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Allister Vale MD National Poisons Information Service

DOES URINE ALKALINIZATION PREVENT OR REDUCE THE SEVERITY OF RHABDOMYOLYSIS-INDUCED RENAL FAILURE IN POISONED PATIENTS?. Allister Vale MD National Poisons Information Service (Birmingham Unit) and West Midlands Poisons Unit City Hospital, Birmingham, UK. RHABDOMYOLYSIS. Aetiology Diagnosis

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Allister Vale MD National Poisons Information Service

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  1. DOES URINE ALKALINIZATION PREVENT OR REDUCE THE SEVERITY OF RHABDOMYOLYSIS-INDUCED RENAL FAILURE IN POISONED PATIENTS? Allister Vale MD National Poisons Information Service (Birmingham Unit) and West Midlands Poisons Unit City Hospital, Birmingham, UK

  2. RHABDOMYOLYSIS • Aetiology • Diagnosis • Complications • Pathogenesis of rhabdomyolysis-induced renal failure • Rationale for urine alkalinization and volume replacement • Experimental and clinical studies

  3. RHABDOMYOLYSIS: AETIOLOGY • Trauma e.g. crush injuries • Drug-or other chemical-induced  Therapeutic  Poisoning Primary caused by direct insult Secondary e.g. local compression as a result of coma, seizures

  4. RHABDOMYOLYSIS: DIAGNOSIS • Dissolution of striated muscle fibres, with leakage of muscle enzymes, myoglobin and other intracellular constituents • Creatine kinase activity > 5x normal (CK-MB fraction < 5%) 2-12 hours after precipitating cause • Creatine kinase activity may continue to rise > 24 hours

  5. RHABDOMYOLYSIS: DIAGNOSIS • Transient increase in serum myoglobin soon after onset of rhabdomyolysis • Visible myoglobinuria (tea or coca-cola coloured urine) • Myoglobinuria >250 mg/L (normal < 0.5 mg/L) in presence of normal renal function

  6. RHABDOMYOLYSIS: DIAGNOSIS • Absence of myoglobinuria does not exclude diagnosis • Positive urine dipstick for haem but no red cells on microscopic examination of urine

  7. RHABDOMYOLYSIS: COMPLICATIONS • Acute renal failure • Nerve damage (compartment syndrome) • Hyperkalaemia (fatal dysrhythmias) • Hypocalcaemia (calcium binding by damaged muscle proteins and phosphates)

  8. RHABDOMYOLYSIS: COMPLICATIONS • Increase in plasma urate concentration (> 750 μmol/L) • Increase in serum phosphate concentration (>2.5 mmol/L) • Increase in AST/ALT activities • Increase in lactic dehydrogenase and aldolase (specific for muscle) activities

  9. RHABDOMYOLYSIS-INDUCED RENAL FAILURE • 5-30 % of patients with rhabdomyolysis develop acute renal failure (Gabow et al, 1982; Ward, 1988) • Rhabdomyolysis accounts for 5-9 % of all cases of acute renal failure (Grossman et al, 1974; Thomas and Ibels, 1985)

  10. URINE ALKALINIZATION AND RHABDOMYOLYSIS-INDUCED RENAL FAILURE • Bywaters et al, 1944 recommended the use of "alkaline diuresis" to prevent renal failure in patients with crush syndrome (Bywaters, 1990) • Since then, urine alkalinization has often been incorporated into treatment regimens • Is this management rational?

  11. PATHOGENESIS OF RHABDOMYOLYSIS-INDUCED RENAL FAILURE • Tubular necrosis initiated by free-radical mediated lipid peroxidation • Renal vasoconstriction by several mechanisms • Tubular obstruction due to binding of free myoglobin to Tamm-Horsfall protein • Tubular obstruction due to hyperuricaemia • Compounded by hypovolaemia and aciduria

  12. PATHOGENESIS OF RHABDOMYOLYSIS-INDUCED RENAL FAILURE 1.Tubular necrosis initiated by free-radical mediated lipid peroxidation • This involves redox cycling between two oxidation states of myoglobin haem: Fe3+ (ferric) and Fe4+ (ferryl) (Moore et al, 1998;Holt and Moore, 2000)

  13. PATHOGENESIS OF RHABDOMYOLYSIS-INDUCED RENAL FAILURE 1.Tubular necrosis initiated by free-radical mediated lipid peroxidation • Ferryl (Fe4+) myoglobin can initiate lipid peroxidation • Its formation requires the presence of lipid hydroperoxides (LOOH)

  14. PATHOGENESIS OF RHABDOMYOLYSIS-INDUCED RENAL FAILURE 1.Tubular necrosis initiated by free-radical mediated lipid peroxidation • Ferryl (Fe4+) myoglobin reacts with lipids (LH) and lipid hydroperoxides (LOOH) to form lipid alkyl (L.) and lipid peroxyl (LOO.) radicals • These radicals cause progressive tubular damage

  15. Moore et al, 1998

  16. PATHOGENESIS OF RHABDOMYOLYSIS-INDUCED RENAL FAILURE 2. Renal vasoconstriction occursdue to: • Reduced circulating blood volume (hypovolaemia) • Activation of the sympathetic nervous system and renin-angiotensin system • Scavenging of the vasodilator, nitric oxide (NO), by myoglobin

  17. PATHOGENESIS OF RHABDOMYOLYSIS-INDUCED RENAL FAILURE 2. Renal vasoconstriction occursdue to: • Release of isoprostanes formed as a result of free radical damage to phospholipid membranes • 15-F2t isoprostaneand 15-E2t isoprostaneare potent vasoconstrictors

  18. PATHOGENESIS OF RHABDOMYOLYSIS-INDUCED RENAL FAILURE 3.Tubular obstruction occurs due toformation of tubular casts • Formed by binding of free myoglobin to Tamm-Horsfall protein (Uromodulin), most abundant renal glycoprotein Zager, 1989 4.Tubular obstruction occurs due to urate crystal deposition (local inflammation)

  19. RATIONALE FOR URINE ALKALINIZATION Experimentally, urine alkalinization: • Suppresses the reactivity of ferryl (Fe4+) myoglobin • Inhibits the cyclical formation of lipid peroxide radicals and limits lipid peroxidation, so reducing tubular damage Moore et al, 1998

  20. RATIONALE FOR URINE ALKALINIZATION Experimentally: • Urine alkalinisation reduces isoprostane release thereby lessening vasoconstriction • Consistent with this, in isolated perfused kidneys, myoglobin induces vasoconstriction at acid pHHeyman et al, 1997

  21. RATIONALE FOR URINE ALKALINIZATION Experimentally: • Urine alkalinization reduces binding of myoglobin to Tamm-Horsfall protein Zager, 1989 • Urine alkalinization increases urate solubility Hediger et al, 2005 • Acidosisexacerbates myoglobin toxicity in isolated perfused kidneys

  22. RATIONALE FOR URINE ALKALINIZATION Experimentally: • Acute or chronic exogenous acid loads prevent renal damagein vivo • This may reflect a beneficial effect of any volume replacement or solute loadHeyman et al, 1997

  23. RATIONALE FOR URINE ALKALINIZATION Experimentally: • Administrationof a neutral non-reabsorbed soluteprevented:  renal retention of myoglobin renal damageto the same extent as urine alkalinization (pH ≥8) Zager, 1989

  24. URINE ALKALINIZATION: CLINICAL STUDIES • There are no adequately controlled studies • Two of the three studies involve traumatic rhabdomyolysis • Concomitant administration of mannitol in all three studies

  25. URINE ALKALINIZATION: CLINICAL STUDIES Eneas et al,1979 • Retrospective review of 20 patients with myoglobinuria (13/20 poisoned with drugs and alcohol) • All patients received crystalloid solutions until volume deficits were corrected

  26. URINE ALKALINIZATION: CLINICAL STUDIES Eneas et al,1979 • 17/20 were administered: Sodium bicarbonate 100 mEq in 1L 5% dextrose and mannitol 25 g  Infused at a rate of 250 mL/hr for 4 hr

  27. URINE ALKALINIZATION: CLINICAL STUDIES Eneas et al,1979 • 2/20 patients received intermittent injections of mannitol and sodium bicarbonate • 1/20 patients received mannitol alone • Supplemental infusions given in many cases

  28. URINE ALKALINIZATION: CLINICAL STUDIES Eneas et al,1979 • 9/20 had increased urine output following treatment (Responders) • Treatment commenced < 48 hours in all cases (5/9 < 24 hours) after admission • None required dialysis and all survived

  29. URINE ALKALINIZATION: CLINICAL STUDIES Eneas et al,1979 • 11/20 no increase in urine output after treatment (Non-responders) • Treatment commenced < 48 hours in all cases (6/11 < 24 hours) after admission • 10/11 required dialysis; one patient died

  30. URINE ALKALINIZATION: CLINICAL STUDIES Eneas et al,1979 • The non-responders had significantly:  Higher peak creatine kinase activities  Higher serum phosphate concentrations  Higher haematocrit

  31. URINE ALKALINIZATION: CLINICAL STUDIES Eneas et al,1979 • "These results demonstrate that some patients with myoglobinuria will respond to infusion of mannitol and sodium bicarbonate" • "This treatment may be effective in altering the clinical course of myoglobinuric acute renal failure"

  32. URINE ALKALINIZATION: CLINICAL STUDIES Homsi et al, 1997 • Retrospective analysis of 24 patients admitted to an ITU with a diagnosis of traumatic rhabdomyolysis (CK >500 IU/L) • Muscle injury <48 hr previously • Serum [creatinine] < 272 µmol/L

  33. URINE ALKALINIZATION: CLINICAL STUDIES Homsi et al, 1997 • 15/24 patients were treated with:  saline 0.9% (mean 204 mL/hr over 60 hr),  mannitol (mean 56 g/day), sodium bicarbonate (mean 225 mEq/day for a mean of 4.7 days) • 9/24 patients received only saline (mean 206 mL/hr over 60 hr)

  34. URINE ALKALINIZATION: CLINICAL STUDIES Homsi et al, 1997 • The initial creatine kinase activity was significantly higher in the group receiving mannitol and sodium bicarbonate • 4/15 (27%) patients died in the mannitol and sodium bicarbonate group and 2/9 (22%) patients died in the saline only group (p > 0.05)

  35. URINE ALKALINIZATION: CLINICAL STUDIES Homsi et al, 1997 • The authors claimed that progression to established renal failure could be avoided with prophylactic treatment • Once saline expansion was provided, the addition of mannitol and bicarbonate was unnecessary

  36. URINE ALKALINIZATION: CLINICAL STUDIES Brown et al, 2004 • Retrospective review of 2,083 trauma admissions to an ICU of whom 85% had abnormal CK activities (CK >520 U/L) • Renal failure (plasma creatinine > 182 µmol/L) occurred in 10% of cases • CK activity of 5,000 u/L was the lowest activity associated with renal failure

  37. URINE ALKALINIZATION: CLINICAL STUDIES Brown et al, 2004 • 382/2,083 (18%) patients had CK activities > 5,000 IU/L • 228/382 patients did not receive mannitol/sodium bicarbonate • 154/382 patients received a bolus of mannitol 0.5 g/kg and sodium bicarbonate 100 mEq diluted in 1L 0.45 normal saline

  38. URINE ALKALINIZATION: CLINICAL STUDIES Brown et al, 2004 • This was followed by mannitol 0.1 g/kg/hr and sodium bicarbonate 100 mEq (diluted in 0.45 normal saline 1L) at a rate of 2-10 mL/kg/hr • There was no significant difference in incidence of renal failure (22% vs 18%; p=0.27), dialysis (7% vs 6%; p=0.37) or mortality (15% vs 18%; p=0.37) between groups

  39. URINE ALKALINIZATION: CLINICAL STUDIES Brown et al, 2004 • The administration of mannitol and sodium bicarbonate did not prevent renal failure, dialysis or mortality if CK >5,000 U/L • "The standard of administering sodium bicarbonate/mannitol to patients with post-traumatic rhabdomyolysis should be re-evaluated"

  40. URINE ALKALINIZATION AND RHABDOMYOLYSIS-INDUCED RENAL FAILURE Conclusions • Experimental data suggest:  Administration of sodium bicarbonate to produce urine alkalinization  Volume replacement  Can reduce the likelihood of rhabdomyolysis-induced renal failure

  41. URINE ALKALINIZATION AND RHABDOMYOLYSIS-INDUCED RENAL FAILURE Conclusions • Limited clinical data suggest that:  Early volume replacement is more important than urine alkalinization  In preventing rhabdomyolysis-induced renal failure

  42. URINE ALKALINIZATION AND RHABDOMYOLYSIS-INDUCED RENAL FAILURE Conclusions • There are no adequate data in poisoned patients • Rational basis for employing early volume replacement and probably urine alkalinisation • To reduce the severity or prevent the onset of rhabdomyolysis-induced renal failure

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