DOES URINE ALKALINIZATION PREVENT OR REDUCE THE SEVERITY OF RHABDOMYOLYSIS-INDUCED RENAL FAILURE IN POISONED PATIENTS?

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

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RHABDOMYOLYSIS

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

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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

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RHABDOMYOLYSIS DIAGNOSIS

• Dissolution of striated muscle fibres, with
  leakage of muscle enzymes, myoglobin and other
  intracellular constituents
• Creatine kinase activity gt 5x normal (CK-MB
  fraction lt 5) 2-12 hours after precipitating
  cause
• Creatine kinase activity may continue to rise gt
  24 hours

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RHABDOMYOLYSIS DIAGNOSIS

• Transient increase in serum myoglobin soon after
  onset of rhabdomyolysis
• Visible myoglobinuria (tea or coca-cola coloured
  urine)
• Myoglobinuria gt250 mg/L (normal lt 0.5 mg/L) in
  presence of normal renal function

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RHABDOMYOLYSIS DIAGNOSIS

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

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RHABDOMYOLYSIS COMPLICATIONS

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

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RHABDOMYOLYSIS COMPLICATIONS

• Increase in plasma urate concentration (gt
  750 µmol/L)
• Increase in serum phosphate concentration (gt2.5
  mmol/L)
• Increase in AST/ALT activities
• Increase in lactic dehydrogenase and aldolase
  (specific for muscle) activities

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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)

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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?

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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

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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)

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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)

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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

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Moore et al, 1998
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PATHOGENESIS OF RHABDOMYOLYSIS-INDUCED RENAL
FAILURE

• 2. Renal vasoconstriction occurs due 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

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PATHOGENESIS OF RHABDOMYOLYSIS-INDUCED RENAL
FAILURE

• 2. Renal vasoconstriction occurs due to
• Release of isoprostanes formed as a result of
  free radical damage to phospholipid membranes
• 15-F2t isoprostane and 15-E2t isoprostane are
  potent vasoconstrictors

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PATHOGENESIS OF RHABDOMYOLYSIS-INDUCED RENAL
FAILURE

• 3.Tubular obstruction occurs due to formation 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)

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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

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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 pH
  Heyman et al, 1997

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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
• Acidosis exacerbates myoglobin toxicity in
  isolated perfused kidneys

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RATIONALE FOR URINE ALKALINIZATION

• Experimentally
• Acute or chronic exogenous acid loads prevent
  renal damage in vivo
  
• This may reflect a beneficial effect of any
  volume replacement or solute load
  
  Heyman et al, 1997

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RATIONALE FOR URINE ALKALINIZATION

• Experimentally
• Administration of a neutral non-reabsorbed solute
  prevented
• ? renal retention of myoglobin
• ? renal damage to the same extent as urine
  alkalinization (pH 8)
  
  Zager, 1989

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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

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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

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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

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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

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URINE ALKALINIZATION CLINICAL STUDIES

• Eneas et al,1979
• 9/20 had increased urine output following
  treatment (Responders)
• Treatment commenced lt 48 hours in all cases (5/9
  lt 24 hours) after admission
• None required dialysis and all survived

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URINE ALKALINIZATION CLINICAL STUDIES

• Eneas et al,1979
• 11/20 no increase in urine output after treatment
  (Non-responders)
• Treatment commenced lt 48 hours in all cases (6/11
  lt 24 hours) after admission
• 10/11 required dialysis one patient died

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URINE ALKALINIZATION CLINICAL STUDIES

• Eneas et al,1979
• The non-responders had significantly
• ? Higher peak creatine kinase activities
  
• ? Higher serum phosphate concentrations
• ? Higher haematocrit

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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"

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URINE ALKALINIZATION CLINICAL STUDIES

• Homsi et al, 1997
• Retrospective analysis of 24 patients admitted to
  an ITU with a diagnosis of traumatic
  rhabdomyolysis (CK gt500 IU/L)
• Muscle injury lt48 hr previously
• Serum creatinine lt 272 µmol/L

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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)

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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 gt 0.05)

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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

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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 gt520 U/L)
• Renal failure (plasma creatinine gt 182 µmol/L)
  occurred in 10 of cases
• CK activity of 5,000 u/L was the lowest activity
  associated with renal failure

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URINE ALKALINIZATION CLINICAL STUDIES

• Brown et al, 2004
• 382/2,083 (18) patients had CK activities gt
  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

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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 p0.27), dialysis
  (7 vs 6 p0.37) or mortality (15 vs 18
  p0.37) between groups

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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 gt5,000 U/L
• "The standard of administering sodium
  bicarbonate/mannitol to patients with
  post-traumatic rhabdomyolysis should be
  re-evaluated"

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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

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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

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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