Effects of inorganic nitrate on ischaemia-reperfusion injury after coronary artery bypass surgery: a randomised controlled trial

Karin E Eriksson, Fredrik Eidhagen, Jan Liska, Anders Franco-Cereceda, Jon O Lundberg, Eddie Weitzberg, Karin E Eriksson, Fredrik Eidhagen, Jan Liska, Anders Franco-Cereceda, Jon O Lundberg, Eddie Weitzberg

Abstract

Background: Nitric oxide (NO) is an important signalling molecule in the cardiovascular system with protective properties in ischaemia-reperfusion injury. Inorganic nitrate, an oxidation product of endogenous NO production and a constituent in our diet, can be recycled back to bioactive NO. We investigated if preoperative administration of inorganic nitrate could reduce troponin T release and other plasma markers of injury to the heart, liver, kidney, and brain in patients undergoing cardiac surgery.

Methods: This single-centre, randomised, double-blind, placebo-controlled trial included 82 patients undergoing coronary artery bypass surgery with cardiopulmonary bypass. Oral sodium nitrate (700 mg×2) or placebo (NaCl) were administered before surgery. Biomarkers of ischaemia-reperfusion injury and plasma nitrate and nitrite were collected before and up to 72 h after surgery. Troponin T release was our predefined primary endpoint and biomarkers of renal, liver, and brain injury were secondary endpoints.

Results: Plasma concentrations of nitrate and nitrite were elevated in nitrate-treated patients compared with placebo. The 72-h release of troponin T did not differ between groups. Other plasma biomarkers of organ injury were also similar between groups. Blood loss was not a predefined outcome parameter, but perioperative bleeding was 18% less in nitrate-treated patients compared with controls.

Conclusion: Preoperative administration of inorganic nitrate did not influence troponin T release or other plasma biomarkers of organ injury in cardiac surgery.

Clinical trial registration: NCT01348971.

Keywords: bleeding; cardiac surgery; ischaemia-reperfusion injury; nitrate; nitric oxide; nitrite; perioperative.

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Fig 1
Fig 1
Enrolment and randomisation in the CABANOS trial. Patients were randomised in blocks of four to intervention with sodium nitrate or sodium chloride (placebo) before coronary artery bypass surgery.
Fig 2
Fig 2
Plasma nitrate (a) and nitrite (b) in the placebo and nitrate groups after induction of anaesthesia and at the end of cardiopulmonary bypass (CPB). Individual values and line indicating median. ∗P<0.001.
Fig 3
Fig 3
The cardiac biomarkers troponin T, creatine phosphokinase-myocardial band (CK-MB) and natriuretic peptide proB-type (pro-BNP) during the 72-h perioperative period. 0=baseline. Data are shown in median and inter-quartile range (IQR). Ane, start of anaesthesia; CPB, end of cardiopulmonary bypass.
Fig 4
Fig 4
Neuron specific enolase (NSE), S100B protein (S100B), and high sensitivity C-reactive protein (hsCRP) during the 72-h perioperative period. 0=baseline. Data are shown in median and inter-quartile range (IQR). Ane, start of anaesthesia; CPB, end of cardiopulmonary bypass.
Fig 5
Fig 5
Perioperative (Perop), postoperative (Postop), and total summarised (Total) blood loss in subjects receiving placebo or nitrate, shown in median and inter-quartile range. ∗P<0.05, ∗∗P<0.01.
Supplement Figure 1
Supplement Figure 1
Renal and hepatic biomarkers, Creatinine, Cystatin C, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and bilirubin during the 72-hour perioperative period. 0 = baseline, Ane = start of anaesthesia, CPB = end of cardiopulmonary bypass. Data are shown in median and interquartile range (IQR).
Supplement Figure 2
Supplement Figure 2
Circulatory parameters and laboratory values during the perioperative period of 24 hours. SAP= systolic artery blood pressure. 0 = baseline, Ane = start of anaesthesia, CPB = end of cardiopulmonary bypass, ICU = Intensive care unit. Data are shown in mean and standard deviation (SD).

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