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Effects of Nitric Oxide on the Endothelium During Hemolysis.

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ClinicalTrials.gov Identifier: NCT03748082
Recruitment Status : Recruiting
First Posted : November 20, 2018
Last Update Posted : March 6, 2019
Sponsor:
Collaborators:
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
Information provided by (Responsible Party):
Lorenzo Berra, MD, Massachusetts General Hospital

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.


Condition or disease Intervention/treatment Phase
Endothelial Dysfunction Hemolysis Intravascular Cardiovascular Diseases Cardiovascular Risk Factor Drug: Nitric Oxide Diagnostic Test: Reactive Hyperemia Index Procedure: Endothelial Cells Collection Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Effects of Nitric Oxide on Vascular Responsiveness and on Endothelial Cells During Hemolysis in Patients With Pre-operative Endothelial Dysfunction Undergoing Prolonged Cardiopulmonary Bypass.
Actual Study Start Date : December 5, 2018
Estimated Primary Completion Date : October 30, 2019
Estimated Study Completion Date : October 30, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Control
Inhaled nitrogen will be administered via the cardiopulmonary bypass (CPB) machine and after CPB via the inspiratory limb of the anesthetic or ventilator circuit, and thereafter via the mechanical ventilator in the Intensive Care Unit (ICU). Test gas administration will commence at the onset of CPB and last for 24 hours.
Diagnostic Test: Reactive 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.

Procedure: Endothelial 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.

Experimental: Nitric 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.
Drug: Nitric 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.
Other Name: iNO

Diagnostic Test: Reactive 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.

Procedure: Endothelial 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.




Primary Outcome Measures :
  1. Reactive Hyperemia Index (RHI) [ Time Frame: 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 Outcome Measures:
  1. Endothelial Nitric Oxide Synthase (eNOS) enzymatic activity [ Time Frame: 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.

  2. Pulmonary vascular resistances (PVR) [ Time Frame: 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.

  3. Systemic vascular resistances (SVR) [ Time Frame: 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03748082


Locations
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United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Lorenzo Berra, MD    617-643-7733    lberra@mgh.harvard.edu   
Boston Medical Center Recruiting
Boston, Massachusetts, United States, 02118
Contact: Naomi Hamburg, MD    617-638-7260    nhamburg@bu.edu   
Sponsors and Collaborators
Massachusetts General Hospital
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
Publications:
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Responsible Party: Lorenzo Berra, MD, MD, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT03748082    
Other Study ID Numbers: EndoNO
First Posted: November 20, 2018    Key Record Dates
Last Update Posted: March 6, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Lorenzo Berra, MD, Massachusetts General Hospital:
Cardiac Surgery
Cardiopulmonary Bypass
Reactive Hyperemia Index
Nitric Oxide
Additional relevant MeSH terms:
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Hemolysis
Cardiovascular Diseases
Pathologic Processes
Nitric Oxide
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Endothelium-Dependent Relaxing Factors
Vasodilator Agents
Gasotransmitters
Protective Agents