Causes of rhabdomyolysis

INTRODUCTION Rhabdomyolysis is a syndrome characterized by muscle necrosis and the release of

intracellular muscle constituents into the circulation. Creatine kinase (CK) levels are typically
markedly elevated, and muscle pain and myoglobinuria may be present.
The severity of illness ranges from asymptomatic elevations in serum muscle enzymes to life-
threatening disease associated with extreme enzyme elevations, electrolyte imbalances, and acute
kidney injury.

PATHOPHYSIOLOGY The clinical manifestations and complications of rhabdomyolysis result from

muscle cell death, which may be triggered by any of a variety of initiating events. The final common
pathway for injury is an increase in intracellular free ionized cytoplasmic and mitochondrial calcium.

CAUSES There are multiple potential causes of rhabdomyolysis

●Traumatic or muscle compression (eg, crush syndrome or prolonged immobilization)
●Nontraumatic exertional (eg, marked exertion in untrained individuals, hyperthermia, or metabolic
myopathies)
●Nontraumatic nonexertional (eg, drugs or toxins, infections, or electrolyte disorders)

Trauma or muscle compression — Trauma or muscle compression is a common cause of

rhabdomyolysis and can be seen in the following settings:
●A crush syndrome
●Individuals struggling against restraints, torture victims, or abused children [15,16].
●Immobilization due to coma of any cause or in conscious individuals forced to lie in one position for
hours.
●Surgical procedures in which there is either prolonged muscle compression due to positioning
during a long procedure, or vascular occlusion because of tourniquet use in orthopedic or vascular
reconstruction procedures.
●Acute lower extremity compartment syndrome, with tibial fractures being the most common cause.
●High-voltage electrical injury (eg, from lightning or high-voltage power supplies) or extensive third-
degree burns, causing direct myofibrillar injury

Nontraumatic exertional rhabdomyolysis — Rhabdomyolysis occurs in individuals with normal

muscles when the energy supply to muscle is insufficient to meet demands. Examples include
extreme exertion or exertion under conditions in which muscle oxygenation is impaired, including
metabolic myopathies.
Subclinical myoglobinemia, myoglobinuria, and elevation in serum creatine kinase (CK) are common
following physical exertion.

●Hypokalemia caused by potassium loss from sweating occurs. The role of potassium in the
regulation of skeletal muscle blood flow appears to be important in the pathogenesis in this setting.

Metabolic myopathies — Rhabdomyolysis may develop in patients with abnormal muscle, such as
individuals with inherited disorders of glycogenolysis, glycolysis, or lipid metabolism.
The metabolic myopathies represent a very small percentage of cases of rhabdomyolysis overall but
are relatively common causes among patients with recurrent episodes of rhabdomyolysis after
exertion.
Thermal extremes and dysregulation — Rhabdomyolysis may occur with hyperthermia associated
with heat stroke . Other causes of rhabdomyolysis in the setting of temperature dysregulation or
thermal extremes include:
●Malignant hyperthermia – Rhabdomyolysis is considered a later manifestation of malignant
hyperthermia (MH).
●Neuroleptic malignant syndrome – The neuroleptic malignant syndrome is a disorder in which high
fever (with or without generalized muscle contraction or tremor) develops after exposure to
neuroleptic drugs and anti-Parkinsonian drugs.

Nonexertional and nontraumatic rhabdomyolysis — Nonexertional and nontraumatic causes of

rhabdomyolysis include drugs and toxins, infections, electrolyte abnormalities, endocrinopathies,
inflammatory myopathies, and others.

Drugs — Both prescribed medications and drugs of abuse have been implicated in rhabdomyolysis. In
addition to alcohol, other drugs of abuse that have been implicated as causes include heroin,
cocaine, amphetamines, methadone, and D-lysergic acid diethylamide (LSD).

●Dietary supplements used for weight loss or enhanced physical performance, which typically
contain multiple ingredients, may lead to rhabdomyolysis, possibly as a result of metabolic stress.

Toxins — Rhabdomyolysis may result from exposures to toxins other than medications [5]. These
include:
●Metabolic poisons, such as carbon monoxide.
●Snake venoms,
●Insect venoms,
●Mushroom poisoning
●An unidentified toxin found in certain types of fish

Infections — Rhabdomyolysis has been associated with a variety of infections, both viral and
bacterial.

Acute viral infections associated with rhabdomyolysis include influenza A and B, Coxsackievirus,
Epstein-Barr, herpes simplex, parainfluenza, adenovirus, echovirus, human immunodeficiency virus,
and cytomegalovirus .
The mechanism of muscle damage due to viral infections has not been established, as the presence
of virus in affected muscle has been difficult to demonstrate consistently.

Other infections associated with rhabdomyolysis include:

●Mycoplasma pneumoniae infection
●Bacterial pyomyositis.
●Bacterial infections with a variety of microbial organisms, including Legionella,
tularemia, Streptococcus and Salmonella, E. coli, leptospirosis, Coxiella burnetii (Q fever), and
staphylococcal infection.
●Human granulocytic anaplasmosis (ehrlichiosis).
●Falciparum malaria.

Electrolyte disorders — Rhabdomyolysis has been associated with a variety of electrolyte disorders,
particularly hypokalemia and hypophosphatemia. The latter association is most often seen in
alcoholic patients and those receiving hyperalimentation without phosphate supplementation. Cases
associated with hyperosmolality due to diabetic ketoacidosis or nonketotic hyperglycemia have also
been described, and hypophosphatemia may contribute to the risk of rhabdomyolysis in some of
these patients.
In both hypokalemic and hypophosphatemic rhabdomyolysis, the serum potassium and phosphate
levels may underestimate or mask the underlying total body depletion because of the release of
these electrolytes from intracellular stores due to the myonecrosis.
Other electrolyte disorders have been occasionally associated with rhabdomyolysis. These include
hypocalcemia; hyponatremia, mostly due to primary polydipsia and hypernatremia.

Endocrine disorders — Several endocrine disorders, including diabetes and thyroid diseases, have
been associated with rhabdomyolysis, sometimes in combination with other causes. As noted in the
previous section, both diabetic ketoacidosis and nonketotic hyperglycemia have been associated
with rhabdomyolysis due at least in part to phosphate depletion and other electrolyte imbalances
associated with this condition.

Hypothyroidism is frequently accompanied by myalgias and mild to moderate serum CK elevations. In

addition, overt rhabdomyolysis has been described, and concurrent statin therapy may be a risk
factor.

Rhabdomyolysis has also been infrequently described in several other endocrine disorders. These
include hyperthyroidism and pheochromocytoma.

Inflammatory myopathies — Rhabdomyolysis has only rarely been described in patients with the
inflammatory myopathies, dermatomyositis and polymyositis.

Miscellaneous — Rhabdomyolysis is associated with a number of other conditions in occasional

patients:
●Viral infections (mostly Epstein-Barr virus [EBV] and coxsackievirus).
●Status asthmaticus, in which muscle injury may be due to respiratory muscle overexertion and/or
generalized muscle hypoxia.
●The administration of non-depolarizing muscle blocking agents to critically ill intensive care unit
patients who require mechanical ventilation.
●The "capillary leak syndrome," a rare condition in which there are sudden, recurrent episodes of
markedly increased capillary permeability, causing shifts of fluid from the intravascular to interstitial
compartments. This shift leads to marked edema, limb swelling and possible compartment
syndrome, hypovolemia, hypotension, and, in some cases, rhabdomyolysis.
●Abrupt withdrawal of the gamma-aminobutyric acid (GABA) agonist baclofen, particularly if given
intrathecally, which can lead to severe muscle spasticity and muscle necrosis.

SUMMARY AND RECOMMENDATIONS

●The clinical manifestations and complications of rhabdomyolysis result from muscle cell death, with
the release of intracellular muscle constituents into the circulation.

The multiple potential causes of rhabdomyolysis can be broadly divided into three categories:
•Traumatic or muscle compression
•Nontraumatic exertional
•Nontraumatic nonexertional

●The most common clinical conditions associated with rhabdomyolysis include trauma,
immobilization, sepsis, and vascular and cardiac surgeries. Other common causes of rhabdomyolysis
include overexertion, and drugs and toxins such as lipid-lowering agents, alcohol, and cocaine. The
majority of patients have more than one etiologic factor, and less than 10 percent have no
identifiable cause. Rhabdomyolysis rarely occurs in association with an inflammatory myopathy.