Rhabdomyolysis

A rhabdomyolysis is a clinico-biological syndrome resulting from the massive destruction of striated muscle cells, leading to the release of their contents into the bloodstream. Its causes are numerous, but the majority of cases result from a crush syndrome (prolonged muscle crushes and polytrauma).

Its diagnosis relies on a poorly defined accumulation of clinical and biological signs. Some authors, however, consider that a serum creatine kinase (CK) level greater than 5000 UI/liter (the usual norms, varying according to reference laboratories, being from 25 to 190 UI/liter) is sufficient to affirm rhabdomyolysis... others set a limit at 1000... others...

In any case, rhabdomyolysis is likely to have serious complications that are difficult to predict, potentially requiring intensive care management. Morbidity and mortality vary significantly depending on the patient’s characteristics, etiology, and complications (the occurrence of acute kidney failure marking a mortality rate of 20 to 50%).

Clinical

Clinical semiology is variable :

• "Classic" signs: weakness, myalgias, and dark urine (classically described as "port wine" due to myoglobinuria) are almost constant but frequently transient
• Muscle edema, tense muscles, and tenderness on palpation
• Signs of hypovolemia (water-sodium sequestration by the injured muscle tissues)
• Possible skin signs: rash, maculopapular eruption, blisters
• Etiological signs varying according to the cause… potentially obscuring or relegating the signs of rhabdomyolysis…
• Complete lesion assessment in cases of traumatic rhabdomyolysis
• "Explosive" presentations (generally occurring in crush syndromes): muscle edema increasing rapidly with signs of ischemia, paralysis, and sensory disturbances (compartment syndrome), signs of hypovolemia or even true shock, neuropsychiatric disturbances, hyperventilation (metabolic acidosis), hyperkalemia with arrhythmias, signs of acute kidney failure, respiratory distress, fever,…

In cases of limb crushes or polytrauma, rhabdomyolysis should always be sought. In other cases, rhabdomyolysis is often in the background of a complex medical condition, and its detection is quite random…

Complementary examinations

• Biology and gasometry :
  • Elevation of muscle enzymes: CK (the most sensitive) [CK-MB may also increase to a lesser extent without indicating cardiac involvement], myoglobin, GOT, GPT, LDH
  • Ionic disorders (sign of severity): hyperkalemia, hypocalcemia, hyperphosphatemia
  • Disorders of renal function (sign of severity): increased creatinine and uric acid
  • Increase in lactate levels
  • Metabolic acidosis and compensatory hyperventilation (potentially leading to respiratory distress)
• Urine : Myoglobinuria
• Electrocardiogram : searching for arrhythmias and signs of hyperkalemia
• Various tests according to complications and etiological orientation

Complications

Acute kidney failure (10 to 30%)

It occurs in 10 to 30% of rhabdomyolyses, indicating a mortality of 20 to 50%. Rhabdomyolyses would represent 5 to 15% of causes of acute kidney failure.

The pathogenesis of kidney involvement remains uncertain. Traditionally, myoglobin precipitation in the tubules was blamed, but recent studies suggest the role of oxidative stress secondary to the release of endotoxins, renal vasoconstriction, and hypovolemia...

Its occurrence is difficult to predict. No study has been able to correlate it with the extent of myoglobinuria or myoglobinemia. However, a link has been established with the magnitude of the CK elevation, the severity of ionic disorders, bicarbonate levels, and hypovolemia.

It should be noted that a transient increase in creatinine levels may be observed at the onset of rhabdomyolysis… without indicating acute kidney failure (release of preformed creatinine from muscle cells).

Compartment syndrome

A compartment syndrome may occur due to muscle edema (> increased pressure > venous occlusion and abolition of venous return > capillary occlusion).

Clinically, intense myalgias resistant to analgesics are found (the disappearance of pain generally indicates an advanced stage), functional impairment of the affected limb, hypoesthesia, a cold limb, abnormalities in peripheral pulse perception,... The viability of the affected limb is compromised.

Treatment consists of immediate fasciotomy.

Ionic disorders

Risk of hyperkalemia, hypocalcemia (secondary to hyperphosphatemia and calcium precipitation in injured tissues), and hyperphosphatemia. They necessitate ionic and electrocardiographic monitoring.

Acute respiratory failure

Due to hyperventilation compensating for metabolic acidosis.

Hypovolemic shock

Due to hypovolemia resulting from muscle water-sodium sequestration, possible hemorrhagic losses in case of trauma, and/or dehydration secondary to prolonged immobilization.

Etiologies

Although dominated by crush syndrome, they are unfortunately countless… the main ones are :

ISCHEMIC		Crush Syndrome (prolonged muscle crush)
		Acute arterial obstruction
		Muscle trauma
		Sickle cell disease
		Burns
		Postural syndrome (prolonged awkward positions) and prolonged surgeries
		Heat stroke
		Convulsants and epileptic seizures
		Intense agitation
DEPENDENT ON GROUND	Acquired muscle fragility	Alcohol
		Heroin, cocaine
		Neuroleptics
		Electrolyte disorders
		Acquired inflammatory myopathies (polymyositis and dermatomyositis)
	Hereditary myopathies	Malignant hyperthermia
		Metabolic myopathies
		Degenerative myopathies (dystrophies)
INDEPENDENT OF GROUND	Known mechanisms	Mitochondrial damage: CO poisoning
		Reticular damage: caffeine, theophylline, amphetamines, phencyclidine
		Sarcolemmal damage: lipid-lowering agents (statins), snake or spider venoms
	Unknown mechanisms	Bacterial, viral, parasitic, or fungal infections
MISCELLANEOUS		Status asthmaticus
		Water intoxication
		Diabetes insipidus
		Hypothyroidism and hyperthyroidism
		Hypothermia

Rhabdomyolysis predominantly ischemic

The crush syndrome (prolonged limb crushing leading to tissue damage, directly and through ischemia) is the main cause of massive rhabdomyolysis.

Terrain-dependent Rhabdomyolyses

Alcoholism is found in 30 to 60% of large series of non-traumatic rhabdomyolyses. Episodes typically occur during a transient exacerbation of chronic alcohol intoxication. This may involve a specific fragility of the muscle in alcoholics (alcoholic myopathy due to direct toxicity on muscle membranes?)… whose lifestyle exposes them to precipitating factors (alcoholic coma, delirium tremens, epileptic seizures, malnutrition, infections, ionic disorders,…).

Heroin (or one of its common adjuncts such as strychnine) could induce a true toxic myopathy. Cocaine, on the other hand, would have a non-specific toxic effect (muscle ischemia due to vasoconstriction, abnormalities in oxidative metabolism). Cases of rhabdomyolysis during a malignant syndrome of neuroleptics have also been reported.

Numerous ionic disorders (hypokalemia, hypomagnesemia, hypophosphatemia, hypercalcemia, hyponatremia, metabolic acidosis,…) have been implicated in cases of rhabdomyolysis. It seems that these are more facilitating factors (disruption of homeostasis and weakening of the cell membrane) rather than true etiologies.

Cases of rhabdomyolysis complicated by acute kidney failure have been exceptionally reported in the context of dermatomyositis and polymyositis.

Malignant hyperthermia is a rare autosomal dominant disorder (1 in 100,000 individuals) of striated muscle characterized by paroxysmal hypercatabolism crises induced by certain anesthetic agents (halogenated agents and succinylcholine) in seemingly healthy subjects (subclinical myopathy). The crisis is characterized by tachycardia, hyperpnea, ventricular arrhythmias, hypertonia, and muscle spasms, rhabdomyolysis, and a rise in body temperature of 1 to 2° every 5 to 10 minutes. Diagnosis is made retrospectively by biopsy of muscle cells exposed to halogenated agents. The progression is rapidly fatal in the absence of treatment (immediate cessation of anesthetics, suspension of surgery, IV dantrolene, pure O2 ventilation, body cooling, management of arrhythmias, hydration and IV alkalization… transfer to intensive care once the patient is stabilized). With prompt and appropriate treatment, mortality remains > 10%.

Other very rare hereditary myopathies may be involved: dystrophies (Duchenne,…) particularly following general anesthesia using succinylcholine, or metabolic myopathies in very particular situations (fasting for carnitine transferase deficiency, exertion for muscle phosphorylase or phosphofructokinase deficiencies).

Terrain-independent Rhabdomyolyses

Cases have been reported during CO intoxications (affecting the mitochondrial respiratory chain), with caffeine or theophylline or amphetamines (affecting the reticular calcium channel). Normolipemic agents (statins!) at therapeutic doses, certain venoms from rattlesnakes or spiders can lead to rhabdomyolysis due to damage to the muscle membrane or sarcolemma.

Numerous infectious agents (viruses, bacteria, parasites, fungi) can, very rarely, cause rhabdomyolysis through mechanisms that are still undetermined (direct action through infection of myocytes? endotoxins? inflammatory mediators? impairment of microcirculation? autoimmunity?…). These cases often occur in the context of ischemia, surgery, trauma, or immunosuppression… During viral infections, muscle damage is most often diffuse or multifocal. During bacterial infections, damage is most often localized. The most implicated agents are: Influenza, enterovirus, HIV.

Countless medications have been implicated in cases of rhabdomyolysis, without a common mechanism being identifiable. Most cases occur in the presence of facilitating factors (agitation, seizures, dehydration, intramuscular injections,…).

Miscellaneous

Finally, various situations characterized by altered homeostasis with compromised oxygen and nutrient supply or muscle microvascularization are likely to lead to rhabdomyolysis: severe acute asthma, water intoxication, diabetes insipidus, hypothyroidism, thyroid storm,…

Therapeutic Management - Treatments

Management is primarily supportive:

• Etiological treatment if possible (e.g.: limb crushing → remove the cause and assess the need for surgery)
• Supportive care:
  • Simple monitoring for 24 to 48 hours in cases of uncomplicated rhabdomyolysis (asymptomatic and absence of ionic disorders and renal function deterioration)
  • Intensive care management in cases of massive or complicated rhabdomyolysis
  • Volume expansion (to prevent or treat secondary acute kidney failure): hyperhydration with crystalloids (IV infusion of 0.9% NaCl at 1.5 l/hour as quickly as possible… in the absence of acute kidney failure and subject to cardiac function: maintain at least 12 l/day for 2 to 3 days). Possible, cautious use of vasoconstrictive agents.
  • Correction of ionic disorders:
    • correct any hyperkalemia…! Warning: conventional medical means are generally ineffective in cases of uncontrolled hyperkalemia without volume expansion → consider earlier recourse to hemodialysis!
    • hypocalcemia should only be corrected (risk of exacerbating myolysis due to calcium precipitation) if it is severe or symptomatic
    • hyperphosphatemia usually does not require correction.
  • Management of other complications (organ support, fasciotomies,…)
  • Empirical antibiotic therapy in cases of open wounds or suspected infection etiology
  • In cases of uncontrollable myolysis (+++ in traumatic rhabdomyolysis), resection of necrotic tissues, or even amputation, should be considered.

Bibliography

Longo DL et al., Harrison - Principes de médecine interne, 18e éd., Lavoisier, 2013

Perazella MA et al., Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis), UpToDate, 2022

Shefner JM, Causes of rhabdomyolysis, UpToDate, 2022

Shefner JM, Clinical manifestations and diagnosis of rhabdomyolysis, UpToDate, 2022

Vincent JL, Le manuel de réanimation, soins intensifs et médecine d'urgence, 2e éd., Springer, 2007