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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
  1. Francesco Marrazzo1,
  2. Stefano Spina1,
  3. Francesco Zadek1,
  4. Tenzing Lama1,
  5. Changhan Xu1,
  6. Grant Larson1,
  7. Emanuele Rezoagli1,
  8. Rajeev Malhotra2,
  9. Hui Zheng3,
  10. Edward A Bittner1,
  11. Kenneth Shelton1,
  12. Serguei Melnitchouk4,
  13. Nathalie Roy4,
  14. Thoralf M Sundt4,
  15. William D Riley5,
  16. Purris Williams6,
  17. Daniel Fisher7,
  18. Robert M Kacmarek8,9,
  19. Taylor B Thompson10,
  20. Joseph Bonventre11,
  21. Warren Zapol1,
  22. Fumito Ichinose1,
  23. Lorenzo Berra1
  1. 1 Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
  2. 2 Department of Medicine, Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA
  3. 3 Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
  4. 4 Department of Cardiac surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
  5. 5 Department of Surgery, Cardiac Surgery, Perfusion Services, Massachusetts General Hospital, Boston, Massachusetts, USA
  6. 6 Respiratory Care Services, Massachusetts General Hospital, Boston, Massachusetts, USA
  7. 7 Respiratory Care Services, Boston Medical Center, Boston, Massachusetts, USA
  8. 8 Department of Respiratory Care, Massachusetts General Hospital, Boston, USA
  9. 9 Department of Anesthesiology, Harvard University, Boston, USA
  10. 10 Department of Medicine, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
  11. 11 Department of Medicine, Division of Renal Medicine, Brigham and Women’s Hospital Department of Medicine, Boston, Massachusetts, USA
  1. Correspondence to Dr Lorenzo Berra; lberra{at}


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.

  • nitric oxide
  • hemolysis
  • acute kidney injury
  • cardiopulmonary bypass
  • endothelial dysfunction

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  • Contributors Authorship for this trial will be given to key personnel involved in trial design, personnel training, recruitment, data collection, statistical plan and data analysis. There are no publication restrictions. LB, WMZ, JVB, TBT, NR, EAB, TMS, DF, ER, FM and FI were responsible for conceptualising trial design. LB managed patient safety protocol. LB, FM, SS, FZ, CX, GL and TSL are responsible for recruitment, enrolment and data collection. RM, HZ and EAB are responsible for power calculation, statistical plan and data analysis. LB, KS, SM, WDR, PW and RMK trained personnel for the clinical trial and built systems for nitric oxide delivery and monitoring. All authors have critically revised the study protocol and approved the final version. All authors agree to be accountable for the accuracy and integrity of all aspects of this trial.

  • Funding Department of Anesthesia, Critical Care and Pain Medicine (Massachusetts General Hospital, Boston, Massachusetts, USA) and the National Institutes of Health (National Heart, Lung, and Blood Institute K23 HL128882-01A1).

  • 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.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent for publication Not required.

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