A patient with polytrauma develops compartment syndrome with an ischaemic leg 24hrs into his admission. He undergoes revascularisation and fasciotomies, but develops rhabdomyolysis and acute kidney injury with a CK that peaks at over 100,000.

Is there a role for mannitol and bicarbonate in the management of his rhabdomyolysis and AKI?

Akshay Shah

What is rhabdomyolysis?
Rhabdomyolysis can be broadly defined as the breakdown or disintegration of striated muscle resulting in the leakage of intracellular muscle constituents into the circulation. The causes of rhabdomyolysis can be broadly divided into physical (trauma, compression, prolonged immobilization, vessel occlusion with subsequent reperfusion injury, excessive exercise, tetanus, electrical shock) and non-physical (drugs, toxins, metabolic syndromes, electrolyte disturbances).(1)

The pathophysiology of rhabdomyolysis involves damage to muscle cell membranes that leads to an influx of fluid, electrolytes, sodium and calcium. The cells swell and high intracytoplasmic calcium concentrations lead to several pathological processes, all of which culminate in cell death and leakage of large quantities of potassium, phosphate, myoglobin, CK and urate into the circulation.(2)

What is the mechanism of AKI in patients with rhabdomyolysis?

10 – 50% of patients with rhabdomyolysis develop acute kidney injury (AKI) and patients with severe injury who develop rhabdomyolysis-induced AKI have a mortality of approximately 20%.(1) The release of myoglobin from damaged myocytes is central to the pathophysiology of rhabdomyolysis-induced AKI. Myoglobin is normally present in small quantities in plasma and loosely bound to plasma globulin. Following rhabdomyolysis, these binding systems become overwhelmed and free plasma myoglobin levels rise and myoglobin is easily filtered through the glomerulus. Myoglobin is not reabsorbed in the renal tubules and increases in concentration as water is reabsorbed from the tubular filtrate resulting in dark, tea-coloured urine. Three key mechanisms have been identified(1,2 ):

• Decreased renal perfusion due to hypovolaemia secondary to the precipitating cause, activation of the renin-angiotensin-aldosterone axis, and renal vasoconstriction secondary to myoglobin.
• Cast formation with tubular obstruction occurs in patients with acidic urine and high tubular concentrations of myoglobin. Myoglobin reacts with Tamm-Horsfell protiens (THP) and precipitates forming casts.(2) These casts are thought to obstruct urinary flow and cause transtubular leakage of glomerular filtrate.
• The haem group of myoglobin may be a direct cause of lipid peroxidation, which subsequent tubular cytotoxicity.

The most sensitive indicator of myocyte injury in rhabdomyolysis is the plasma CK level which rises within 12 hours of muscle injury and peaks in 1-3 days. CK levels >5000 U.l-1 have been shown to be associated with an increased risk of developing AKI.(3)

General Management
The management of rhabdomyolysis involves resuscitation and stabilization whilst simultaneously treating the underlying cause, managing life-threatening complications such as hyperkalaemia and preventing AKI. Early aggressive fluid resuscitation is crucial in trying to prevent AKI. Several retrospective studies have shown that patients who developed AKI had a longer delay in receiving supportive therapy than those who did not develop AKI.(4) Fluid resuscitation should be targeted to achieve a urine output of 200 – 300 mls.hour-1 although no high level evidence exists to support this.

The rationale for mannitol and bicarbonate
Both these agents are often used in addition to normal saline for fluid resuscitation.
Mannitol is thought to work by promoting a diuresis that minimizes formation of myoglobin casts. It may also reduce blood viscosity and act as a renal venodilator. Mannitol is also a free-radical scavenger and therefore may protect the kidneys from oxidant injury. Other diuretics such as furosemide have also been used in attempts to initiate diuresis from oliguric/anuric renal failure.

As mentioned before, acidic urine promotes the formation of myoglobin casts. On the basis of this it can be postulated that alkalinization of the urine can potentially minimise the extent of kidney injury. This is commonly done with a continuous infusion of 1.26% sodium bicarbonate aiming for a urinary pH >7. In addition it can also be beneficial in treating hyperkalaemia and metabolic acidosis.

Is there any evidence that mannitol and bicarbonate reduce the incidence of AKI?
Majority of the evidence to answer this question comes from retrospective studies and there are no prospective randomized controlled trials as yet.

Brown et al.(3) reviewed their Trauma Registry and ICU database consisting of 1,771 trauma patients with elevated CK levels. 382 patients had a CK levels >5000 U.l-1 (High-CK group) of which 74 went on to develop AKI compared to 143 of 1,701 patients (8%) with CK levels <5000 U.l-1 (p<0.0001). In the ‘High CK’ group, 154 patients (40%) received bicarbonate/mannitol therapy, whereas 288 patients (60%) did not. There was no difference in the incidence of AKI, dialysis requirement or mortality between the two groups.

Another retrospective analysis(5) compared 15 patients who received normal saline, bicarbonate and mannitol to 9 patients who received normal saline alone to assess for any reduction in incidence of established AKI. The authors concluded that progression to established AKI can be prevented solely by volume expansion with normal saline and the addition of bicarbonate and mannitol offers no additional benefit. Other retrospective studies have echoed similar findings.(4)

A recent systematic review on preventing AKI following rhabdomyolysis found no Level 1-3 evidence that fluid therapy +/- mannitol +/- bicarbonate was superior to fluid therapy alone in preventing AKI in patients with rhabdomyolysis.(6) The authors also recommend that intravenous sodium bicarbonate should be administered only if necessary to correct systemic acidosis and mannitol should only be administered to maintain a desired urine output of >300 mls.hour-1 despite adequate fluid resuscitation – both Level D recommendations (expert opinion without critical appraisal or based on physiology or bench research). It is worth noting that of the 27 studies included in this review – 7 were level 2b studies (cohort studies or low-quality randomized clinical trials) and the rest were level 4 studies (case series or case-control or poor-quality cohort).

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Lessons learnt
AKI following rhabdomyolysis is common.
CK levels, especially if greater that >5000 U.l-1, are associated with an increased risk of developing AKI.
Probably the most influential intervention in trying to prevent AKI following rhabdomyolysis is aggressive, early fluid resuscitation as opposed to the type of fluid used.
No high level evidence exists to support to the use of fluid therapy with mannitol +/- bicarbonate over normal saline alone in trying to prevent AKI.

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References

1. Huerta-Alardin AL, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis – an overview for clinicians. Critical Care 2005; 9 (2): 158-69.
2. Hunter JD, Gregg K, Damani Z. Rhabdomyolysis. Continuing Education in Anaesthesia, Critical Care and Pain 2006; 6 (4): 141-43.
3. Brown CV, Rhee P, Chan L, Evans K, Demetriades D, Velmahos GC. Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference? The Journal of Trauma: Injury, Infection and Critical Care 2006; 56 (6): 1191-96.
4. Bosch X, Poch E, Grau JM. Rhabdomyolysis and Acute Kidney Injury. New England Journal of Medicine 2009; 361: 62-72.
5. Homsi E, Barriero M, Orlando J, Higa E. Prophylaxis of acute renal failure in patients with rhabdomyolysis. Renal Failure 1997; 19: 283-88.
6. Scharman EJ, Troutman WG. Prevention of Kidney Injury Following Rhabdomyolysis: A Systematic Review. The Annals of Pharmacotherapy 2013; 47: 90-105.