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

Effect of Inhaled Nitric Oxide on Major Adverse Events Requiring Intensive Life Support in Adults Undergoing Cardiac Surgery With Cardiopulmonary Bypass: A Phase III, Double-Blind, Multicenter, Randomized Controlled Trial (Nitric Oxide for Reduced Intensive Support in Cardiac Surgery With Cardiopulmonary Bypass, the NORISC Trial)

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.

Study Overview

• Status: Recruiting
• Conditions: Cardiac Surgery; Cardiopulmonary Bypass; Nitric Oxide; Adult Patients Undergoing Cardiovascular Surgery With Cardiopulmonary Bypass
• Intervention / Treatment: Drug: Nitric Oxide Gas; Drug: Standard Care Arm

Detailed Description

Cardiac surgery is a procedure that is commonly performed worldwide, and often requires the use of the cardiopulmonary bypass (CPB) machine to perform surgery on a non-beating heart. It was reported that the total volume of all cardiac surgical procedures in 2019 was 301,077 in US7 and 263, 292 in China in 2022, respectively.

Diseases of cardiovascular system confidently occupy the first place among the causes of disability and mortality in developed countries. In recent years, many clinicians, scientists, and engineers have been involved in efforts to develop safer procedures, novel biomaterials, heart substitutes, life-support systems, and safer methods to control cardiac arrhythmias and improve ventricular remodeling after injury. Progress in medicine over the past decades is clearly manifested in the rapid development of cardiovascular surgery. Despite these technological advances, cardiac surgery remains a high-risk surgery.

Cardiac surgery is accompanied by a number of complications. The perioperative mortality rate in the general population of cardiac surgery patients ranges from 2 to 10% depending on the type of surgery, the severity of left ventricular dysfunction and the presence of concomitant diseases . This pattern is true even for routine interventions with a relatively low risk of organ dysfunction , and with certain types of operations (combined interventions, reconstructive interventions on the ascending aorta and aortic arch, multivalve heart surgery) the incidence of severe organ dysfunction can increase to 70% with the need for supportive therapy in 16% of cases. Fundamental rationale, development and implementation of perioperative organ protection technologies into clinical practice will save the lives of up to 20 thousand people a year and save up to 1 billion US dollars for the healthcare system.

The search for an optimal strategy for adjuvant organ protection continues. It is extremely promising to identify potential pharmacological agents that are direct triggers or mediators of the implementation of the organoprotective phenotype during cardiac surgery. Among post-operative complications, acute kidney injury and renal failure, prolonged ventilation, 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) is a selective pulmonary vasodilator approved by the U.S. Food and Drug Administration(FDA) in 1999 for the treatment of persistent pulmonary hypertension of the newborn(PPHN). Inhaled NO has been largely used in Europe since 1992, and obtained the status of drug in France in 2001 and in Belgium in 2008. The European market authorizations (MA) defined 2 labeled indications: PPHN and treatment of PH related to cardiac surgery. The most common scenario for the commencement of iNO therapy in rountine cardiac surgery is postoperative right ventricular dysfunction of failure in the setting of increased pulmonary vascular resistance, which is related to pulmonary hypo-perfusion or activation of systemic inflammatory response. Cardiac procedures with prolonged CPB are associated with progressively high level of hemolysis, causing the release of free hemoglobin (fHb) and increase of NO inhibitor asymmetric dimethylarginine. The deoxygenation reaction with fHb and the inhibition of the endothelial NO synthetase cause vascular NO depletion leading to endothelial dysfunction and vasoconstriction. Inhaling NO can oxidize plasma Oxy-Hb to Met-Hb, thereby reducing plasma NO scavenging in the context of hemolysis. In a previous study, iNO showed promising benefits in lowering plasma NO consumption in presence of hemolysis. Supplementing NO into the CPB circuit could reduce NO consumption, possibly lowering postoperative systemic and pulmonary vascular resistance, and thus improving ventriculo-arterial coupling, cardiac output, and organ perfusion. In addition, CPB could induce systemic inflammation due to ischemic-reperfusion injury, which could contribute to myocardial dysfunction and to further decrease endogenous NO production. In this setting, inhaled NO could exert immune modulation and limit myocardial dysfunction. As many aspects of cardiac surgery including the pulmonary ischemia, the deleterious effects of cardiopulmonary bypass on pulmonary vasoactive impacts on PVR, endothelial dysfunction and NO pathways, treatment by supplemental delivery of NO seems logical. iNO has also been used following cardiac surgery, including after heart transplant to reduce afterload on the right ventricle with the goal of augmenting cardiac output and decreasing the risk of RV failure.

Two studies have been released showing that the addition of gaseous NO into the CPB circuit resulted in myocardial protection, a reduction in the length of mechanical ventilation, and postulated that this effect may be due to the anti-inflammatory properties of NO.In a recent multicenter, double-blind, randomized controlled trial of inhalation of NO in 250 patients with ST-elevation myocardial infarction (STEMI). Inhalation of NO at 80 ppm for 4 hrs in these patients after cardiac catheterization was safe, and there was a tendency toward decreased rates of adverse events at 4 months (P=0.10) and 1 year (P=0.06) in patients who received NO. The improvement in cardiac output in response to inhaled NO in patient undergoing cardiac surgery had been demonstrated in series of studies, the existing evidence fails to provide long-term morbidity or mortality data to support a benefit of these agents on clinical outcomes. Based on the available clinical evidence, there are only weak 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.

The improvement in cardiac output in response to inhaled NO in patient undergoing cardiac surgery had been demonstrated in series of studies, the existing evidence fails to provide long-term morbidity or mortality data to support a benefit of these agents on clinical outcomes. Recent evidence continued to demonstrate biological benefits, hemodynamically important physiological benefit and have begun to demonstrate some meaningful clinical outcomes such as reduction in duration of mechanical ventilation and stay in the intensive care unit. A few isolated reports also have suggested that the administration of inhaled NO improved the ability to separate from cardiopulmonary bypass during cardiac operations, decreased the need for inotropic or vasopressor support, decreased the duration of postoperative mechanical ventilation, and decreased intensive care unit (ICU) length of stay. It was demonstrated that iNO led to a small reduction of ICU stay in patients undergoing valve surgery in a sub analysis of a systemic review of 18 RCTs of adult cardiac surgery. However, these observed benefits have not been reproduced in other studies.

Whether or not treatment of pulmonary hypertension with Inhaled NO during cardiac surgery alters clinically important patient outcomes (ie, mortality and the length of ICU stay and hospitalization) is unknown. Recent systemic review that NO has minimal or null effect on major clinical outcomes. In a recent systemic review and meta-analysis of 10 studies including 434 patients, The authors concluded that inhaled NO improved right ventricular performance when compared to intravenously administered agents. However, iNO were not superior to placebo in terms of decreasing mortality and had no effect on length of hospitalization in adult patients undergoing cardiac surgery with cardiopulmonary bypass. The therapeutic potential of NO, combined with a good safety profile, justifies its use, despite the lack of definitive evidence demonstrating improved long-term outcomes or survival among cardiac surgery patients, heart transplant patients, lung transplant patients, and patients with implantable mechanical circulatory support devices. Despite an almost 30-year history of use, there is still no convincing evidence base and clear recommendations for the use of NO in cardiac surgery. There is insufficient evidence to reach a consensus regarding dosage, duration of therapy, or effect on patient outcomes, even for routine indications.

Based on the available clinical evidence, there are only weak 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.

Of the complications, acute kidney injury (AKI) is the single most common organ failure associated with cardiac surgery. Epidemiological data report that AKI associated with cardiac surgery may occur in about 30-70% of cases after cardiac surgery requiring CPB and up to 20% of patients need post-operative renal replacement therapy. Occurrence of AKI is associated with prolonged intensive care and step-down unit admission, increased perioperative cost of care, and most significantly, a higher postoperative morbidity and mortality. Prolonged CPB causes hemolysis with high levels of circulating plasma hemoglobin that scavenges NO via the deoxygenation reaction, depleting endogenous NO and casuing vasoconstriction, proximal renal tubular injury, and AKI.

Previously, our research group hypothesized that administration of 80 ppm NO during the prolonged CPB process and thereafter would preserve kidney function by converting plasma Hb into Met-Hb and preventing intrarenal oxidative reactions and NO scavenging. Then we conducted a single center, prospective, randomized, double-blind controlled trial involving 244 patients with normal kidney function who underwent elective multiple valve replacement surgery that required prolonged CPB. Inhaled NO at 80 ppm was delivered at the onset of CPB via the oxygenator and subsequently through the mechanical ventilator for up to 24 hours. The incidence of AKI in patients treated with NO decreased from 64% to 50% (P=0.014). The beneficial impact of NO was associated with a 22% relative risk reduction in AKI incidence, which translated into a 42% relative reduction of chronic renal function impairment. NO treatment resulted in fewer patients transitioning to stage 3 chronic kidney diseases (estimated glomerular filtration rate, eGFR < 60 ml/min/1.73 m2, 18% versus 31%). The Major Adverse Kidney Event (MAKE) index, defined as a composite outcome of loss of 25% of eGFR from baseline, end-stage renal disease requiring a continuous renal replacement therapy, and mortality, at 30 days, 90 days, and 1 year was more than halved in the NO treatment group. Among these Chinese patients requiring prolonged CPB, 80 ppm NO exposure not only decreased AKI incidence, and further reduced the transition to stage 3 CKD at 90 days and 1 year. However, due to the small sample size, only a trend of decreased mortality in the NO group was observed. Furthur, the leading PI of current trial of Russia, Kamenshchikov N.O et al. showed the nephroprotective effect of nitric oxide, by reducing markers of damage and improving the functional status of kidneys in the perioperative period in cardiac surgical patients operated on under CPB. The authors assessed the concentration of pro-inflammatory and anti-inflammatory mediators, the level of plasma free hemoglobin (fHb), as well as hemodynamic parameters, which did not differ significantly between groups. There were no clinically significant increases in NO2 in the inhaled air-gas mixture or serum methemoglobin (MetHb) concentrations.

To date, data from meta-analyses on the effect of nitric oxide on outcomes in cardiac surgery remain contradictory. Thus, it was shown that perioperative delivery of inhaled nitric oxide resulted in no or minimal benefit in patients with pulmonary hypertension undergoing cardiac surgery. In another meta-analysis, 5 studies and 579 patients were enrolled to investigate the effect of NO on renal function in patients undergoing cardiopulmonary bypass. It turned out that NO was associated with reduced risk of AKI when started from the beginning of CPB, which indicates the benefits of NO can only be exerted when NO was administered before the damage caused by CPB occur. The limitation of these systemic review is that the effect of iNO on mortality was not stated. The most recent meta-analysis to date has shown that using inhaled nitric oxide during cardiopulmonary bypass reduces the length of stay in the intensive care unit, and for children, it reduces the duration of mechanical ventilation. Thus, large randomized studies are required to ascertain the effect of NO on clinical outcomes in cardiac surgery under CPB and further determine the dosage, timing and duration of NO administration. A recent updated meta-analysis conducted by the our research group with 27 studies included, the pooled result demonstrated that iNO reduced the duration of mechanical ventilation, no significant benefits were detected on the ICU stay, hospital stay, and mortality in patients undergoing cardiac surgery. This may be attributed to the small sample size of the most included studies and heterogeneity in timing, dosage and duration of iNO administration.

Preliminary data support the effect of inhaled NO on reducing biomarkers of organ injury and clinical signs of organ dysfunction in cardiac surgery under CPB. Potentially, NO may improve clinical outcomes in cardiac surgery. However, the optimal therapeutic regimen for perioperative NO therapy is unknown. For this study, we chose NO concentration doses of up to 40 ppm during mechanical ventilation and 80 ppm during CPB as optimal for maximizing the organ-protective effects, as shown in previous studies, and at the same time such doses are considered safe. The results of current meta-analyses indicate that the strategy of iNO-mediated protection can reduce major complications. We hypothesize that the use of inhaled NO during surgery, during CPB, and also in the early postoperative period in the ICU at concentrations acceptable in clinical practice can prevent major organ failure and reduce the need for intensive replacement/maintenance therapy. The results of this study, if our hypothesis is confirmed, may bring benefits to society as improved outcomes of cardiac surgery, reduction of the financial burden and logistics challenges for the treatment of postoperative complications and subsequent rehabilitation of patients for the healthcare system, as well as the emotional and financial burden on patients and their families. To test this hypothesis we have designed this multicenter RCT.

In this, multi-center, randomized (1:1) controlled, parallel-arm superiority trial, we hypothesized that administration of NO gas starting from the initiation of CPB lasted until 6-hours after ICU admission or until extubation, whichever comes first, will decrease the incidence of major adverse events with reduced needs for intensive life supports, and so as to improved postoperative prognosis. This study was designed to determine whether NO administered during and after cardiac surgery reduces prespecified composite outcomes at 30 days after surgery.

• Study Type: Interventional
• Enrollment (Estimated): 3650
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Chong Lei, M.D., & phd; Phone Number: 18629011362; Email: crystalleichong@126.com
• Study Contact Backup: Name: ziyu Zheng, ph.D.; Phone Number: 13228082320; Email: zhengziyu@126.com

Study Locations

• China
  • Shaanxi
    • Xi'an, Shaanxi, China, 710032
      • Recruiting
      • Xijing Hospital
      • Contact: Chong Lei, MD & phD; Phone Number: 86-18629011362; Email: crystalleichong@126.com
      • Contact: Zefei Zhang, M.D.; Phone Number: 86-18811797795; Email: zzfanita7@163.com
• Russia
  • Tomsk, Russia, 634012
    • Not yet recruiting
    • Cardiology Research Institute, Tomsk National Research Medical Center
    • Contact: Nikolay O. Kamenshchikov, M.D.; Phone Number: 79138183657; Email: nikolajkamenof@mail.ru
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Not yet recruiting
      • Massachusetts General Hospital, Department of Anesthesia, Critical Care and Pain Medicine
      • Contact: Lorenzo Berra, M.D.; Phone Number: 6176437733; Email: lberra@mgh.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

Exclusion Criteria:

1. Immediate emergency cardiac surgery;
2. Cardiac surgery that requires deep hypothermic circulatory arrest;
3. Planned cardiac surgery for congenital heart disease repair;
4. Planned for heart transplatation
5. 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
6. Already accepted or currently on inhaled NO therapy or inhaled/aerosolized prostacyclin in the week prior to the enrollment;
7. Endstage kidney disease with estimated glomerular filtration rate (eGFR) < 15 ml/min or already on renal replacement surgery.
8. Hemophilia A or B
9. Other terminal stage of chronic disease with life expectancy less than 1 year per evaluation and adjudication of the attending physicians.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention: iNO Group; 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; 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.; Other Names: Nitric Oxide inhalation
Placebo Comparator: Standard Care/Control Group; 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; 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.; Other Names: Nitrogen inhalation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total number of major adverse events (MAEs)	Total number of major adverse events( MAEs) listed as the components of the primary outcomes.	within 30 days after operation
Incidence of the MAEs	Incidence of the MAEs listed as the components of the primary outcomes.	within 30 days after operation
All AKI incidence	AKI incidence which will be diagnosed by KDIGO criteria	within 7 days of surgery
Length of mechanical ventilation	Length of mechanical ventilation in hours	within 30 days after operation
Readmission	Readmission after hospital discharge	within 30 days after operation
Length of ICU stay	Length of postoperative ICU stay	From the date of surgery until the date patient discharge from hospital, assessed up to 1 year
Length of postprocedural hospital stays	Length of postprocedural hospital stays	From the date of surgery until the date patient discharge from hospital, assessed up to 1 year.
All cause 90 d mortality	Death within 90 days after surgery for any reason	within 90 days after operation
All cause 1 year mortality	Death within 1 year after surgery.	within 1 year after operation
Change in organ-specific and total sepsis-related SOFA scores	Change in organ-specific and total sepsis-related Sequential Organ Failure Assessment (SOFA) scores from enrollment through study day 7.	from the day of surgery to postoperative day 7.
Basal level of hemolysis	Serum free hemoglobin levels at baseline (g/L)	after entering operation room and before anaesthesia induction
Incidence of acute intraoperative hemolysis	measurement will be defined based on the level of free hemoglobin after CPB.	Immediately after the end of cardiopulmonary bypass (CPB)
The extent of hemolysis progression	Measured based on the free hemoglobin levels at baseline and immediately after CPB (free hemoglobin levels immediately after CPB/ baseline free hemoglobin)	taken at immediately after CPB finishes

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood transfusion	Amount of each type of blood product transfused (red blood cells, fresh frozen plasma, platelets)	during postoperative hospitalization, with an average of 10 days
Blood loss	Total amount of blood loss (chest tube drainage) in ml	during the first 72 hours after surgery
Incidence of prolonged cardiovascular support	cardiovascular support by using inotropes for more than 48 hours	during postoperative hospitalization, with an average of 10 days.
Maximum vasoactive-inotropic score (VIS)	The VIS will be calculated using the formula: Dopamine dose (mcg/Kg/min) + Dobutamine dose (mcg/Kg/min) + 100 x Epinephrine dose (mcg/Kg/min) + 100 x Norepinephrine dose (mcg/Kg/min) + 50 x Levosimendan dose (mcg/Kg/min) + Enoximone dose (mcg/Kg/min) + 10.000 x Vasopressin dose (UI/kg/min). The maximum VIS will be recorded each day.	record the maximun of the day for the first 7 days after surgery
local infections	Postoperative local infections, including pneumonia, deep sternal wound infection/mediastinitis, endocarditis, central line infection, and urinary tract infection.	within 30 days after surgery.
Other non-cardiac postoperative complications	including hepatobiliary disorders, pneumothorax, pleural effusion, and delirium	within 30 days after surgery
Quality of life	Quality of life meaurement with the Kansas City Cardiomyopathy Questionnaire (KCCQ) or Activities of Daily Living (ADL) score . KCCQ includes 23 items that map to 7 domains: symptom frequency; symptom burden; symptom stability; physical limitations; social limitations; quality of life; and self-efficacy. All scores are represented on a 0-to-100-point scale, where lower scores represent more severe symptoms and/or limitations and scores of 100 indicate no symptoms, no limitations, and excellent quality of life. Activities of daily living (ADLs) are important tasks one can do on a regular basis. BasicADLs, incluiding bathing, personal hygiene and grooming, toileting and continence, eating and feeding, dressing, moving/transferring. Katz ADL scale ranges from 0-6, one point for each task can do independently. Higer score stands for more indenpendent in daily life.	assessed at 1 year after surgery.

Collaborators and Investigators

• Sponsor: Xijing Hospital
• Collaborators: Nikolay O. Kamenshchikov., M.D., Tomsk National Research Medical Center of the Russian Academy of Sciences; Lorenzo Berra., M.D., Massachusetts General Hospital; Jiange Han, Tianjin Chest Hospital, Tianjin, China; Qingping Wu, Wuhan Union Hospital, Wuhan, China; Evgeniy Grigoriev, Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russian Federation; Vladimir Boboshko, E. Meshalkin National Medical Research Center, Novosibirsk, Russian Federation; Andrei Bautin, The Almazov National Medical Research Centre, St. Petersburg, Russian Federation; Vladimir Pichugin, Specialized Cardiac Surgery Clinical Hospital named after Academician B.A. Korolev, Nizhny Novgorod, Russian Federation; Evgeniy Rosseykin, Federal Center of Cardiovascular Surgery, Khabarovsk, Russian Federation; Jing Shi, The Afffliated Hospital of Guizhou Medical University, Guiyang, China.; Grigoryev Evgeny, Scientific Research Insitute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia.; Mikhail Vasilev, Meshalkin National Medical Research Center, Мeshalkin of the ministry of health of the Russian Federation,Novosibirsk,Russia.; Jia Min, The First Affiliated Hospital of Nanchang University, Nanchang, China.; Jiawan Wang, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Zongbin Song, Xiangya Hospital, Central South University, Changsha, China.
• Investigators: Principal Investigator: Chong Lei, M.D., & phd, Xijing Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 19, 2025
• Primary Completion (Estimated): March 31, 2028
• Study Completion (Estimated): March 31, 2029

Study Registration Dates

• First Submitted: November 18, 2024
• First Submitted That Met QC Criteria: November 21, 2024
• First Posted (Actual): November 25, 2024

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 26, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: cardiac surgery; complications; cardiopulmonary bypass; Nitric Oxide; Organ protection; major adverse events
• Additional Relevant MeSH Terms: Vasodilator Agents; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses; Cardiovascular Agents; Endothelium-Dependent Relaxing Factors
• Other Study ID Numbers: KY20242322

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The sharing of Individual Patient Data (IPD) will be considered at 1 year after the publication of the primary results of the project. Any request for IPD sharing should be submitted as a proposal to the Principal Investigator (PI), clearly outlining the intended use of the data.

The Steering Committee of the project will review the proposal and assess whether sharing the data aligns with the project's goals, ethical considerations, and any applicable regulations. Based on this review, the Steering Committee will make a decision regarding the approval of data sharing.

• IPD Sharing Time Frame: beginning 12 months after publication of the primary results
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No