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

Rhabdomyolysis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00391911
• Other study ID #: RHABDO 2006
• Secondary ID: Health Canada Co
• Status: Completed
• Phase: Phase 2
• First received: October 24, 2006
• Last updated: March 1, 2012
• Start date: November 2006
• Est. completion date: December 2010

Study information

• Verified date: March 2012
• Source: Royal Alexandra Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Ethics Review CommitteeCanada: Health Canada
• Study type: Interventional

Clinical Trial 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

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

1. 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.

2. 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3
• Est. completion date: December 2010
• Est. primary completion date: December 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Randomization within 96 hours of medical or surgical diagnosis consistent with rhabdomyolysis

2. >18 yrs old

3. 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

4. Clinical suspicion of high probability of developing acute renal failure

5. Informed consent

Exclusion Criteria:

1. Allergic reaction to N-acetylcysteine.

2. Previous wish not to include dialysis as part of medical therapy.

3. 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.

4. 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

5. RIFLE category Loss - persistent ARF =complete loss of kidney function > 4 weeks

6. Pregnancy

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Rhabdomyolysis

Intervention

Drug:
• N-Acetylcysteine
Patients are assigned to either N-Acetylcysteine or placebo. Dose is weight based Placebo is normal saline or D5W

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
• 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
• 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

Locations

Country	Name	City	State
Canada	Royal Alexandra Hospital	Edmonton	Alberta
Saudi Arabia	King Fahad National Guard Hospital	Riyadh

Sponsors (3)

Lead Sponsor	Collaborator
Royal Alexandra Hospital	Gambro Renal Products, Inc., University of Alberta

Countries where clinical trial is conducted

Canada,  Saudi Arabia, 

References & Publications (6)

Abul-Ezz SR, Walker PD, Shah SV. Role of glutathione in an animal model of myoglobinuric acute renal failure. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9833-7. — View Citation

Birck R, Krzossok S, Markowetz F, Schnülle P, van der Woude FJ, Braun C. Acetylcysteine for prevention of contrast nephropathy: meta-analysis. Lancet. 2003 Aug 23;362(9384):598-603. — View Citation

Briguori C, Manganelli F, Scarpato P, Elia PP, Golia B, Riviezzo G, Lepore S, Librera M, Villari B, Colombo A, Ricciardelli B. Acetylcysteine and contrast agent-associated nephrotoxicity. J Am Coll Cardiol. 2002 Jul 17;40(2):298-303. — View Citation

Sochman J. N-acetylcysteine in acute cardiology: 10 years later: what do we know and what would we like to know?! J Am Coll Cardiol. 2002 May 1;39(9):1422-8. Review. — View Citation

Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med. 2000 Jul 20;343(3):180-4. — View Citation

Ward MM. Factors predictive of acute renal failure in rhabdomyolysis. Arch Intern Med. 1988 Jul;148(7):1553-7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Secondary outcome measures include all-cause ICU mortality and hospital mortality, ICU and hospital length of stay.		ICU admission until hospital discharge	No
Secondary	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	No