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出境医 / 临床实验 / Effects of Prolonged Delivery of Nitric Oxide Gas on Plasma Reduction-Oxidation Reactions in Cardiac Surgical Patients

Effects of Prolonged Delivery of Nitric Oxide Gas on Plasma Reduction-Oxidation Reactions in Cardiac Surgical Patients

Study Description
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 plasma reduction-oxidation reactions of patients undergoing cardiac surgery requiring prolonged cardiopulmonary bypass.


Condition or disease Intervention/treatment Phase
Cardiovascular Diseases Oxidative Stress Endothelial Dysfunction Drug: Nitrogen Gas for Inhalation Other: Blood withdrawal Drug: Nitric Oxide Phase 2

Detailed Description:

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.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Effects of Prolonged Delivery of Nitric Oxide Gas on Plasma Reduction-Oxidation Reactions in Cardiac Surgical Patients
Actual Study Start Date : July 25, 2019
Estimated Primary Completion Date : February 28, 2021
Estimated Study Completion Date : July 31, 2022
Arms and Interventions
Arm Intervention/treatment
Placebo Comparator: Nitrogen
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.
Drug: Nitrogen Gas for Inhalation
See arm description
Other Name: N2

Other: Blood withdrawal
Blood samples will be collected over four time-points: (I) baseline (before surgery) (II) end of the surgery, (III) end of 24 hours of gas delivery and (IV) 24 hours from the gas suspension.

Experimental: Nitric Oxide
Inhaled nitric oxide (iNO) 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 ICU. Test gas administration will commence at the onset of CPB and last for 24 hours. At the end of 24 hours, inhaled nitric oxide (iNO) will be weaned and discontinued.
Other: Blood withdrawal
Blood samples will be collected over four time-points: (I) baseline (before surgery) (II) end of the surgery, (III) end of 24 hours of gas delivery and (IV) 24 hours from the gas suspension.

Drug: Nitric Oxide
See arm description
Other Name: iNO

Outcome Measures
Primary Outcome Measures :
  1. Changes in the concentration of glutathione/glutathione disulfide (GSH/GSSG) and the cysteine/ cysteine disulfide (Cys/CysSS) couples in the plasma after cardiac surgery. [ Time Frame: Plasma will be sampled before the cardiac surgery and during the first 48 hours from surgery ]
    The investigators will measure the changes in plasma concentration of GSH, GSSG, Cys, CysSS, of subjects undergoing cardiac surgery with prolonged cardiopulmonary bypass, using ultrahigh-performance liquid chromatography in combination with electrospray-ionization tandem mass spectrometry. The concentration will be expressed in microMoles.

  2. Changes in the electrical potential of glutathione/glutathione disulfide (GSH/GSSG) and the cysteine/ cysteine disulfide (Cys/CysSS) couples in the plasma after cardiac surgery. [ Time Frame: Plasma will be sampled before the cardiac surgery and during the first 48 hours from surgery ]
    The investigators will compare the changes of plasma redox state from baseline of patients receiving either 80 ppm of nitric oxide (study group) or nitrogen (placebo group), during cardiac surgery. The redox state will be assessed by measuring the electrical potential of GSH/GSSG and the Cys/CysSS couples in the plasma, using Nerst's equation. The electrical potential will be express in milliVolt.


Secondary Outcome Measures :
  1. Changes of concentration in plasma and red blood cells of nitric oxide metabolites after cardiac surgery. [ Time Frame: Plasma will be sampled before the cardiac surgery and after the first 48 hours from surgery ]
    The investigators will describe the trends in plasma and red blood cells of nitric oxide (NO) metabolites after the surgery. Nitric oxide (NO) metabolites concentrations will be measured using chemiluminescence. The concentrations will be expressed in microMoles.


Eligibility Criteria
Layout table for eligibility information
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

Contacts and Locations

Contacts
Layout table for location contacts
Contact: Lorenzo Berra, MD (617) 643 7733 ext +1 LBERRA@mgh.harvard.edu
Contact: Francesco Zadek, MD 6178344809 ext +1 fzadek@mgh.harvard.edu

Locations
Layout table for location information
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Lorenzo Berra, MD    617-643-7733    lberra@mgh.harvard.edu   
United Kingdom
MP 825 Southampton General Hospita Active, not recruiting
Southampton, Hampshire, United Kingdom, SO16 6YD
Sponsors and Collaborators
Massachusetts General Hospital
Zadek, Francesco, M.D., Massachusetts General Hospital
Spina, Stefano, M.D., Massachusetts General Hospital
Marrazzo, Francesco, M.D., Massachusetts General Hospital
University of Southampton
Investigators
Layout table for investigator information
Principal Investigator: Lorenzo Berra, MD Massachusett General Hospital
Tracking Information
First Submitted Date  ICMJE July 10, 2019
First Posted Date  ICMJE July 16, 2019
Last Update Posted Date November 10, 2020
Actual Study Start Date  ICMJE July 25, 2019
Estimated Primary Completion Date February 28, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 14, 2019)
  • Changes in the concentration of glutathione/glutathione disulfide (GSH/GSSG) and the cysteine/ cysteine disulfide (Cys/CysSS) couples in the plasma after cardiac surgery. [ Time Frame: Plasma will be sampled before the cardiac surgery and during the first 48 hours from surgery ]
    The investigators will measure the changes in plasma concentration of GSH, GSSG, Cys, CysSS, of subjects undergoing cardiac surgery with prolonged cardiopulmonary bypass, using ultrahigh-performance liquid chromatography in combination with electrospray-ionization tandem mass spectrometry. The concentration will be expressed in microMoles.
  • Changes in the electrical potential of glutathione/glutathione disulfide (GSH/GSSG) and the cysteine/ cysteine disulfide (Cys/CysSS) couples in the plasma after cardiac surgery. [ Time Frame: Plasma will be sampled before the cardiac surgery and during the first 48 hours from surgery ]
    The investigators will compare the changes of plasma redox state from baseline of patients receiving either 80 ppm of nitric oxide (study group) or nitrogen (placebo group), during cardiac surgery. The redox state will be assessed by measuring the electrical potential of GSH/GSSG and the Cys/CysSS couples in the plasma, using Nerst's equation. The electrical potential will be express in milliVolt.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 14, 2019)
Changes of concentration in plasma and red blood cells of nitric oxide metabolites after cardiac surgery. [ Time Frame: Plasma will be sampled before the cardiac surgery and after the first 48 hours from surgery ]
The investigators will describe the trends in plasma and red blood cells of nitric oxide (NO) metabolites after the surgery. Nitric oxide (NO) metabolites concentrations will be measured using chemiluminescence. The concentrations will be expressed in microMoles.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effects of Prolonged Delivery of Nitric Oxide Gas on Plasma Reduction-Oxidation Reactions in Cardiac Surgical Patients
Official Title  ICMJE Effects of Prolonged Delivery of Nitric Oxide Gas on Plasma Reduction-Oxidation Reactions in Cardiac Surgical Patients
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 plasma reduction-oxidation reactions of patients undergoing cardiac surgery requiring prolonged cardiopulmonary bypass.

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Condition  ICMJE
  • Cardiovascular Diseases
  • Oxidative Stress
  • Endothelial Dysfunction
Intervention  ICMJE
  • Drug: Nitrogen Gas for Inhalation
    See arm description
    Other Name: N2
  • Other: Blood withdrawal
    Blood samples will be collected over four time-points: (I) baseline (before surgery) (II) end of the surgery, (III) end of 24 hours of gas delivery and (IV) 24 hours from the gas suspension.
  • Drug: Nitric Oxide
    See arm description
    Other Name: iNO
Study Arms  ICMJE
  • Placebo Comparator: Nitrogen
    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.
    Interventions:
    • Drug: Nitrogen Gas for Inhalation
    • Other: Blood withdrawal
  • Experimental: Nitric Oxide
    Inhaled nitric oxide (iNO) 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 ICU. Test gas administration will commence at the onset of CPB and last for 24 hours. At the end of 24 hours, inhaled nitric oxide (iNO) will be weaned and discontinued.
    Interventions:
    • Other: Blood withdrawal
    • Drug: Nitric Oxide
Publications *
  • Marrazzo F, Spina S, Zadek F, Lama T, Xu C, Larson G, Rezoagli E, Malhotra R, Zheng H, Bittner EA, Shelton K, Melnitchouk S, Roy N, Sundt TM, Riley WD, Williams P, Fisher D, Kacmarek RM, Thompson TB, Bonventre J, Zapol W, Ichinose F, Berra L. Protocol of a randomised controlled trial in cardiac surgical patients with endothelial dysfunction aimed to prevent postoperative acute kidney injury by administering nitric oxide gas. BMJ Open. 2019 Jul 4;9(7):e026848. doi: 10.1136/bmjopen-2018-026848.
  • Sutton TR, Minnion M, Barbarino F, Koster G, Fernandez BO, Cumpstey AF, Wischmann P, Madhani M, Frenneaux MP, Postle AD, Cortese-Krott MM, Feelisch M. A robust and versatile mass spectrometry platform for comprehensive assessment of the thiol redox metabolome. Redox Biol. 2018 Jun;16:359-380. doi: 10.1016/j.redox.2018.02.012. Epub 2018 Feb 19.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 14, 2019)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 31, 2022
Estimated Primary Completion Date February 28, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lorenzo Berra, MD (617) 643 7733 ext +1 LBERRA@mgh.harvard.edu
Contact: Francesco Zadek, MD 6178344809 ext +1 fzadek@mgh.harvard.edu
Listed Location Countries  ICMJE United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04022161
Other Study ID Numbers  ICMJE RedOx-NO
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Lorenzo Berra, MD, Massachusetts General Hospital
Study Sponsor  ICMJE Massachusetts General Hospital
Collaborators  ICMJE
  • Zadek, Francesco, M.D., Massachusetts General Hospital
  • Spina, Stefano, M.D., Massachusetts General Hospital
  • Marrazzo, Francesco, M.D., Massachusetts General Hospital
  • University of Southampton
Investigators  ICMJE
Principal Investigator: Lorenzo Berra, MD Massachusett General Hospital
PRS Account Massachusetts General Hospital
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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