Renal dysfunction is one of the important postoperative complications following coronary artery bypass grafting.1 The potential risk factors are advanced age and presence of comorbid conditions such as hypertension, diabetes mellitus, cardiac failure and preexisting renal disease.2,3 These factors may collectively contribute to renal hypoxia and ischaemia. Hypoxic ischaemic insults result in direct toxic effects within renal tubular epithelial cells with depletion of local antioxidants and the formation of reactive oxygen species (ROS). Off-pump coronary artery bypass grafting (OP-CABG) has revolutionized the surgical approach for the treatment of coronary artery disease by avoiding extracorporeal circulation.
Recently, several meta analyses and randomized controlled trials have demonstrated that N-acetylcysteine (NAC) attenuates contrast-induced declines in renal function because of its antioxidant and ROS scavenger properties.4–6 If NAC proves to be effective in preventing the deterioration of renal function following OP-CABG, it would be a highly cost-effective strategy, as NAC is inexpensive and rarely associated with any toxicity.
This was a randomized, prospective, open-label study with two parallel groups. The study was carried out between January 2006 and June 2007. After approval by the ethics committee of the hospital, patients admitted for elective OP-CABG surgery and deemed high risk (as defined by the presence of one or more of the criteria listed for inclusion) for postoperative renal dysfunction were included in the study. The inclusion and exclusion criteria are as follows.
- Inclusion criteria:
- age older than 70 years,
- diabetes mellitus,
- baseline serum creatinine level higher than 133 μmol l−1 (1.5 mg dl−1) and
- ejection fraction less than 35%.
- Exclusion criteria:
- known allergy or hypersensitivity to NAC,
- use of nephrotoxic drugs and nonsteroidal anti-inflammatory drugs,
- history of current or previous dialysis,
- prior renal transplant,
- conversion to cardiopulmonary bypass during surgery,
- patients needing intra-aortic balloon pump (IABP),
- patients on large doses of inotropes and
Seventy-four patients were enrolled after obtaining written informed consent. This study was confined to patients undergoing OP-CABG and hence four patients were excluded from the study because of conversion to on-pump coronary artery bypass surgery. These patients were followed up in the postoperative period. Random numbers were generated from a random number table and patients were assigned to either the NAC group or the control group according to the numbers. The NAC group (37 patients) received oral NAC 600 mg twice a day on the preoperative day and intravenous NAC 600 mg prior to the induction of anaesthesia on the day of surgery. This was followed by intravenous NAC 600 mg twice a day until the second postoperative day (total dose of NAC administered was 4.8 g). The control group comprising 37 patients did not receive NAC or placebo. All the patients were assessed preoperatively and baseline parameters (Table 1) were collected by the first author.
Patients underwent coronary artery bypass surgery under general anaesthesia. On the day of surgery, the patients with normal ejection fraction were premedicated with diazepam 10 mg and atenolol 50 mg orally. Atenolol 12.5 mg was administered to patients with an ejection fraction less than 35%. Induction was done using a combination of intravenous midazolam (0.1 mg kg−1) and fentanyl (5–10 μg kg−1), followed by paralysis with intravenous pancuronium (0.1 mg kg−1). Anaesthesia was maintained with a gas mixture of isoflurane (1–2%) in oxygen. The five-lead electrocardiogram, peripheral oxygen saturation, end-tidal carbon dioxide, intra-arterial pressure, central venous pressure, nasopharyngeal temperature and urine output were continuously monitored. The patients were anticoagulated using intravenous heparin to maintain the activated clotting time (ACT) of more than 420 s during grafting as per the institutional protocol. At the end of the procedure, anticoagulation was reversed using protamine. The heart was stabilized with an ‘OCTOPUS’ suction device (Medtronic Inc., Minneapolis, Minnesota, USA, 2001; model-28400) to perform OP-CABG. Administration of intravenous fluids, blood products, inotropes and vasodilators were left to the discretion of the attending anaesthesiologist. Postoperatively patients were sedated and ventilated in the intensive care unit.
A postoperative increase in the serum creatinine level of more than 44 μmol l−1 (0.5 mg dl−1) or a rise in the creatinine level by 25% from the basal level was taken as the criterion for deterioration of renal function.2
Serum creatinine level and glomerular filtration rate (GFR) were measured preoperatively and postoperatively on the first, second and fifth day. This was the primary outcome measurement of the study. GFR was calculated using the Cockroft–Gault equation.7
The secondary outcome measures included adverse reactions, duration of elective ventilation, duration of intensive care unit stay and duration of hospital stay.
A pilot study recruiting 20 patients (10 in each group) was done initially. The mean and standard deviation of serum creatinine and GFR values were calculated. Using these values, it was found that a sample size of 70 patients (35 in each group) would give a 95% confidence interval (5% level of significance) and a power of 80%. Independent sample t-test (Student's t-test) and χ2-test were employed to compare the two groups with respect to continuous and categorical variables respectively. Repeated measures analysis of variance was used to compare the creatinine values (as well as GFR) over the four assessment intervals between the groups. The level of significance was fixed at 0.05. Statistical Package for Social Sciences (SPSS, version 11; SPSS, Chicago, Illinois, USA) was used for data analysis.
The results were analysed for 70 patients (35 in each group). The anthropometric and demographic data were comparable in both the NAC and the control group (Table 1). The two groups did not differ significantly in the intraoperative characteristics (Table 1).
Serum creatinine and GFR were measured preoperatively and on first, second and fifth postoperative days (Table 2). There was no difference in the mean serum creatinine levels between the two groups (P value 0.798; F value 0.066). There was no difference in the mean GFR between the groups (P value 0.597; F value 0.283). Three patients in the NAC group and four patients in the control group developed postoperative renal dysfunction and the difference between the groups was not statistically significant (Table 3). There were no differences in the secondary outcome measures between the groups.
In one patient in the NAC group, mechanical ventilation was reinstituted on the first postoperative day because of haemodynamic instability. Another patient from the same group underwent re-exploration surgery because of postoperative bleeding and subsequent hypotension, 6 h following OP-CABG. Both the patients recovered uneventfully. One patient in the control group underwent sternal wound debridement 1 month following OP-CABG and recovered with no complications.
Four patients who were excluded from the study neither developed renal dysfunction (as per the criteria chosen for the study) nor suffered any other complication. The secondary outcome measures were similar to those patients who were included for analysis.
Occurrence of postoperative renal dysfunction remains one of the important complications following cardiac surgery and has a multifactorial etiology. In patients undergoing cardiac surgery on cardiopulmonary bypass (CPB), the duration of CPB, systemic inflammatory response, hypoperfusion and loss of pulsatile perfusion are thought to have a role in the development of postoperative renal dysfunction.8 Preoperative, intraoperative and postoperative haemodynamic factors have a prominent role in the development of postoperative acute renal failure.9 Circulatory failure during cardiac surgery can cause ischaemic and toxic injury to the kidneys, which leads to the depletion of local antioxidants and formation of free oxygen radicals.10
Several drugs (dopamine, diuretics, atrial natriuretic peptide and fenoldopam) have been evaluated for preventing postoperative renal dysfunction with inconsistent results. NAC has anti-inflammatory and antioxidant properties, which can attenuate several mechanisms of renal injury (systemic inflammatory response, free radical injury and ischaemia10) during cardiac surgery. It may provide renal protection by acting as an antioxidant and vasodilator via the nitric oxide pathway.11
This prospective randomized controlled study did not show any beneficial renal protective effect of NAC, in patients who are at high risk of developing postoperative renal dysfunction, following elective OP-CABG.
Similar results were seen in studies done by Burns et al.,2 Hynninen et al.,12 Ristikankare et al.,13 Haase et al.,14 Hamamsy et al.15 and Wijeysundera et al.16 in patients undergoing cardiac surgery. The studies conducted so far have been in patients undergoing cardiac surgery (CABG, valvular surgeries, aortic aneurysm repair) using cardiopulmonary bypass.2,12–17 We studied the effect of NAC on renal dysfunction in patients undergoing off-pump CABG, as 70% of coronary bypass graft operations are carried out using the off-pump technique at our centre.
It is proposed that OP-CABG has a less detrimental effect on renal function than CABG using cardiopulmonary bypass.8,18 This finding was not confirmed by the studies conducted later.19 The controversy regarding the beneficial effect of OP-CABG over CABG using cardiopulmonary bypass continues. We consider that the off-pump CABG is less invasive than the on-pump technique and hence we used a lower dose of NAC than in the studies done by Hynninen et al.,12 Ristikankare et al.,13 Haase et al.,14 Hamamsy et al.15 and Wijeysundera et al.16
The dose of NAC used in this study is based on the dosing regimen adopted for preventing radiocontrast-induced nephropathy.4,6,11 Marenzi et al.20 used NAC for two postoperative days to prevent renal dysfunction in patients undergoing angioplasty. Nitescu et al.21 proposed that the repeated administration of lower doses of NAC may be as effective in attenuating renal ischaemic reperfusion injury as higher doses when given immediately following the ischaemic insult, as shown in their study in rats subjected to renal ischaemia reperfusion injury. Laisalmi-Kokki et al.22 indicated a probable increase in the risk of remote renal injury with the use of NAC in the clinical setting of renal ischaemia/reperfusion.
The primary outcome of this study was to determine the proportion of patients developing postoperative renal dysfunction by measuring serum creatinine and GFR in the postoperative period. In order to adjust creatinine values for age, sex and body weight, the GFR was calculated according to the Cockroft–Gault equation. Other studies have employed additional parameters like urinary N-acetyl-beta-D-glucosaminidase (NAG)/creatinine,12,13 urinary albumin/creatinine ratio12 and serum cystatin C.12–14 The effect of NAC on serum creatinine values and estimated GFR without any effect on serum cystatin C levels has been shown in volunteers with a normal renal function, indicating the need to consider the direct effects of NAC on serum creatinine levels and estimated GFR.23
In our study, the incidence of renal failure was low in both the groups and a total of 10% patients developed postoperative renal dysfunction (as defined by a postoperative rise in serum creatinine level of more than 25% from the preoperative value). The incidence of renal dysfunction did not differ between the groups (Table 3). Thus, it is evident that NAC did not have any beneficial effect in preventing renal dysfunction. The study by Fischer et al.17 showed a beneficial effect of using NAC in cardiac surgery. This study, however, is retrospective with a small sample size. The patients had normal preoperative renal function and there was no mention of preoperative comorbidities in the selected patients. Barr and Kolodner24 showed a renoprotective effect of perioperative NAC and fenoldopam in patients with chronic renal insufficiency undergoing cardiac surgery.
Our study was prospective and randomized with a statistically significant sample size involving a homogeneous group of patients undergoing OP-CABG. So far, we are not aware of any study done on the effect of NAC in preventing renal dysfunction in OP-CABG patients. The groups of patients selected for the study were at high risk of developing postoperative renal dysfunction. The assessment of serum creatinine and GFR using the Cockroft–Gault equation has proven to be economical and reliable for estimating postoperative renal dysfunction.25,26
The limitations of the present study are that the data were not analysed with the intention-to-treat principle, the dose of NAC was low, which may not adequately prevent the antioxidant injury, and we used serum creatinine levels and the calculation of creatinine clearance (estimated GFR) to represent true GFR in the nonsteady state. Postoperative creatinine clearance values do not necessarily approximate directly measured GFR because creatinine concentration is not in a steady state. Timed measurements of creatinine clearance become inaccurate with decreasing GFR. However, other alternative measures of GFR using clearance of inulin or radiolabelled compounds are limited and not feasible.
The authors would like to thank Dr Lloyd Vincent MD (Med) DM (Neph) for his valuable suggestions.
1 Mangano CM, Diamondstone LS, Ramsay JG, et al
dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization. The Multicenter Study of Perioperative Ischemia Research Group. Ann Intern Med 1998; 128:194–203.
2 Burns KEA, Chu MWA, Novick RJ, et al
. Perioperative N
-acetylcysteine to prevent renal
dysfunction in high-risk renal
patients undergoing CABG surgery
: a randomized controlled trial. JAMA 2005; 294:342–350.
3 Conlon P, Smith MS, White W, et al
. Acute renal failure
following cardiac surgery
. Nephrol Dial Transplant 1999; 14:1158–1162.
4 Tepel M, van der Giet M, Schwarzfeld C, et al
. Prevention of radiographic-contrast-agent-induced reductions in renal
function by acetylcysteine. N Engl J Med 2000; 343:180–184.
5 Shyu KG, Cheng JJ, Kuan P. Acetylcysteine protects against acute renal
damage in patients with abnormal renal
function undergoing a coronary procedure. J Am Coll Cardiol 2002; 40:1383–1388.
6 Kay J, Chow WH, Chan TM, et al
. Acetylcysteine for prevention of acute deterioration of renal
function following elective coronary angiography and intervention: a randomized controlled trial. JAMA 2003; 289:553–558.
7 Sladen RN. Renal
physiology. In: Miller RD, editor. Miller's anesthesia. 6th ed. Philadelphia: Elsevier Churchill Livingstone; 2005. pp. 788.
8 Pramodh K, Vani, Muralidhar K. Renal
function following CABG: on-pump vs. off-pump. Indian J Thorac Cardiovasc Surg
9 Zanardo G, Michielon P, Paccagnella A, et al
. Acute renal failure
in the patient undergoing cardiac operation: prevalence, mortality rate and main risk factors. J Thorac Cardiovasc Surg 1994; 107:1489–1495.
10 Gormley SM, McBride WT, Armstrong MA, et al
. Plasma and urinary cytokine homeostasis and renal
dysfunction during cardiac surgery
. Anesthesiology 2000; 93:1210–1216.
11 MD CONSULT (E JOURNAL PORTAL). Drug Information Provided by Gold Standard Inc.; 2007. www.rguhs.ac.in/HELINET
. [Access on November 2007]
12 Hynninen M, Niemi T, Poyhia R, et al
-Acetylcysteine for prevention of kidney
injury in abdominal aortic surgery
: a randomized double-blind, placebo-controlled trial. Anesth Analg 2006; 102:1638–1645.
13 Ristikankare A, Kuitunen T, Kuitunen A, et al
. Lack of renoprotective effect of i.v. N
-acetylcysteine in patients with chronic renal failure
undergoing cardiac surgery
. Br J Anaesth 2006; 97:611–616.
14 Haase M, Fielitz AH, Bagshaw SM, et al
. Phase II, randomized, controlled trial of high-dose N
-acetylcysteine in high-risk cardiac surgery
patients. Crit Care Med 2007; 35:1324–1331.
15 Hamamsy IE, Stevens LM, Carrier M, et al
. Effect of intravenous N
-acetylcysteine on outcomes after coronary artery bypass surgery
: a randomized, double blind, placebo-controlled clinical trial. J Thorac Cardiovasc Surg 2007; 133:7–12.
16 Wijeysundera DN, Beattie WS, Rao V, et al
-Acetylcysteine for preventing acute kidney
injury in cardiac surgery
patients with preexisting moderate renal
insufficiency. Can J Anesth 2007; 54:872–881.
17 Fischer UM, Tossios P, Mehlhorn U. Renal
protection by radical scavenging in cardiac surgery
patients. Curr Med Res Opin 2005; 21:1161–1164.
18 Loef BG, Epema AH, Navis G, et al
. Off-pump coronary revascularization attenuates transient renal
damage compared with on-pump coronary revascularization. Chest 2002; 121:1190–1194.
19 Schwann NM, Horrow JC, Strong MD III, et al
. Does off-pump coronary artery bypass reduce the incidence of clinically evident renal
dysfunction after multivessel myocardial revascularization? Anesth Analg 2004; 99:959–964.
20 Marenzi G, Assanelli E, Marana I, et al
-Acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med 2006; 354:2773–2782.
21 Nitescu N, Ricksten SE, Marcussen N, et al
-Acetylcysteine attenuates kidney
injury in rats subjected to renal
ischaemia-reperfusion. Nephrol Dial Transplant 2006; 21:1240–1247.
22 Laisalmi-Kokki M, Pesonen M, Kokki H, et al
. Potentially detrimental effects of N
-acetylcysteine on renal
function in knee arthroplasty. Free Radic Res 2009; 43:691–696.
23 Hoffmann U, Banas B, Fischereder M, et al
-Acetylcysteine in the prevention of radiocontrast-induced nephropathy: clinical trials and end points. Kidney
Blood Pressure Res 2004; 27:161–166.
24 Barr LF, Kolodner K. N
-Acetylcysteine and fenoldopam protect the renal
function of patients with chronic renal
insufficiency undergoing cardiac surgery
. Crit Care Med 2008; 36:1427–1435.
25 Wang F, Dupuis JY, Nathan H, Williams K. An analysis of the association between preoperative renal
dysfunction and outcome in cardiac surgery
: estimated creatinine clearance or plasma creatinine level as measures of renal
function. Chest 2003; 124:1852–1862.
26 Noyez L, Plesiewicz I, Verheugt FW. Estimated creatinine clearance instead of plasma creatinine level as prognostic test for postoperative renal
function in patients undergoing coronary artery bypass surgery
. Eur J Cardiothorac Surg 2006; 29:461–465.