Nitric Oxide for Reduced Intensive Support in Cardiac Surgery With Cardiopulmonary Bypass

NCT06702553 | Recruiting Phase 3 DMC FDA Drug

• 1 other identifier: KY20242322
• Study Type: interventional
• Target: 3,650
• Locations: 3 countries
• Sites: 3

Brief Summary

Cardiac surgery is a procedure that is commonly performed worldwide. Despite these technological advances, cardiac surgery remains a high-risk surgery. Among post-operative complications, acute kidney injury, respiratory failure, myocardial infarction, and stroke as well as cognitive dysfunction are significant causes of mortality in patients undergoing and following cardiac surgery. Inhaled nitric oxide (NO) therapy as a selective pulmonary vasodilator in cardiac surgery has been one of the most significant pharmacological advances in managing pulmonary hemodynamics and life threatening right ventricular dysfunction and failure. In addition, newer applications show greater promise of inhaled NO as a therapy in the area of cardiac surgery associated acute kidney injury and ischemia reperfusion. However, this remarkable expectation to inhaled NO has experienced a roller-coaster ride with high hopes and nearly universal demonstration of physiological benefits but disappointing translation of these benefits to harder clinical outcomes, like mortality. Most of our understanding on the iNO field in cardiac surgery stems from small observational or single center randomized trials, which failed to ascertain strong evidence base. As a consequence, there are only week clinical practice guidelines on the field and only European expert opinion for the use of iNO in routine and more specialized cardiac surgery. There is need for a large multicenter randomized controlled study to confirm the administration of iNO as an effective weapon for the battle against life threatening complication in high risk cardiac surgical patients. In a previous meta analysis with 27 studies included, we demonstrated that inhaled nitric oxide (NO) could reduce the duration of mechanical ventilation and reducing biomarkers of organ injury and clinical signs of organ dysfunction in cardiac surgery under cardiopulmonary bypass (CPB) , but had no significance in the ICU stay, hospital stay, and mortality. This may be attributed to the small sample size of the most included studies (of the 27 studies included, 20 studies with sample size less than 100) and heterogeneity in timing, dosage and duration of iNO administration. Well-designed, large-scale, multicenter clinical trials are needed to further explore the effect of iNO in improving postoperative prognosis in cardiovascular surgical patients. We are planning a large multicenter controlled randomized trial to demonstrate that inhaled nitric oxide can reduce composite outcome of death and Major Adverse Events (MAEs), including need for intensive supports due to heart failure, low cardiac output sydrome, or renal failure, respiratory failure, etc., and myocardial infarction, stroke, and sepsis at 30 days after surgery from 20% to 16% in patient undergoing cardiac surgery with cardiopulmonary bypass. If the hypothesis had been proved and validated, the results of this study can provide strong evidence for guidelines to facilitate the routine use of iNO in all cardiopulmonary bypass assisted cardiac procedures with 31,800 postoperative outcomes improved per year in US and in China.

Conditions

Nitric Oxide; Cardiac Surgery; Cardiopulmonary Bypass; Adult Patients Undergoing Cardiovascular Surgery With Cardiopulmonary Bypass

Keywords

Nitric Oxide; cardiopulmonary bypass; major adverse events; cardiac surgery; complications; Organ protection

Outcome Measures

Primary Outcomes (1)

• Composite outcome of death and major adverse events requiring intensive life supports

  It is composite outcome including: * all cause mortality; * ischemic events(myocardial infarction, ischemic stroke, and pulmonary embolism) , * Cardiac arrest that had been successfully resuscitated or new onset of acute cardiac failure (low output syndrome) requiring IABP, ECMO, left ventricular assist device, cardiac dysfunction need for large dose of inotrope support, ---Stage 3 AKI or Renal failure that required renal replacement therapy, * prolonged mechanical ventilation (\> 24h ), * re-sternotomy for any indication, * major arrhythmia ((Ventricular fibrilliation or ventricular tachycardia after weaning-off cardiopulmonary bypass, new onset atrial fibrillation requiring anticoagulant therapy or other intervention upon discharge from the hospital); * sepsis

  within 30 days after operation

Secondary Outcomes (13)

• Total number of major adverse events (MAEs)

  within 30 days after operation

• Incidence of the MAEs

  within 30 days after operation

• All AKI incidence

  within 7 days of surgery

• Length of mechanical ventilation

  within 30 days after operation

• Readmission

  within 30 days after operation

Other Outcomes (7)

• Blood transfusion

  during postoperative hospitalization, with an average of 10 days

• Blood loss

  during the first 72 hours after surgery

• Incidence of prolonged cardiovascular support

  during postoperative hospitalization, with an average of 10 days.

Study Arms (2)

Intervention: iNO Group

EXPERIMENTAL

Patients will receive 80 parts per million (ppm) NO during CPB through the oxygenator. After weaning of CPB, test gases will be delivered via inspiration limb of ventilator at a dose range of 40-80 ppm until 6 hours after ICU admission or until extubation after surgery, whichever comes first.

Drug: Nitric Oxide Gas

Standard Care/Control Group

PLACEBO COMPARATOR

Patients in this group will receive standard care and 80 ppm nitrogen (N2, control group) are added to the gas mixture as control. In the circumstances when the N2 is not applicable, such as when the plasma-chemical NO synthesis device is employed for NO generatiaon and delivery, the device will be connected to the CPB and ventilator circuits, but the synthesis will remain inactive in the control group. Consequently, the circuit will be supplied with air devoid of NO.

Drug: Standard Care Arm

Interventions

Nitric Oxide Gas DRUG

Patients will receive 80 parts per million (ppm) NO during CPB through the oxygenator. After weaning of CPB, test gases will be delivered via inspiration limb of ventilator at a dose range of 40-80 ppm until 6 hours after ICU admission or until extubation after surgery, whichever comes first.

Also known as: Nitric Oxide inhalation

Intervention: iNO Group

Standard Care Arm DRUG

Patients in this group will receive standard care and 80 ppm nitrogen (N2, control group) are added to the gas mixture as control. In the circumstances when the N2 is not applicable, such as when the plasma-chemical NO synthesis device is employed for NO generatiaon and delivery, the device will be connected to the CPB and ventilator circuits, but the synthesis will remain inactive in the control group. Consequently, the circuit will be supplied with air devoid of NO.

Also known as: Nitrogen inhalation

Standard Care/Control Group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years.
• Elective cardiac or aortic surgery requiring CPB
• Without history of previous open heart surgery.

You may not qualify if:

• Immediate emergency cardiac surgery;
• Cardiac surgery that requires deep hypothermic circulatory arrest;
• Planned cardiac surgery for congenital heart disease repair;
• Planned for heart transplatation
• Ongoing heart failure or low output syndrome already on intensive support (IABP, ECMO, left ventricular assist device such as impella, mechanical ventilation), left ventricular ejection fraction of \< 30% or comparable, equivalent preoperative conditions
• Already accepted or currently on inhaled NO therapy or inhaled/aerosolized prostacyclin in the week prior to the enrollment;
• Endstage kidney disease with estimated glomerular filtration rate (eGFR) \< 15 ml/min or already on renal replacement surgery.
• Hemophilia A or B
• Other terminal stage of chronic disease with life expectancy less than 1 year per evaluation and adjudication of the attending physicians.

Sponsors & Collaborators

• Xijing Hospital: lead
• Nikolay O. Kamenshchikov., M.D., Tomsk National Research Medical Center of the Russian Academy of Sciences: collaborator
• Lorenzo Berra., M.D., Massachusetts General Hospital: collaborator
• Jiange Han, Tianjin Chest Hospital, Tianjin, China: collaborator
• Qingping Wu, Wuhan Union Hospital, Wuhan, China: collaborator
• Evgeniy Grigoriev, Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russian Federation: collaborator
• Vladimir Boboshko, E. Meshalkin National Medical Research Center, Novosibirsk, Russian Federation: collaborator
• Andrei Bautin, The Almazov National Medical Research Centre, St. Petersburg, Russian Federation: collaborator
• Vladimir Pichugin, Specialized Cardiac Surgery Clinical Hospital named after Academician B.A. Korolev, Nizhny Novgorod, Russian Federation: collaborator
• Evgeniy Rosseykin, Federal Center of Cardiovascular Surgery, Khabarovsk, Russian Federation: collaborator
• Sheng Wang, Anzhen Hospital, Beijing, China: collaborator

Study Sites (3)

Massachusetts General Hospital, Department of Anesthesia, Critical Care and Pain Medicine

Boston, Massachusetts, 02114, United States

NOT YET RECRUITING

Xijing Hospital

Xi'an, Shaanxi, 710032, China

RECRUITING

Cardiology Research Institute, Tomsk National Research Medical Center

Tomsk, 634012, Russia

NOT YET RECRUITING

Related Publications (15)

• Yan Y, Kamenshchikov N, Zheng Z, Lei C. Inhaled nitric oxide and postoperative outcomes in cardiac surgery with cardiopulmonary bypass: A systematic review and meta-analysis. Nitric Oxide. 2024 May 1;146:64-74. doi: 10.1016/j.niox.2024.03.004. Epub 2024 Mar 29.

  PMID: 38556145 BACKGROUND

• Abouzid M, Roshdy Y, Daniel JM, Rzk FM, Ismeal AAA, Hendawy M, Tanashat M, Elnagar M, Daoud N, Ramadan A. The beneficial use of nitric oxide during cardiopulmonary bypass on postoperative outcomes in children and adult patients: a systematic review and meta-analysis of 2897 patients. Eur J Clin Pharmacol. 2023 Nov;79(11):1425-1442. doi: 10.1007/s00228-023-03554-9. Epub 2023 Aug 31.

  PMID: 37650923 BACKGROUND

• Strong C, Raposo L, Castro M, Madeira S, Tralhao A, Ventosa A, Rebocho MJ, Almeida M, Aguiar C, Neves JP, Mendes M. Haemodynamic effects and potential clinical implications of inhaled nitric oxide during right heart catheterization in heart transplant candidates. ESC Heart Fail. 2020 Apr;7(2):673-681. doi: 10.1002/ehf2.12639. Epub 2020 Feb 11.

  PMID: 32045139 BACKGROUND

• Liu K, Wang H, Yu SJ, Tu GW, Luo Z. Inhaled pulmonary vasodilators: a narrative review. Ann Transl Med. 2021 Apr;9(7):597. doi: 10.21037/atm-20-4895.

  PMID: 33987295 BACKGROUND

• Janssens SP, Bogaert J, Zalewski J, Toth A, Adriaenssens T, Belmans A, Bennett J, Claus P, Desmet W, Dubois C, Goetschalckx K, Sinnaeve P, Vandenberghe K, Vermeersch P, Lux A, Szelid Z, Durak M, Lech P, Zmudka K, Pokreisz P, Vranckx P, Merkely B, Bloch KD, Van de Werf F; NOMI investigators. Nitric oxide for inhalation in ST-elevation myocardial infarction (NOMI): a multicentre, double-blind, randomized controlled trial. Eur Heart J. 2018 Aug 1;39(29):2717-2725. doi: 10.1093/eurheartj/ehy232.

  PMID: 29800130 BACKGROUND

• Signori D, Magliocca A, Hayashida K, Graw JA, Malhotra R, Bellani G, Berra L, Rezoagli E. Inhaled nitric oxide: role in the pathophysiology of cardio-cerebrovascular and respiratory diseases. Intensive Care Med Exp. 2022 Jun 27;10(1):28. doi: 10.1186/s40635-022-00455-6.

  PMID: 35754072 BACKGROUND

• Bowdish ME, D'Agostino RS, Thourani VH, Schwann TA, Krohn C, Desai N, Shahian DM, Fernandez FG, Badhwar V. STS Adult Cardiac Surgery Database: 2021 Update on Outcomes, Quality, and Research. Ann Thorac Surg. 2021 Jun;111(6):1770-1780. doi: 10.1016/j.athoracsur.2021.03.043. Epub 2021 Mar 29.

  PMID: 33794156 BACKGROUND

• Schaer DJ, Schaer CA, Humar R, Vallelian F, Henderson R, Tanaka KA, Levy JH, Buehler PW. Navigating Hemolysis and the Renal Implications of Hemoglobin Toxicity in Cardiac Surgery. Anesthesiology. 2024 Dec 1;141(6):1162-1174. doi: 10.1097/ALN.0000000000005109.

  PMID: 39159287 BACKGROUND

• Azem K, Novakovsky D, Krasulya B, Fein S, Iluz-Freundlich D, Uhanova J, Kornilov E, Eidelman LA, Kaptzon S, Gorfil D, Aravot D, Barac Y, Aranbitski R. Effect of nitric oxide delivery via cardiopulmonary bypass circuit on postoperative oxygenation in adults undergoing cardiac surgery (NOCARD trial): a randomised controlled trial. Eur J Anaesthesiol. 2024 Sep 1;41(9):677-686. doi: 10.1097/EJA.0000000000002022. Epub 2024 May 28.

  PMID: 39037709 BACKGROUND

• Kamenshchikov NO, Anfinogenova YJ, Kozlov BN, Svirko YS, Pekarskiy SE, Evtushenko VV, Lugovsky VA, Shipulin VM, Lomivorotov VV, Podoksenov YK. Nitric oxide delivery during cardiopulmonary bypass reduces acute kidney injury: A randomized trial. J Thorac Cardiovasc Surg. 2022 Apr;163(4):1393-1403.e9. doi: 10.1016/j.jtcvs.2020.03.182. Epub 2020 Jun 25.

  PMID: 32718702 BACKGROUND

• Lei C, Berra L, Rezoagli E, Yu B, Dong H, Yu S, Hou L, Chen M, Chen W, Wang H, Zheng Q, Shen J, Jin Z, Chen T, Zhao R, Christie E, Sabbisetti VS, Nordio F, Bonventre JV, Xiong L, Zapol WM. Nitric Oxide Decreases Acute Kidney Injury and Stage 3 Chronic Kidney Disease after Cardiac Surgery. Am J Respir Crit Care Med. 2018 Nov 15;198(10):1279-1287. doi: 10.1164/rccm.201710-2150OC.

  PMID: 29932345 BACKGROUND

• Muenster S, Zarragoikoetxea I, Moscatelli A, Balcells J, Gaudard P, Pouard P, Marczin N, Janssens SP. Inhaled NO at a crossroads in cardiac surgery: current need to improve mechanistic understanding, clinical trial design and scientific evidence. Front Cardiovasc Med. 2024 Apr 5;11:1374635. doi: 10.3389/fcvm.2024.1374635. eCollection 2024.

  PMID: 38646153 BACKGROUND

• David N, Lakha S, Walsh S, Fried E, DeMaria S Jr. Novel inhaled pulmonary vasodilators in adult cardiac surgery: a scoping review. Can J Anaesth. 2024 Aug;71(8):1154-1162. doi: 10.1007/s12630-024-02770-w. Epub 2024 May 23.

  PMID: 38782851 BACKGROUND

• Ghadimi K, Cappiello JL, Wright MC, Levy JH, Bryner BS, DeVore AD, Schroder JN, Patel CB, Rajagopal S, Shah SH, Milano CA; INSPIRE-FLO Investigators. Inhaled Epoprostenol Compared With Nitric Oxide for Right Ventricular Support After Major Cardiac Surgery. Circulation. 2023 Oct 24;148(17):1316-1329. doi: 10.1161/CIRCULATIONAHA.122.062464. Epub 2023 Jul 4.

  PMID: 37401479 BACKGROUND

• Benedetto M, Romano R, Baca G, Sarridou D, Fischer A, Simon A, Marczin N. Inhaled nitric oxide in cardiac surgery: Evidence or tradition? Nitric Oxide. 2015 Sep 15;49:67-79. doi: 10.1016/j.niox.2015.06.002. Epub 2015 Jul 14.

  PMID: 26186889 BACKGROUND

MeSH Terms

Interventions

Endothelium-Dependent Relaxing Factors

Intervention Hierarchy (Ancestors)

Vasodilator Agents; Cardiovascular Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Chong Lei, M.D., & phd

  Xijing Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Chong Lei, M.D., & phd

CONTACT

18629011362; crystalleichong@126.com

ziyu Zheng, ph.D.

CONTACT

13228082320; zhengziyu@126.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The intervention gas tanks and the gas delivery systems or the intervention gas generator system in the OR and at the bedside when patients in ICU are covered with drapes and masked that cannot be distinguished on the basis of appearance. This allows to keep participants, clinicians and investigators blind to the assignment group. For safety and gas monitoring, the clinician (or respiratory therapist) administering the test gas remains unblinded to the treatment. This unblinded clinician(or respiratory therapist) is solely responsible for gas tank preparation and test gas delivery and monitoring.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 18, 2024
• First Posted: November 25, 2024
• Study Start: May 19, 2025
• Primary Completion (Estimated): March 31, 2028
• Study Completion (Estimated): March 31, 2029
• Last Updated: July 15, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR, ANALYTIC CODE
• Time Frame: beginning 12 months after publication of the primary results
• Access Criteria: Investigators who provide a methodologically sound proposal and whose proposed use of data has been approved by the steering committee of NORISC. For instance for using IPD data for meta- analysis. Proposals should be submitted to principle investigator and the steering committee of the NORISC trial. To gain access, data requestors will need to sign a data access agreement.

Locations

RU (1); US (1); CN (1)