Intensive Care Medicine

, Volume 42, Issue 11, pp 1744–1752 | Cite as

Nitric oxide administration during paediatric cardiopulmonary bypass: a randomised controlled trial

  • Christopher James
  • Johnny Millar
  • Stephen Horton
  • Christian Brizard
  • Charlotte Molesworth
  • Warwick Butt
Pediatric Original



Cardiopulmonary bypass induces an ischaemia–reperfusion injury and systemic inflammatory response, which contributes to low cardiac output syndrome following cardiac surgery. Exogenous nitric oxide during cardiopulmonary bypass has shown potential to ameliorate such injury. We undertook a large randomised controlled trial to investigate the clinical effects of administering nitric oxide to the cardiopulmonary bypass circuit in children.


After written informed consent, children were randomised to receive 20 ppm nitric oxide to the gas inflow of the cardiopulmonary bypass oxygenator, or standard conduct of bypass.


101 children received nitric oxide and developed low cardiac output syndrome less frequently (15 vs. 31 %, p = 0.007) than the 97 children who did not receive nitric oxide. This effect was most marked in children aged less than 6 weeks of age (20 vs. 52 %, p = 0.012) and in those aged 6 weeks to 2 years (6 vs. 24 %, p = 0.026), who also had significantly reduced ICU length of stay (43 vs. 84 h, p = 0.031). Low cardiac output syndrome was less frequent following more complex surgeries if nitric oxide was administered (17 vs. 48 %, p = 0.018). ECMO was used less often in the nitric oxide group (1 vs. 8 %, p = 0.014).


Delivery of nitric oxide to the oxygenator gas flow during paediatric cardiopulmonary bypass reduced the incidence of low cardiac output syndrome by varying degrees, according to age group and surgery complexity.

Clinical Trial Registration: ACTRN12615001376538.


Cardiopulmonary bypass Nitric oxide Low cardiac output syndrome Congenital heart disease 


Compliance with ethical standards

Funding sources


Conflicts of interest

WB has received payment for educational activities by Ikaria Australia.

Supplementary material

134_2016_4420_MOESM1_ESM.docx (18 kb)
Supplementary material 1 (DOCX 18 kb)
134_2016_4420_MOESM2_ESM.tif (93 kb)
Supplementary Figure 1. Time of diagnosis of LCOS


  1. 1.
    Wernovsky G, Wypij D, Jonas RA, Mayer JE, Hanley FL, Hickey PR, Walsh AZ, Chang AC, Castaneda AR, Newburger JW, Wesser DL (1995) Postoperative course and haemodynamic profile after the arterial switch operation in neonates and infants: a comparison of low-flow cardiopulmonary bypass and circulatory arrest. Circulation 92:2226–2235CrossRefPubMedGoogle Scholar
  2. 2.
    Hoffman TM, Wernovsky G, Atz AM, Kulik TJ, Nelson DP, Chang AC, Bailey JM, Akbary A, Kocsis JF, Kaczmarek R, Spray TL, Wessel DL (2003) Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Circulation 107:996–1002CrossRefPubMedGoogle Scholar
  3. 3.
    Ma M, Guavreau K, Allan CK, Mayer JE, Jenkins JK (2007) Causes of death after congenital heart surgery. Ann Thorac Surg 83(4):1438–1445CrossRefPubMedGoogle Scholar
  4. 4.
    Paparella D, Yau TM, Young E (2002) Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. An update. Eur J Cardiothorac Surg 21:232–244CrossRefPubMedGoogle Scholar
  5. 5.
    Guzik TJ, Korbut R, Adamek-Guzik T (2003) Nitric oxide and superoxide in inflammation and immune regulation. J Physiol Pharmacol 54(4):469–487PubMedGoogle Scholar
  6. 6.
    Rossaint R, Lewandowski K, Zapol WM (2014) Our paper 20 years later: inhaled nitric oxide for the acute respiratory distress syndrome—discovery, current understanding, and focussed targets of future applications. Intensive Care Med 40(11):1649–1658CrossRefPubMedGoogle Scholar
  7. 7.
    Uchiyama T, Otani H, Okada T, Ninomiya H, Kido M, Imamura H (2002) Nitric oxide induces caspase-dependent apoptosis and necrosis in neonatal rat cardiomyocytes. J Mol Cell Cadiol 34:1049–1061CrossRefGoogle Scholar
  8. 8.
    Sawicki G, Salas E, Murat J, Miszta-Lane H, Radomski MW (1997) Release of gelatinase A during platelet activation mediates aggregation. Nature 386:616–619CrossRefPubMedGoogle Scholar
  9. 9.
    Comini L, Bachetti T, Agnoletti L, Gaia G, Curello S, Milanesi B (1999) Induction of functional inducible nitric oxide synthetase in monocytes of patients with congestive heart failure: link with tumour necrosis factor-alpha. Eur Heart J 20:1503–1513CrossRefPubMedGoogle Scholar
  10. 10.
    Van Dervort AL, Yan L, Madara PJ, Cobb JP, Wesley RA, Corriveau CC (1994) Nitric oxide regulates endotoxin-induced TNF-alpha production by human neutrophils. J Immunol 152:4102–4109PubMedGoogle Scholar
  11. 11.
    Zakkar M, Guida G, Suleiman MS, Angelini GD (2015) Cardiopulmonary bypass and oxidative stress. Oxid Med Cell Longev 2015:189863CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Phillips L, Toledo AH, Lopez-Neblina F, Anaya-Prado R, Toledo-Pereyra LH (2009) Nitric oxide mechanism of protection in ischaemia and reperfusion injury. J Invest Surg 22(1):46–55CrossRefPubMedGoogle Scholar
  13. 13.
    Godiez-Rubi M, Rojas-Mayorquin AE, Ortuno-Satiaguin D (2013) Nitric oxide donors as neuroprotective agents after ischaemic stroke related inflammatory reaction. Oxid Med Cell Longev 2013:297357. doi: 10.1155/2013/297357
  14. 14.
    Jones SP, Bolli R (2006) The ubiquitous role of nitric oxide in cardioprotection. J Mol Cell Cardiol 40(1):16–23CrossRefPubMedGoogle Scholar
  15. 15.
    Lin X, Huang Y, Pokreisz P, Vermeersch P, Marsboom G, Swinnen M, Verbeken E, Santos J, Pelles M, Gillijns H, Van de Wert F, Bloch K, Janssens S (2007) Nitric oxide inhalation improves microvascular flow and decreases infarction size after myocardial ischaemia and reperfusion. J Am Coll Cardiol 50(8):808–817CrossRefGoogle Scholar
  16. 16.
    Nagasaka Y, Fernandez BO, Garcia-Saura MF, Petersen B, Ichinose F, Bloch KD, Feelisch M, Zapol WM (2008) Brief periods of nitric oxide inhalation protect against myocardial ischaemia-reperfusion injury. Anesthesiology 109(4):675–682CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gianetti J, Del Sarto P, Bevilacqua S, Vassalle C, De Filippis R, Kacila M, Farreti PA, Clerico A, Glauber M, Biagini A (2004) Supplemental nitric oxide and its effect on myocardial injury and function in patients undergoing cardiac surgery with extracorporeal circulation. J Thorac Cardiovasc Surg 127(1):44–50CrossRefPubMedGoogle Scholar
  18. 18.
    Checchia P, Bronicki R, Muenzer J, Dixon D, Raithel S, Gandhi S, Huddleston C (2013) Nitric oxide delivery during cardiopulmonary bypass reduces postoperative morbidity in children—a randomised controlled trial. J Thorac Cardiovasc Surg 146(3):530–536CrossRefPubMedGoogle Scholar
  19. 19.
    James C, Horton S, Brizard C, Molesworth C, Millar J, Butt W (2015) Nitric oxide during cardiopulmonary bypass improves clinical outcome: a blinded, randomized controlled trial. Circulation 132:A14827Google Scholar
  20. 20.
    Gaies M, Gurney J, Yen A, Napoli M, Gajarski R, Ohye R, Charpie J, Hirsch J (2010) Vasoactive-inotrope score as a predictor of morbidity and mortality in infants after cardiopulmonary bypass. Pediatr Crit Care Med 11:234–238CrossRefPubMedGoogle Scholar
  21. 21.
    Duke T, Stocker C, Butt W (2004) Monitoring children after cardiac surgery: a minimalist approach might be maximally effective. Crit Care Res 6:306–310Google Scholar
  22. 22.
    Robert S, Borasino S, Dabal R, Cleveland D, Hock K, Alten J (2015) Postoperative hydrocortisone infusion reduces the prevalence of low cardiac output syndrome after neonatal cardiopulmonary bypass. Pediatr Crit Care Med 16(7):629–636CrossRefPubMedGoogle Scholar
  23. 23.
    Oualha M, Urien S, Spreux-Varoquaux O, Bordessoule A, D’Agostino I, Pouard P, Treluyer JM (2014) Pharmacokinetics, haemodynamic and metabolic effects of epinephrine to prevent post-operative low cardiac output syndrome in children. Crit Care 18(1):R23CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kleiber N, de Wildt S, Cortina G, Clifford M, van Rosmalen J, van Dijk M, Tibboel D, Millar J (2016) A comparative analysis of pre-emptive versus targeted sedation on cardiovascular stability after high-risk cardiac surgery in infants. Pediatr Crit Care Med 17(4):321–331CrossRefPubMedGoogle Scholar
  25. 25.
    Kozik DJ, Tweddell JS (2006) Characterizing the inflammatory response to cardiopulmonary bypass in children. Ann Thorac Surg 81(6):S2347–S2354CrossRefPubMedGoogle Scholar
  26. 26.
    Bronicki RA, Chang AC (2011) Management of the postoperative pediatric cardiac surgical patient. Crit Care Med 39(8):1974–1984CrossRefPubMedGoogle Scholar
  27. 27.
    Mascio CE, Austin EH, Jacobs JP, Jacobs ML, Wallace AS, He X, Pasquali SK (2014) Perioperative mechanical circulatory support in children: an analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database. J Thorac Cardiovasc Surg 147(2):658–665CrossRefPubMedGoogle Scholar
  28. 28.
    Lei C, Berra L, Rezoagali E, Yu B, Strelow S, Nordio F, Bonventre J, Xiong L, Zapol W (2015) Prevention of acute kidney injury by nitric oxide during and after prolonged cardiopulmonary bypass. A double blind randomized controlled trial. Abstract presentation, American Heart Association Scientific Sessions, Orlando, Florida, Nov 2015Google Scholar
  29. 29.
    Rassaf T, Kleinbongard P, Kelm M (2005) Circulating NO pool in humans. Kidney Blood Press Res 28:341–348CrossRefPubMedGoogle Scholar
  30. 30.
    Bhatraju P, Crawford J, Hall M, Lang JD (2015) Inhaled nitric oxide: current clinical concepts. Nitric Oxide 31(50):114–128CrossRefGoogle Scholar
  31. 31.
    Liu C, Liu X, Janes J, Stapley R, Patel RP, Gladwin MT, Kim-Shapiro DB (2014) Mechanism of faster NO scavenging by older stored red blood cells. Redox Biol 10(2):211–219CrossRefGoogle Scholar
  32. 32.
    Zimring JC (2015) Established and theoretical factors to consider in assessing the red cell storage lesion. Blood 125(14):2185–2190CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Fischer UM, Schindler R, Brixius K, Mehlhorn U, Bloch W (2007) Extracorporeal circulation activates endothelial nitric oxide synthase in erythrocytes. Ann Thorac Surg 84(6):2000–2003CrossRefPubMedGoogle Scholar
  34. 34.
    Bolli R (2001) Cardioprotective function of inducible nitric oxide synthase and role of nitric oxide in myocardial ischaemia and preconditioning: an overview of a decade of research. J Mol Cell Cardiol 33(11):1897–1918CrossRefPubMedGoogle Scholar
  35. 35.
    Lang JD, Smith AB, Brandon A, Bradley KM, Liu Y, Li W, Crowe DR, Jhala NC, Cross RC, Frennette L, Martay K, Vater YL, Vitin AA, Dembo GA, DuBay DA, Bynon JS, Szychowski JM, Reyes JD, Halldorson JB, Rayhill SC, Dick AA, Bakthavatsalam R, Brandenberger J, Broeckel-Elrod JA, Sissons-Ross L, Jordan T, Chen LY, Siriussawakul A, Eckhoff DE, Patel RP (2014) A randomized clinical trial testing the anti-inflammatory effects of preemptive inhaled nitric oxide in human liver transplantation. PLoS One 9(2):e86053CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Mathru M, Huda R, Solanki DR, Hays S, Lang JD (2007) Inhaled nitric oxide attenuates reperfusion inflammatory responses in humans. Anesthesiology 106(2):275–282CrossRefPubMedGoogle Scholar
  37. 37.
    Keh D, Gerlach M, Kurer KJ, Gerlach H (1996) Reduction of platelet trapping in membrane oxygenators by transmembraneous application of gaseous nitric oxide. Int J Artif Organs 19(5):291–293PubMedGoogle Scholar
  38. 38.
    Mellgren K, Friberg LG, Mellgren G, Hedner T, Wennmalm A, Wadenvik H (1996) Nitric oxide in the oxygenator sweep gas reduces platelet activation during experimental perfusion. Ann Thorac Surg 61(4):1194–1198CrossRefPubMedGoogle Scholar
  39. 39.
    Chello M, Mastroroberto P, Marchese AR, Maltese G, Santangelo E, Amantea B (1998) Nitric oxide inhibits neutrophil adhesion during experimental extracorporeal circulation. Anesthesiology 89(2):443–448CrossRefPubMedGoogle Scholar
  40. 40.
    Harvey MJ, Gaies MG, Prosser LA (2015) US and international in-hospital costs of extracorporeal membrane oxygenation: a systematic review. Appl Health Econ Health Policy 13(4):341–357CrossRefPubMedGoogle Scholar
  41. 41.
    Maitre B, Djibre M, Katsahian S, Habibi A, Stankovic Stojanovic K, Khellaf M, Bourgeon I, Lionnet F, Charles-Nelson A, Brochard L, Lemaire F, Galacteros F, Brun-Buisson C, Fartoukh M, Mekontso Dessap A (2015) Inhaled nitric oxide for acute chest syndrome in adult sickle cell patients: a randomized controlled study. Intensive Care Med 41(12):2121–2129CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2016

Authors and Affiliations

  1. 1.Department of Intensive CareRoyal Children’s HospitalMelbourneAustralia
  2. 2.Murdoch Children’s Research InstituteMelbourneAustralia
  3. 3.Perfusion DepartmentRoyal Children’s HospitalMelbourneAustralia
  4. 4.Department of Cardiac SurgeryRoyal Children’s HospitalMelbourneAustralia
  5. 5.Department of PaediatricsUniversity of MelbourneMelbourneAustralia

Personalised recommendations