Author: Andrew Parfitt / Editor: Steve Fordham / Reviewer: Michael Perry / Codes: HAP19 / Published: 10/12/2018
Rhabdomyolysis is the breakdown of muscle fibres resulting in the release of muscle fibre cell contents into the bloodstream.
Presentations in the emergency department (ED) range from the well patient with an asymptomatic elevation of creatine kinase (CK) to a life threatening, multi system problem with massive CK rise, electrolyte disturbance, acute kidney injury and disseminated intravascular coagulation.
Rhabdomyolysis has many causes such as:
- Change in medication
- Drug abuse
- Genetic disorders
Definition – Creatine Kinase (CK)
Rhabdomyolysis literally means striated muscle dissolution or disintegration.
The syndrome is characterised by muscle breakdown and necrosis resulting in leakage of intracellular muscle constituents (Myoglobin, proteins and electrolytes) into the extracellular fluid and circulation.
Clinically, the most apt definition of rhabdomyolysis is an acute increase in serum concentration of creatine kinase (CK) to greater than five times the upper limit of normal (with myocardial infarction excluded).
The image shows discoloured ‘tea coloured’ urine, a clinical manifestation of rhabdomyolysis.
The cause of rhabdomyolysis is usually easily identified from the clinical history. There are many causes that fall into four main groups:
Medications and Toxic Substances
The following drugs and toxins cause direct myotoxicity, and increase the risk of rhabdomyolysis.
HMG CoA reductase inhibitors, i.e. statins
Indirect muscle damage is caused by drugs and toxins such as:
Traumatic causes include:
Immobilisation, e.g. following a fall or prolonged period of unconsciousness
Heat related causes of rhabdomyolysis relate to extremes of temperature and include:
Neuroleptic malignant syndrome
Ischaemic causes (Ischaemic limb injury)
Exertional related causes include:
Exertion of those untrained and unfit, e.g. participants of a fun run and military recruits
Pathological muscle exertion
Physical overexertion in Sickle Cell Disease
Amongst the infections that cause rhabdomyolysis are:
Inflammatory causes of rhabdomyolysis include:
Metabolic disorders that can lead to rhabdomyolysis include:
There are also genetic causes of rhabdomyolysis such as:
Duchenne muscular dystrophy
Lactate dehydrogenase deficiency
Phosphorylase kinase deficiency
Rhabdomyolysis is caused by muscle injury. Regardless of the mechanism, the muscle injury sets in motion a cascade of events that leads to leakage of extracellular calcium ions into the intracellular space.
The excess calcium ions lead to a pathological interaction of actin and myosin. This in turn activates cellular proteases and these cause destruction and necrosis of muscle.
The calcium ions released in the cytosol lead to cell permeability and capillary leakage. Membrane pumps such as Sodium Potassium ATPase (Na K ATPase) are damaged by toxins, exercise and muscle compression.
Large quantities of potassium, myoglobin, phosphate, CK and urate leak into the extracellular space and circulation. In addition, muscle cell hypoxia depletes levels of Adenosine Triphosphate (ATP).
This has an effect on the renal system and if the renal threshold is exceeded, myoglobin (a dark red protein) appears in the urine.
Exceeding the Renal Threshold
Once the renal threshold has been exceeded, myoglobin can then precipitate in the renal glomerular filtrate leading to tubular obstruction and renal damage.
Myoglobin injures tubules in 3 ways:
- Forming casts, along with uric acid, and causing direct tubule obstruction leading to sludging and acute tubular necrosis
- Pigment induced intrarenal vasoconstriction occurs decreasing glomerular filtration rate (GFR) by scavenging nitrous oxide from the microcirculation
- Direct haem protein induced cytotoxicity
The GFR is also reduced in rhabdomyolysis by increased sympathetic tone, decreased prostaglandin synthesis and increased levels of Anti-Diuretic Hormone (ADH).
Acute Kidney Injury
Serum myoglobin levels rise within hours of muscle damage but can return to normal within 1-6 hours if continuing muscle injury is not present.
The myoglogin sludging and obstruction can easily lead to complete blockage of tubules and acute kidney injury. This is usually reversible but its development increases the mortality risk.
Estimates of mortality in those rhabdomyolysis patients who develop acute kidney injury vary widely, with estimates ranging between 7% and 80%. This figure serves only to illustrate the importance of early detection and aggressive replacement therapy.
AKI dramatically increases the risk of mortality.
The clinical features of rhabdomyolysis fall into two categories, local and systemic.
- Muscle pain
- Dark urine (tea coloured urine)
- Nausea and vomiting
The common scenarios that are associated with rhabdomyolysis will be evident from the patients history or presentation.
In immobilisation, crush injury and illicit drug use consideration of the diagnosis is obvious.
Rhabdomyolysis must also be considered when there is history of recent medication changes, especially statins.
Remember that in non-traumatic rhabdomyolysis patients may only demonstrate muscle weakness, tenderness or stiffness.
Paralysis and severe weakness may suggest very extensive myonecrosis or coexistent potassium disturbances that can occur as AKI is impaired.
Do not dismiss as dehydration a patient who complains of darker than normal urine. Obtain a myoglobin dipstick.
In every case of suspected rhabdomyolysis a full blood count (FBC) and clotting test must be performed in addition to renal function and CK.
Full blood count and clotting test
A full blood count must be obtained in all cases of rhabdomyolysis:
- Disseminated Intravascular Coagulation (DIC) can occur and serial coagulation and platelet studies with prothrombin time (PT) are required
- Activated Partial Thromboplastin Time (APTT), fibrin degradation products and fibrinogen may need to be monitored to direct therapeutic intervention
Always obtain a full blood count and clotting test.
DIC and its attendant complications carry a poor prognosis.
In the ED, the muscle damage can be determined by imaging.
In the imaging investigations the considerations are that:
- MRI is more sensitive at detecting muscle damage than ultrasound or CT
- There are clear logistical problems in obtaining MRI
- Ultrasound shows decreased echogenicity compared with normal muscle imaging
In addition, other investigations are carried out to identify the following:
Myoglobinuria does not have to be present to make the diagnosis. Healthy patients that are well hydrated can clear myoglobin quickly with preserved renal function.
The initial clue to the presence of rhabdomyolysis may be a dipstick positive for blood but with no red cells present in the urine. When the dipstick and a requested urinalysis do not correspond, myoglobinuria and rhabdomyolysis are likely to be present.
Hyperkalaemia can be life threatening in rhabdomyolysis. Early measurement and frequent monitoring are necessary. The high level of serums potassium released by necrosed muscle are further elevated by the development of acute kidney injury and acidosis.
Serum Creatinine and Urea will be elevated and the ratio of creatinine is increased relative to urea as large amounts are released from the damaged muscle.
Calcium levels may be low in serum initially as calcium is deposited in necrotic muscle tissue. Symptoms of hypocalcaemia are, however, rare early in the course of the disease. This calcium is later released into the circulation and symptoms of hypercalcaemia may occur.
Clearly caution must be exercised if calcium is to be administered in cases where hyperkalaemia is a feature.
When muscle damage occurs myocytes release Phosphate which can bind with calcium forming calcium phosphate. This can exacerbate hypocalcaemia.
Muscle cells release purines that the liver can convert to urate. Fluid rehydration will facilitate excretion.
Other enzyme levels, such as lactate dehydrogenase, aldolase, and hydroxybutyric dehydrogenase may all be elevated but these are non-specific to the condition.
The condition leading to rhabdomyolysis must be managed. Particular caution must be directed towards compartment syndromes that are commonly present in patients with rhabdomyolysis.
The cornerstone of management is aggressive intravascular fluid rehydration. The sooner this commences the lower the risk of developing acute kidney injury. Ideally rehydration commences pre-hospitally at the same time as extrication.
In significant rhabdomyolysis it may be necessary to administer up to 10 litres of fluid.
No specific fluid algorithms exist and attention must be paid to strict fluid balance, urine output and serial monitoring of renal function and acid base status.
Rhabdomyolysis can lead to cardiac arrhythmias as a consequence of metabolic acidosis and hyperkalaemia. These disturbances are as important to correct as the arrhythmia itself.
There are two treatments which are unproven and are considered here, the administration of sodium bicarbonate and the use of mannitol.
Administration of sodium bicarbonate
Sodium bicarbonate has been long advocated as a treatment for rhabdomyolysis.
The theory was alkalinisation of the urine would clear an increasingly acid load delivered to the kidney.
There is no evidence to substantiate this. Furthermore large doses of bicarbonate may worsen the hypocalcaemia especially if hypovolaemia is corrected.
It is likely that large volume of crystalloid alone will produce a diuresis sufficient to alkalinise urine.
Use of mannitol
Mannitol has been suggested, and demonstrated in experimental models, to produce a diuresis that protects against acute kidney injury.
However robust evidence is lacking from the literature to confirm its efficacy.
Mannitol, like furosemide, is a renal vasodilator and osmotic diuretic and both have been used to attempt to initiate diuresis when the patient becomes anuric.
Again there is little evidence and retrospective studies suggest there is no additional benefit over fluid hydration.
The prognosis in rhabdomyolysis is related to coexistent illness and injury but the acute kidney injury is usually reversible.
- Calcium levels can be high or low during the development of the condition be wary of using calcium to treat hyperkalaemia
- The increase in serum potassium appears to be most marked during the first 12-36 hours after muscle injury. Treat potassium levels with caution remember the ECG changes are non-specific
- Fluid status must be monitored closely as patients are easily under or overfilled
- Early fluid resuscitation must be commenced as soon as possible and preferably pre-hospitally if possible
- Do not delay renal replacement therapy if other measures fail to correct the metabolic disturbances
- CK levels do not determine prognosis
- Skeletal muscle is able to tolerate warm ischaemia for up to 2 hours after this time damage is often irreversible
- HUERTA-ALARDIN AL, VARON J, MARIK PE. Bench-to-bedside review: Rhabdomyolysis An Overview for Clinicians. Critical care. 2005 Apr;9(2):158-69. Epub 2004 (Oct 20)
- BAGLEY WH, YANG H, SHAH KH. Rhabdomyolysis. Intern Emergency Medicine. 2007 Oct;2(3):210-8. Epub 2007 Oct 1
- MALINOSKI DJ, SLATER MS, MULLENS RJ. Crush Injury and Rhabdomyolysis. Critical Care Clinics. 2004 Jan;20(1):171-92
- SAURET JM, MARINIDES G, WANG GK. Rhabdomyolysis. American Family Physician. 2002 Mar 1;65(5):907-12
- LANE R, PHILLIPS M. Rhabdomyolysis. BMJ. 2003 Jul 19;327(7407):115-6
- MELLI G, CHAUDHRY V, CORNBLATH DR. Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine (Baltimore). 2005 Nov;84(6):377-85