Rhabdomyolysis

Normally, adenosine triphosphate dependent channels manage the functioning of our muscle cells (myocytes). These channels make sure that there are enough ion levels in the cells and also allow the release of calcium from the myocytes.

In case of damage to the membrane covering the myocyte (for reasons such as trauma), calcium levels inside the cells can rise. This increase may lead to cell death due to the release of enzymes that destroy the protein content of the cells.

As a consequence, muscle death or necrosis occurs that releases numerous substances into the blood. These substances include myoglobin, phosphate, potassium, creatinine kinase and uric acid. 

This process is capable of perpetuating itself as the calcium that is released from the damaged myocytes is taken up by the surrounding normal myocytes, resulting in further muscle death and release of more of these substances (myoglobin, phosphate, potassium, creatinine kinase and uric acid) in the blood. 

Myoglobin is a protein present in the skeletal muscles. This protein is important for metabolism. When myoglobin is released into the blood by the process described above, it is filtered by the kidneys and can result in acute damage to the kidneys due to accumulation of these substances or direct toxicity or both.

The presence of myoglobin in the urine (myoglobinuria) causes the urine to appear tea-coloured and also gives a positive urine dipstick test for blood. Therefore, it causes confusion between the presence of blood and myoglobin in the urine.

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Patients who develop rhabdomyolysis usually present with symptoms that are nonspecific. The patient profile that is commonly observed is an elderly patient with a history of trauma or fall followed by a long period when he or she is lying on the floor. 

• Clinical features due to the underlying cause: Patients usually have swollen muscles that are painful. Tingling sensation and tenderness of muscles are common features of compartment syndrome (when internal bleeding or swelling causes pressure to build up in different parts of the body like the legs or abdomen.
• Fever: Can be of varying duration and severity
• Malaise and fatigue
• Anorexia or decreased appetite
• Nausea and vomiting
• Old patients who are suffering from rhabdomyolysis usually present with confusion, agitation and delirium (an acute confusional state). 
• Inability to pass urine may be seen (anuria)
• Clinical signs of dehydration; for example, dry oral mucosa and dry skin
• Myalgia (muscle pain)
• Muscle weakness
• Urine may appear to be tea-coloured. This is due to the presence of myoglobin in the urine. 
• Clinical features that may occur as a result of the release of electrolytes like potassium from the cells. This phenomenon may be dangerous.
• Increase in blood potassium levels may result in heart block, asystole (no electrical activity in the heart) and ventricular tachycardia (abnormal electrical activity of the lower chambers of the heart, that is, ventricles). 
• A decrease in blood calcium levels may be associated with abnormalities in heart rhythms (arrhythmias) and hypocalcemic tetany (a contraction of muscles of the hands causing carpal spasm with the extension of joints of the fingers and feet along with a tingling sensation around the mouth and the limbs). 
• Disseminated intravascular coagulation: It is a condition in which numerous blood clots form all over the body, resulting in blocked blood vessels. Patients may experience chest pain, leg pain, shortness of breath and issues while moving body parts. Patients may also suffer from bleeding due to abnormal levels of clotting factors and platelets.

Anything that results in muscle death can cause the release of myoglobin in urine and increase the risk of developing rhabdomyolysis. These risk factors may include the following:

• Excessive alcohol abuse
• Prolonged epileptic seizures (status epilepticus)
• Activities that result in excessive exertion
• Traumatic injuries
• Burns
• Compartment syndrome: This issue may occur more commonly due to natural disasters. Compartment syndrome occurs due to excessive pressure and compression of the affected muscles.
• Certain drugs may result in rhabdomyolysis. For example, erythromycin (an antibiotic), statins (used to keep blood cholesterol in check), corticosteroids, heroin, ecstasy, cocaine, atropine, ethylene glycol and amphetamines that result in muscular death due to spasm of blood vessels supplying the muscles (known as vasospasm).
• Heatstroke
• Infections: Viral infections such as influenza (flu), Epstein-Barr virus disease and bacterial infections caused by bacteria such as Streptococcus and Legionella. 
• Myositis or inflammation of muscles
• Snake bites, especially sea snake bite very commonly results in rhabdomyolysis 
• Chemotherapy or tumour destruction (lysis) may result in rhabdomyolysis
• Thyroid diseases: Low or high thyroid levels may cause rhabdomyolysis
• Complications of diabetes such as diabetic ketoacidosis
• Genetic diseases, especially anomalies of lipid metabolism (example, carnitine deficiency) or abnormalities of carbohydrate metabolism. 
• Meyer-Betz disease: Patients with this disease would experience muscle pain and myoglobinuria after excessive exertion.

Rhabdomyolysis is usually diagnosed based on medical history, examination and supportive investigations. Patients present with a typical history of fall or injury followed by being on the floor for hours. The following examinations and tests may also be done to diagnose rhabdomyolysis:

• Urine
  • Patients may have tea-coloured urine.
  • Dipstick urine testing (a basic diagnostic tool to understand pathological problems through the patient’s urine) in patients suffering from rhabdomyolysis is positive for blood.
  • Presence of haemoglobin in urine looks macroscopically similar. Both rhabdomyolysis and haemoglobinuria change the urinalysis dipstick reagent, even in cases when there are actually no red blood cells on microscopic examination. Therefore, they can be differentiated using techniques like electrophoresis (based on the mobility of charged particles in a fluid in the presence of an electric field), spectrophotometry (part of spectroscopy that involves the measurement of radiant energy being transmitted or reflected by a certain body based on the function of wavelength).
  • Some direct tests may also be useful in detecting the presence of myoglobin in the urine; for example, immunoassays (a procedure that involves the detection and measurement of certain proteins, antigens and antibodies). But the issue with the detection of myoglobinuria is that it is only present for a limited amount of time. Hence, it is not considered to be very useful and convenient. 
• Creatinine kinase level measurement: The level of creatine kinase in the blood of a patient with rhabdomyolysis would be considerably higher than normal. It may be increased to by a factor of tens-of-thousands. According to some studies, the diagnosis for rhabdomyolysis should be made after an increase of creatine kinase to at least five times the baseline.
• Electrolyte levels: Patients with rhabdomyolysis are expected to have raised potassium (hyperkalemia), low calcium (hypocalcemia) and high phosphate levels in the blood (hyperphosphatemia).
• Investigations to detect the underlying cause may also be performed. These tests may include a muscle biopsy and performing genetic testing in patients who have a history of recurring rhabdomyolysis.

Patients of rhabdomyolysis might suffer from numerous complications that may result in morbidity and mortality in these patients. These complications might include the following: 

• Increased potassium levels: This is termed as hyperkalemia. This results in numerous issues with the heart such as abnormal heart rhythms called arrhythmias and cardiac arrest (sudden loss of blood flow due to the inability of the heart to pump blood effectively). 
• Low blood calcium levels: Patients might experience a tingling sensation in their limbs (paresthesia), muscular spasms, muscular cramping, circumoral numbness (numbness around the mouth), seizures or convulsions and hypocalcemic tetany (a contraction of the muscles of the hands, causing carpal spasm with the extension of joints of the fingers and feet along with a tingling sensation around the mouth and the limbs).
• Liver problems: Patients might undergo a liver function test which may show an increased level of aspartate aminotransferase (AST).   
• Metabolic acidosis: Metabolic acidosis is a major electrolyte disorder occurring due to an imbalance in the acid-base balance of the body. Metabolic acidosis has three main causes which may include excessive acid production, loss of bicarbonate and failure of the kidney to excrete the acid from the body. 
• Acute kidney injury: Kidney damage may occur acutely due to an accumulation and obstruction of the tubules in kidneys by myoglobin.  
• Disseminated intravascular coagulation: The formation of a number of blood clots all over the body could result in blocked blood vessels. Chest pain, leg pain, shortness of breath and issues with moving body parts are common signs of this condition. Some patients could also suffer from bleeding because of problems with the level of clotting factors and platelets in their blood.
• Hypovolemia: Fluid accumulation in the damaged muscle which further results in low fluid volume in the body (hypovolemia). 
• Other problems: Complications may result from the underlying cause; for example, burns leading to sepsis—a dangerous condition that occurs as a response of the body to an infection.

Patients who have hyperkalemia, metabolic acidosis and acute kidney failure are most commonly associated with a higher rate of morbidity and mortality.

The treatment of patients with rhabdomyolysis may involve:

• Fluid therapy: Rehydration is the first line and most appropriate treatment for patients with rhabdomyolysis. It helps to reduce the accumulation and toxicity of myoglobin in the kidneys. It also dilutes the toxins.
• Treatment of hyperkalemia: Calcium gluconate is extremely important in patients with hyperkalemia, to avoid the heart problems associated with high blood potassium level. Dextrose-insulin infusion may also be indicated. 
• Diuretic treatment: Studies may recommend the use of diuretics like mannitol. Other diuretic agents have not demonstrated any improvement in kidney function. Diuretic treatment should not be given to patients till adequate amounts of fluids have been given as diuretics may worsen dehydration. 
• Alkaline diuresis: Your doctor may recommend the use of bicarbonate to alkalize the urine to reduce the risk of acute kidney failure.
• Haemodialysis: In patients whose kidney function does not improve after initial treatment and who are at risk of acute tubular death (necrosis), dialysis may be indicated.
• Managing mineral levels: Low calcium levels and raised phosphate levels may not require immediate correction. Their levels may improve spontaneously as creatine kinase reduces.
• Treating underlying conditions: Treatment of the underlying cause of rhabdomyolysis

Statins are commonly used drugs that result in low levels of morbidity and mortality in patients with ischemic heart disease (like coronary artery disease) and cerebrovascular diseases such as stroke.

• Statins are associated with myalgia and muscular pains and may result in fatal complications like myositis and rhabdomyolysis. 
• The statin that was most commonly linked with rhabdomyolysis was Cerivastatin. This drug is not used any more. 
• The risk of developing rhabdomyolysis in patients who take statins may increase in old patients who have thyroid disorders and take other medications that interact with statins like fibrates. 
• In patients who are on statins and develop myalgia or myositis, the drug should be stopped and blood tests like blood creatine kinase levels should be done immediately. If the creatine kinase comes out normal, the drug should be changed or restarted at a lower dose.