Cardiovascular Diseases, Cardiovascular Risk Factor, Endothelial Dysfunction, Hemolysis Intravascular
Conditions
Keywords
Cardiac Surgery, Cardiopulmonary Bypass, Reactive Hyperemia Index, Nitric Oxide
Brief 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 vascular responsiveness and on endothelial function during hemolysis in patients with pre-operative endothelial dysfunction undergoing cardiac surgery requiring prolonged cardiopulmonary bypass.
Detailed description
Endothelial cells regulate tissue perfusion by releasing nitric oxide (NO), a potent endogenous dilator of vascular smooth muscle cells, which modifies vascular tone. Under normal physiological conditions, vascular NO is released by endothelial NO synthase (eNOS). Impairment of the eNOS, as seen in patients with atherosclerosis, peripheral vascular disease, hypertension, obesity, and diabetes, is a feature of endothelial dysfunction.The inability to increment eNOS activity is particularly evident in conditions of decreased vascular NO bioavailability, such as during hemolysis associated with prolonged cardiopulmonary bypass (CPB\>90 min). During hemolysis, ferrous plasma free hemoglobin (Oxy-Hb) is released into the circulation and can be injurious for the endothelial cells by exerting an oxidative and proinflammatory effect. Moreover, plasma free Oxy-Hb can scavenge vascular NO, reducing its bioavailability as ferrous Oxy-Hb is transformed into ferric methemoglobin (Met-Hb). The clinical results of reduced bioavailability of vascular NO have been found to be associated with both systemic and pulmonary vasoconstriction, ultimately leading to reduced tissue perfusion. The exogenous administration of NO has been shown to prevent the scavenging of endogenous NO by inactivating the highly oxidative-reactive ferrous plasma Oxy-Hb to ferric Met-Hb. 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 CPB and randomized to receive NO or placebo. However, the mechanisms underlying the beneficial systemic effects of NO administration have still to be determined. This is an ancillary study that aims to (I) assess the effects of hemolysis on vascular responsiveness and on endothelial function in patients with pre-operative endothelial dysfunction and (II) to determine the vascular protective effects of NO administration.
Interventions
DRUGNitric Oxide
Inhaled nitric oxide (iNO) will be administered via the CPB machine and after CPB via the inspiratory limb of the anesthetic or ventilator circuit, and thereafter via the mechanical ventilator in the ICU. Test gas administration will commence at the onset of CPB and last for 24 hours. At the end of 24 hours, iNO will be weaned and discontinued.
DIAGNOSTIC_TESTReactive Hyperemia Index
Vascular responsiveness will be assessed with peripheral arterial tonometry which measures the transient increase in forearm blood flow (Reactive Hyperemia Index, RHI) in response to a five-minute occlusion of the brachial artery with a pressure cuff.
PROCEDUREEndothelial Cells Collection
Endothelial cells are collected before and after surgery from a peripheral vessel using a soft J-shaped wire inserted through an intravascular catheter.
Sponsors
Spina, Stefano, M.D., Massachusetts General Hospital
Marrazzo, Francesco, M.D., Massachusetts General Hospital
Zadek, Francesco, M.D., Massachusetts General Hospital
Jennifer En-Sian Ho M.D., Massachusetts General Hospital
Naomi M Hamburg, M.D., Boston University
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reactive Hyperemia Index (RHI) | The test will be performed perioperatively before anesthesia induction and at 24 hours after CPB during ICU admission. | A finger plethysmograph will measure the transient increase in forearm blood flow (Reactive Hyperemia Index, RHI) in response to a 5 minutes occlusion of the brachial artery with a pressure cuff (Peripheral Artery Tonometry). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Endothelial Nitric Oxide Synthase (eNOS) enzymatic activity | Endothelial Cells will be collected perioperatively before anesthesia induction and at 24 hours after CPB during ICU admission. | eNOS enzymatic activity will be measured in endothelial cells. Activation of eNOS will be assessed through quantification of its expression by quantitative immunofluorescence and through evaluation of phosphorylation levels at different enzymatic sites at baseline and in response to specific agonists; NO bioavailability will be evaluated through fluorescence intensity after challenge with agonists as A23187; additionally, nitrotyrosine levels and other markers will be measured to evaluate endothelial oxidative stress. |
| Pulmonary vascular resistances (PVR) | PVR will be measured every 6 hours after surgery for 24 hours after cardiopulmonary bypass start. | PVR will be measured through a pulmonary artery catheter (PAC) placed in the internal jugular vein after induction of anesthesia. Cardiac output will be measured with the thermodilution technique and pulmonary vascular resistances will be calculated. |
| Systemic vascular resistances (SVR) | SVR will be measured every 6 hours after surgery for 24 hours after cardiopulmonary bypass start. | SVR will be measured through a pulmonary artery catheter (PAC) placed in the internal jugular vein after induction of anesthesia. Cardiac output will be measured with the thermodilution technique and systemic vascular resistances will be calculated. |
Countries
United States
Outcome results
None listed