effects of prolonged delivery of nitric oxide gas on plasma reduction-oxidation reactions in cardiac surgical patients

Conditions: Cardiovascular Diseases; Oxidative Stress; Endothelial Dysfunction

Summary: this study is an ancillary (add-on) study to the clinical trial entitled "effect of nitric oxide in cardiac surgery patients with endothelial dysfunction", which has clinical trials.gov identifier nct02836899. nct02836899 trial randomizes cardiac surgical patients to receive either nitric oxide (no) or a placebo during and after cardiac surgery. this ancillary study aims to assess the effects of nitric oxide on plasma reduction-oxidation reactions of patients undergoing cardiac surgery requiring prolonged cardiopulmonary bypass.

the endothelial dysfunction is a pathologic process characterized by impaired endothelial nitric oxide (no) signaling and metabolism leading to decreased vascular response to vasodilation. cardiac surgical patients affected by multiple cardiovascular risk factors (e.g., hypertension, diabetes, dyslipidemia) commonly present with endothelial dysfunction due to a chronic unbalance of the redox state caused by an increased oxidative stress. moreover, the use of cardiopulmonary bypass, the hemolysis, the ischemia and the inflammation associated with the surgery magnifies the oxidative stress, which has been shown to contribute to post-operative complications. in order to decrease oxidative stress, several antioxidant drugs and vitamins have been trialed with marginal health benefits. recently, different research groups reported that no delivered during cardiac surgery improved outcomes both in children and adults. nitric oxide decreased the incidence and the severity of postoperative acute kidney injury, the extension of infarction size, the duration of mechanical ventilation, the length of stay and the use of rescue therapies as postoperative venous-arterial extra-corporeal membrane oxygenation. the exogenous administration of no has been shown to prevent the scavenging of endogenous no by inactivating the highly oxidative-reactive ferrous plasma oxy-hemoglobin to ferric met-hemoglobin. our group is conducting a randomized controlled trial at massachusetts general hospital (boston, usa) in patients with signs and symptoms of endothelial dysfunction, undergoing cardiac surgery requiring prolonged cardiopulmonary bypass and randomized to receive no or placebo. however, the mechanisms underlying the effects of no admistration on plasmatic redox equilibrium have still to be determined. the aim of this ancillary study is (i) to determine the changes of redox state in the plasma of surgical patients receiving either 80 ppm of no (study group) or nitrogen (placebo group). (ii) to evaluate whether the degree of change in redox state is associated to postoperative complication.

Eligibility criteria:
inclusion criteria: * eligible and randomized in the trial nct02836899 * provide written informed consent * age ≥ 18 years of age * elective cardiac or aortic surgery with cpb \>90 minutes * clinical evidence of endothelial dysfunction assessed by a specifically designed questionnaire exclusion criteria: * estimated glomerular filtration rate less than 30 ml/min/1.73 m2 * emergent cardiac surgery * life expectancy \< 1 year at the time of enrollment * hemodynamic instability as defined by a systolic blood pressure \<90 mmhg. * mean pulmonary artery pressure ≥ 40 mm hg and pvr \> 4 wood units. * left ventricular ejection fraction \< 30% by echocardiography obtained within three months of enrollment * administration of one or more packed red blood cell (prbc) transfusions in the week prior to enrollment * x-ray contrast infusion less than 48 hours before surgery * evidence of hemolysis from any other origin: a. intravascular: i. intrinsic rbc defects leading to hemolytic anemia (eg, enzyme deficiencies, hemoglobinopathies, membrane defects) ii. extrinsic: liver disease, hypersplenism, infections (eg, bartonella, babesia, malaria), treatment with oxidizing exogenous agents (eg, dapsone, nitrites, aniline dyes), exposure to other hemolytic agents (eg, lead, snake and spider bites), lymphocyte leukemia, autoimmune hemolytic disorders b. extravascular: infection (eg, clostridial sepsis, severe malaria), paroxysmal cold hemoglobinuria, cold agglutinin disease, paroxysmal nocturnal hemoglobinuria, iv infusion of rho(d) immune globulin, iv infusion of hypotonic solutions

Keywords: cardiac surgery nitric oxide oxidative stress redox thiols couples lipids peroxidation protein oxidation