Protocol of a randomised controlled trial in cardiac surgical patients with endothelial dysfunction aimed to prevent postoperative acute kidney injury by administering nitric oxide gas

Abstract

Introduction: Postoperative acute kidney injury (AKI) is a common complication in cardiac surgery. Levels of intravascular haemolysis are strongly associated with postoperative AKI and with prolonged (>90 min) use of cardiopulmonary bypass (CPB). Ferrous plasma haemoglobin released into the circulation acts as a scavenger of nitric oxide (NO) produced by endothelial cells. Consequently, the vascular bioavailability of NO is reduced, leading to vasoconstriction and impaired renal function. In patients with cardiovascular risk factors, the endothelium is dysfunctional and cannot replenish the NO deficit. A previous clinical study in young cardiac surgical patients with rheumatic fever, without evidence of endothelial dysfunction, showed that supplementation of NO gas decreases AKI by converting ferrous plasma haemoglobin to ferric methaemoglobin, thus preserving vascular NO. In this current trial, we hypothesised that 24 hours administration of NO gas will reduce AKI following CPB in patients with endothelial dysfunction.

Methods: This is a single-centre, randomised (1:1) controlled, parallel-arm superiority trial that includes patients with endothelial dysfunction, stable kidney function and who are undergoing cardiac surgery procedures with an expected CPB duration >90 min. After randomisation, 80 parts per million (ppm) NO (intervention group) or 80 ppm nitrogen (N2, control group) are added to the gas mixture. Test gases (N2 or NO) are delivered during CPB and for 24 hours after surgery. The primary study outcome is the occurrence of AKI among study groups. Key secondary outcomes include AKI severity, occurrence of renal replacement therapy, major adverse kidney events at 6 weeks after surgery and mortality. We are recruiting 250 patients, allowing detection of a 35% AKI relative risk reduction, assuming a two-sided error of 0.05.

Ethics and dissemination: The Partners Human Research Committee approved this trial. Recruitment began in February 2017. Dissemination plans include presentations at scientific conferences, scientific publications and advertising flyers and posters at Massachusetts General Hospital.

Trial registration number: NCT02836899.

Keywords: acute kidney injury; cardiopulmonary bypass; endothelial dysfunction; hemolysis; nitric oxide.

Conflict of interest statement

Competing interests: FM and LB salaries are partially supported by NIH/NHLBI 1 K23 HL128882-01A1. JB is co-inventor on patents that are assigned to Partners Healthcare. RMK is a consultant for Medtronic and Orange Medical and has received research grants from Medtronic and Venner Medical.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Study design. After placement of pulmonary artery catheter, to ensure balance between study groups with respect to the likelihood of receiving NO after surgery, patients are randomised based on mPAP measured by the pulmonary artery catheter placed on the day of surgery (mPAP 2, nitrogen; NO, nitric oxide.

Figure 2

Screening questionnaire to detect endothelial dysfunction. The questionnaire above aims to systematically detect endothelial dysfunction in patients undergoing a cardiac surgical procedure. If ‘yes’ is answered to at least one of the above questions, the patient can be considered to have endothelial dysfunction and he/she may be enrolled in the study. BMI, body mass index; CABG, coronary artery bypass surgery; IDDM, insulin-dependent diabetes mellitus; LDL, low-density lipoprotein; NIDDM, non-insulin dependent diabetes mellitus; PTCA, percutaneous transluminal coronary angioplasty; SBP, systolic blood pressure.

Figure 3

Schema of the NO delivery systems in the operating room. (A) Figure illustrating how the NO or N2 is delivered into the CPB oxygenator. Tanks of pure N2 are used in the control group and tanks of 850 ppm NO in N2 are used in the intervention group. A ‘Y’ adaptor is inserted into the sweep gas input line leading to the oxygenator. This allows for the mixing of the test gas with the sweep gas (O2+medical air). This mixture is periodically monitored with an NO/NO2 analyser directly before entering the oxygenator. (B) Figure illustrating how the NO or N2 is delivered into the anaesthesia ventilator once ventilation has been resumed. The test gas is delivered by placing a ‘Y’ adaptor into the inspiratory limb of the circuit. The mixture is scrubbed of NO2 by a large volume scavenger containing calcium hydroxide and is periodically analysed with a NO/NO2 analyser before being inhaled by the patient. CPB, cardiopulmonary bypass; N2, nitrogen; NO, nitric oxide.

Figure 4

Schema of the NO delivery systems in the cardiac surgical intensive care unit. (A) Figure illustrating how the NO or N2 is delivered through the mechanical ventilator at bedside in the intensive care unit. Tanks of pure N2 are used in the control group and tanks of 850 ppm NO in N2 are used in the intervention group. Test gas is blended with medical air and enters the air inlet of the ventilator. The high pressure O2 hose is directly connected to the ventilator. If there is any change of FiO2, the amount of NO/N2 delivered is regulated by the RT by adjusting the blender setting and the ventilator FiO2 setting, ensuring that the patient is still receiving the target concentration of 80 ppm NO. The mixture obtained is then scrubbed of NO2 through a large volume scavenger and a small volume scavenger placed in series on the inspiratory limb of the circuit. The final amount of NO and NO2 delivered is periodically analysed with a NO/NO2 analyser directly before the mixture is inhaled by the patient. (B) Figure illustrating how the NO or N2 is delivered into the high flow nasal cannula device. The test gas is delivered to the system by placing ‘Y’ adaptor before the humidifier. A commercially available blender mixes O2 and medical air and is regulated by the RT to reach the target FiO2. The flow of NO2 or N2 is titrated to reach the desired concentration 80 ppm NO or placebo. This mixture is then humidified and heated to a temperature of 34°C. FiO2, inspired fraction of oxygen; N2, nitrogen; NO, nitric oxide; O2, oxygen; ppm, parts per million; RT, respiratory therapist