Reply to Coutrot et al.: Is Nitric Oxide Nephro- or Cardioprotective?

From the Authors:

We read the comment by Dr. Coutrot and colleagues concerning our trial in Xijing Hospital (Xi’an, China) (1). They postulate that the observed effects on kidney function in patients undergoing cardiac surgery and receiving nitric oxide (NO) compared with control subjects receiving a placebo (nitrogen) could be due to NO improving right heart function.

In our trial, we found that delivering 24 hours of 80 ppm NO (both through the cardiopulmonary bypass circuit during surgery and subsequently through the ventilator) resulted in short-term and long-term renal benefits (1). A 22% relative risk reduction in acute kidney injury (AKI) (incidence: 64% for controls vs. 50% in the NO group, P = 0.014) translated into long-lasting renal protection. One year after surgery, stage 3 chronic kidney disease (defined as an estimated glomerular filtration rate below 60 ml/min/1.73 m²) was found in 18% of patients in the NO group, compared with 31% in the control group (relative risk, 0.59; 95% confidence interval, 0.36–0.96; P = 0.017). We also found that although the two groups had similar levels of hemolysis (assessed by plasma levels of hemoglobin), plasma NO consumption activity was increased only in the placebo group, suggesting that the administration of NO successfully oxidized circulating plasma ferrous hemoglobin (oxy-hemoglobin) to ferric hemoglobin (met-hemoglobin), preventing depletion of vascular NO (2). Unfortunately, right heart function was not monitored in our trial. Intraoperative transesophageal echocardiography and pulmonary artery catheterization were not standard of care in Xijing Hospital at the time of the trial. Thus, we are unable to confirm the NO-mediated cardioprotective hypothesis of Dr. Coutrot and colleagues. This hypothesis is valid and thoughtful, and it builds on the knowledge that inhaled NO is a potent selective vasodilator of the pulmonary circulation (3). Right heart function might benefit greatly from a decreased workload, as pulmonary vascular resistance is decreased during NO therapy.

In a recent cardiac surgical randomized controlled trial (sample size n = 71) presented by Kamenshchikov and colleagues at the annual meeting of the American Heart Association, supplemental NO was added only during surgery to the cardiopulmonary bypass circuit (4). Gas was never delivered directly to the lungs. The authors reported a decrease in AKI from 44.4% in the control group to 14.3% in the NO group (P = 0.0053), suggesting a directly nephroprotective role of NO. However, no assesment of right heart function and no detailed hemodynamic measurements were presented.

To determine both the cardiac and renal protective effects of NO during cardiac surgery and the potential cardio–renal interactions that might occur, we are now conducting a randomized trial in 250 cardiac surgery patients at the Massachusetts General Hospital (Boston, MA) with intraoperative echocardiography and pulmonary artery catheterization. We will measure renal biomarkers, assess pre- and postoperative redox states, and evaluate pre- and postoperative levels of plasma NO metabolomics. The primary endpoint of this ongoing study in Boston is to determine whether NO is effective in the prevention of AKI as defined by Kidney Disease Improving Global Outcomes criteria (ClinicalTrials.gov Identifier: NCT02836899). However, in contrast to our first trial in China in patients primarily with rheumatic heart disease, Americans undergoing heart surgery are generally older and are affected by endothelial dysfunction. Endothelial dysfunction is a condition characterized by impaired endothelial NO synthase. In these patients, the diseased endothelium is unable to provide appropriate vasodilation during and after ischemic events, and is unable to replenish plasma NO after consumption of NO from intravascular hemolysis (5). At present (January 2019), we are halfway through enrollment (n = 125). We believe that the results of this ongoing trial will be able to address the hypothesis of Dr. Coutrot and colleagues.