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

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) conce

• Total number of major adverse events (MAEs) [Срок оценки: within 30 days after operation]
• Incidence of the MAEs [Срок оценки: within 30 days after operation]
• All AKI incidence [Срок оценки: within 7 days of surgery]
• Length of mechanical ventilation [Срок оценки: within 30 days after operation]
• Readmission [Срок оценки: within 30 days after operation]
• Length of ICU stay [Срок оценки: From the date of surgery until the date patient discharge from hospital, assessed up to 1 year]
• Length of postprocedural hospital stays [Срок оценки: From the date of surgery until the date patient discharge from hospital, assessed up to 1 year.]
• All cause 90 d mortality [Срок оценки: within 90 days after operation]
• All cause 1 year mortality [Срок оценки: within 1 year after operation]
• Change in organ-specific and total sepsis-related SOFA scores [Срок оценки: from the day of surgery to postoperative day 7.]
• Basal level of hemolysis [Срок оценки: after entering operation room and before anaesthesia induction]
• Incidence of acute intraoperative hemolysis [Срок оценки: Immediately after the end of cardiopulmonary bypass (CPB)]