Clinical manifestations

Presentation and course

Muscle symptoms. The acute skeletal muscle injury that produces myoglobinuria typically causes myalgia and muscle swelling, the latter attributable to a shift of extracellular water into necrotic muscle. The severity of these symptoms is conditioned by the extent and location of muscle injury. With severe generalized muscle injury, the patient is prostrate, is unable to move because of widespread muscle pain and weakness, has tight, swollen muscles causing stiffness and exquisite pain to muscle palpation or attempted movement (46). Compared to common muscle soreness, the weakness and stiffness seems to be more acute and sustained in rhabdomyolysis. Also, pain tends to be present even at rest in the latter, and abates with rest in muscle soreness (67). In other circumstances, muscle injury and symptoms may be focal. Muscle swelling in a restricted anatomic region may lead to a compartment syndrome in which the swelling blocks muscle blood flow leading to a “second wave” of ischemic muscle necrosis and further swelling that ultimately leads to neural and vascular injury (46). Organ failure can occur, depending upon the extent and severity of muscle damage, and is the cause of death in about 8% of cases (10). At the other extreme, muscle symptoms may be relatively minor or overshadowed by complications of myoglobinuria or by symptoms of the acute event or illness that triggered muscle injury (26).

Renal manifestations. The most important complication is acute kidney injury or acute renal failure, occurring in 13% to 50% due to renal vasoconstriction, intraluminal cast formation, and direct myoglobin toxicity (87; 70). Pigmenturia typically occurs in close temporal relation to the acute muscle injury or when circulation is restored to necrotic muscle and is attributable to the release of myoglobin into the bloodstream with rapid clearance by the kidney. Oliguria may herald the onset of acute renal failure. The likelihood of renal failure is greatly increased by the presence of hypotension, decreased renal perfusion, dehydration, acidosis, or nephrotoxic drugs (18). Increased serum levels of myoglobin greater than 15,000 micrograms/L were also found to have significant correlation with developing acute kidney injury in both adult and pediatric groups (72; 70; 49).

Other symptoms and complications. With catastrophic rhabdomyolysis, hypotension or shock may occur because of large fluid shifts (third spacing). In these instances, the common finding of acute hypoalbuminemia probably indicates an associated endothelial injury. Cardiac arrhythmia may occur because of hyperkalemia due to potassium release from necrotic muscle and renal compromise. Aside from hyperkalemia, other electrolyte abnormalities can also be observed: hypocalcemia, hypercalcemia, hyponatremia, hyperphosphatemia, and metabolic acidosis (70). Disseminated intravascular coagulation, possibly attributable to thromboplastin release from injured muscle, could complicate severe rhabdomyolysis and hemorrhagic complications may also result. Acute respiratory distress syndrome attributable to involvement of the muscles of respiration or to pulmonary capillary hyperpermeability has been described. Ischemic or infarcted bowel has also been reported.

Skin changes of ischemic tissue injury, such as discoloration or blisters, may also be seen but are present in less than 10% of patients (32).

Laboratory findings. The major laboratory features of myoglobinuria are pigmenturia and elevation of cytoplasmic enzymes liberated from injured muscle. The myoglobin level in urine is a function of the mass of injured muscle and the rate of urine flow. Visible discoloration of the urine is apparent with myoglobin concentrations of 100 µg/mL; levels above 1 µg/mL are detectable by peroxidase sensitive chromogens such as orthotolidine. This qualitative measurement utilizes urine dipstick testing for blood on an ultrafiltrated or precipitated urine sample. This extra step removes hemoglobin and assumes a positive result is due to myoglobin. However, due to false positive and negative results, utilization of this has declined (77). Radioimmune assay quantitatively detects myoglobin to about 5 ng/mL. Normal serum levels are 30 to 80 micrograms/L, whereas urine levels are 3 to 20 micrograms/L. Myoglobinuria is diagnosed when urine concentrations are more than 20 micrograms/L (18; 70). In a study Schifman and Luevano found that reflex testing of urinalysis with a negative or trace hemoglobin count averted over-testing using quantitative methods (77).

The period of frank myoglobinuria is generally brief (hours). Levels of creatine kinase tend to peak 24 to 72 hours after the acute injury (79), usually reaching levels of 10s to 100s of thousand international units (IU) per liter. CK levels then decline by about 50% approximately every 48 hours. Serum aldolase, transaminases, and lactate dehydrogenase are correspondingly elevated. Additional laboratory abnormalities may include hyperkalemia, particularly in the setting of renal failure; hyperphosphatemia; hypocalcemia related to the deposition of calcium salts in injured muscle; and hyperuricemia. Myoglobinuric renal failure characteristically produces a disproportionately elevated creatinine relative to blood urea nitrogen. Hemoconcentration accompanies fluid shifts into injured muscle.

Although the pathologic processes responsible for rhabdomyolysis are diverse, the histologic features often are similar. Typically, a population of muscle fibers shows evidence of injury and are all at a similar stage of necrosis or regeneration depending on the timing of the biopsy, consistent with injury affecting a susceptible population of muscle fibers within a limited time frame. A biopsy temporally remote from the episode of myoglobinuria (4-6 weeks later) commonly reveals virtually normal muscle morphology, reflecting the remarkable regenerative capacity of skeletal muscle. It may also reveal the underlying cause (metabolic, mitochondrial myopathy, etc.)

Prognosis and complications

Massive muscle injury triggered by severe exertion or myotoxins may result in multiple organ failure and death. However, myoglobinuria generally has a good prognosis if renal failure is avoided or aggressively treated. Muscle has a remarkable capacity to regenerate, and most patients recover muscle function fully. Even patients who have had multiple episodes of myoglobinuria may have no lasting skeletal muscle effects. However, muscle weakness and focal loss of muscle mass, possibly attributable to recurrent muscle injury, could occur late in life in muscle phosphorylase deficiency and muscle phosphofructokinase deficiency.

Clinical vignette

After an hour of unaccustomed weightlifting to “get in shape,” a 28-year-old white male experienced pain affecting muscles of the upper arms, chest, and back. Urine was noted to be Coca-Cola colored on voiding an hour later. Twelve hours later the patient's arms were swollen and it hurt to move them. He felt generally unwell and nauseated and was treated symptomatically for possible flu. The following day on presentation to an emergency room, creatine kinase was 100,000 IU, and serum creatinine and blood urea nitrogen were elevated. The patient underwent hemodialysis for acute renal failure. The admitting physician obtained a history of virtually lifelong exercise intolerance. An ischemic forearm test showed no increase in lactate; and a subsequent muscle biopsy revealed absent muscle phosphorylase reactivity (McArdle disease). Genetic testing showed compound heterozygous missense and nonsense mutations (p.R50X) in the PYGM gene.

Biological basis

Etiology and pathogenesis

The number of hereditary and acquired disease processes that may produce myoglobinuria, including drugs, toxins, and underlying metabolic errors, is continually expanding (Tables 1 and 2). Correspondingly, myoglobinuria has gone from a medical oddity to a commonly recognized event.

The main hereditary disorders that predispose to recurrent episodes of myoglobinuria include inborn errors of muscle metabolism affecting carbohydrate or lipid metabolism. These disorders may present with exercise intolerance, cramps, or myoglobinuria. In muscle glycogenolytic or glycolytic defects, myoglobinuria typically is triggered by brief intense exercise. The responsible metabolic defects are deficiency of: phosphorylase (McArdle), phosphofructokinase (Tarui), phosphoglycerate mutase (20), phosphoglycerate kinase (20), lactate dehydrogenase (Kanno), phosphorylase b kinase (21), and phosphoglucomutase (62).

The major lipid disorder causing recurrent rhabdomyolysis is carnitine palmitoyltransferase II deficiency (DiMauro and Costanza 2001; 50). Prolonged and submaximal exercise, particularly when associated to fasting, is most often implicated; intercurrent infection may also trigger muscle injury in this disorder. Approximately two thirds of patients with fatty acid oxidation defects suffer from episodic myalgias, elevated creatine kinase, and myoglobinuria (75). Fatty acid oxidation defects disrupting the oxidation of long-chain fatty acids are more often associated with recurrent myoglobinuria, whereas enzyme deficiencies disrupting the oxidation of short- and medium-chain fatty acids result in myoglobinuria on rare occasions (83; 73; 40; 75) (Table 1).

A disorder involving lipid homeostasis has been described. It involves a muscle-specific phosphatidic acid phosphatase, which is a key enzyme in triglyceride and membrane phospholipid biosynthesis. Patients present in early childhood with recurrent episodes of myoglobinuria precipitated by febrile illness.

Mutations in the LPIN1 gene encoding for this enzyme have been detected in these patients (92). It was postulated that secondary accumulation of lysophospholipids during stress periods results in acute rhabdomyolysis.

Respiratory chain and other mitochondrial disorders are becoming increasingly recognized as causes of exercise intolerance with or without myoglobinuria. Such conditions include cytochrome c and b oxidase deficiencies, complex I deficiency, complex III deficiency, and primary coenzyme Q10 deficiency (20; 62). Mutations in mtDNA, including multiple deletions or point mutations in tRNA genes, have also been associated with recurrent myoglobinuria (81; 52; 22). A deficiency of the lipoamide dehydrogenase enzyme was characterized by recurrent attacks of vomiting, abdominal pain, and encephalopathy accompanied by elevated liver transaminases, prolonged prothrombin time, and occasionally associated with lactic and ketoacidemia or with myoglobinuria (78).The E3 subunit of the pyruvate dehydrogenase complex, dihydrolipoamide dehydrogenase/dihydrolipoyl dehydrogenase (DLD)/lipoamide dehydrogenase (LAD), is a mitochondrial matrix enzyme and a part of the branched-chain ketoacid dehydrogenase and alpha-ketoglutarate dehydrogenase complexes. DLD deficiency is relatively frequent in the Ashkenazi Jewish population but occurs in other populations as well. Data was gathered from the files of 17 pediatric patients with DLD deficiency, confirmed by enzymatic and genetic analysis in an Israeli study in 2013 (30).

A previously described disorder in patients from Northern Sweden had been characterized by exercise intolerance and myoglobinuria and associated with succinate dehydrogenase and aconitase deficiency (51; 28) and was later elucidated as a defect in the iron-sulfur cluster scaffold protein (ISCU) (59). These patients present depletion of mitochondrial ISCU in muscle that leads to a deficiency in mitochondrial iron-sulfur proteins and impaired muscle oxidative metabolism.

Other biochemical defects associated with myoglobinuria include glucose 6-phosphate dehydrogenase deficiency (pentose pathway) and, rarely, myoadenylate deaminase deficiency (purine nucleotide cycle) (88).

Other causes of hereditary myoglobinuria include some of the skeletal muscle channelopathies causing hyperexcitability and resulting in susceptibility to malignant hyperthermia (38). Malignant hyperthermia is a genetic predisposition to develop muscle rigidity, hypermetabolism, fever, and myoglobinuria triggered by volatile anesthetics or depolarizing muscle relaxants. In the majority of families with this condition, there is linkage to the gene encoding for the skeletal muscle ryanodine receptor (RYR1). RYR1 is a calcium channel mediating calcium release from the sarcoplasmic reticulum during excitation-contraction coupling. To date, more than 41 pathogenic point mutations in RYR1 have been identified (OMIM *180901). Additional chromosomal loci mapped in malignant hyperthermia include the region of a dihydropyridine receptor subunit gene (CACNA1S) (38) and the voltage-gated skeletal muscle sodium channel gene SCN4A (61). Central core disease is often associated with malignant hyperthermia susceptibility, and is allelic to malignant hyperthermia due to mutations in the RYR1 gene (38).

Further causes of hereditary myoglobinuria include muscular dystrophies. Exercise-induced myoglobinuria has been reported in a few cases with dystrophinopathies, including Becker muscular dystrophy, as well as in limb-girdle muscle dystrophies 2C, 2D, and 2E, and sarcoglycanopathies (12). A high incidence of myoglobinuria and muscle pain has been reported in limb-girdle muscular dystrophy 2I due to FKRP gene mutations (55; 50). There have also been a few case reports of bisphosphonate induced rhabdomyolysis in Duchenne muscular dystrophy (33). Dysferlinopathy, ano-5 myopathy, and FSHD also had few reports of recurrent rhabdomyolysis (62). Myotonic dystrophy has been reported in cases of ritodrine-induced rhabdomyolysis (74; 63; 60; 64).

Recurrent myoglobinuria precipitated by infection has been reported in yet another known hereditary condition, Marinesco-Sjögren syndrome with demyelinating neuropathy. The biological basis of this condition remains unknown (58). Late onset thymidine kinase 2 deficiency was also found to result in recurrent rhabdomyolysis, myoglobinuria, and exercise intolerance in 1 patient. The authors placed importance in considering this in the differential of recurrent rhabdomyolysis due to an ongoing clinical trial for this (NCT03845712) (25).

Autoimmune myopathies, such as dermatomyositis and polymyositis, may present with rhabdomyolysis (62). Myoglobinuria may also occur in Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) immune-mediated necrotizing myopathy (IMNM) (80). It has to be noted though that baseline CK in these conditions may be more than 1000. Having symptoms of acute pain and new weakness may be clues to an episode of rhabdomyolysis (62).

Single episodes of myoglobinuria in individuals without hereditary predisposition occur in several clinical settings. Trauma or crush injuries occur when individuals are pinned by falling debris (09) and in comatose or anesthetized individuals when muscles are compressed for prolonged periods by the weight of the patient’s body (68). In this context, it is important to highlight a report of child abuse presenting with myoglobinuria (19). In these clinical settings of trauma and compression, intramuscular pressure exceeds arterial pressure and render the muscle ischemic (66). Hypotension, respiratory depression, and metabolic inhibition (when barbiturates, carbon monoxide, or related agents are involved) may contribute to muscle injury. Acute vascular occlusion with muscle infarction also produces myoglobinuria (01). When circulation is restored, soluble constituents of necrotic muscle are released into the bloodstream, myoglobinuria occurs, and the cascade of medical complication of acute muscle necrosis.

Among the active or well-conditioned individuals, sporadic myoglobinuria may also occur in setting of extreme and excessive exercise or with potentiating factors of dehydration, hyperthermia, or sickle cell trait (42; 54). Muscle glycogen depletion may play a role. Military recruits and weekend athletes engaging in unusual, intense exercise are the typical victims, and men are affected much more commonly than women. Exercise involving lengthening (eccentric) muscle contractions is often involved (07). In these circumstances (for example, running downhill), the muscle is both contracted and stretched, acting as a shock absorber. This type of muscle injury characteristically results in delayed onset muscle soreness with minimal symptoms immediately after exercise but with progressive muscle pain and restricted range of motion of affected muscle groups developing 12 to 48 hours later. The onset of myoglobinuria may similarly be delayed to 24 to 48 hours after exercise. Poor physical conditioning and high body mass index predisposes to exertional muscle injury. Physical conditioning is protective; however, even physically fit individuals who push beyond their normal limits may still develop catastrophic myoglobinuria (43; 54). Exertion-related myoglobinuria may also follow generalized or focal seizures and as a result of muscle hyperactivity induced by drugs. Severe rapidly progressive dystonia (“dystonic storm”) has also been associated with myoglobinuria (36). Acquired hyperthermic syndromes such as heat stroke can lead to muscle damage and myoglobinuria. Prolonged hypothermia can also cause rhabdomyolysis (88).

Toxins, drugs, and substance abuse represent a major cause of acquired myoglobinuria. Epidemics of paralytic myoglobinuria in humans and animals occurred in the 1920s and 1930s near the Frishes Haff of the Baltic Sea (Haff disease) and in Sweden. The mechanism may have involved eating fish contaminated with an unknown myotoxin. Quail poisoning (coturnism) is an analogous condition in which individuals ingesting quail develop myoglobinuria. The biblical quail episode (Numbers 11:31-33) may represent epidemic myoglobinuria. It is unclear whether what caused this was the ingested sweet parsley seeds, henbane or hemlock. Similar accounts have been found with other birds that have ingested hemlock. Myoglobinuria due to venoms of insects (hornet, tarantula) and snakes (sea snake, rattlesnake) has been documented. Mushrooms, such as Russula spp and Tricholoma spp may also induce rhabdomyolysis, especially those with genetic predispositions (03).

More recently, barbiturates, heroin, cocaine, amphetamines, phencyclidine, phenylpropanolamine, inhalants, and related agents have all been associated with myoglobinuria (88). Coma with crush injury (barbiturates), direct myotoxic effects (heroin, cocaine, toluene), and muscle hyperactivity (amphetamines, phencyclidine, ecstasy, and lysergic acid diethylamide) may be involved. Ethanol abuse is one of the most common causes of myoglobinuria. A direct toxic effect of ethanol may be the predominant mechanism of alcoholic rhabdomyolysis, but crush injury, seizures, hypokalemia, and hypophosphatemia are often present (26; 44; 62).

A number of therapeutic agents can cause muscle injury and myoglobinuria (Table 2), including lipid-lowering agents such as clofibrate and lovastatin. The incidence of myoglobinuria was greatly increased when lovastatin and gemfibrozil (a fibrate related to clofibrate) are combined (71) or when cholesterol lowering agents and cyclosporine are combined. Hypokalemia induced by K+ wasting agents (eg, amphotericin B, diuretics, laxative abuse) or pseudohyperaldosteronism (eg, glycyrrhizic acid in licorice) is an additional common mechanism of drug-related myolysis (88).

In a review by Coco and Klasner, several drugs of common use in the pediatric population, such as acetaminophen and antihistamines, have also been associated with myoglobinuria (17).

Neuroleptic malignant syndrome, a known complication of neuroleptic drugs or of abrupt discontinuation of dopaminergic agents, can cause rhabdomyolysis. In addition, neuroleptics can also be associated with myoglobinuria in the absence of neuroleptic malignant syndrome (57).

Serotonergic syndrome due to excess serotonin activity, resulting most commonly from the combination of a selective serotonin reuptake inhibitor with monoamine oxidase inhibitors, has also been associated with myoglobinuria (88). Valproic acid can cause acute metabolic decompensation in patients with underlying inborn errors of metabolism. One patient with carnitine palmitoyltransferase II deficiency had acute myoglobinuria triggered by valproic acid (48).

Metabolic derangements that may cause myoglobinuria include hypokalemia attributable to drugs, endocrine disorders, renal tubular acidosis, or GI disorders; hypophosphatemia (47); hyperosmolar states attributable to hyperglycemia, diabetic ketoacidosis, and hypernatremia; and heat stroke (42).

Numerous viral infections can cause myoglobinuria. Influenza is the most common viral etiology followed by HIV infection and enteroviral infection. In the Covid-19 pandemic, some cases of rhabdomyolysis and concomitant myoglobinuria due to Sars-Cov-19 have been reported (41; 34). Some of these patients did not have any comorbidities whereas others had diabetes mellitus, hypertension, obesity, or chronic kidney disease. There were no other new medications aside from either acetaminophen. Cases presented with symptoms of fever, shortness of breath, cough or sore throat, and had accompanying myalgia or dark brown urine prior to or on the day of presentation to the hospital. There were no illicit drug use or prior history of rhabdomyolysis (05; 16; 27; 41; 85). The cause of muscle injury during a Covid-19 infection is still unknown. It is hypothesized that there may be direct muscle invasion of the virus or damage from the elicited immunologic response (27). It is also hypothesized that kidney injury may not only result from effects of rhabdomyolysis but also from direct viral infiltration. Viral particles are able to attach to ACE2 receptors, which are present in different types of kidney cells. Inflammatory response results to additional kidney damage (65).

Late onset rhabdomyolysis was also reported in Covid-19 infected patients (37; 82). However, in these cases, other possible etiologies were present, and rhabdomyolysis may not entirely be due to Covid-19 infection. Medications used to treat the infection, such as meropenem, and secondary complications from the Covid-19 infection, such as hypoxia and hypercoagulability, may also lead to rhabdomyolysis (13). One case has been reported of an adolescent who developed rhabdomyolysis on presentation and died in a few days (06). However, this patient had similar symptoms a year prior, thus it is unknown whether the patient had existing predisposing factors for developing rhabdomyolysis aside from Covid-19 infection. Rhabdomyolysis should be considered a presentation to watch out for in patients with Covid-19 infection in order to institute early treatment and prevent acute kidney injury.

Table 1. Hereditary Causes of Myoglobinuria

Table 2. Major Categories of Acquired (Sporadic) Myoglobinuria

Mechanism of injury. Myoglobin is an approximately 17,500 molecular weight heme protein that is found in the cytoplasm of skeletal muscle in concentrations of 1 to 4 mg/g wet weight: lower in low-oxidative fibers or deconditioned muscle, higher in conditioned, highly oxidative muscle. Myoglobin has a greater affinity for oxygen than hemoglobin at low partial oxygen pressures and plays a critical role in mediating the transport of oxygen from red cells to muscle mitochondria (90). The exterior of the myoglobin molecule is composed mainly of hydrophilic residues, thus, facilitating molecular movement and oxygen transfer in concentrated solutions. These same properties account for the rapid diffusion of myoglobin from lysed muscle cells into the blood.

The mechanisms of muscle injury in myoglobinuria are likely diverse, but 2 general themes are common. Sudden, widespread muscle injury due to trauma, toxins, venoms, or drugs (especially intravenous drugs) suggests that these agents cause direct muscle membrane injury. Muscle necrosis may follow as a result of increased cellular levels of sodium and calcium.

Another common theme is a low level of cellular energy availability relative to demand as in muscle ischemia, carbon monoxide poisoning, exhaustive exercise, or muscle energy defects. Illustrative are metabolic myopathies in which a superimposed stress (usually exercise) exposes a weak link in energy production and results in an acute energy crisis. The precise mechanism by which impaired muscle energy availability produces muscle cellular injury is, however, unknown. One hypothesis is that ATP is depleted to critical levels. Some data suggest that ATP produced via substrate-level phosphorylation in glycolysis preferentially supports or regulates sarcolemmal function (35; 70). This could account for the propensity of muscle glycolytic defects to produce recurrent exertional rhabdomyolysis. Alternatively, muscle injury could be mediated by hydrolysis products of ATP. A small decline in ATP is associated with a much greater relative increase in the concentration of ADP, inorganic phosphate (Pi), and related metabolites (eg, [H+]). Physiologic studies suggest that high levels of these metabolites may impair muscle function by inhibiting enzymes (ATPases) that couple ion transport to ATP hydrolysis leading to premature muscle fatigue and cramping.

A decrease of Na+, K+ - ATPase activity reduces the transmembrane electric voltage and promotes cellular accumulation of sodium ions. The resulting diminution of the sodium gradient reduces 2Na+: Ca++ exchange, promoting accumulation of Ca++ in the cytosol that in turn can activate hydroxylases, nucleases, phospholipases, and neutral proteases. Activation of these enzymes has been related to sarcolemmal injury and other organelle damage, including the mitochondria, leading to further ATP depletion and production of free radicals (45; 70).

Renal failure is more likely to occur in the presence of volume depletion, fever, metabolic acidosis, and the excretion of concentrated, acid urine (11). There appears to be a direct relationship between the concentration of myoglobin in the urine and the propensity to develop acute renal failure (23).

There are 3 mechanisms believed to cause renal failure:

(1) Renal vasoconstriction that results from reduced renal blood flow due to decreased extracellular fluid causing activation of the renin angiotensin aldosterone system. In addition, myoglobin appears to form complexes with nitric oxide, which exaggerates vasoconstriction of renal vasculature.

(2) Formation of intratubular casts as myoglobin interacts with Tamm-Horsfall protein, which can be potentiated further by decreased renal blood flow and acidic environment.

(3) Direct toxicity of myoglobin to kidney tubular cells as heme oxygenase-1 in proximal tubular cells degrade myoglobin and release free iron. Reactive oxygen species are then made from redox cycling between ferric (Fe 3+) and ferryl (Fe4) myoglobin, which has negative effects on the tubular cells and its surrounding organelles. This myoglobin induced lipid peroxidation is prevented in alkaline conditions because Fe4 is stabilized in this pH, decreasing reactivity of myoglobin to lipids and lipid hydroperoxides. Aside from these, there are still unknown pathways of organelle damage occurring that still need further elucidation (70).

Epidemiology

Sporadic myoglobinuria can occur in normal individuals The global incidence is still unknown but certain populations may have increased risk, such as morbidly obese patients, chronic lipid lowering drug users, and postoperative patients (14). The fact that only few subjects exposed to exhaustive exercise, drugs, or toxins develop this complication is consistent with the possibility that unrecognized genetic factors may influence individual susceptibility. For example, the sickle cell trait apparently increases the risk of exertional rhabdomyolysis, particularly at high altitudes, possibly by impairing blood flow to working muscle. Additionally, a study assessing the genetic risk factors associated with lipid lowering drug-induced myopathies reported a higher prevalence of underlying muscle disease than expected in the general population. In this study, among the patients who developed statin-induced myopathy, 10% were heterozygous or homozygous for mutations causing common hereditary metabolic myopathies: 6.5% had myoadenylate deaminase deficiency, 0.9% had carnitine palmitoyl transferase II deficiency, and 0.9% had McArdle disease. The authors concluded that the effect of statins on energy metabolism combined with a genetic susceptibility to triggering of muscle symptoms may account for myopathic outcomes in certain high-risk groups (86).

Other epidemiological studies assessing the etiology of sporadic myoglobinuria disclose variable results. In a cohort of 177 cases of rhabdomyolysis, Alpers and Jones showed that exertion-induced myoglobinuria occurred in 35%, trauma in 20%, toxins in 13%, infections in 7%, heat illness in 7%, seizures in 4%, metabolic myopathy in 3%, and endocrine disturbances in 2% (04). In a study by Melli and colleagues, illicit drugs, alcohol, and prescribed drugs were responsible for 46% of the cases of rhabdomyolysis in a cohort of 475 hospitalized patients (56). Among the prescription drugs, antipsychotics, statins, zidovudine, colchicine, selective serotonin reuptake inhibitors, and lithium were the most frequently involved. Multiple factors may be detected in 9% to 60% of cases (26; 56; 04).

In patients with recurrent myoglobinuria, with a positive family history, or in whom common acquired causes of myoglobinuria can be excluded, an underlying muscle metabolic error is likely. Analysis of 77 patients with adult-onset myoglobinuria, where alcohol and drug abuse had been excluded, showed that 46% of the patients had an underlying enzyme deficiency. The most frequent enzyme defect was carnitine palmitoyltransferase II deficiency (22%) followed by phosphorylase deficiency (13%) and phosphorylase kinase deficiency (5%) (84). Analysis of 22 adult patients from Finland with recurrent myoglobinuria showed that 23% had an identifiable enzyme deficiency and 18% had muscle dystrophy or myopathy. The most frequent enzyme deficiency among this population was phosphorylase deficiency (18%) followed by phosphofructokinase deficiency (5%) and phosphorylase kinase deficiency (5%). The authors concluded that the prevalence of enzyme defects causing rhabdomyolysis may vary in different populations (52).

The exact incidence of rhabdomyolysis in the pediatric population is unclear. In a retrospective review of 19 children with acute myoglobinuria, where cases with recurrent rhabdomyolysis had been excluded, the most frequent etiology was trauma (26%) followed by nonketotic hyperosmolar coma (11%), viral myositis (11%), dystonia (11%), and malignant hyperthermia (11%) (89). In a cohort of 210 children with acute rhabdomyolysis, Mannix and colleagues found that 38% had a viral myositis, 26% had trauma, and 5% had connective tissue disease (53). A third cohort of 130 pediatric cases of rhabdomyolysis, 22% had viral myositis, 18% had trauma, 18% had surgery, 9% had hypoxia, 6% had drug reaction, and 1% had metabolic myopathy (69). In 13% of cases, no definite diagnosis could be made. Among 52 pediatric patients with nontraumatic rhabdomyolysis, 72% of cases were due to viral infection, with influenza A and B being the most common etiologies, 9.3% due to physical exertion, and 1.9% were unidentified (49). Other causes were convulsion and dystonia.

Prevention

Patients with known inborn metabolic errors should undertake changes in lifestyle to avoid circumstances known to trigger myoglobinuria (29). In patients with muscle glycolytic defects, this includes avoiding intense or ischemic exercise (eg, sprinting, lifting heavy weights) and warming up before exercise to increase blood flow and the availability of blood born fuels such as free fatty acids. Patients with lipid defects should avoid fasting and prolonged exercise, consume a high-carbohydrate diet, and take carbohydrate snacks between meals if they must be active for prolonged periods. One case reported a patient with very-long chain acyl-coenzyme A dehydrogenase deficiency given IV glucose infusion during fasting periods perioperatively to avoid hypoglycemia (91). Postoperative shivering was also avoided by keeping the patient warm, as shivering increases energy use. By doing so, Yuasa and colleagues were able to avoid rhabdomyolysis in this patient.

Differential diagnosis

The differential diagnosis of myoglobinuria includes 2 aspects. First is the differentiation of myoglobinuria from other causes of pigmenturia. A triad of findings establishes the clinical diagnosis of myoglobinuria: (1) a heme-positive orthotolidine reaction in spun urine or in urine that contains no microscopic blood, (2) the absence of hemolysis, and (3) elevated serum creatine kinase.

The second aspect of differential diagnosis is consideration of the cause of rhabdomyolysis. In individuals with recurrent myoglobinuria, with muscle symptoms apart from the acute episode or with a positive family history, an inborn error of metabolism should be considered. In individuals with single episodes of myoglobinuria in clinical settings known to cause myoglobinuria (Table 2), a tentative diagnosis can be established.

Diagnostic workup

Diagnosis involves excluding other causes of pigmenturia such as hematuria, hemoglobinuria, or porphyria. Next, the cause of myoglobinuria should be established. The workup should include a careful history and a toxicology screen to identify drugs or toxins known to produce myoglobinuria, and screening for metabolic derangements known to cause myoglobinuria (Table 2). Glycogen metabolism disorders should be suspected in early rhabdomyolysis from activity, with elevated baseline CK. In muscle phosphorylase deficiency, second wind phenomenon during exercise occurs wherein fatigue and pain abate after resting and activity can then be resumed. Phosphofructokinase deficiency may have the same symptoms as McArdle disease but without the second wind phenomenon, and with an additional finding of compensated hemolysis, evidenced by hyperuricemia and reticulocytosis. Lactate dehydrogenase deficiency can be considered in those with reduced LDH level, erythematous rash on extensor surfaces, or uterine stiffness in pregnancy. In contrast, disorders of fatty acid oxidation are suspected with rhabdomyolysis triggered by prolonged submaximal exertion, fasting, stress or illness. These symptoms are suggestive of an inborn error of muscle metabolism and if suspected, appropriate diagnostic testing should be undertaken with an ischemic forearm exercise test, muscle biopsy, biochemical testing for known metabolic errors, or a genetic test. If muscle biopsy is indicated, it is recommended to obtain the muscle sample at least 4 to 6 weeks after the patient has recovered from rhabdomyolysis. Better diagnostic outcomes with biopsies are observed in patients with myopathic electromyography, second wind phenomenon, or muscle hypertrophy/atrophy (62). Zutt and colleagues suggested the illustrated scheme in working up cases with rhabdomyolysis (93).

Antibody tests may also be warranted, especially in those with autoimmune myopathies (62).

Management

The major complications of myoglobinuria are outlined in Table 3. Because volume depletion greatly increases the risk of acute renal failure, early and adequate fluid replacement (normal saline or one-half normal saline in dextrose) is essential to maintain renal perfusion. Ideally, this should be started within 6 hours of symptoms onset (15). Most studies recommend maintaining urine output of 200 to 300 ml/hour until myoglobinuria resolves. In a systematic review of treatment of exertional rhabdomyolysis, the range of IV fluid resuscitation rate ranged from 120 to 300 ml/hour. Average length of stay in the hospital was 4.5 days (54).

Intravenous mannitol (25 g) and furosemide (200 mg) may be required to maintain urine output. Mannitol helps decreasing cast formation and increases renal blood flow. However, there are conflicting views on whether this helps in preventing renal failure in patients with CK greater than 5000 in posttraumatic rhabdomyolysis (70; 54). Alkalization of the urine with intravenous sodium bicarbonate reduces cast formation and thereby promotes excretion of myoglobin. Increasing urine pH to around 6.5 may help reducing heme toxicity to the tubules (02). Persistent oliguria (urine flow less than 20 cc/hour) despite correction of hypotension and the use of mannitol, furosemide, and sodium bicarbonate suggests acute tubular necrosis. Further volume replacement in this setting risks interstitial and pulmonary edema. Such patients often require early and aggressive hemodialysis. Oliguria is an independent risk factor for compartment syndrome or acute respiratory distress syndrome (70). Hyperkalemia due to release of intracellular potassium from necrotic muscle may cause life-threatening cardiac arrhythmias or even cardiac arrest, particularly in the setting of renal failure, and thus should be rapidly corrected (15). The effect of hyperkalemia is potentiated by hypocalcemia, attributable to hyperphosphatemia and deposition of calcium salts in injured muscle. The electrocardiogram assesses hyperkalemic cardiotoxicity more sensitively than serum [K+] levels per se. Emergent treatment of hyperkalemia includes intravenous glucose and insulin, calcium salts, and hyperventilation to promote cellular uptake of potassium. Oral disodium polystyrene sulfonate is useful but acts more slowly. Hemodialysis may be required. Repeating blood tests 24 to 72 hours from initial draws is warranted to monitor the trend of CK and electrolytes (49).

Muscle compartment syndrome may require fasciotomy to avert limb-threatening ischemia and peripheral nerve injury.

Table 3. Mechanisms and Management of Complications of Rhabdomyolysis and Myoglobinuria

Outcomes

Among the exertional rhabdomyolysis cohort, after resolution of kidney injury and returning of CK to baseline, slow progression or graded return to activity was done.

Special considerations

Pregnancy

Intravenous glucose may reduce the likelihood of muscle injury during delivery in carnitine palmitoyltransferase deficiency and muscle phosphorylase deficiency by improving fuel availability. However, fluids containing glucose potentiate the energy crises in phosphofructokinase deficiency; intravenous fluids containing lactate should be substituted.

Anesthesia

The precautions are the same as for malignant hyperthermia.