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

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

Interventions

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.

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.

Sponsors & Collaborators

• Nikolay O. Kamenshchikov., M.D., Tomsk National Research Medical Center of the Russian Academy of Sciences

  collaborator UNKNOWN

• Lorenzo Berra., M.D., Massachusetts General Hospital

  collaborator UNKNOWN

• Jiange Han, Tianjin Chest Hospital, Tianjin, China

  collaborator UNKNOWN

• Qingping Wu, Wuhan Union Hospital, Wuhan, China

  collaborator UNKNOWN

• Evgeniy Grigoriev, Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russian Federation

  collaborator UNKNOWN

• Vladimir Boboshko, E. Meshalkin National Medical Research Center, Novosibirsk, Russian Federation

  collaborator UNKNOWN

• Andrei Bautin, The Almazov National Medical Research Centre, St. Petersburg, Russian Federation

  collaborator UNKNOWN

• Vladimir Pichugin, Specialized Cardiac Surgery Clinical Hospital named after Academician B.A. Korolev, Nizhny Novgorod, Russian Federation

  collaborator UNKNOWN

• Evgeniy Rosseykin, Federal Center of Cardiovascular Surgery, Khabarovsk, Russian Federation

  collaborator UNKNOWN

• Sheng Wang, Anzhen Hospital, Beijing, China

  collaborator UNKNOWN

• Xijing Hospital

  lead OTHER

Principal Investigators

• Chong Lei, M.D., & phd · Xijing Hospital

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2025-05-19

Primary Completion

2028-03-31

Completion

2029-03-31

FDA Drug

Yes

Countries

• United States
• China
• Russia

Study Locations