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

Sponsor

Royal Alexandra Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT00391911

Collaborator

University of Alberta (Other), Gambro Renal Products, Inc. (Industry)

Enrollment

Locations

Arms

Duration (Months)

1.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Rhabdomyolysis has many causes including trauma, muscle crush injuries, lack of blood supply to an arm or leg, burns, seizures, drugs and hereditary disorders. Rhabdomyolysis causes the breakdown of muscle cells and the release of a molecule called myoglobin. Myoglobin is very harmful to the kidneys and can lead to kidney failure.

Continuous dialysis has been shown to remove the myoglobin molecule from the blood in patients with rhabdomyolysis. N-Acetylcysteine (NAC) has been used in patients receiving contrast dye for x-rays and has shown less worsening of kidney function compared to patients not receiving NAC.

Early and aggressive treatment of patients with rhabdomyolysis with standard therapy, continuous dialysis and a drug called N-acetylcysteine (NAC) may prevent the development of acute kidney failure. Patients who develop kidney failure from this disorder are often critically ill and have a much higher chance of not surviving than those who do not develop kidney failure.

The purpose of this study is to determine if the use of NAC and Continuous Veno-Venous hemo(dia)filtration (CRRT)early in the course of rhabdomyolysis (in addition to standard therapy)decreases the chance of developing acute renal failure

Condition or Disease	Intervention/Treatment	Phase
Rhabdomyolysis	Drug: N-Acetylcysteine Other: N-Acetylcystine and Non CRRT Other: Placebo and CRRT Other: Placebo and Non CRRT	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

3 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

A Randomized Factorial Trial of N-Acetylcysteine and Continuous Veno-Venous Hemo(Dia)Filtration for Rhabdomyolysis

Study Start Date :

Nov 1, 2006

Actual Primary Completion Date :

Dec 1, 2010

Actual Study Completion Date :

Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: NAC and CRRT N-Acetylcysteine and CRRT Patients are assigned to N-Acetylcysteine and CRRT. The N-Acetylcysteine is blinded to everyone except pharmacy. The CRRT is open label,	Drug: N-Acetylcysteine Patients are assigned to either N-Acetylcysteine or placebo. Dose is weight based Placebo is normal saline or D5W Other Names: NAC
Other: NAC and non CRRT Patients are assigned to N-Acetylcysteine and CRRT. The N-Acetylcysteine is blinded to everyone except pharmacy. The CRRT is open label as would be impossible to blind	Other: N-Acetylcystine and Non CRRT Patients are assigned to N-Acetylcysteine and CRRT. The N-Acetylcysteine is blinded to everyone except pharmacy. The CRRT is open label as would be impossible to blind Other Names: NAC only
Other: Placebo and CRRT Patients are assigned to placebo treatment and CRRT. The N-Acetylcysteine/placebo is blinded to everyone except pharmacy. The CRRT is open label.	Other: Placebo and CRRT Patients are assigned to Placebo and CRRT. The N-Acetylcysteine/Placebo is blinded to everyone except pharmacy. The CRRT is open label Other Names: Placebo
Other: Placebo and Non CRRT Patients are assigned to Placebo and non-CRRT. This is the standard of care arm. The N-Acetylcysteine/placebo is blinded to everyone except pharmacy. The CRRT/non CRRT is open label as would be impossible to blind	Other: Placebo and Non CRRT Patients are assigned to Placebo and non-CRRT. The N-Acetylcysteine/placebo is blinded to everyone except pharmacy. The CRRT/non CRRT is open label as would be impossible to blind Other Names: Placebo - no CRRT

Outcome Measures

Primary Outcome Measures

The primary outcome measures include serial measurements of markers of renal glomerular function and damage and markers of renal tubular function and damage [day 1-28]

Secondary Outcome Measures

Secondary outcome measures include all-cause ICU mortality and hospital mortality, ICU and hospital length of stay. [ICU admission until hospital discharge]
Renal specific outcomes will include the development of Renal Failure, Loss or End Stage Kidney Disease based on the RIFLE classification system. [at day 28]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.