Discussion
It is intriguing that despite NAC’s well documented effect as an antioxidant, vasodilator and free radical scavenger, overall data analysis was inconclusive in showing that NAC could provide significant renal protection in major cardiac surgery. In addition, NAC has been shown to be effective in preventing radiocontrast nephropathy [11] and protecting renal function after cardiopulmonary bypass [12], possibly by inhibiting transforming growth factor beta1 (TGFβ1) [13]. Animal models have also shown the administering of NAC would reduce total, cortical, and medullary vascular resistance by 7% to 10%, improving renal function [14] which further suggests that NAC would confer protection against acute kidney injury after cardiac surgery.
It is likely that the main reason for the controversial effect of NAC is due to the different dosage administered, timing when NAC was first administered, and the overall duration. Firstly, NAC effect on preventing renal failure was also more pronounced in studies where it was administered at a much higher dosage. All 5 studies that reported higher doses of NAC [16] [17] [18] [19] [20] showed a trend pointing towards the reno-protective effect of NAC, with an odds ratio of less than 1. This is further supported when meta analytic estimates of NAC administered at high dosage (Fig 5) were compared to that of low estimates (Fig 6). The odds ratio of all studies that administered high dosages of NAC was at 0.66 (95% CI: 0.44-1.01) while that of studies that administered low dosages of NAC was at 0.98 (95% CI: 0.67-1.42). Secondly, NAC’s effect on preventing against renal failure was more pronounced in studies where it was administered perioperatively. In 2 studies conducted by Prasad [15] and Santana [16], perioperative usage of NAC resulted in a decrease in incidence of renal failure, with an odds ratio of 0.73 and 0.30 respectively. It is also worth noting that the study conducted by Santana and associates showed a significant benefit in perioperative usage of NAC (OR: 0.30, 95% CI: 0.11-0.81). However, when meta analytic estimates of all perioperative usages of NAC (Fig 3) was compared to that of intraoperative to postoperative usages of NAC (Fig 4), the trend seems to show that intraoperative to postoperative usage of NAC had a more pronounced effect (OR: 0.71, 95% CI: 0.50-0.99) as compared to perioperative usage of NAC (OR:0.95, 95%CI: 0.55-1.63). However, this is likely due to the fact that a low dosage was administered in all three studies on the perioperative usage of NAC that had an odds ratio of more than one, resulting in the overall meta analytic estimate incorrectly favouring intraoperative to postoperative usage of NAC. Therefore, it is likely that the reno-protective effect of NAC is best elicited when administered in high doses perioperatively. It is worth noting that among all 10 studies, only 1 study reported the administration of high doses of NAC perioperatively [16], and that study was the sole study to show a significant benefit (OR: 0.30, 95% CI: 0.11-0.81). This study was accorded a greater weightage compared to other studies due to it having a significant number of patients and being of better scientific design, as a double blind randomised controlled trial.
Other possible explanations for NAC’s inconsistent effect on renal function could be due to differences in off pump and on pump coronary artery bypass grafting which could result in varying effects of NAC in attenuating immune responses due to the fact that the systematic inflammatory response is more likely to be activated when exposed to extracorporeal CPB circuit only found in on pump coronary artery bypass grafting. The multifactorial pathophysiology of acute kidney injury after cardiac surgery could suggest that other mechanisms unaffected by NAC could have resulted in renal failure despite administration of NAC, such as low cardiac output and decreased reperfusion pressure. Lastly, for studies which focused on patients with chronic kidney disease or moderate renal insufficiency undergoing cardiac surgery, the effect of NAC may be insufficient in protecting renal function since renal function was already compromised prior to cardiac surgery.
One limitation worth mentioning is that due to studies using different metrics to report dosages administered, discretion was used to decide which dosage was considered high or low.