With regards to rhabdomyolysis in the ICU patient:
a) List five causes. (20% marks)
b) What are the important features in the history and clinical examination, and what specific laboratory investigations would you request? (30% marks)
c) Outline the management. (50% marks) 

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College answer

a)

Causes (2 marks; 0.5 marks per cause. No additional marks for multiple causes under same heading. Examples of medications/infections etc. required for marks.)

1.    Trauma - Crush injury, electrocution, extensive burns, compartment syndrome
2.    Exertional - Prolonged exertion, refractory seizures, severe agitation
3.    Medications - corticosteroids, statins, antipsychotics, neuroleptics
4.    Toxins - methanol, ethylene glycol, barbiturates, amphetamine, MDMA, CO poisoning, cyanide, snake, spider envenomation
5.    Body temperature changes - Heat stroke, malignant hyperthermia, malignant neuroleptic syndrome, hypothermia
6.    Infections - Influenza A and B, coxsackievirus, Epstein–Barr virus, primary HIV, legionella
7.    Rarer causes – electrolyte disturbances (hypoPO4, K, Ca, Na), endocrine (HONK etc.)
 

b)

Review history to identify risk factors or causes. .History of pre-existing renal injury or conditions that might predispose to acute kidney injury or conditions that might predispose to it.

History of Trauma, seizures, immobility, drug exposure, muscle pain, dark coloured urine,

Clinical examination/assessment: Muscle compartment swelling, tenderness, weakness, fever, myoglobinuria, peripheral perfusion

Laboratory Tests

Elevated CK

Renal dysfunction Cr – elevated; urea:Cr ratio may be decreased

electrolyte abnormalities (hyperkalemia, hypocalcemia, hyperphosphataemia, hyperuricemia, lactic acidosis). Elevated AG – due to phosphates and organic acids released from muscle

Further investigations will depend on need to further identify underlying cause e.g. urine drug screen, blood alcohol, glucose, TFTs etc

c)

Management (5 marks)

Stop further skeletal muscle damage

Interventions will vary depending on cause; e.g. discontinuation of medications, control agitation, treat infection, correct metabolic abnormalities, cool or warm, surgery etc

Rapidly identify life or limb-threatening complications

If compartment syndrome needs orthopaedic consultation – monitor pressures +/- decompressive fasciotomy

Treat any significant electrolyte abnormalities, e.g. hyperkalaemia or hypocalcaemia Prevent acute renal failure

Early and aggressive volume resuscitation with 0.9% N/saline. Dilutes nephrotoxins and promotes renal tubule flow. Urinary alkalization, forced mannitol diuresis and frusemide have been described; (candidates were not given marks for mentioning these or penalised for omitting them)

Renal replacement therapy: for usual traditional indications (hyperkalaemia, metabolic acidosis, volume overload and uraemia). Not advocated for myoglobin removal

Examiners Comments:

Candidates are reminded to read the question carefully; some answers included investigations such as CT scans and exploratory surgery, which are not “laboratory tests”.

Well answered overall.

Discussion

a)

Though the question asked for only five causes, this table was compiled so as to accommodate a range of wacky differentials. It is pleasing to see the examiners tip their hand- they specify that only five classes of causes would yield full marks, i.e. one would score poorly if one just gave five different kinds of embolic phenomena. 

Causes of Rhabdomyolysis

Vascular causes

  • Embolic phenomena
  • Vascular insufficiency

Infectious causes

  • Bacterial causes
    • S.pyogenes or C.perfringens infections
    • Necrotising fasciitis
  • Viral causes:
    • Influenza A and B
    • HIV
    • Cioxsackie virus
    • Epstein-Barr virus
    • Echovirus
    • Cytomegalovirus
    • Adenovirus
    • Herpes simplex
    • Parainfluenza
    • Varicella zoster

Neoplastic causes

  • Paraneoplastic cause of autoimmune myositis

Drug-related causes

  • Antipsychotics (neuroleptic-malignant syndrome)
  • SSRIs (serotonin syndrome)
  • Statins
  • Alcohol
  • Cocaine
  • MDMA
  • Volatile anaesthetics (malignant hyperthermia)
  • Propofol infusion syndrome
  • Imatinib, sunatinib (tyrosine kinase inhibitors)
  • Daptomycin (Hohenegger, 2012)
  • Envenomation by spiders, hornets, bees and snakes

Idiopathic causes

  • Extreme exertion, eg. strenuous exercise
  • Seizures

Congenital causes

  • Congenital abnormalities of glycogenesis, lipid metabolism, mitochondrial disorders, and G6PD deficiency

Autoimmune causes

  • Myositis and dermatomyositis

Traumatic causes

  • Crush injury
  • Prolonged immobilisation, eg. for prolonged surgery as in Question 5 from the first paper of 2017
  • Heat stroke
  • Hypothermia (eg. frostbite)
  • Compartment syndrome
  • Trauma to arteries supplying the extremities

Endocrine causes

  • HONK
  • DKA
  • Hypokalemia

b)

"History and clinical examination, and what specific laboratory investigations" allocates only 10% of the mark to each aspect, which means one cannot afford to dwell too long on this answer.

  • Historical features: Trauma, seizures, immobility, drug exposure
  • Symptoms:- muscle pain, decreased mobility, weakness, tea-coloured urine
  • Signs: Muscle compartment swelling, tenderness, weakness, fever
  • Biochemistry: Elevated CK, AST, LDH, urinary myoglobin; renal dysfunction and electrolyte abnormalities (particularly hyperkalemia, hypocalcemia, hyperphosphataemia, hyperuricemia, lactic acidosis). DIC may also result.

c)

  • Commence IV fluids within 6 hours - as early as possible
  • Aim for a urine output greater than 300ml/hr
  • Manage or prevent compartment syndrome (invasive compartment pressure monitoring or fasciotomy)
  • Use of sodium bicarbonate is only indicated to correct systemic acidosis. There is no evidence for any benefit in rhabdomyolysis-induced AKI except for some uncontrolled case series, which does not stop people from recommending it anyway. It appears in the 2010 college answer, which pre-dates this 2013 meta-analysis. The savvy trainee seeking to remain in the good books with examiners who use forced alkaline diuresis will want to mention this therapy in their answer, with the caveat that it is may not be helpful, but is also probably not harmful.
  • Free radical scavengers have been recommended historically, without much evidence to support their use (allopurinol, pentoxifylline)
  • Avoid replacing calcium: it may exacerbate muscle injury (Chatzizisis et al, in 2008, believed that it would "intensify the accumulation of calcium in the muscular tissue and consequently reinforce the mechanism of rhabdomyolysis")
  • Use of mannitol is only indicated if urine output >300ml/hr cannot be maintained 
  • Dialysis may be commenced to improve the removal of myoglobin, if a high-permeability membrane filter is available. Even if it is not, standard CVVHDF seems to decrease the risk of renal injury.

References

The best shortcut for the time-poor exam candidate is this UpToDate article.

Vanholder, Raymond, et al. "Rhabdomyolysis." Journal of the American Society of Nephrology 11.8 (2000): 1553-1561.

Bosch, Xavier, Esteban Poch, and Josep M. Grau. "Rhabdomyolysis and acute kidney injury." New England Journal of Medicine 361.1 (2009): 62-72.

Shapiro, Mark L., Anthony Baldea, and Fred A. Luchette. "Rhabdomyolysis in the intensive care unit." Journal of intensive care medicine 27.6 (2012): 335-342.

Holt, S., and K. Moore. "Pathogenesis and treatment of renal dysfunction in rhabdomyolysis." Intensive care medicine 27.5 (2001): 803-811.

Bosch, Xavier, Esteban Poch, and Josep M. Grau. "Rhabdomyolysis and acute kidney injury." New England Journal of Medicine 361.1 (2009): 62-72.

Allison, Ronald C., and D. Lawrence Bedsole. "The other medical causes of rhabdomyolysis." The American journal of the medical sciences 326.2 (2003): 79-88.

Brown, Carlos VR, et al. "Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference?." Journal of Trauma-Injury, Infection, and Critical Care 56.6 (2004): 1191-1196.

Scharman, Elizabeth J., and William G. Troutman. "Prevention of kidney injury following rhabdomyolysis: a systematic review." Annals of Pharmacotherapy47.1 (2013): 90-105.

Sorrentino, Sajoscha A., et al. "High permeability dialysis membrane allows effective removal of myoglobin in acute kidney injury resulting from rhabdomyolysis." Critical care medicine 39.1 (2011): 184-186.

Tang, Wanxin, et al. "Renal protective effects of early continuous venovenous hemofiltration in rhabdomyolysis: improved renal mitochondrial dysfunction and inhibited apoptosis." Artificial organs 37.4 (2013): 390-400.

Ioannidis, Konstantinos, et al. "Safety and effectiveness of the combination acetazolamide and bicarbonates to induce alkaline diuresis in patients with rhabdomyolysis." European Journal of Hospital Pharmacy 22.6 (2015): 328-332.

Hohenegger, Martin. "Drug induced rhabdomyolysis." Current opinion in pharmacology 12.3 (2012): 335-339.