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

This study has been completed.
Sponsor:
Collaborators:
University of Alberta
Gambro Renal Products, Inc.
Information provided by (Responsible Party):
Demetrios J. Kutsogiannis, Royal Alexandra Hospital
ClinicalTrials.gov Identifier:
NCT00391911
First received: October 24, 2006
Last updated: March 1, 2012
Last verified: March 2012
  Purpose

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 Intervention Phase
Rhabdomyolysis
Drug: N-Acetylcysteine
Other: N-Acetylcystine and Non CRRT
Other: Placebo and CRRT
Other: Placebo and Non CRRT
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: A Randomized Factorial Trial of N-Acetylcysteine and Continuous Veno-Venous Hemo(Dia)Filtration for Rhabdomyolysis

Resource links provided by NLM:


Further study details as provided by Royal Alexandra Hospital:

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 [ Time Frame: day 1-28 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Secondary outcome measures include all-cause ICU mortality and hospital mortality, ICU and hospital length of stay. [ Time Frame: ICU admission until hospital discharge ] [ Designated as safety issue: No ]
  • Renal specific outcomes will include the development of Renal Failure, Loss or End Stage Kidney Disease based on the RIFLE classification system. [ Time Frame: at day 28 ] [ Designated as safety issue: No ]

Enrollment: 3
Study Start Date: November 2006
Study Completion Date: December 2010
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: NAC
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 Name: NAC only
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 Name: Placebo
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 Name: Placebo - no CRRT

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

  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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00391911

Locations
Canada, Alberta
Royal Alexandra Hospital
Edmonton, Alberta, Canada, T5H 3V9
Saudi Arabia
King Fahad National Guard Hospital
Riyadh, Saudi Arabia, 11426
Sponsors and Collaborators
Royal Alexandra Hospital
University of Alberta
Gambro Renal Products, Inc.
Investigators
Principal Investigator: Demetrios J. Kutsogiannis, M.D. University of Alberta
  More Information

Publications:
Responsible Party: Demetrios J. Kutsogiannis, MD MHS FRCPC, Royal Alexandra Hospital
ClinicalTrials.gov Identifier: NCT00391911     History of Changes
Other Study ID Numbers: RHABDO 2006, Health Canada Control # 108739
Study First Received: October 24, 2006
Last Updated: March 1, 2012
Health Authority: Canada: Ethics Review Committee
Canada: Health Canada

Keywords provided by Royal Alexandra Hospital:
Rhabdomyolysis
CRRT
N-Acetylcysteine

Additional relevant MeSH terms:
Rhabdomyolysis
Muscular Diseases
Musculoskeletal Diseases
Acetylcysteine
N-monoacetylcystine
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes

ClinicalTrials.gov processed this record on September 22, 2014