N-Acetylcysteine for Preventing Renal Injury After Cardiac Surgery

The PRIME (Perioperative Renal Insufficiency Management) Study: A Randomized, Double-blinded, Placebo-controlled Trial of N-acetylcysteine for Preventing Renal Injury After Cardiac Surgery.

Cardiac surgery improves the survival and quality of life of people with heart disease. Nonetheless, several complications continue to adversely affect outcomes following cardiac surgery. Kidney failure is a particularly important complication that is associated with increased death and duration of hospitalization. The most severe form of postoperative kidney failure, the need for dialysis, is uncommon at present. It is however likely to increase in the future. Patients undergoing cardiac surgery are getting older with more heart failure, diabetes, high blood pressure, and pre-existing kidney disease. Given that these are risk factors for postoperative kidney injury, dialysis rates will likely increase. Although multiple therapies have been tested, none have prevented postoperative kidney failure. N-acetylcysteine (NAC) is a drug that is commonly used to treat Tylenol overdoses. Over the past 2 years, it has also been used to prevent kidney damage after exposure to IV dye. There is good evidence that NAC will reduce kidney damage after IV dye exposure. There are strong reasons to believe that NAC may also prevent postoperative kidney failure. NAC is safe. Its major side-effects are allergic reactions, but serious reactions are rare. Since dialysis is uncommon, large studies are needed to determine if NAC prevents postoperative dialysis. In this situation, a pilot study is needed to determine if such a large trial is feasible. This proposal describes a pilot study. We will determine NAC's effects on creatinine clearance, a measure of how well the kidney works. Reduced creatinine clearance is closely related to dialysis and death after cardiac surgery. This biological marker allows us to determine NAC's effects on kidney function with a reduced sample size. If NAC improves creatinine clearance, it would suggest that NAC prevents postoperative dialysis, and would justify a larger study. A pilot study will help us estimate how many patients will be willing to participate in similar studies, vital for planning a future large study. Finally, our results will estimate how well NAC will reduce dialysis rates. This is needed for calculating the sample size for future studies.The study design is a randomized, double-blinded, placebo-controlled clinical trial among patients undergoing bypass surgery or heart valve surgery at the Toronto General Hospital (Toronto, ON). We will recruit 176 people who are at increased risk for developing kidney failure after surgery. Participants will receive either NAC or sugar solution during their operation. If participants have returned home within a month of surgery, they will be contacted at home on the 30th day after surgery to determine if they had any kidney-related problems since returning home. All participants will return to the Toronto General Hospital (TGH) during the 8th week after surgery for creatinine blood test and weight.

Study Overview

• Status: Completed
• Conditions: Heart Disease; Acute Renal Failure
• Intervention / Treatment: Drug: N-acetylcysteine; Other: 5% dextrose solution

• Study Type: Interventional
• Enrollment (Actual): 176
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto General Hospital, UHN

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• CABG surgery under cardiopulmonary bypass AND/OR Valve replacement/repair surgery under cardiopulmonary bypass
• Preoperative creatinine clearance (Cockcroft-Gault equation) <= 60 mL/min.
• Age above 18 years
• Informed consent

Exclusion Criteria:

• Preoperative need for renal replacement therapy
• Preoperative serum creatinine concentration >= 300 mmol/L
• Prior adverse reaction to NAC with significant systemic symptoms (generalized rash, urticaria, bronchospasm, hypotension)
• Preoperative intra-aortic balloon pump support and/or inotropes/vasopressors
• Recent coronary angiography or intravenous dye exposure (<= 24 hours) preceding surgery
• Planned intraoperative deep hypothermic circulatory arrest
• Pregnancy
• Chronic hepatitis or hepatic cirrhosis

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: N-Acetylcysteine; IV NAC as a 100mg/kg bolus at the start of the surgical procedure (prior to the initiation of CPB), followed by a 10 mg/kg/hr infusion until 4 hours after completion of surgery	Drug: N-acetylcysteine
Placebo Comparator: Placebo; The control arm will instead receive placebo (5% dextrose solution), both as a bolus and infusion.	Other: 5% dextrose solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum percent decline in calculated creatinine clearance (Cockcroft-Gault formula) in first 72 hours following surgery.	72 hours following surgery

Secondary Outcome Measures

Outcome Measure	Time Frame
Maximum increase in serum creatinine concentration over first 72 hours following surgery.	72 hours following surgery
Increase in serum creatinine >= 0.5 mg/dL from baseline over first 72 hours following surgery (dichotomous outcome).	72 hours following surgery
Maximum percent decline in calculated creatinine clearance (Cockcroft-Gault formula) >= 25% in first 72 hours following surgery (dichotomous outcome).	72 hours following surgery
Percent change in calculated creatinine clearance (Cockcroft-Gault formula) at hospital discharge.	hospital discharge
Maximum percent decline in calculated creatinine clearance (Cockcroft-Gault formula) at 8 weeks following surgery.	8 weeks followiing surgery
30-day need for renal replacement therapy	30 day inclusive
30-day all-cause mortality	30 day follow up
Length of stay in intensive care unit (postoperative)	Duration of stay in the ICU
Length of stay in hospital (postoperative)	Until discharge form hospital
24-hour fluid perioperative fluid balance	24 hours
24-hour urine output	24 hour
Adverse perioperative event	Intra operative measure

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Collaborators: Heart and Stroke Foundation of Ontario
• Investigators: Principal Investigator: William S Beattie, MD, Toronto General Hospital, University Health Network

Publications and helpful links

General Publications

• Wijeysundera DN, Karkouti K, Rao V, Granton JT, Chan CT, Raban R, Carroll J, Poonawala H, Beattie WS. N-acetylcysteine is associated with increased blood loss and blood product utilization during cardiac surgery. Crit Care Med. 2009 Jun;37(6):1929-34. doi: 10.1097/CCM.0b013e31819ffed4.

Study record dates

Study Major Dates

• Study Start: July 1, 2003
• Primary Completion (Actual): February 1, 2007
• Study Completion (Actual): July 1, 2007

Study Registration Dates

• First Submitted: September 9, 2005
• First Submitted That Met QC Criteria: September 12, 2005
• First Posted (Estimate): September 16, 2005

Study Record Updates

• Last Update Posted (Estimate): April 20, 2011
• Last Update Submitted That Met QC Criteria: April 19, 2011
• Last Verified: April 1, 2011

More Information

Terms related to this study

• Keywords: Cardiac Surgery; N-acetylcysteine; Cardiopulmonary bypass; Acute Renal Failure
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Heart Diseases; Renal Insufficiency; Acute Kidney Injury; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: UHN REB 03-0376-B; HSFO5231