Define Rhabdomyolysis and its epidemiology, pathophysiology, diagnosis, recovery with pictures

What is rhabdomyolisis?

Contents

Rhabdomyolysis is a condition characterized by injury to skeletal muscle that results in release of the intracellular contents into the extracellular fluid and circulation. Authoritative thresholds for creatine kinase (CK) range between 1000 and 10,000 U/L, but some definitions additionally mandate the presence of myoglobinuria. Rhabdomyolysis can occur secondary to trauma, exertion, muscle hypoxia, genetic defects, infections, changes in body temperature, metabolic and electrolyte disorders, drugs and toxins, and idiopathic causes.

How do you get rhabdomyolysis?

Various categorizations of rhabdomyolysis have been proposed: traumatic versus atraumatic, reversible versus irreversible, endogenous versus exogenous, and hereditary versus acquired. More than half of all cases of rhabdomyolysis are multifactorial

Rhabdomyolisis epidemiology

Rhabdomyolysis afflicts more than 25,000 individuals in the United States each year. Morbidity and mortality vary tremendously depending on etiology, available treatment, time course, and comorbid factors.

Acute kidney injury is a potential major complication of rhabdomyolysis and worldwide occurs in 15% to 45% of cases. In contrast, 7% to 10% of cases of acute kidney injury in the United States are caused by rhabdomyolysis. Mortality generally ranges from 3% to 10% but can be as high as 25% in mass casualty incidents that involve crush injuries.

Certain populations appear to be at increased risk for the development of rhabdomyolysis. Alcohol and recreational drug abusers, patients taking numerous medications, military recruits, and athletes training well above their level of conditioning are of particular concern. Athletes with a predominance of type II fast twitch fibers (typically sprinters and weight lifters) are at higher risk for rhabdomyolysis than are those with a majority of type I slow twitch fibers (e.g., marathon runners). A large number of genetic disorders are linked to rhabdomyolysis as well.

Rhabdomyolysis pathophysiology

Rhabdomyolysis is a condition characterized by injury to skeletal muscle that alters the integrity of the cell membrane. Despite the large number of causes of rhabdomyolysis, the underlying pathology involves direct damage to the sarcolemma or depletion of adenosine triphosphate (ATP) within the myocyte resulting in an unregulated increase in intracellular calcium. This leads to constant contraction, energy depletion, and eventual necrosis and death of the muscle cell with release of its intracellular contents into the circulation. The most important products released include potassium, phosphorus, myoglobin, CK, aspartate transaminase, alanine transaminase, lactate dehydrogenase, urate, cytokines, and purines.

Direct muscle injury as a cause of rhabdomyolysis

Traumatic rhabdomyolysis is primarily the result of motor vehicle crashes, occupational injuries, or environmental tragedy (i.e., mine collapse, earthquakes, war). Muscle compression may also occur during torture and abuse, long-term confinement in the same position (as with orthopedic injuries or during restraint of psychiatric patients), prolonged surgical interventions with improper positioning (high lithotomy or lateral decubitus position), and coma. Compression causes muscle ischemia as tissue pressure exceeds capillary perfusion pressure. Additionally, direct mechanical injury to the sarcolemma causes an incipient rise in intracellular calcium. Calcium activates destructive enzymes within the cell that facilitate necrosis and death of the myocyte.

Infection as a cause of rhabdomyolysis

Bacterial, viral, parasitic, and rickettsial infections have been associated with rhabdomyolysis. The most common viral cause is influenza. Viruses cause rhabdomyolysis both by direct muscle invasion and by endotoxins and exotoxins that are responsible for skeletal muscle injury and subsequent release of myoglobin. Legionella is the most common bacterial cause, with its myotoxic effects mediated through and endotoxin. Salmonella and Streptococcus also induce rhabdomyolysis through direct myocyte invasion and inhibition of glycolytic enzymes.

Bacterial infection and rhabdomyolysis

Following bacteria may cause rhabdomyolisis:

  • Gas gangrene
  • Group A β-hemolytic streptococci
  • Legionnaires disease
  • Salmonella
  • Septic shock
  • Shigella
  • Staphylococcus aureus
  • Streptococcus pneumonia
  • Tetanus

Viral infection and rhabdomyolisis

Following viruses may cause rhabdomyolisis:

  • Coxsackievirus
  • Cytomegalovirus
  • Echovirus
  • Epstein-Barr virus
  • Hepatitis
  • Herpes simplex virus
  • Human immunodeficiency virus
  • Influenza A and B
  • Parainfluenza
  • Rotavirus

Excessive muscle contractions as a cause of rhabdomyolisis

Strenuous exercise by both trained and untrained athletes can cause rhabdomyolysis. The degree of muscle injury is related to the duration and intensity of the exercise, and damage is frequently confined to the lower extremities. Muscle injury is exacerbated by hot, humid conditions; lack of heat acclimatization; prolonged, profuse sweating; and insufficient intake of salt. Patients at increased risk include athletes, marathon runners, new military recruits (“march myoglobinuria”), outdoor workers, and persons unaccustomed to strenuous exercise (“white collar rhabdomyolysis”). Pathologic causes of excessive muscle activity such as status epilepticus, myoclonus, dystonia, tetanus, chorea, and mania also lead to rhabdomyolysis. Additionally, patients suffering from a multitude of intoxications, including isoniazid, strychnine, amoxapine, loxapine, theophylline, water hemlock, and lithium, may experience excessive motor activity and seizures producing rhabdomyolysis. Excessive muscle activity causes rhabdomyolysis through dehydration, increased activity of heat-sensitive degradative enzymes, and depletion of cellular energy (ATP) with prolonged exercise. These insults lead to failure of the sarcolemmal sodium-potassium adenosine triphosphatase (Na+,K+-ATPase) and Ca2+ pumps, which results in increased intracellular calcium and cell necrosis.

Medications that can cause rhabdomyolisis

Drugs in almost every category have been implicated as a cause of rhabdomyolysis. The medications of most concern are the lipid-lowering agents, including 3-hydroxy-3- methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors (lovastatin, simvastatin) and fibric acid derivates that decrease triglyceride synthesis (gemfibrozil and clofibrate). HMG-CoA reductase inhibitors block the production of coenzyme Q, which plays an important role in the production of ATP in mitochondria. The resultant decrease in ATP production leads to cell death and subsequent rhabdomyolysis. Patients with preexisting renal dysfunction are at increased risk. Immediate withdrawal of these drugs is mandatory if patients complain of muscle dysfunction or if their CK level rises to more than three times normal. The risk for drug induced muscle disease is aggravated by the simultaneous administration of danazol, nicotinic acid, cyclosporine, itraconazole or erythromycin. The combination of HMG-CoA reductase inhibitors with gemfibrozil also carries a high rate of myotoxicity.

In conclusion, following drugs may provoke rhabdomyolysis:

  • Amphotericin B
  • Antihistamines
  • Azathioprine
  • Barbiturates
  • Benzodiazepines
  • Butyrophenones
  • Chlorpromazine
  • Cimetidine
  • Codeine
  • Clofibrate
  • Colchicine
  • Corticosteroids
  • Cotrimoxazole
  • Cyclosporine
  • Erythromycin
  • 3-Hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA)
  • reductase inhibitors
  • Inhalational anesthetics
  • Isoniazid
  • Itraconazole
  • Lindane
  • Lithium
  • Lovastatin
  • Methadone
  • Monoamine oxidase inhibitors
  • Narcotics
  • Neuroleptic agents
  • Organic solvent
  • Pentamidine
  • Phenothiazine
  • Phenylpropanolamine
  • Phenytoin
  • Procainamide
  • Quinine
  • Salicylates
  • Serotonergic agents
  • Succinylcholine
  • Theophylline
  • Total parenteral nutrition
  • Tricyclic antidepressants
  • Trimethoprim-sulfamethoxazole
  • Vasopressin
  • Zidovudine

Statins and rhabdomyolysis

The link between statins, statins and drug-induced myalgia and rhabdomyolysis has been largely investigated since the introduction of this drug class in the 1980s. Statins have very fast become the most widely prescribed class of drugs in the world because of their therapeutic benefit on the mortality of

patients with cardiovascular disease, which is the leading cause of death in industrialized nations. However, the risk for myopathy caused by statins is real and should always be considered when prescribing this class of drugs to a patient’s regimen. In 2012, the FDA issued a note of concerning the use of statins and their potential side effects, including liver injury, cognitive decline, type 2 diabetes mellitus, and myopathy/rhabdomyolysis. The warning labels on all statin were expanded in order to include these potential side effects. In particular, the label for

Mevacor (lovastatin) was essential to include contraindications to taking the drug with a diversity of other agents, including human immunodeficiency virus (HIV) protease inhibitors and certain antibacterial and antifungal medications. At the same time, the FDA removed its need to occasionally monitor the liver enzymes of patients administrating statins, because monitoring had shown no benefit in detecting or preventing serious liver injury. The FDA now recommends obtaining baseline levels of liver enzymes prior to starting statin treatment and checking enzyme levels if clinically necessary thereafter.

Clinical studies have been shown the incidence of myopathic events in patients taking statins at 1.5%-5.0%. Risk factors for the development of statin-induced rhabdomyolysis include high dosages, advanced age, female sex, renal or hepatic insufficiency, and diabetes mellitus.

Despite the high incidence of general muscle toxicity because of statin use, rhabdomyolysis secondary to statin use has proven to be extremely rare.

Drugs abuse as a cause of rhabdomyolysis

Substance abuse is one of the most common causes of rhabdomyolysis, largely because of the high incidence of ethanol abuse and its direct toxicity to the myocyte membrane. Other drugs of abuse implicated in cases of rhabdomyolysis include cocaine, heroin, methamphetamine, phencyclidine hydrochloride (PCP), lysergic acid diethylamide (LSD), 3,4 methylenedioxymethamphetamine (MDMA; “ecstasy”), benzodiazepines, and barbiturates. Most abused drugs cause muscle damage through direct toxic effects or immunologic reactions to the contaminants found mixed with the drug. Cocaine is also toxic to the sarcolemma and induces vasospasm resulting in ischemia. Cocaine increases energy demands of the cell that outstrip energy production. Besides its direct toxicity, ethanol has multiple additional mechanisms by which it causes muscle damage. Its sedative and hypnotic properties may cause prolonged immobilization of a body part, with external compression of its blood supply leading to ischemia. Rhabdomyolysis can be induced by excessive motor activity when associated with alcohol-related seizures and delirium tremens. Poor nutrition inhibits the rate of ethanol metabolism, and the resultant higher blood ethanol concentration at the cell membrane for prolonged periods leads to increased sarcolemmal damage.

In conclusion, abuse of following drugs may lead to rhabdomyolysis:

  • Amphetamines
  • Caffeine
  • Cocaine
  • Methylenedioxymethamphetamine (MDMA; “ecstasy”)
  • Ethanol
  • Gasoline
  • Heroin
  • Lysergic acid diethylamide (LSD)
  • Marijuana
  • Mescaline
  • Methamphetamines
  • Opiates
  • Phencyclidine (PCP; “angel dust”)
  • Toluene

Toxins as a cause of rhabdomyolysis

Toxins that cause direct myocyte damage include venom from the European adder, the Australian tiger snake, the Australian king brown snake, the death adder, and North and South American rattlesnakes. These snakes deploy a single venom with multiple myocyte toxins that cause direct muscle injury and rhabdomyolysis. Stings from Africanized bees (killer bees) and honeybees mediate rhabdomyolysis through myotoxins. Quail fed hellebores or hemlock have also been associated with outbreaks of rhabdomyolysis (coturnism). Outbreaks of Haff disease occur intermittently in the United States as a result of contaminated fish. Toxins that act at the molecular level by interfering with the production of ATP are capable of producing damage to skeletal muscle. Carbon monoxide, cyanide, hydrogen sulfide, and phosphine inhibit electron transport in mitochondria; salicylates and chlorphenoxy herbicides uncouple oxidative phosphorylation; and iodoacetate and sodium fluoroacetate inhibit glycolysis in the Krebs cycle.

Genetic disorders as a cause of rhabdomyolysis

Rhabdomyolysis can result from genetic defects in glycolysis, glycogenolysis, fatty acid oxidation, and mitochondrial function. These disorders cause inappropriate use of carbohydrate and lipids, which leads to an imbalance between energy supply and demand in myocytes. Genetic defects should be suspected in patients in whom the cause of rhabdomyolysis is obscure. Symptoms often begin before the age of 20 years, and attacks occur intermittently. Examples include recurrent rhabdomyolysis after minimum to moderate exercise, after viral infections starting in childhood, or in patients with a family history of rhabdomyolysis. In glycogenolytic disorders, the mode of inheritance is usually autosomal dominant; phosphoglycerate kinase deficiency is X-linked. Diagnosis of an inherited muscle enzyme defect is based on muscle biopsy findings demonstrating abnormally increased glycogen or lipid deposits, as well as histochemical staining demonstrating a decrease or absence of specific enzymes.

Presenting signs and symptoms of rhabdomyolysis

Common symptoms include myalgias, fatigue, and red or brown urine; however, atypical findings are customary for rhabdomyolysis. Only 50% of patients complain of specific muscle symptoms, and less than 10% have muscle tenderness. Liberal testing for rhabdomyolysis is therefore warranted in high-risk populations. Rhabdomyolysis should be considered in patients with hyperkalemia, disseminated intravascular coagulation (DIC), sepsis, cardiovascular collapse, compartment syndrome, heat stroke, altered mental status, and acute kidney injury. These patients may have occult primary rhabdomyolysis or suffer from rhabdomyolysis as a complication of their primary disease process.

Rhabdomyolysis tests and diagnosis

Creatine kinase testing for rhabdomyolisis diagnosis

CK is the enzyme responsible for reversible transfer of the terminal phosphate group of ATP to creatine to form phosphocreatine. Serum CK begins to rise 2 to 12 hours after the destruction of more than 200 g of muscle, with the peak level occurring between 1 and 3 days. Levels decline within 3 to 5 days after the muscle injury ceases. Serum CK levels remain elevated longer than those of myoglobin because of relatively slow plasma clearance (serum t1/2 = 1.5 days). CK decreases at a steady rate of 39% per day. Rhabdomyolysis is suspected at minimum thresholds for CK of between 1000 and 10,000 U/L. A rise in serum CK follows the rise in serum myoglobin. Three isoenzymes of CK exist in human tissues: MM, MB and BB. The predominant source of the CK-MM isoenzyme is skeletal and cardiac muscle; CK-BB is found in brain tissue and CK-MB mainly in cardiac muscle. In rhabdomyolysis, the primary CK isoenzyme elevated is CK-MM. Creatine phosphokinase is a serum marker of CK-MM reported by many clinical laboratories.

Myoglobin testing for rhabdomyolisis diagnosis

Myoglobin is a small protein with a free circulating concentration that is very low under normal physiologic conditions. Myoglobin functions as an oxygen reservoir in muscles; serum myoglobin levels rise within 1 hour of skeletal muscle damage. Myoglobin levels become normal within 1 to 6 hours after the cessation of muscle injury because of rapid clearing both by renal excretion and by metabolism to bilirubin. When myoglobin levels reach 15 mg/L, it can be detected by urine dipstick, and at 1 g/L it may cause the color of urine to appear dark, like cola. Myoglobinuria does not always result in dark urine, however; discoloration depends on (1) the amount of myoglobin released from muscle into plasma, (2) the glomerular filtration rate, and (3) the urine concentration.

Urinalysis for rhabdomyolisis diagnosis

The urine dipstick is a commonly used screening test for rhabdomyolysis. The orthotoluidine test on the urine dipstick will react in the presence of either myoglobin or hemoglobin. A report of “large blood” on the urine dipstick and absence of red blood cells on microscopy classically suggests the presence of free myoglobin in urine. Unfortunately, clinical data do not fully support this screening practice, with microscopic hematuria occurring in about 30% of patients with rhabdomyolysis. In addition, myoglobinuria may be transient and not identified at the time of urinalysis despite the presence of significant clinical rhabdomyolysis. Dipstick testing will detect a urine myoglobin level higher than 1.0 mg/dL, which correlates with a serum value of approximately 100 mg/dL. Other common findings on urinalysis include the presence of tubular casts, proteinuria, and evidence of acute tubular necrosis.

Renal function tests for rhabdomyolisis diagnosis

Though not consistently observed in all analyses, creatinine has at times been shown to rise faster with rhabdomyolysis than with other causes of acute renal failure. Markedly high creatinine levels or a relatively low ratio of blood urea nitrogen to creatinine should raise suspicion for rhabdomyolysis.

Acute kidney injury as a complication of rhabdomyolysis

Acute kidney injury is the most important cause of morbidity in patients with rhabdomyolysis. Rhabdomyolysis induces acute kidney injury by three main pathophysiologic mechanisms. First, the heme protein in myoglobin exerts direct toxicity on renal tubular cells by initiating lipid peroxidation. This toxicity is potentiated by an acidic urine. Second, myoglobin precipitates in the renal tubules and causes intraluminal cast formation and tubular obstruction. Degradation of intratubular myoglobin results in the release of unbound iron, which catalyzes free radical production and further enhances the ischemic damage. Third, renal vasoconstriction is promoted by platelet-activating factor and endothelin. Acute kidney injury caused by rhabdomyolysis may be oliguric (most common), nonoliguric, or occasionally anuric. It typically results in a higher anion gap acidosis and higher uric acid levels and often leads to a more rapid increase in serum creatinine than do other forms of acute kidney injury. Fractional excretion of sodium is often less than 1%, in contrast to other forms of acute tubular necrosis. It is difficult to predict the patients in whom acute kidney injury will develop based on laboratory values at initial evaluation.

Metabolic and electrolit derangements as complications of rhabdomyolysis

Hyperkalemia occurs in 10% to 40% of patients with rhabdomyolysis. It is the most serious electrolyte derangement observed with rhabdomyolysis because of its potential lethal effect on cardiac rhythm and function. More than 15 mmol of potassium is released with necrosis of only 150 g of muscle and results in an acute 1.0-mmol/L increase in extracellular potassium. The degree of increase is further dependent on renal function, which is often concurrently impaired. Hypocalcemia is the most common metabolic complication of rhabdomyolysis; low calcium levels are present early and are usually asymptomatic. Hypocalcemia results from deposition of calcium salts in necrotic muscle secondary to hypophosphatemia and decreased 1,25-dihydroxycholecalciferol. Soft tissue calcifications can be seen on radiographs of the involved limbs. Hypocalcemia should be treated only if severe symptoms or hyperkalemia develops and leads to cardiac arrhythmias, muscular contraction, and seizures. Later, as calcium is mobilized from tissues, serum calcium levels rise and symptomatic hypercalcemia may develop. Hypercalcemia usually occurs in patients with acute renal failure during the diuretic phase, typically when urinary output is greater than 1500 mL/24 hr. Hypercalcemia also occurs more frequently if Ca2+ is supplemented in the hypocalcemic stage. Volume expansion alone is usually adequate treatment, but diuretics may be needed. Hyperphosphatemia is caused by leakage of phosphate from injured myocytes and is higher in azotemic patients. Phosphate binders should be used when phosphate levels exceed 7 mg/dL. Hypophosphatemia may be seen later in the disease course but rarely requires treatment. Hypermagnesemia may occur in patients with renal insufficiency. Standard management is appropriate. Hyperuricemia is especially common in crush injury as a result of the release of muscle adenosine nucleotides, which are subsequently converted to uric acid in the liver. Uric acid levels typically correlate with serum CK levels. Organic acids, especially lactic acid, are released from hypoxic, necrotic muscle cells and produce a pronounced anion gap acidosis.

Compartment syndrome as a complication of rhabdomyolysis

Most striated muscles are contained within rigid compartments formed by fascia and bones. When the muscle is traumatized, marked swelling and edema occur within a closed osteofascial compartment, and muscle perfusion is reduced to a level below that required for cellular viability. As intracompartmental pressure rises above 30 to 35 mm Hg, compartment syndrome develops and significant muscle ischemia ensues and requires decompressive fasciotomy.  Classic signs and symptoms of compartment syndrome include pain, pallor, paresthesias, poikilothermia, paralysis, and pulselessness. Paresthesias are the most reliable sign muscle edema exerts pressure on peripheral nerves, which results in neuronal ischemia, paresthesias, and paralysis. Decompressive fasciotomy reverses the peripheral neuropathies within a few days to weeks, although symptoms may be permanent in a minority of patients.

Can rhabdomyolysis kill you?

Disseminated intravascular coagulation (DIC) as a complication of rhabdomyolysis

DIC occurs in patients with severe rhabdomyolysis when extensive injury results in multisystem organ failure. Although this disorder is more common with severe trauma and crush injury, rhabdomyolysis from medical causes may lead to DIC. Severe bleeding is most pronounced on days 3 to 5 of illness. If severe bleeding does not occur, spontaneous improvement can be expected by days 10 to 14. When severe bleeding does occur, infusion of fresh frozen plasma (to replace coagulation factors) and transfusion of platelets may be indicated

Hepatic dysfunction as a complication of rhabdomyolysis

Hepatic dysfunction occurs in approximately 25% of patients with rhabdomyolysis. The proteases released from injured muscle may be implicated in hepatic inflammation.

What CK level indicates rhabdomyolysis?

General treatment of rhabdomyolysis

Rhabdomyolysis is physiologically and clinically similar to cell degradation states such as tumor lysis syndrome and sepsis. An organized, aggressive treatment strategy should focus on clinical end points similar to those for other cell lysis conditions. The main goal of therapy is prevention of acute renal failure through high-volume resuscitation. The two most common reasons for the development of acute kidney injury are slow fluid resuscitation and inadequate fluid resuscitation. Normal saline is superior to lactated Ringer solution for the treatment of rhabdomyolysis because normal saline is not associated with risk for phosphate toxicity. More than 10 L of normal saline is typically administered in the first 24 hours of therapy to maintain high-volume dilute urine output. Initial fluid administration with normal saline is titrated to achieve a goal urine output of 200 to 300 mL/hr. It is important that intravenous (IV) fluid resuscitation be started as soon as possible; fluid resuscitation before the extrication of crushed and trapped patients is preferred. After diuresis is established and urine pH is less than 6.5, fluids are changed to a more alkaline solution (i.e., 75 mmol of sodium bicarbonate added to 1 L of one-half isotonic saline), with the rate titrated to achieve the goal of 200 to 300 mL/hr of urine output. Alternating normal saline with sodium bicarbonate is also an option. If urine pH is higher than 6.5, normal saline is continued. Mannitol, an osmotic diuretic, can be considered in this situation, but only after adequate fluid repletion has been attained. With moderate to severe alkalemia (serum pH higher than 7.5), acetazolamide can be considered. The goal urine output remains 200 to 300 mL/hr. Fluid repletion is continued until the CK level falls below 5000 to 10,000 U/L and the myoglobinuria clears. If initial diuresis is not achieved with fluid replacement alone or the patient has contraindications to further fluid replacement, additional diuretics should be considered and a nephrologist consulted for possible renal replacement therapy. Vital signs, cardiac rhythm, and urine output should be monitored continuously. Medication dosages should be adjusted according to renal function, and drugs that are potentially nephrotoxic should be avoided.

Mannitol for treating rhabdomyolysis

Mannitol theoretically exhibits several protective mechanisms. It is a potent diuretic that may increase myoglobin solubility and excretion in the renal tubules, thereby reducing cast formation. It decreases sodium reabsorption in the kidney, which may promote renal conservation by decreasing the energy requirement of the renal medulla. Additionally, mannitol is probably a potent oxygen free radical scavenger. Mannitol also improves compartment pressures in compartment syndromes that result from crush injuries. The available literature regarding the effectiveness of mannitol in preventing kidney injury from heme pigment is conflicting. No randomized, controlled trial has supported the general use of mannitol for rhabdomyolysis. However, limited evidence suggests that mannitol along with sodium bicarbonate may be beneficial when CK levels are higher than 20,000 to 30,000 U/L. Mannitol therapy can be given in both an intermittent and continuous fashion. Intermittent therapy is preferred, with a dose of 0.5 to 1 g/kg (averaged as 400 g over a 60-hour period) to achieve a urine output of 300 mL/hr. Serum sodium and osmolarity should be checked frequently to avoid a hyperosmolar state. Acute kidney injury is more likely to occur with doses higher than 200 g/day and a cumulative dose higher than 800 g.

Sodium Bicarbonate for treating rhabdomyolysis

Patients with idiopathic rhabdomyolysis may not need bicarbonate therapy, but severely injured or hypotensive patients generate a tremendous organic acid load that often requires treatment with supplemental sodium bicarbonate. Bicarbonate infusion of more than 500 mEq in 24 hours may be indicated. Urine alkalinization with sodium bicarbonate potentially reduces heme protein precipitation and cast formation. As with mannitol, no randomized, controlled trials have demonstrated that sodium bicarbonate therapy is more effective than normal saline alone. Caution should be exercised when administering large doses of bicarbonate because treatment may exacerbate hypocalcemia, alkalemia, and related arrhythmias.

Acetazolamide for treating rhabdomyolysis

Acetazolamide prevents the complications of serum alkalemia caused by bicarbonate therapy. It promotes the excretion of sodium bicarbonate in the renal tubules, thereby inhibiting cast formation. When serum pH exceeds 7.50, a standard dose of acetazolamide (250 mg) may be administered.

Renal replacement therapy and hemodialysis for treating rhabdomyolysis

Early hemodialysis is not necessary unless crush injuries or certain complications have occurred (e.g., severe hyperkalemia, refractory metabolic acidosis, oliguria or anuria, volume overload). Early consultation with a nephrologist is warranted. Myoglobin molecules can be removed by hemofiltration, but not by hemodialysis or peritoneal dialysis. Reductions in morbidity and mortality have been observed in victims of mass casualty incidents who underwent dialysis within 4 to 6 hours of injury.

Promising therapy for rhabdomyolysis treatment

Several promising experimental therapies for rhabdomyolysis have been studied in animal models but have not been well tested in humans. Nitric oxide may prevent acute renal failure by promoting renal vasodilation, and lazaroids (21-aminosteroids) inhibit oxidant-induced lipid peroxidation in animals. Other experimental treatment modalities include deferoxamine (an iron chelator), glutathione, vitamin E, carvedilol, and dantrolene.

What medicines should be avoided?

Patients with rhabdomyolysis often have acute hypocalcemia. The hypocalcemia results from deposition of calcium salts in necrotic muscle. Supplemental calcium administration should be avoided if possible because it can exacerbate the cytoplasmic injury. During the rebound and recovery phases of rhabdomyolysis, calcium is remobilized and hypercalcemia becomes a true risk. Only if the patient is symptomatic or if severe hyperkalemia is present should calcium be considered, and even then other measures to ameliorate the hyperkalemia should be undertaken first.

Loop diuretics (e.g., furosemide) should generally be avoided because they contribute to urine acidification and tubular cast formation. Forced diuresis is best facilitated with mannitol. Under alkalemic conditions, acetazolamide can be considered.

What is Crush syndrome?  Crush syndrome and rhabdomyolysis

Rhabdomyolysis and crush syndrome often emerge as the leading causes of delayed mortality. Crush syndrome, perhaps the most dramatic manifestation of rhabdomyolysis, results from both the initial blunt force trauma and the marked reperfusion injury that occurs after release of the crushing pressure. Commonly, crush syndrome will occur epidemically because of structural failure from earthquakes or warfare with resultant entrapment of victims beneath debris. Although acute renal failure is the most life-threatening manifestation, crush syndrome can occur with failure of any organ system, much like rhabdomyolysis. Frequently, management of the obvious concomitant traumatic injuries can overshadow the emergency of crush syndrome. Crush syndrome and compartment syndrome act synergistically on the degradation of muscle. Acute musculoskeletal compartment syndrome can damage myocytes and induce rhabdomyolysis. Rhabdomyolysis in turn exacerbates the inflammatory cascade associated with crushing of the muscle compartment, thereby worsening compartment pressures. Crush syndrome may worsen acute renal failure. During mass casualty situations in which crush injuries would be expected (earthquakes, building collapse, bombings), it is important to start IV volume restoration in all survivors as quickly as possible (see the Tips and Tricks box “Management of Crush Syndrome”). Emergency medical service and ED personnel should be instructed to begin IV resuscitation even before the victims have actually been extricated from the scene. This may involve placing an IV line in a confined space on any free limb.

Surgical treatment for rhabdomyolysis

Surgical therapy is a consideration for patients with rhabdomyolysis caused by crush syndrome. Amputation removes damaged muscle that serves as the source of cellular toxins. Physiologic amputation can act as temporizing measure when immediate surgical care is not available, particularly in the setting of disasters or military combat. To perform physiologic amputation, one or two tourniquets are applied firmly to the extremity above the level of injury or entrapment, and dry ice is applied distal to the tourniquet. Combat surgery hospitals beginning in World War II through current conflicts have performed this procedure with success. Physiologic amputation rapidly reduces myoglobin and other intracellular toxins associated with crushed, ischemic, or septic extremities. This can dramatically reduce myoglobinuria and reperfusion injury. Physiologic tourniquets have allowed definitive surgery to be delayed for up to 32 days. Emergency physicians must be aware, however, that physiologic amputation will inevitably result in loss of the affected limb.

Early prophylactic fasciotomy increases the need for transfusions and the risk for both sepsis and death. Fasciotomy is not indicated unless signs of compartment syndrome are observed.

Anesthetic considereation for rhabdomyolysis

Data related to anesthetic choices in patients with rhabdomyolysis are lacking, perhaps because of the rarity of the disease. However, many retrospective studies discuss the treatment of patients with muscular dystrophies. These patients are at an increased risk of general anesthetic-related hazards, including rhabdomyolysis. In a review by Muenster et al of 232 patients with Duchenne muscular dystrophy, the patients were treated with total intravenous anesthesia, using no volatile anesthetic agents, and with opioids and nondepolarizing muscle relaxants depending on the type and duration of the surgical procedure at the discretion of the anesthetist. If a muscle relaxant is used, succinylcholine must be avoided, and monitoring of muscle relaxation is performed by acceleromyography. Nitrous oxide and propofol were used for induction. Muenster et al found no serious anesthetic complications and no cases of rhabdomyolysis.  Segura et al found in their review of 117 patients with dystrophinopathies that succinylcholine may trigger rhabdomyolysis, hyperkalemia, and cardiac arrest; however, evidence regarding the use of inhalational anesthetics was lacking. Segura et al also found no cases of rhabdomyolysis with total intravenous anesthesia in their retrospective study and no evidence for or against volatile anesthetic usage in this patient population. No anesthetic agent is risk free; rhabdomyolysis has been reported with nontriggering anesthetics, barbiturates, benzodiazepines, propofol, ketamine, and fasting.

Follow-up and patient education for rhabdomyolysis

Most patients with rhabdomyolysis should be admitted to a telemetry floor staffed by a physician or to an intensive care unit. If there is uncertainty regarding the diagnosis or severity, patients should be admitted for observation, testing, and treatment.

Rhabdomyolysis can be associated with acute kidney injury. Patients with renal failure should be admitted to the hospital and a nephrologist consulted early in the treatment course. Patients with minimal elevations in CK and no identifiable complications may be managed as an outpatient if urgent follow-up with a primary care provider can be ensured.

Rhabdomyolysis in animals

Rhabdomyolysis is recognized in horses. Horses can develop a number of muscle disorders, many of which may progress to rhabdomyolysis. Of these, some cause isolated attacks of rhabdomyolysis (e.g., dietary deficiency in vitamin E and selenium, poisoning associated with pasture or agricultural poisons such as organophosphates), while others predispose to exertional rhabdomyolysis (e.g., the hereditary condition equine polysaccharide storage myopathy). 5–10% of thoroughbred horses and some standardbred horses suffer from the condition equine exertional rhabdomyolysis; no specific cause has been identified, but an underlying muscle calcium regulation disorder is suspected.

Rhabdomyolysis affecting horses may also occur in outbreaks; these have been reported in many European countries, and later in Canada, Australia, and the United States. It has been referred to as “atypical myopathy” or “myoglobinuria of unknown etiology”. No single cause has yet been found, but various mechanisms have been proposed, and a seasonal pattern has been observed.Very high creatine kinase levels are detected, and mortality from this condition is 89%.

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