Study of N-Acetylcysteine (NAC) and Continuous Renal Replacement Therapy (CRRT) for the Treatment of Rhabdomyolysis

Rhabdomyolysis may be defined as a clinical or biochemical syndrome which may result from a large variety of diseases, trauma, or toxic insults to skeletal muscle. The damage to the integrity of the sarcolemma of skeletal muscle leads to the release of potentially toxic muscle cell components into the circulation, specifically myoglobin into the plasma.

The three main principals of therapy for myoglobinuric renal failure include 1) correction of hypovolemia/ renal ischemia, 2) increase the clearance of heme proteins from both the circulation and the kidneys, 3) attenuate the adverse effects of heme proteins on the proximal tubule epithelium. Consequently, therapy for rhabdomyolysis is limited to aggressive rehydration with Ringer's lactate or normal saline, forced diuresis with mannitol, and urinary alkalinization with intravenous bicarbonate.

Hypothesis

• The use of N-acetylcysteine (NAC) and continuous veno-venous hemo(dia)filtration (CRRT) early in the course of rhabdomyolysis as an adjunct to 'standard therapy' (rehydration, mannitol diuresis, systemic alkalinization) respectively decreases the nephrotoxicity and improves elimination of systemic myoglobin. Consequently both therapies independently prevent the deterioration of renal glomerular and tubular function and establishment of acute renal failure.
• There exists a positive interaction between the use of N-acetylcysteine and CRRT in the prevention of acute renal failure secondary to rhabdomyolysis.

Objectives Primary objective is to compare creatinine and myoglobin clearance as well as the glomerular filtration rate over the course of 192 hours in patients with rhabdomyolysis treated with NAC, early CRRT, both CRRT and NAC or neither of the two therapies. Secondary objectives are to : 1) Compare excretion of urine B-NAG, B1-macroglobulin, and microalbumin, as indicators of renal tubular and glomerular damage over the course of 192 hours in subjects with rhabdomyolysis treated with NAC, early CRRT, both therapies, or neither therapies 2) To compare ICU and hospital mortality and length of stay as well as the proportion of subjects with recovery of renal function at 14 and 28 days following randomization in patients with rhabdomyolysis treated with NAC, early CRRT, both therapies, or neither therapies 3) To determine clinical and biochemical risk factors for renal failure development in subjects with rhabdomyolysis.

Inclusion criteria

• Randomization within 96 hours of medical or surgical diagnosis consistent with rhabdomyolysis
• >18 yrs old
• Meeting any one of the following (estimated ARF risk >20% )

• CK >25,000 IU/L
• Injury Severity Score >16 and CK >5000 IU/L
• Age >55 and CK >5000 IU/L
• Clinical suspicion of high probability of developing acute renal failure
• Informed consent

Exclusion criteria

• Allergic reaction to N-acetylcysteine.
• Previous wish not to include dialysis as part of medical therapy.
• Clinical and biochemical indications for dialysis or ultrafiltration at the time of screening:

• Massive fluid overload unresponsive to diuretics and requiring ultrafiltration.
• Refractory acidosis with a persistent serum pH < 7.20 despite HCO3 therapy.
• Hyperkalemia with EKG changes necessitating dialysis for the removal of potassium.
• Pericardial friction rub from uremic pericarditis.
• RIFLE category Failure defined by one of:

• Increase serum creatinine x 3, GFR decrease 75% OR
• SCreat ≥ 4mg/dl (354 umol/L) (acute rise ≥ 0.5mg/dl [44 umol/L])
• UO < 0.3ml/kg/h x 24h or anuria x 12 hours
• RIFLE category Loss - persistent ARF =complete loss of kidney function > 4 weeks
• Pregnancy