Volume 133, Issue 1 , Pages 7-12, January 2007
Effect of intravenous N-acetylcysteine on outcomes after coronary artery bypass surgery: A randomized, double-blind, placebo-controlled clinical trial
Article Outline
Objective
N-acetylcysteine, a potent anti-inflammatory and antioxidant agent, is known to decrease the production of reactive oxygen species after cardiac surgery. The objective of this study was to evaluate the effects of intravenous N-acetylcysteine on clinical and biochemical outcomes after coronary artery bypass surgery with cardiopulmonary bypass.
Methods
One hundred patients (mean age 60.5 years, range 43-78 years, 89% male) undergoing coronary artery bypass grafting at the Montreal Heart Institute were randomized to receive either N-acetylcysteine (600 mg orally the day before and the morning of the operation, a bolus of 150 mg/kg of intravenous N-acetylcysteine before skin incision, followed by perfusion at 12.5 mg · kg−1 · h−1 over 24 hours; n = 50) or placebo (n = 50). The patients and clinical team were blinded to group assignments. Preoperative characteristics were similar between the two groups. Postoperative clinical data (death, myocardial infarction, low-output syndromes, arrhythmias, bleeding, transfusion requirements, and intensive care unit and hospital lengths of stay) and biochemical markers (creatine kinase MB, troponin T, creatinine, hemoglobin, and platelet levels) were evaluated serially over 4 days.
Results
Clinical outcomes were not significantly different between the two groups with regard to the incidence of death, myocardial infarction, bleeding, transfusion requirements, intubation time, and hospital length of stay. No differences were found in postoperative biochemical markers (troponin T, creatine kinase MB, creatinine, hemoglobin, and platelets) between the groups. No differences were observed between the groups in interleukin-6 production (P = not significant).
Conclusions
Prophylactic use of N-acetylcysteine in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass does not lead to improvement in clinical results or biochemical markers. Further strategies to decrease reperfusion injury should be devised.
Abbreviations and Acronyms: CABG, coronary artery bypass grafting, CK-MB, creatine kinase, CPB, cardiopulmonary bypass, ICU, intensive care unit, IL-6, interleukin 6, NAC, N-acetylcysteine, NS, not significant, ROS, reactive oxygen species
The role of cardiopulmonary bypass (CPB) in the pathophysiology of events after cardiac surgery is well established but incompletely understood. The advent of off-pump coronary artery surgery, although showing some benefits in population subsets, has not led to significant improvements as was expected by avoiding CPB. Therefore, various strategies are needed to counteract the deleterious effects associated with on-pump surgery, which include myocardial ischemia-reperfusion and protection from the systemic reaction affecting the neurologic, renal, and hematologic systems. End-organ damage is attributed to the inflammatory reaction after CPB and to a significant oxidative stress resulting from the ischemia-reperfusion cycle. Indeed, reactive oxygen species (ROS), such as superoxide radical (O2−), hydroxyl radical (OH−), hydrogen peroxide (H2O2), and peroxynitrite (ONOO−), have all been incriminated in the pathogenesis of post-CPB ROS-mediated myocardial and systemic structural and functional damage.
N-acetylcysteine (NAC) is an antioxidant agent widely known as an antidote for acetaminophen intoxication. Recently, it has gained renewed interest and wide use because of its role in the minimization of reperfusion injury after acute myocardial infarction and its protective effects on renal function in diabetic patients after contrast injection.1 NAC acts in several ways, namely, by neutralizing oxygen radicals, by protecting the cellular membrane through its sulfhydril groups, and by preserving endothelial function.2 Several reports have previously studied the effects of NAC after CPB in patients having cardiac surgery, which showed a reduction in markers of ROS-mediated myocardial injury.3, 4, 5 The purpose of the present study was to analyze the impact of NAC supplementation before cardiac surgery with CPB on clinical and biochemical markers in a randomized, placebo-controlled, double-blind trial in patients undergoing primary coronary artery bypass grafting (CABG). The primary hypothesis was that NAC supplementation would lead to improved myocardial protection after CPB in patients undergoing primary CABG surgery. The secondary hypothesis was that NAC supplementation would lead to less postoperative bleeding and less renal dysfunction.
Patients and Methods
Patient Population
A prospective, randomized, placebo-controlled, double-blind study was conducted at the Montreal Heart Institute after approval from the local ethics committee and written informed consent from the patients. Between January 2003 and March 2004, 100 patients (89 men and 11 women; mean age 60.6 ± 7.6 years) undergoing primary CABG with CPB were randomly assigned to receive NAC before surgery (group 1; n = 50) or placebo (group 2; n = 50). Patients in group 1 received 600 mg of oral NAC the day before and the morning of the operation. Additionally, patients in group 1 received a bolus of 150 mg/kg of intravenous NAC over a 15-minute period immediately before skin incision, followed by perfusion at 12.5 mg · kg−1 · h−1 over 24 hours. Patients in the control group (group 2) received oral and intravenous placebo throughout this period. Oral and intravenous preparations were similar to those of the NAC group. Exclusion criteria were emergency operations, acute myocardial infarction within fewer than 3 weeks, prior cardiac surgery, age older than 80 years, ejection fraction less than 20%, and concomitant procedures. The primary end point was the mean postoperative release of cardiac troponin T levels between the two groups (1, 2, 4, 8, 12, and 24 hours postoperatively, then 2, 3, and 4 days postoperatively). Secondary end points included the rate of myocardial infarction (as defined by creatine kinase (CK-MB) level >50 and/or new Q wave on electrocardiogram in a given territory), renal function (creatinine), bleeding, low cardiac output syndromes, arrhythmias, and mean levels of CK-MB.
Clinical Protocol
All patients underwent CABG with CPB under moderate hypothermia (34°C). Tepid antegrade blood cardioplegia (4:1 solution at 28°C) was used in all cases. No hypothermia and no retrograde cardioplegia were used. No topical cooling methods were used. The left internal thoracic artery was used in all cases but 1 in group 2. Aprotinin (Trasylol; Bayer Inc, West Haven, Conn) was administered in all cases according to the full-dose Hammersmith protocol.6 This institutional policy represented standard of care at the Montreal Heart Institute during the study period, although it has changed after recent reports on the effects of aprotinin on renal function.
Study Protocol
Several variables were evaluated after surgery. Clinical variables included death, myocardial infarction, low cardiac output syndrome (postoperative intra-aortic balloon pump insertion or vasopressive medication requirements for >30 minutes), bleeding, transfusion requirements, cerebrovascular accidents, arrhythmias (supraventricular and ventricular), atrial fibrillation, intubation time, and intensive care unit (ICU) and hospital lengths of stay. All electrocardiograms were interpreted by 2 independent observers (ICU physicians) who were blinded to the study groups. Myocardial infarction was defined as a new Q wave based on the Minnesota Code or as maximum perioperative CK-MB levels at any time point greater than 50 units. Biochemical markers included mean cardiac troponin T and CK-MB levels (1, 4, 8, 12, and 24 hours postoperatively, then 2, 3, and 4 days postoperatively), serum creatinine levels (preoperatively and daily postoperatively until day 5), hemoglobin and platelet levels, and alveolocapillary gradients (preoperatively and 1, 3, and 6 hours postoperatively). All data were collected by an independent research nurse assigned to this research study and blinded to the groups. Regarding cardiac troponin, CK-MB units, and serum creatinine, the mean levels at each time point were evaluated and compared between the two groups.
Furthermore, so that the anti-inflammatory effects of NAC in this patient population could be evaluated, blood was withdrawn from the coronary sinus circulation of 12 patients and levels of interleukin-6 (IL-6) were quantified by high-sensitivity enzyme-linked immunosorbent assay (Quantikine HS; R&D Systems, Minneapolis, Minn) at various time points (preoperatively, 1 hour after bypass in the coronary sinus, and then 4, 8, 12, and 24 hours postoperatively in the systemic venous circulation).
Statistical Analysis
All data were analyzed with the help of the Biostatistics Department at the Montreal Heart Institute. χ2 analyses were performed for all categorical variables. Repeated analysis of variance measures were used to evaluate the postoperative differences over time of troponin, CK-MB, creatinine, hemoglobin, platelets, and alveolocapillary gradients between the two groups. For troponin and CK-MB analysis, a logarithmic transformation of variables was performed to correct for their skewed distribution. The study sample size was determined to show a 25% reduction of the average levels of postoperative troponin T levels in patients who were administered NAC with an α-error of 5% and a β of 20% yielding a power of 80%.
Results
Preoperative Data
There were no differences between the two groups in terms of gender, age, New York Heart Association functional class, left ventricular ejection fraction, distribution of coronary disease, the incidence of previous myocardial infarction, or unstable angina (P = not significant [NS]) (Table 1). The two groups were also similar in terms of preoperative oral medications (β-blockers, calcium-channel blockers, and angiotensin-converting enzyme inhibitors; P = NS).
TABLE 1. Preoperative patient characteristics
| Patient characteristics | NAC group (n = 50) | Control group (n = 50) | P value |
|---|---|---|---|
| Age | 59.8 ± 7.8 | 61.3 ± 7.4 | .3 |
| Sex (% male) | 86 | 92 | .3 |
| NYHA III-IV/IV (%) | 39 | 50 | .7 |
| Unstable angina (%) | 44 | 44 | .9 |
| Previous MI (%) | 33 | 46 | .2 |
| Cardiac output | 2.5 ± 0.7 | 2.2 ± 0.5 | .2 |
| β-blockers (%) | 88 | 76 | .1 |
| Calcium-channel blockers (%) | 44 | 42 | .8 |
| ACE inhibitors (%) | 56 | 48 | .4 |
| Left main coronary stenosis (%) | 22 | 26 | .7 |
| Three-vessel disease (%) | 82 | 82 | .9 |
| LV dysfunction (%) | 8 | 12 | .3 |
Intraoperative Data
No differences were found between the two groups in terms of number of grafted arteries, left internal thoracic artery use, CPB time, crossclamp time, or blood losses (P = NS) (Table 2). One patient in group 1 underwent a coronary endarterectomy on the left anterior descending artery for severely calcified plaques.
TABLE 2. Intraoperative patient characteristics
| Patient characteristics | NAC group (n = 50) | Control group (n = 50) | P value |
|---|---|---|---|
| No. of grafts | 3.0 | 3.1 | .6 |
| LITA-LAD (%) | 100 | 98 | .9 |
| Aortic crossclamp time (min) | 42 ±18 | 43±19 | .9 |
| Duration of CPB (min) | 71±23 | 70±24 | .8 |
| Blood losses (mL) | 419±240 | 341±171 | .07 |
| Postop cardiac index | 2.5±0.7 | 2.6±0.6 | .4 |
Anti-inflammatory Effect
Baseline IL-6 levels were similar between the two groups (P = NS). There were no demonstrable differences in coronary sinus IL-6 levels between the groups 1 hour after discontinuation of CPB (180.6 ± 203.7 in the NAC group versus 187.5 ± 78.8 in the placebo group; P = NS). Although average IL-6 levels at 4, 8, 12, and 24 hours postoperatively were lower in the NAC group, these differences did not reach statistical significance (Figure 1).
Figure 1.
IL-6 levels at different time points between NAC and placebo groups (P = NS). IL-6, interleukin-6; NAC, N-acetylcysteine.
Myocardial Protection
There were 3 deaths in the NAC group. No deaths occurred in the placebo group (P = NS). Three patients in the NAC group had a postoperative myocardial infarction (1 of whom had an endarterectomy on the left anterior descending coronary artery) versus 1 patient in the placebo group (P = .5). Troponin levels were not statistically different between groups at 1, 4, 8, 12, and 24 hours nor at 2, 3, and 4 days postoperatively (Figure 2). No significant differences were noted for CK-MB levels at the same time intervals (Figure 3).
Figure 2.
Comparison of postoperative troponin T levels between NAC group and placebo. NAC, N-acetylcysteine.
Figure 3.
Comparison of postoperative CK-MB levels between NAC group and placebo. CK-MB, creatine kinase; NAC, N-acetylcysteine.
Renal Function
Postoperative creatinine levels did not show any differences between the two groups (P = NS) (Figure 4).
Figure 4.
Comparison of serum creatinine levels between NAC group and placebo (μmol/L). NAC, N-acetylcysteine. POD, Postoperative day.
Clinical Outcomes
No statistically significant differences were noted either for hemoglobin levels, platelet levels, or alveolocapillary gradients between the two groups (P = NS). The incidence of low cardiac output, surgical re-exploration, atrial fibrillation, and ventricular arrhythmias was not statistically different between the two groups (P = NS). Also, no statistically significant differences were found in terms of intubation time and hospital length of stay (P = NS) (Table 3). No cases of cerebrovascular accidents were reported.
TABLE 3. Postoperative patient characteristics
| Patient characteristics | NAC group (n = 50) | Control group (n = 50) | P value |
|---|---|---|---|
| Death (30 days) | 3 | 0 | .1 |
| Myocardial infarction (n) | 3 | 1 | .2 |
| Low-output syndrome (n) | 2 | 0 | .2 |
| Supraventricular arrhythmia (%) | 34 | 24 | .4 |
| Atrial fibrillation (%) | 7 | 12 | .7 |
| Ventricular arrhythmia (%) | 12 | 10 | .7 |
| Surgical re-exploration (n) | 4 | 1 | .2 |
| Intubation (h)⁎ | 6.5 | 8.6 | .5 |
| Hospital length of stay (d) | 5.4 ± 2.3 | 5.3 ± 2.5 | .7 |
⁎Intubation times expressed as median. |
Discussion
The results of the present study show that perioperative intravenous NAC administration in patients undergoing primary CABG with CPB does not improve clinical or biochemical outcomes after surgery. Myocardial protection and renal function were unchanged despite NAC supplementation perioperatively.
Previous research shows histologic evidence of ischemia-reperfusion injury in up to 25% of pathologic specimens of patients having died after cardiac surgery with cardioplegic arrest. Therefore, reduction of the ischemia-reperfusion reaction and its cellular and structural consequences after CABG is an inherent goal and has been the focus of much research in the past 20 years. Ischemia may occur in patients with unstable angina awaiting surgery, it can occur at the time of induction, as well as during the period of aortic crossclamping. Several strategies have been tested both experimentally and in clinical settings, including different routes of cardioplegia administration,7 different temperatures,8 and supplementation with l-arginine,9 vitamin C,10 and allopurinol.11 However, no single strategy has consistently or significantly altered postoperative clinical outcomes.
NAC was first suggested as an additive to cardioplegia by Menasché and associates in 1992.12 They showed an improvement in postarrest recovery of function, presumably through an enhancement of the reduced thiol pool, which increases the capacity of reperfused myocardium to handle the postischemic burst of free radical production.
The absence of observed benefit is somewhat disappointing considering the body of literature showing positive results pertaining to reduction of ROS and mediators of inflammatory reaction.3, 4, 5, 13, 14, 15 Indeed, recent publications by Fischer and colleagues4 showed a reduction in oxidative stress, myocardial edema, and cardiomyocyte apoptosis after CPB. These findings were attributed to the powerful antioxidant and anti-inflammatory effects of NAC. In most protocols, NAC was added to the pump prime or was administered immediately before CPB initiation and maintained for 60 minutes after its discontinuation. In the present study, NAC was administered as 600 mg of oral NAC the day before the operation and the morning of the operation, followed by intravenous administration before skin incision and for 24 hours postoperatively. The oral dosing regimen is based on the dosing regimen used for renal protection before angiographic procedures.2 The decision to start patients on NAC preoperatively was based on the observations suggesting that ROS are present before CPB initiation, probably owing to anesthesia induction, to surgical trauma, or both. Thus, as suggested by Tossios and coworkers,3 NAC application should begin before anesthesia induction to yield maximal benefit of its ROS-scavenging properties. Moreover, considering the short half-life of NAC estimated at 2.2 hours,16 NAC was maintained as a continuous intravenous infusion for 24 hours after CPB to ensure prolonged protection from oxidative injury after reperfusion. Despite these modifications, no clinical or biochemical myocardial benefit was observed. Moreover, no statistical differences were observed between the groups in IL-6 levels at different time points after CPB discontinuation and during the initial 24 postoperative hours. This absence of observed statistical difference comes despite a more aggressive NAC administration protocol than used in previous studies.
Acute renal failure after CABG is a frequent complication occurring in up to 7% of patients.17 Acute renal failure is an independent factor associated with increased mortality after CABG.18 Therefore, all strategies that help reduce the incidence of acute renal failure after CABG are beneficial for patients’ prognosis. NAC has been used increasingly recently after reports of renal function preservation in patients undergoing radiographic procedures with contrast injection.3 Although in the present study patients were not at a particularly high risk of acute renal failure, no differences were noted in the incidence of renal dysfunction over a 4-day period after CPB in the present study population. This suggests that the etiology of post-CPB renal dysfunction is not as much a matter of ischemia-reperfusion injury as it is a question of maintaining adequate renal perfusion pressures throughout CPB and adequate hemodynamic and volemic states after surgery. In fact, in another study in which NAC prophylaxis was used in patients undergoing cardiac surgery, looking at renal function as the primary end point, no differences in the incidence of acute renal failure were noted postoperatively.19
The present study has several limitations. First, according to institutional policy, all patients received full-dose aprotinin. Although it could have limited the power to discern the true difference in bleeding between the groups, it did not, however, introduce a bias because it was administered equally to all patients. Furthermore, despite a trend towards less IL-6 production in patients receiving NAC, no statistically significant differences were observed between the groups. However, on the basis of prior studies, the NAC protocol used in this study was more aggressive and prolonged (24-hour infusion).
Conclusions
In the present study, prophylactic use of NAC in patients undergoing primary CABG with CPB does not lead to improved myocardial protection, renal function, or biochemical markers. Furthermore, NAC administration in this patient population did not exert a significant anti-inflammatory effect. However, considering the positive and encouraging results of more fundamental research on its use in a CPB setting, further strategies to decrease the impact of ischemia-reperfusion injury should be sought, by combining different strategies, by targeting a specific population, or by modifying administration strategies.
References
- . Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med. 2000;343:180–184
- . N-acetylcysteine in acute cardiology: 10 years later. J Am Coll Cardiol. 2002;39:1422–1428
- N-acetylcysteine prevents reactive oxygen species–mediated myocardial stress in patients undergoing cardiac surgery: results of a randomized, double-blind, placebo-controlled trial. J Thorac Cardiovasc Surg. 2003;126:1513–1520
- . The antioxidant N-acetylcysteine preserves myocardial function and diminishes oxidative stress after cardioplegic arrest. J Thorac Cardiovasc Surg. 2003;126:1483–1488
- . The role of N-acetylcystein administration on the oxidative response of neutrophils during cardiopulmonary bypass. Perfusion. 1995;10:21–26
- . Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet. 1987;2:1289–1291
- . Antegrade/retrograde cardioplegia for valve replacement: a prospective study. Ann Thorac Surg. 1999;68:1681–1685
- . Intermittent antegrade warm versus cold blood cardioplegia: a prospective randomized study. Ann Thorac Surg. 1994;58:41–49
- Cardioplegic arrest with l-arginine improves myocardial pretection: results of a prospective randomized clinical trial. Ann Thorac Surg. 2002;73:837–842
- Effect of preoperative supplementation with alpha-tocopherol and ascorbic acid on myocardial injury in patients undergoing cardiac operations. J Thorac Cardiovasc Surg. 1997;113:942–948
- Allopurinol pretreatment improves postoperative recovery and reduces lipid peroxidation in patients undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. 1994;107:248–256
- . Maintenance of the myocardial thiol pool by N-acetylcysteine: an effective means of improving cardioplegic protection. J Thorac Cardiovasc Surg. 1992;103:936–943
- . Myocardial apoptosis prevention by radical scavenging in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg. 2004;128:103–108
- N-acetylcysteine pretreatment of cardiac surgery patients influences plasma neutrophil elastase and neutrophil influx in bronchoalveolar lavage fluid. Intensive Care Med. 1996;22:900–908
- N-acetylcysteine for preventing pump-induced oxidoinflammatory response during cardiopulmonary bypass. Surg Today. 2004;34:237–242
- . Pharmacokinetics of N-acetylcysteine in man. Eur J Clin Pharmacol. 1986;31:217–222
- Perioperative renal risk stratification. Circulation. 1997;95:878–884
- . Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization. Ann Intern Med. 1998;128:194–203
- Perioperative N-acetylcysteine to prevent renal dysfunction in high-risk patients undergoing CABG surgery: a randomized controlled trial. JAMA. 2005;294:342–350
Dr Perrault, Dr El-Hamamsy
PII: S0022-5223(06)01566-2
doi:10.1016/j.jtcvs.2006.05.070
© 2007 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Volume 133, Issue 1 , Pages 7-12, January 2007
