Rhabdomyolysis refers to a clinical syndrome characterised by skeletal muscle necrosis.
Rhabdomyolysis is a condition that develops due to skeletal muscle necrosis and release of toxic intracellular contents including myoglobin and electrolytes. It is characterised by markedly elevated levels of creatinine kinase (CK).
Rhabdomyolysis is a potentially life-threatening condition and the full clinical syndrome is defined by evidence of myoglobinuria from muscle breakdown, and acute tubular necrosis (ATN) causing acute kidney injury (AKI).
It is a common condition in the adult population that occurs from a variety of causes.
The aetiology of rhabdomyolysis is very broad, but it is classically seen in crush injuries or secondary to medications.
The cause of rhabdomyolysis can broadly be divided into three groups:
The actual cause is usually suggested from the history and examination. For example, a patient presenting with a traumatic injury, an elderly patient presenting after a long period of immobilisation following a fall, or a patient recently started on a statin.
Crush injuries following a car accident or multi-trauma may lead to rhabdomyolysis.
Patients with crush injuries may be at risk of compartment syndrome. This often occurs during treatment of rhabdomyolysis as intravenous fluids cause the compartment to swell.
This commonly occurs in elderly patients who have been unable to move from a single position for many hours. This may occur following a fall and subsequent fracture or due to general frailty.
May be seen during a surgical operation that involves muscle compression or tourniquet use to restrict blood supply.
This refers to increased pressure in a fascial compartment that leads to restricted blood flow. The reduced blood supply damages surrounding tissue including muscle and nerves. It is associated with severe pain.
Compartment syndrome leading to muscle necrosis and subsequent rhabdomyolysis is commonly seen with lower extremity fractures (e.g. tibial fracture).
Causes direct damage to muscle. Examples include lightening strike or touching a powerline. Similar effects are seen with severe burns.
Rhabdomyolysis in this context can occur when there is an energy supply/demand mismatch to the muscles.
Most commonly occurs in untrained individuals who subsequently undergo marked physical exertion (e.g. marathon).
Often concurrent risk factors such as:
This refers to conditions that markedly increase, and typically sustain, muscle contraction.
These are inherited disorders of metabolisn. Typically due to a mutation in an enzyme that governs glycogenolysis, glycolysis or lipid metabolism.
Both high and low temperatures can cause rhabdomyolysis due to the loss of thermoregulation.
A wide variety of drugs, infections, toxins and electrolyte disturbances can induce rhabdomyolysis.
These can precipitate rhabdomyolysis by several mechanisms.
Many illicit drugs have been implicated in rhabdomyolysis by various mechanisms
A variety of viral, bacterial and other pathogens can cause rhabdomyolysis
Hypokalaemia and hypophosphataemia are the main disturbances that can lead to rhabdomyolysis
Injury to myocytes leads to ATP depletion, increased intracellular calcium and leakage of intracellular contents.
In rhabdomyolysis, regardless of aetiological mechanisms there is a final common pathway leading to muscle injury and leakage of intracellular content including CK and myoglobin.
Myocyte injury leads depletion of adenosine triphosphate (ATP), which is the the main cellular source of energy. This causes increased intracellular calcium due to dysfunction of the normal Na/K-ATPase and Ca2+ATPase pumps. This require ATP to function and maintain myocyte integrity.
High levels of intracellular, and mitochondrial, calcium causes a series of events that result in muscle necrosis including activation of proteases, muscle cell contractility, mitochondrial dysfunction and production of damaging reactive oxygen species (ROS). These events result in loss of myocyte integrity and leakage of intracellular content.
Myoglobin is an important protein within myocytes. Release into the circulation results in haptoglobin binding to prevent toxic effects. However, this buffer system is overburdened in massive muscle injury.The excess myoglobin is filtered through the kidneys where it causes damage.
Myoglobin damages the kidneys in three ways:
Collectively, this enhances renal tubular ATP loss leading to ATN and AKI. In severe cases, this may require dialysis. Risk of AKI is highest with higher levels of CK as this suggest more extensive muscle necrosis. CK levels bellow 15,000-20,000 are unlikely to cause AKI unless there is concurrent pathology (e.g. hypovolaemia, sepsis, acidosis).
Rhabdomyolysis is characterised by a triad of myalgia, muscle weakness and dark urine (due to myoglobin).
Presenting clinical features may be suggestive of the underlying cause. For example, a recent tibial fracture or crush injury. Clinical features of rhabdomyolysis itself are vague with generalised myalgia and muscle weakness.
The classic triad of myalgia, muscle weakness and dark urine is only seen in around 50% (much less common in children).
Serum CK is the principle investigation for the diagnosis of rhabdomyolysis.
Anyone at risk, or suspected of having, rhabdomyolysis should have a serum CK. This includes unexplained AKI, long period of immobilisation, crush injury, consistent electrolyte disturbances or muscle tenderness.
CK is an important marker of skeletal muscle breakdown and used to define rhabdomyolysis.
An elevation in CK > 5x the upper limit of normal is suggestive of rhabdomyolysis. However, the range of elevation is highly variable (1500 to >100,000 IU/L) and this usually depends on the extent of injury.
There are different isoforms of CK (three cytosolic and two mitochondrial) but in rhabdomyolysis the rise in CK is almost entirely from the skeletal muscle isofrom (CK-MM). The rise in CK usually occurs within 12 hours after muscle injury and peaks within 24-72 hours. When the muscle injury has resolved, CK falls over 3-5 days.
The key finding in the urine is identification of myoglobin, which causes it to change colour to the characteristic dark red/coca cola. Myoglobin is rapidly excreted from the urine and therefore myoglobinuria may only be identified in 50% of patients.
On urine dipstick, both haemoglobin and myoglobin are detected as ‘blood’. However, much larger quantities of blood are required to invoke a colour change. Under the microscope, features supportive of myoglobinuria would be a significant colour change with minimal red blood cells.
Approximately 15-50% of patients with rhabdomyolysis have evidence of AKI. The risk of AKI increases with higher concentrations of CK and in patients with risk factors such as sepsis, dehydration or acidosis. All patients with suspected rhabdomyolysis need an urgent renal function.
Fluid resuscitation is essential to prevent severe acute kidney injury.
Management of rhabdomyolysis should focus on treatment of the underlying cause, usually by removing the offending agent or trigger, and preventing severe renal injury.
In patients with suspected rhabdomyolysis it is critical to correction dehydration and prevent worsening ATN. This involves early, and aggressive, administration of intravenous fluids.
Intravenous fluids help in multiple ways:
There is no set administration of fluid volume or rate. Usually it is advised to give 1-2 litres over the first hour in severe cases at risk of AKI. However, this should be decided based on the suspected volume deficit, co-morbidities of the patients (e.g. heart failure, chronic liver disease) and severity of illness. It requires close monitoring of the patient with regular assessment of fluid balance.
Once CK levels are < 5000 IU/L, further fluid resuscitation purely for rhabdomyolysis is not required as the risk of AKI is so low.
In patients with severe AKI, dialysis may be needed. Indications for dialysis are the same as other causes of AKI:
Additional therapeutic options exist for the treatment of rhabdomyolysis, but this should be a senior or ITU-led decision as specific parameters are usually required prior to administration and some are not without risk.
Rhabdomyolysis can be a life-threatening condition.
Patients with rhabdomyolysis are at risk of dangerous electrolyte disturbances due to the release of intracellular content that has a high concentration of phosphate and potassium.
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