential to maintain a urine output of 300 cc/hour or more. Alkalinization of urine prevents the dissociation of myoglobulin into globin and ferrihemate, which are toxic to the renal tubules. The possibility of aggravation of hypocalcemia by large doses of bicarbonate should be borne in mind, although this is rather uncommon, especially if hypovolemia is corrected. The administration of mannitol also reduces intracompartment pressure and its attendant complications. Hemodialysis The indications for hemodialysis are standard and include failure of conservative measures in the management of acute tubular necrosis, severe acidosis, rapid increase in serum potassium levels, and hypocalcemia. Other Measures Supplement of calcium in hypocalcemia is rarely required. Its administration may not only enhance the deposition of calcium in damaged muscles and lead to further muscle damage, but may also increase the level of hypercalcemia during the recovery phase. Hyperkalemia may require treatment with sodium bicarbonate (usually 50-100 mmol), glucose (50 mL of 50% dextrose) and insulin (10 units regular), resin preparation, such as sodium polystyrene sulphonate (25-50 g resin mixed with 100 mL of 20% sorbitol given orally, or 50 g of resin and 50 mL of 70% sorbitol, mixed in 150 mL of tap water, given as a retention enema), or as indicated above by dialysis. Prognosis The prognosis depends on the underlying drug toxicity, which may contribute to the reported mortality of about 5% observed in serious rhabdomyolysis. Most cases are, however, mild. If there are no other underlying complications, acute renal failure in rhabdomyolysis is reversible and has an excellent prognosis, although recovery may be delayed. Early recognition and treatment of compartment syndrome prevents permanent disability. Most cases of drug intoxication may be associated with rhabdomyolysis. It is thus fairly common. In a majority of cases, however, symptoms may be absent or mild. Its recognition and diagnosis, therefore, depend on a high index of clinical suspicion. The prognosis depends on the other effects of the offending drug, complications and severity of rhabdomyolysis. However, with appropriate treatment, the outcome is generally good.