Rhabdomyolysis and myoglobinuria

What is rhabdomyolysis?¹

Rhabdomyolysis (lysis of skeletal muscle cells) is a clinical syndrome of acute or subacute localised or generalised myalgia and weakness, associated with a rapid rise in the serum creatine kinase (CK) level:

• In isolation, the clinical symptoms combined with a CK cut-off value of above 1000 IU/L or CK more than 5 times upper limit of normal represents mild rhabdomyolysis.

• Additional myoglobinuria and acute kidney injury indicate severe rhabdomyolysis.

This definition holds true after exclusion of elevated CK due to other aetiologies such as myocardial infarction, status epilepticus or chronic neuromuscular disease. The coexistence of rhabdomyolysis in these aetiologies is also a possibility with acute elevation of CK.

What is myoglobinuria?¹

Myoglobin is normally bound to plasma globulins, and has a rapid renal clearance with a half-life of 2-3 hours. A small quantity of filtered myoglobin (0.01-5%) is normally excreted with urine. The normal concentration of myoglobin in the serum is below 5.7nmol/L (100 μg/L) and in urine below 0.57nmol/L (10 μg/L).

After the occurrence of muscle damage, the circulating myoglobin levels exceed the plasma protein binding capacity, reach the glomeruli and are eventually excreted in the urine. Before the urine becomes discoloured (dirty-brown) by myoglobin, the level of myoglobin in the urine must exceed 57000 nmol/L (100 mg/ dl).

In rhabdomyolysis, the level of myoglobin in the serum increases within 1–3 hours, reaches its peak in 8–12 hours, and then returns to normal within 24 hours after the onset of the injury. The detection of myoglobin in the blood or urine is pathognomonic for the diagnosis of rhabdomyolysis, provided that it is made in the initial phases of the syndrome (within the first 24 hours). Myoglobinuria is detected in 17% of the patients with rhabdomyolysis.

Pathophysiology of rhabdomyolysis

Myocyte function under normal circumstances is maintained by adenosine triphosphate-dependent channels which ensure effective cell ion levels and play a role in calcium efflux from myocytes.² Damage to the myocyte membrane (for example, due to trauma or lack of energy for the cell membrane channels) causes an increase in the amount of calcium in the cell, which leads to apoptosis through various proteolytic enzymes.³ This leads to the muscle necrosis and the release of various substances into the circulation - for example, myoglobin, potassium, phosphate, creatine kinase (CK) and urate.⁴

The process is self-perpetuating in that damage to muscle cells releases further calcium which can then be taken up by the surrounding myocytes, causing further muscle necrosis and further leakage of ions and proteins into the circulation.⁵

Myoglobin is a skeletal muscle protein involved in metabolism, and myoglobinaemia usually occurs before a rise in creatine kinase (CK) in rhabdomyolysis. Any myoglobin that reaches the circulation will be filtered by the kidneys and can lead to acute kidney injury through either direct toxicity or precipitation, or both.⁶ This process is facilitated by an acidotic environment and hypovolaemia.⁶ Myoglobin can appear in the urine (myoglobinuria) causing 'tea-coloured' urine with a positive urine dipstick for blood. The latter can cause confusion with haematuria and haemoglobinuria.

How common is rhabdomyolysis? (Epidemiology)⁷

About 25,000 cases of rhabdomyolysis are reported each year in the USA. The prevalence of acute kidney injury in rhabdomyolysis is about 5-30%. It can occur at any age but most cases are seen in adults. It is more common in men. African-American race, obesity, and age over 60, are factors that demonstrate a higher incidence of rhabdomyolysis. In children, infection is the most common cause.

High incidences occur during calamities such as earthquakes and war due to the occurrence of crush syndrome. .

Causes of rhabdomyolysis (aetiology)^{5 7}

Any process which leads to muscle necrosis can lead to myoglobinuria and therefore an increased risk of rhabdomyolysis. For example:

Symptoms of rhabdomyolysis (presentation)⁷

Many features are nonspecific and therefore a high index of clinical suspicion is required - for example, elderly patients, history of trauma, history of a fall followed by long duration of lying on the floor.

• There may be features relating to the underlying cause - for example, swollen and painful muscles, paraesthesia of limbs in compartment syndrome or muscle tenderness.

• Nonspecific symptoms - for example, fever, malaise, anorexia, nausea and vomiting.

• Elderly patients may present with confusion, agitation and delirium.

• Patients may be anuric and clinically dehydrated.

• Myalgia and muscle weakness.

• 'Tea-coloured' urine may be present.

• Presenting features may also relate to the release of the intracellular electrolytes, which may be fatal:
  

  • Increased potassium ions - heart block, ventricular tachycardia, asystole.

  • Decreased calcium ions - may also be associated with arrhythmias and tetany.

• Disseminated intravascular coagulation.

Diagnosis of rhabdomyolysis⁷

• This is based on clinical grounds - for example, the supportive case history.

• CK levels are persistently raised.

• Urine - 'tea-coloured' and positive for blood on dipstick testing. Haemoglobinuria will look similar macroscopically and both will change the common urinalysis dipstick reagent even when there are no RBCs on the microscopy. They can be distinguished by using electrophoresis, spectrophotometry, or other techniques. There are also direct tests for myoglobinuria, such as immunoassays, but as the time course suggests myoglobinuria is present very early, their usefulness may be limited.

• Electrolytes - high potassium, low calcium, high phosphate.

• Bone scintigraphy, MRI, CT scan or ultrasound may be helpful in some cases.

• Investigations to delineate the underlying cause may be indicated - for example, muscle biopsy and genetic testing in recurrent cases.

Complications of rhabdomyolysis⁷

The complications of rhabdomyolysis are the cause of mortality and morbidity in these patients. These include:

• Hyperkalaemia causing arrhythmias and cardiac arrest.

• Hypocalcaemia (worsened by hyperphosphataemia).

• Hepatic abnormalities - but AST may be high representing muscle AST.

• Metabolic acidosis.

• Acute kidney injury from precipitation and obstruction of renal tubules by myoglobinuria and hypovolaemia.

• Disseminated intravascular coagulation.

• Pooling of fluid in the damaged muscle which adds to hypovolaemia and can lead to a compartment syndrome.

There may also be complications resulting from the original insult - for example, burns associated with sepsis. The presence of hyperkalaemia, metabolic acidosis and acute kidney injury are most likely to be associated with higher morbidity and mortality.

Treatment for rhabdomyolysis⁷

• Fluid rehydration - needs to be prompt; this is the most important aspect of treatment, as it will lead to less precipitation and toxicity of myoglobin at the kidneys and dilute nephrotoxins.

• Treat hyperkalaemia - calcium gluconate (if indicated) and dextrose-insulin infusions.

• Diuretics - loop diuretics have been used but their use is controversial and the benefits appear to be marginal.

• Alkaline diuresis - alkalinisation of the urine with bicarbonate can reduce the risk of acute kidney injury. Acetazolamide administration might prove useful, as it enhances urine alkalinisation.

• If renal function fails to improve, patients are at risk of acute tubular necrosis, in which case haemodialysis may be necessary.

• Hypocalcaemia and hyperphosphataemia need not be corrected unless dangerously low - they improve as CK falls.

• Treat the underlying cause if needed.

Statins and myotoxicity¹⁵

• Statins are widely used and their use has been associated with a reduction in mortality and morbidity in coronary heart disease and cerebrovascular disease.

• They are associated with muscle aches and pains and can cause myositis and rhabdomyolysis which can be fatal.

• Cerivastatin was the most frequently used statin with associated rhabdomyolysis and was subsequently withdrawn.

• The risk of rhabdomyolysis with statins is increased in the elderly, with use of interacting medications (for example, fibrates) and hypothyroidism.

• If patients on statins develop myositis (muscle pain, muscle tenderness and weakness) or myalgia then the statin should be stopped and CK checked urgently. If CK level is normal, consider changing to another member or restart at a lower dose with cautious monitoring. Presence of rhabdomyolysis will require termination of treatment, and management as described above.