Rhabdomyolysis

As mentioned in the last section on Crush Syndrome, the term rhabdomyolysis originates from the Greek words rhabdos meaning rod, myo meaning muscle and lusis meaning loosening, dissolving, or dissolution.  Rhabdomyolysis is depicted by skeletal muscle damage that leads to the leakage of cytoplasmic contents from ruptured skeletal muscle cells (myofibers/myocytes).  Leaked cellular components include proteins such as: myoglobin, myosin, actin, troponin, tropomyosin, and creatine kinase as well as cellular electrolytes (e.g., sodium, calcium, potassium and phosphate) that spill into the interstitial spaces.  Many of these cellular components are then taken up by blood and lymph vessels giving rise to myoglobinemia, elevated serum creatine kinase levels and electrolyte imbalances.  High levels of serum myoglobin result in renal tubular obstruction, causing tubular injury and renal ischemia giving rise to Acute Kidney Injury (AKI), which can lead to renal failure if not treated (or prevented).  In short, rhabdomyolysis, if not treated, can lead to acute kidney injury.

Pathogenesis – Rhabdomyolysis

Significant damage to skeletal muscles that causes myofibers to rupture is termed rhabdomyolysis.  Myofibers can be damaged by shear or blunt force, extreme temperatures, hypoxia, infection, toxins, various chemicals, free radicals, lack of ATP, pH imbalances, and electrolyte imbalances, as well as dehydration.  As muscle cells die, their spilled contents fill interstitial spaces, creating a hypertonic environment that draws in more water from nearby blood vessels, increasing the swelling in the affected area.  As noted above, leaked myofiber components include proteins (e.g., myoglobin, myosin, actin, troponin, tropomyosin, and creatine kinase) and cellular electrolytes (e.g., sodium, calcium, potassium and phosphate).  Some components (e.g., K⁺, Ca⁺⁺, and ATP) released by dead muscle cells, which induce the immune response.  Macrophages and mast cells migrate to the area and release pro-inflammatory cytokines (e.g., histamine, prostaglandins, bradykinin) which stimulates vasodilation and increased capillary permeability.  This effect on blood vessels leads to the leaking of plasma exudate, swelling, hyperemia (causing warmth and redness and influx of activated white blood cells and platelets).

At the same time, white blood cells (WBCs) such as macrophages, mast cells and neutrophils are involved in phagocytosing debris, any infecting agents, and/or toxins, as well as stimulating the repair of tissue.  If necrosis is significant and swelling continues to develop within a contained fascial compartment(s), this edema can lead to rising intracompartmental pressure and compartment syndrome.

Compartment syndrome is detailed in the previous section, and if not treated, can lead to ischemia within the compartment, causing further death of muscle cells and other cells in the region (e.g., sensory and motor neurons).  Compartment syndrome is depicted by the progressive development of the 5Ps of symptoms of acute muscle necrosis (severe pain, pallor, pulselessness, pallor, paresthesia and paralysis).

Pain is caused by the triggering of nociceptors by chemicals released from both damaged cells and activated WBCs, as well as by increases in swelling and pressure.   Increased intracompartmental pressure leads to pinching off of blood vessels resulting in pulselessness, pallor, paresthesia (sensory dysfunction depicted by numbness, tingling or complete loss of feeling), partial/full paralysis).

Increases in intracompartmental pressure pinch off blood vessels causing ischemia and hypoxia as well as pallor and pulselessness (particularly distal to the injury).

Reduced blood flow (and therefore oxygen and nutrients) within the compartment is detrimental to the functioning of cells that require a constant supply.  Sensory neuron dysfunction gives rise to paresthesias such as tingling, numbness and eventual absences of sensation (e.g., as noted in 2-point discrimination tests).  Motor neuron dysfunction gives rise to partial/full temporary/permanent flaccid paralysis of the muscle involved.

Rhabdomyolysis in addition to potentially causing muscle and neuron infarctions can also cause Acute Kidney Injury and renal failure.  As myofibers die and burst, spilled myoglobin enters the bloodstream, leading to myoglobinemia.  High levels of serum myoglobin can accumulate in renal glomeruli, causing damage and the release of nephrotoxic breakdown products, including the production of free radicals.  The glomeruli become leaky and the ensuing damage to nephron tubules leads to the formation of obstructive urinary casts and renal vasoconstriction and hypoxia which increase the amount of renal injury.  This is a serious condition as acute kidney injury potentially leads to oliguria, acidosis (due to failure to excrete excess H⁺ ions), as well as uremia and uricemia (due to failure to excrete excess nitrogenous wastes, urea and uric acid respectively).  Conditions of acidosis, elevated blood urea nitrogen levels and hyperuricemia can lead to cardiac arrest, loss of consciousness, and brain damage.

Rhabdomyolysis can also give rise to cardiac arrhythmias due to the electrolyte imbalances and acidosis.

Risk Factors – Rhabdomyolysis

Rhabdomyolysis is caused by severe skeletal muscle damage that occurs in a short period of time.  Instances that can cause significant acute skeletal muscle damage resulting in rhabdomyolysis include trauma, muscle compression, compartment syndrome, bone fracture, thromboemboli, burns, heat stroke, dehydration, some viral, bacterial and fungal infections, electrolyte imbalances, drug/alcohol abuse, vigorous physical exertion, seizures, hyperthermia/hypothermia, and inherited disorders.

Signs and Symptoms – Rhabdomyolysis

The cellular damage within the affected muscle induces the inflammatory response, leading to pain, swelling, redness, warmth and possibly loss of function (depending on the extent of the injury).

Typically individuals report myalgia (muscle pain), muscle weakness and may have noticed dark tea-coloured urine.  Myoglobin is a heme pigment containing protein which gives rise to dark coloured urine (i.e., myoglobinuria) when myoglobinemia and damaged nephrons are present.

The affected muscle may appear swollen and signs of compartment syndrome may be present.  When untreated compartment syndrome can lead to acute ischemic necrosis which can give rise to the 5Ps (pain, pulselessness distal to affected site, pallor, paresthesia, and paralysis) with a 6th P being pressure (or feeling fullness or swelling).

Elevated tonometer (or needle manometer) readings will be present if compartment syndrome has developed.  See compartment syndrome section for more details.

Elevated serum creatine kinase, hyperkalemia, hyperphosphatemia, hyperuricemia, and hypoalbuminemia may occur with electrolyte disturbances leading to increases in swelling of the affected muscle as well as cardiac arrhythmias, nausea, vomiting, confusion, and coma.

If third-spacing is significant, hypovolemia will occur coupled with hypotension and reduced cardiac output.  This condition can lead to hypovolemic shock, oliguria, and reflex tachycardia.

Shock is defined as insufficient blood flow that can lead to organ dysfunction and failure and is often accompanied by the following signs and symptoms:  tachycardia, pallor, delayed capillary refill, nausea, vomiting, diaphoresis, anxiety, confusion, loss of consciousness and signs of organ-failure.

Diagnostic Tools – Rhabdomyolysis

Blood tests can be used to track the levels of serum creatine kinase, myoglobin, electrolytes (K+, Ca++, PO4), pH as well as blood urea nitrogen (BUN) levels, in addition to other factors (e.g., complete blood count, platelets) that can be used to rule out other issues.

Urine tests will reveal the levels of myoglobin and other factors (proteinuria, hematuria) indicative of kidney function.

Blood urea nitrogen (BUN) and serum creatinine tests can also provide information on kidney function.

Imaging can be used to assess the extent of damage, bleeding and/or inflammation.

Electrocardiography (ECG) readings will help to indicate whether cardiac conduction has been affected by any electrolyte imbalances that may have occurred (e.g., hyperkalemia, hyperphosphatemia and calcium imbalances).

Intracompartmental pressure measurements using a tonometer or needle manometer will be taken if the individual is at risk of compartment syndrome.

Causative factors that include genetic, autoimmune, and infection can be tested for using immunoassays, muscle biopsies, and PCR tests.

Treatment – Rhabdomyolysis

Fluid resuscitation, possibly intravenous (IV) fluids with sodium bicarbonate buffer will be used to help correct electrolyte and blood pH levels as well as rehydrate (if dehydration has occurred, and may be a contributing factor to the rhabdomyolysis and/or acute kidney injury that is occurring).

Decompression therapy (e.g., fasciotomy) may be required if compartment syndrome has developed.

Hemodialysis may be used if there is a risk of acute kidney injury, to help remove excess myoglobin, H+, K+, PO4, urea and other excess electrolytes, metabolites, and waste products.

Possibly lifestyle-related modifications may be required if lifestyle was a contributing factor (e.g., intense vigorous exercise, dehydration, drug/alcohol abuse)

Potential Complication – Rhabdomyolysis

Potential Complications include:

Compartment Syndrome can arise as a result of significant inflammation and accumulation of inflammatory exudate and/or blood within a deep fascia compartment that is housing the affected muscle.  The layer of deep fascia is composed of dense irregular connective tissue that does not expand readily, meaning that added fluid volume will increase intracompartmental pressure, leading to the pinching off of veins, capillaries and eventually arteries, causing ischemia.  If not treated, compartment syndrome can lead to ischemic necrosis causing further muscle destruction, in addition to dysfunction and death of neurons and other cells within the compartment. Compartment syndrome can lead to renal failure, muscle infarction, neuron dysfunction, Volkmann’s contractures, renal failure, cardiac arrhythmias, shock, organ-failure, and cardiac arrest.  This is discussed in detail in the Compartment Syndrome section as well.

Disseminated Intravascular Coagulation (DIC) can be triggered when severe damage to the body occurs that triggers a widespread immune response.  The activation of platelets can become excessive leading to the formation of blood clots that block blood vessels throughout the body causing ischemia, hypoxia and potentially failure of multiple organs.  This is coupled with the fact that the excessive clotting of platelets can leave a person susceptible to hemorrhaging as the number of available platelets and clotting factors diminishes.  DIC can be a fatal condition if not prevented/treated promptly.

Summary

• Myoglobin spilling out of damaged skeletal muscle can damage the kidneys.
• Rhabdomyolysis: rapid breakdown of skeletal muscle, releasing myoglobin into extracellular space and bloodstream.
• Kidneys filter blood, accumulating myoglobin in nephrons, leading to myoglobin entering urine.
• Occurs in crush injury, burn injury, compression injury, drug overdoses.
• Myoglobin gums up nephrons, causing inflammation and necrosis, leading to acute renal failure.
• High blood potassium levels from muscle rupture can cause cardiac arrhythmias.
• Symptoms: pain, weakness, swelling, dark urine (myoglobinuria), difficulty urinating, hyperkalemia, low blood pressure, nausea, vomiting, confusion, coma.
• Elevated levels of creatine kinase, potassium, phosphates, and myoglobin in blood.
• Treatment: fasciotomy for compartment syndrome, hydration, bicarbonate for metabolic acidosis, maintain urinary flow, dialysis.
• Risks: kidney damage due to myoglobin breakdown products, kidneys unable to regenerate.