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

Complications

Pathogenesis of rhabdomyolysis-induced renal failure

Rationale for urine alkalinization and volume replacement

Experimental and clinical studies

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

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


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


Absence of myoglobinuria does not exclude diagnosis

Positive urine dipstick for haem but no red cells on microscopic examination of urine

RHABDOMYOLYSIS: COMPLICATIONS

Acute renal failure

Nerve damage (compartment syndrome)

Hyperkalaemia (fatal dysrhythmias)

Hypocalcaemia (calcium binding by damaged muscle proteins and phosphates)

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

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)

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?

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


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)



Ferryl (Fe4+) myoglobin can initiate lipid peroxidation

Its formation requires the presence of lipid hydroperoxides (LOOH)



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

Moore et al, 1998

LOO.LOOH

LH

O2

Lipid peroxidation

Mb3+

Mb2+

LOOH

LOO.

Lipid peroxidation

LO.

LOOH

OLOO.

O2

Lipid peroxidation ROOH

L.

OLOOH

IsoprostanesIsoprostanes

Isoprostanes

Mb4+


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


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


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)

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


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


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


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


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

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


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


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


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


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


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


Eneas et al,1979

The non-responders had significantly:

Higher peak creatine kinase activities

Higher serum phosphate concentrations

Higher haematocrit


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"


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


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)


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)


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


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


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


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


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"


Conclusions

Experimental data suggest:

Administration of sodium bicarbonate to produce urine alkalinization

Volume replacement

Can reduce the likelihood of 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


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

allister vale md national poisons information service

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