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

March 1, 2012 updated by: Demetrios J. Kutsogiannis, Royal Alexandra Hospital

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

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

3

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Alberta
      • Edmonton, Alberta, Canada, T5H 3V9
        • Royal Alexandra Hospital
  • Saudi Arabia
      • Riyadh, Saudi Arabia, 11426
        • King Fahad National Guard Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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
day 1-28

Secondary Outcome Measures

Outcome Measure
Time Frame
Secondary outcome measures include all-cause ICU mortality and hospital mortality, ICU and hospital length of stay.
Time Frame: ICU admission until hospital discharge
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.
Time Frame: at day 28
at day 28

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Royal Alexandra Hospital

Collaborators

University of Alberta
Gambro Renal Products, Inc.

Investigators

  • Principal Investigator: Demetrios J. Kutsogiannis, M.D., University of Alberta

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2006

Primary Completion (Actual)

December 1, 2010

Study Completion (Actual)

December 1, 2010

Study Registration Dates

First Submitted

October 24, 2006

First Submitted That Met QC Criteria

October 24, 2006

First Posted (Estimate)

October 25, 2006

Study Record Updates

Last Update Posted (Estimate)

March 5, 2012

Last Update Submitted That Met QC Criteria

March 1, 2012

Last Verified

March 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RHABDO 2006
  • Health Canada Control # 108739 (Other Identifier: Health Canada)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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