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.