Rhabdomyolysis and Myoglobinuria

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Treatment of almost all medical conditions has been affected by the COVID-19 pandemic. NICE has issued rapid update guidelines in relation to many of these. This guidance is changing frequently. Please visit https://www.nice.org.uk/covid-19 to see if there is temporary guidance issued by NICE in relation to the management of this condition, which may vary from the information given below.

Rhabdomyolysis can be defined as a clinical syndrome associated with the breakdown of skeletal muscle fibres and myocyte cell membranes, leading to release of muscle contents into the circulation, resulting in multiple complications, including hyperkalaemia. It is a medical emergency and can lead to cardiac arrest if not promptly treated. Myoglobinuria is an early feature of rhabdomyolysis, but it may be cleared within a few hours despite other sequelae continuing.

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[1]. Damage to the myocyte membrane (eg, 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[2]. This leads to the muscle necrosis and the release of various substances into the circulation - eg, myoglobin, potassium, phosphate, creatine kinase (CK) and urate[3].

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[4].

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[5]. This process is facilitated by an acidotic environment and hypovolaemia[5]. 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.

Epidemiology[6]

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. .

Aetiology[4, 6]

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

  • Alcohol misuse.
  • Status epilepticus.
  • Over-exertion.
  • Trauma, burns and compartment syndromes (including major disasters (eg, earthquakes) where a significant amount of muscle injury is likely to occur).
  • Drugs[7]. For example: statins, erythromycin, corticosteroids, ecstasy[8], heroin, cocaine, atropine[9], ingestion of ethylene glycol and amfetamines (likely to cause muscle necrosis through a number of mechanisms such as, vasospasm).
  • Heatstroke.
  • Neuroleptic malignant syndrome.
  • Myositis and myocarditis.
  • Infections, such as influenza virus, Epstein-Barr virus (EBV), streptococcus, legionella and malaria[10].
  • Snake bites - eg, a bite from the sea snake[11].
  • Acute tumour lysis - massive tumour lysis which occurs after starting chemotherapy[12].
  • Hypothyroidism and hyperthyroidism .
  • Diabetic ketoacidosis.
  • Meyer-Betz disease - muscle pain, weakness and myoglobinuria following strenuous exercise[13].
  • Genetic disorders - eg, abnormalities of lipid metabolism (eg, carnitine deficiency) or abnormalities of carbohydrate metabolism (eg, phosphofructokinase deficiency).

Presentation[6]

Many features are nonspecific and therefore a high index of clinical suspicion is required - eg, 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 - eg, swollen and painful muscles, paraesthesia of limbs in compartment syndrome or muscle tenderness.
  • Nonspecific symptoms - eg, 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 rhabdomyolysis

  • This is based on clinical grounds - eg, 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 - eg, muscle biopsy and genetic testing in recurrent cases.

Complications

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

There may also be complications resulting from the original insult - eg, 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 of rhabdomyolysis[6]

  • 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 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 (eg, 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.

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Further reading and references

  • Aleckovic-Halilovic M, Pjanic M, Mesic E, et al; From quail to earthquakes and human conflict: a historical perspective of rhabdomyolysis. Clin Kidney J. 2020 May 2214(4):1088-1096. doi: 10.1093/ckj/sfaa075. eCollection 2021 Apr.

  • Anwar H, Al Lawati A; Adolescent COVID-19-Associated Fatal Rhabdomyolysis. J Prim Care Community Health. 2020 Jan-Dec11:2150132720985641. doi: 10.1177/2150132720985641.

  1. Braithwaite JP, Al Khalili Y; Physiology, Muscle Myocyte

  2. Del Re DP, Matsuda T, Zhai P, et al; Mst1 promotes cardiac myocyte apoptosis through phosphorylation and inhibition of Bcl-xL. Mol Cell. 2014 May 2254(4):639-50. doi: 10.1016/j.molcel.2014.04.007. Epub 2014 May 8.

  3. Beetham R; Biochemical investigation of suspected rhabdomyolysis. Ann Clin Biochem. 2000 Sep37 ( Pt 5):581-7.

  4. Keltz E, Khan FY, Mann G; Rhabdomyolysis. The role of diagnostic and prognostic factors. Muscles Ligaments Tendons J. 2014 Feb 243(4):303-12. eCollection 2013 Oct.

  5. Torres PA, Helmstetter JA, Kaye AM, et al; Rhabdomyolysis: pathogenesis, diagnosis, and treatment. Ochsner J. 2015 Spring15(1):58-69.

  6. Stanley M, Chippa V, Aeddula NR, et al; Rhabdomyolysis

  7. Valiyil R, Christopher-Stine L; Drug-related myopathies of which the clinician should be aware. Curr Rheumatol Rep. 2010 Jun12(3):213-20.

  8. Liechti ME, Kunz I, Kupferschmidt H; Acute medical problems due to Ecstasy use. Case-series of emergency department visits. Swiss Med Wkly. 2005 Oct 29135(43-44):652-7.

  9. Akhtar S, Rai MK, Dutta TK, et al; Atropine-induced rhabdomyolysis: an uncommon and potentially fatal adverse drug J Postgrad Med. 2010 Jan-Mar56(1):42-3.

  10. Mishra SK, Pati SS, Mahanta KC, et al; Rhabdomyolysis in falciparum malaria--a series of twelve cases (five children and seven adults. Trop Doct. 2010 Apr40(2):87-8.

  11. Kularatne SA, Hettiarachchi R, Dalpathadu J, et al; Enhydrina schistosa (Elapidae: Hydrophiinae) the most dangerous sea snake in Sri Lanka: three case studies of severe envenoming. Toxicon. 2014 Jan77:78-86. doi: 10.1016/j.toxicon.2013.10.031. Epub 2013 Nov 12.

  12. Adeyinka A, Bashir K; Tumor Lysis Syndrome

  13. Kasap B, Soylu A, Turkmen M, et al; An adolescent girl with Meyer-Betz syndrome. Clin Rheumatol. 2006 Nov25(6):904-6. doi: 10.1007/s10067-005-0091-3. Epub 2005 Nov 19.

  14. Camerino GM, Tarantino N, Canfora I, et al; Statin-Induced Myopathy: Translational Studies from Preclinical to Clinical Evidence. Int J Mol Sci. 2021 Feb 1922(4). pii: ijms22042070. doi: 10.3390/ijms22042070.

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