Traumatic injury is a risk factor for acute kidney injury (AKI). The cause of AKI is likely multifactorial and may include renal hypoperfusion and renal hypoxia secondary to hypovolemic shock and/or increased abdominal pressure, rhabdomyolysis and direct nephrotoxic effects of therapy including general anesthesia (Harris et al., 2017). The osmotic diuretic, mannitol, has been used both in the prevention, and the treatment of AKI. It has been used peri-operatively to prevent the development of AKI and in the management of AKI secondary to traumatic rhabdomyolysis (Sharman et al., 2013; Yang et al., 2014). However, mannitol itself has nephrotoxic potential and therefore the benefits of its use should be considered in light of its potential to cause adverse effects (Perez-Perez et al., 2002; Fang et al., 2010)
To explore the utility of mannitol in the management of AKI secondary to traumatic rhabdomyolysis, let’s consider a case.
A 1 year-old male neutered Chihuahua presented to referral center 12 hours post a dog bite to the lumbar and quadricep muscles. The dog has undergone initial fluid resuscitation which included crystalloid and blood products, and the dog is normotensive (systolic blood pressure of 120mmHg). Significant blood work findings revealed the following: creatinine kinase 122,000U/L (RI 67-446 IU/L), ALT 351 (RI 19.8-124 U/L), urea 52.37mg/dL (RI 8.68-28.8umol/L), creatinine 2.54mg/dL (RI 0.23-1.63mg/dL), potassium 6.2mEq/L (RI 3.6-5.6mEq/L) phosphate 10.5mg/dL (RI 2.48-4.95mg/dL), total calcium 7.06mg/dL (8.72-11.16mg/dL), glucose 98mmol/L (RI 90-216mg/dL). Pigmenturia was evident and a red/brown supernatant was visualised when the urine was spun down (Figure 1). Glucosuria, proteinuria and granular casts were noted on urine analysis and sediment examination. Urine output over the following few hours was between 0.5-0.8ml/kg/hr. The dog required general anesthesia for limb amputation. Should mannitol therapy be considered in this case?
This dog has clinical findings indicative of rhabdomyolysis secondary to traumatic crush injury; history of severe trauma, marked elevation in CK and associated myoglobinuria (Knockel, 1982). The dog also has evidence of AKI; azotemia with evidence of tubular injury -renal casts and proteinuria and glucosuria in the face of normoglycemia (IRIS, 2013). Acute kidney injury is a known complication of rhabdomyolysis and is reported to occur in up to 50% people with rhabdomyolysis (Melli, 2005). The pathogenesis of rhabdomyolysis-induced acute kidney injury is thought to be multifactorial and includes intrarenal vasoconstriction and renal ischemia, myoglobin induced tubular injury and tubular obstruction. Renal vasoconstriction occurs secondary to activation of the sympathetic and renin-angiotensin systems due intravascular volume depletion secondary to fluid sequestration within damaged muscles, alongside local renal vasodilation secondary to nitric oxide scavenging by free radicals (Zager, 1989). Myoglobin is an iron-containing (ferrous oxide Fe2+) and oxygen-binding heme protein that is freely filtered by the renal glomeruli (Klocke, 1982). In acidic urine myoglobin interacts with the urinary glycoprotein Tamm Horsfall protein and undergoes precipitation in the renal tubules which can cause tubular obstruction and decreased glomerular filtration rate (Zager, 1989). Under acidic conditions myoglobin can also cause direct nephrotoxic effects; the reduction of molecular oxygen and subsequent formation of oxygen reactive species promotes the oxidation of ferrous oxide (Fe2+) to ferric oxide (Fe3+) which generates hydroxyl free radicals (Figure 2). Hydroxyl radicals are thought to be the critical mediators of renal tubular damage (Zager, 1992).
Mannitol, an osmotic diuretic has potential renal-protective effects. Proposed mechanisms of renoprotection include increase in renal blood flow secondary to an increase in intra-vascular blood volume and reduction in blood viscosity, reduction of renal tubular swelling, free radical scavenging and maintenance of tubular flow (Hilliday et al., 2009; Karajala et al., 2009). Mannitol has been shown to promote renal vasodilation and therefore is proposed as a therapy to prevent peri-operative AKI (Johnston et al., 1918; Bragadottir et al., 2012). However, systemic reviews and meta-analyses have failed to show a clinical benefit of mannitol for the prevention of AKI (Yang et al., 2014; Waskowski et al., 2019). An experimental study of healthy dogs given either a bolus of 0.5g/kg or continuous rate infusion of 1 mg/kg/min diluted mannitol after an initial bolus found mannitol to cause only a mild increase in GFR and urine output and this was not different from that, which occurred secondary to infusion of an equivalent volume of hypotonic fluid, further questioning the clinical benefit of mannitol in the management of AKI (Segev et al., 2019).
Mannitol is proposed to be particularly beneficial for the treatment of rhabdomyolysis-induced AKI. The maintenance of tubular flow with mannitol administration is proposed to reduce the risk of tubular obstruction by myoglobin casts and its free radical scavenging may prevent hydroxyl radical tubular injury as well as reducing intra-abdominal pressure secondary to skeletal muscle oedema (Better, 1990). Treatment with bicarbonate therapy and mannitol has been shown to increase urine output and improve renal function in people with myoglobinuria (Eneas et al., 1979). However, the beneficial effect of mannitol beyond promoting diuresis has been questioned (Brown et al., 2004) and no randomized controlled trials support the evidence-based use of mannitol.
When considering mannitol therapy in the prevention and management of AKI, it is important to be aware of potential risks associated with mannitol administration. Prolonged and high dose mannitol therapy has the potential to cause AKI secondary to renal vasoconstriction and tubular injury (Viswswaran et al., 1997; Shi et al., 2018). An experimental study of intravenous administration of 2 g/kg/day mannitol to dogs for 2-3 weeks caused renal tubular vacuolization (Stuart et al., 1970). Hypertonic hyponatremia and seizures have been reported in a dog given 6g/kg mannitol in a 24 hour period (Clabots et al., 2019). Due to the risks associated with mannitol therapy in people it is recommended monitor the plasma osmolality and osmol gap when administering mannitol. Discontinuation of therapy is recommended if the osmol gap rises above 55 mOsm/kg or if adequate diuresis is not achieved (Visweswaran et al., 1997).
In light of the significant sequestration of water in damaged muscles, the mainstay of therapy for the management of rhabdomyolysis induced AKI is early aggressive fluid repletion to support renal perfusion. In those cases that progress to anuric AKI with associated hyperkalemia, acidosis and volume overload, renal replacement therapy is recommended (Bosch et al., 2009). Due to its size, conventional hemodialysis does not effectively remove myoglobin; however, convective clearance methods may have a role in myoglobin elimination (Bosch et al., 2009). Hemodialysis may however, be useful in the management of the electrolyte and acid base disturbances associated with traumatic rhabdomyolysis and AKI secondary to crush injury (Chen et al., 2018).
In this case mannitol therapy has no additional advantage over diuretic therapy with the potential to cause tubular injury. The risk of tubular injury is somewhat exacerbated in light of the prevailing oliguria despite normotension. Mannitol would therefore not be recommended in this case.
The Bottom Line
Mannitol may have a role in promoting diuresis and maintaining tubular flow in patients at risk of AKI. However, careful attention should be given to the dose to mannitol given over time and its use should be avoided in anuric patients.
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