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)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 3,650
- 试验地点
- 5
- 主要终点
- Composite outcome of death and major adverse events requiring intensive life supports
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years.
- •Elective cardiac or aortic surgery requiring CPB
- •Without history of previous open heart surgery.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Nitric Oxide Gas (Drug)
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.
干预措施: Standard Care Arm (Drug)
结局指标
主要结局
Composite outcome of death and major adverse events requiring intensive life supports
时间窗: within 30 days after operation
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
次要结局
- 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(within 90 days after operation)
- All cause 1 year mortality(within 1 year after operation)
- 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)
- Length of ICU stay(From the date of surgery until the date patient discharge from hospital, assessed up to 1 year)
- Change in organ-specific and total sepsis-related SOFA scores(from the day of surgery to postoperative day 7.)
- Basal level of hemolysis(after entering operation room and before anaesthesia induction)
- Incidence of acute intraoperative hemolysis(Immediately after the end of cardiopulmonary bypass (CPB))
- The extent of hemolysis progression(taken at immediately after CPB finishes)
研究者
Chong Lei, MD & phD
Principal Investigator
Xijing Hospital