Prevention of Acute Kidney Injury by N-Acetylcystein in Patients Undergone Cardiac Valve Replacement

This is a randomized clinical trial, double-blind, placebo-controlled study with the goal to assess the influence of using N-AcetylCysteyn (NAC) for prevention of AKI (Acute Kidney Injury) in post operatory of valve replacement until their discharge or death

Study Overview

• Status: Unknown
• Conditions: Acute Kidney Injury; Surgery--Complications; Post-Op Complication; Cardiac Valve Disease; Oxygen Radical Damage
• Intervention / Treatment: Drug: N Acetyl Cysteine; Drug: Placebos

Detailed Description

Acute kidney injury (AKI) is a serious complication after cardiovascular surgery. Pharmacologic interventions to prevent postoperative AKI have been, in general, unsuccessful. N-Acetylcystein (NAC) is a scavenger of reactive oxygen species that prevents renal dysfunction caused by radiocontrast agents but its ability to prevent AKI in cardiovascular surgery remains controversial. Lack of dose standardization and route of administration contributes to conflicting results in the literature. ln a earlier prospective, double-blind, placebo-controlled study 1 the investigators showed that high-dose NAC reduced the incidence of AKI in patients undergoing coronary artery bypass graft surgery. In this research the investigators aim to validate the results of the abovementioned work in a larger group of patients undergoing cardiac valve replacement, using the same protocol. Methods: This will be a unicentric, prospective, double-blind, placebo-controlled investigation. The Institutional Review Board has already approved the study protocol and all participants will sign a written informed consent. Adult patients of both sex scheduled to undergo elective cardiac valve replacement (aortic and/or mitral) at the Heart Institute, University of São Paulo Medical School, will be considered for inclusion. Exclusion criteria: patients younger than 18 years, dialysis, and participation in other studies, allergy to NAC, active infection, emergency cardiac surgery and malignancies. One-hundred fifty-four patients will be randomly allocated (1:1 ratio) to receive either NAC (Fluimucil, Zambon Laboratories, São Paulo, Brazil) 150 mg/kg in 500 mL 0.9% IV saline in 2 hours, started 2 hours before surgery, followed by NAC 50 mg/kg in 500 mL 0.9% IV saline over 6 hours (NAC group) or 0.9% IV saline (control group) at the same volume. This dose was selected because it is the highest dose sanctioned for clinical use 2 and because it has been shown to reduce the oxidative burst response to Cardiopulmonary Bypass (CPB). Allocation will be based on random computer generated numbers. Patients and investigators will be blinded to treatment assignment. Blood samples will be collected 24 hours before surgery and up to 1 week postoperatively. Serum neutrophil gelatinase associated lipocalin (NGAL) and thiobarbituric acid reactive substances will be determined at the same intervals.2 The primary outcome is the incidence of AKI, as defined by the KDIGO and Acute Kidney Injury Network classification 3 , stages 1, 2, or 3, in the first 72 hours after surgery. The secondary outcomes are death by any cause, cardiovascular events (myocardial infarction, stroke, heart failure, and life-threatening arrhythmia), time in the intensive care unit, time of hospitalization and need of dialysis. The investigators will determine thiobarbituric acid reactive substances to verify if changes in renal function would coincide with changes in oxidative stress and NGAL as an additional marker of renal damage. Patients will be followed up until death or hospital discharge. The renoprotective effect of NAC is attributed to its ability to attenuate the oxidative stress burst associated with cardiac surgery and Cardiopulmonary BYPASS (CPB). The present investigation pretend not only to address this problem, but also to offer evidence that NAC abolishes the increase in circulating reactive oxygen species thus giving a plausible explanation for the renoprotective effect of NAC. Given the clinical relevance of AKI associated to cardiac surgery, lack of dependable methods to prevent that complication and the reduced number of prospective, randomized studies addressing the problem, this work has potential practical relevance.

• Study Type: Interventional
• Enrollment (Anticipated): 154
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • São Paulo, Brazil, 05403-900
    • José Jayme Galvão de Lima

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults
• Both sex
• Elective replacement valve (mitral or aortic) procedure

Exclusion Criteria:

• Chronic dialysis patients
• Emergency procedures
• Percutaneous procedures
• Pregnants
• Oncologic patients

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: N Acetyl Cysteine; NAC in pre operatory 150mg/kg infusion in 2 hours. NAC during the surgery 50mg/kg in 6 hours. The influence of NAC will be assess in post operatory moment with routine exams	Drug: N Acetyl Cysteine; Administrate NAC in the pre operatory and intra operatory moments and assess the influence in the outcomes; Other Names: NAC; experimental
Placebo Comparator: Placebos; Saline solution in pre operatory. Saline Solution duing the surgery. The post operatory datas of both groups will be compare	Drug: Placebos; These participants will receive a saline solution in pre operatory with the same volume as the experimental group, and this solution will be administrated in 2 hours. During the surgery they will receive a new solution with the same volume of the experimental group, and this solution will be administrated in 6 hours too. The solutions will be covered by an opaque bag, so the participant will not see what is being administrated; Other Names: control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
NAC and acute kidney injury (AKI)	Assess the influence of using NAC in the incidence of AKI by using the Kidney diagnosis improving outcomes (KDIGO) score and Acute kidney injury network (AKIN) score that use the creatinine seric and urine output values to define if we can or not diagnosis acute kidney injury in this pacient. The incidence of AKI will be defined by KDIGO criterea: AKI if creatinine raises up to 1,5 times the baseline, until 7 days. Or if seric creatinine raises 0,3mg/dL up to baseline in 48 hours. Urine output: less than 0,5ml/kg/h for 6-12 hours AKIN criterea: AKI if creatinine raises up to 1,5 times the baseline, until 7 days. Or if seric creatinine raises 0,3mg/dL up to baseline in 48 hours. Urine output: less than 0,5ml/kg/h for 6-12 hours	The participants will be assess in the day before the surgery (baseline), and daily until 7 days of post operatory

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
NAC and kidney replacement therapy (KRT)	Assess the influence of using NAC in the incidence of the necessity of KRT.	From the post operatory until the necessity of KRT, assessed up 2 months
NAC and death	Assess the influence of using NAC in the incidence of death	From the post operatory until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 months

Collaborators and Investigators

• Sponsor: University of Sao Paulo General Hospital
• Investigators: Principal Investigator: José J Galvão de Lima, PhD, USP InCor

Publications and helpful links

General Publications

• Spector A. Review: Oxidative stress and disease. J Ocul Pharmacol Ther. 2000 Apr;16(2):193-201. doi: 10.1089/jop.2000.16.193.
• Suen WS, Mok CK, Chiu SW, Cheung KL, Lee WT, Cheung D, Das SR, He GW. Risk factors for development of acute renal failure (ARF) requiring dialysis in patients undergoing cardiac surgery. Angiology. 1998 Oct;49(10):789-800. doi: 10.1177/000331979804900902.
• Bahar I, Akgul A, Ozatik MA, Vural KM, Demirbag AE, Boran M, Tasdemir O. Acute renal failure following open heart surgery: risk factors and prognosis. Perfusion. 2005 Oct;20(6):317-22. doi: 10.1191/0267659105pf829oa.

Study record dates

Study Major Dates

• Study Start (Anticipated): March 15, 2018
• Primary Completion (Anticipated): March 15, 2019
• Study Completion (Anticipated): March 15, 2020

Study Registration Dates

• First Submitted: January 5, 2018
• First Submitted That Met QC Criteria: February 13, 2018
• First Posted (Actual): February 22, 2018

Study Record Updates

• Last Update Posted (Actual): March 5, 2018
• Last Update Submitted That Met QC Criteria: March 1, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: cardiac surgery; Acute kidney injury; post operatory complications; N-acetylcystein
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Renal Insufficiency; Wounds and Injuries; Acute Kidney Injury; Postoperative Complications; Heart Valve Diseases; 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: NAC Valve

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: We don't have fixed reviewers for our data until our submission for publication

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No