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Effect of Nitric Oxide in Cardiac Surgery Patients With Endothelial Dysfunction. (MGHK23)

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ClinicalTrials.gov Identifier: NCT02836899
Recruitment Status : Recruiting
First Posted : July 19, 2016
Last Update Posted : August 14, 2019
Sponsor:
Collaborators:
Ichinose, Fumito, M.D., Ph.D., Massachusetts General Hospital
Kenneth, Shelton, M.D., Massachusetts General Hospital
Kacmarek, Robert M., Ph.D., Massachusetts General Hospital
Sundt, Thoralf M., M.D., Massachusetts General Hospital
Villavicencio-Theoduloz, Mauricio A., M.D., Massachusetts General Hospital
Thompson, Boyd Taylor, M.D., Massachusetts General Hospital
Bonventre, Joseph V., M.D., Brigham Women Hospital
Shann, Kenneth G., Massachusetts General Hospital
Zapol, Warren M., M.D.
Marrazzo, Francesco, M.D., Massachusetts General Hospital
Spina, Stefano, M.D., Massachusetts General Hospital
Zadek, Francesco, M.D., Massachusetts General Hospital
Rezoagli, Emanuele, M.D., Massachusetts General Hospital
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Lorenzo Berra, MD, Massachusetts General Hospital

Brief Summary:
The purpose of this study is to determine whether nitric oxide is effective in the treatment of acute kidney injury in cardiac surgical patients with sign and laboratory data suggesting endothelial dysfunction undergoing prolonged cardiopulmonary bypass.

Condition or disease Intervention/treatment Phase
Acute Kidney Injury Drug: Nitric Oxide Other: Placebo Phase 3

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 250 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: Prevention of Acute Kidney Injury by Nitric Oxide in Prolonged Cardiopulmonary Bypass. A Double Blind Controlled Randomized Trial in Cardiac Surgical Patients With Endothelial Dysfunction.
Actual Study Start Date : February 8, 2017
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2021

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). Once patients are extubated they will breathe test gas via a facemask or nasal cannula. Test gas administration will commence at the onset of CPB and last for 24 hours.
Other: Placebo
This is the placebo group. Nitrogen will be added instead of nitric oxide.

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. Once patients are extubated they will breathe test gas via a facemask or nasal cannula. 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 while carefully monitoring hemodynamics for a period of 2-4 hours.
Drug: Nitric Oxide
Inhaled nitric oxide will be administered in a final concentration of 80 ppm. The treatment will begin at the onset of the cardiopulmonary bypass until to 24h after Intensive Care Unit (ICU) admission, including 2-4 hours of weaning from nitric oxide and careful hemodynamics monitoring.




Primary Outcome Measures :
  1. Acute kidney injury [ Time Frame: 7 days ]
    Incidence of Acute Kidney injury according to KDIGO criteria.


Secondary Outcome Measures :
  1. AKI severity [ Time Frame: 7 days after cardiac surgery ]
    Difference in AKI severity between the two groups using following KDIGO stages.

  2. Renal replacement therapy [ Time Frame: up to 1 year ]
    To study the incidence of acute renal failure requiring RRT

  3. Major Adverse Kidney Events (MAKE) [ Time Frame: 6 weeks after cardiac surgery ]
    Difference between groups of MAKE at 6 weeks after surgery. MAKE is a composite outcome of death, new dialysis and worsened renal function (defined as a 25% or greater decline in eGFR compared to the baseline).

  4. Organ dysfunction [ Time Frame: 7 days ]
    Assessment of organ dysfunction through the evaluation of SOFA score

  5. Prolonged cardiovascular support [ Time Frame: 48 hours after cardiac surgery ]
    Difference between groups of prolonged cardiovascular support defined as need for vasopressors, inotropic agents, balloon pump, or ventricular-assist device for more than 48 hours after cardiac surgery.

  6. Vasoactive-inotropic score (VIS) [ Time Frame: 7 days after cardiac surgery ]
    Difference between groups of maximum daily VIS and duration of vasopressors and or inotropic agents support. VIS is calculated as Dopamine dose (mcg/kg/min) + Dobutamine dose (mcg/kg/min) + 100 x Epinephrine dose (mcg/kg/min) + 10 x Milrinone dose (mcg/kg/min) + 10,000 x Vasopressin dose (units/kg/min) + 100 x Norepinephrine dose (mcg/kg/min) + 10 x Phenilephrine dose (mcg/kg/min).

  7. Duration of mechanical ventilation [ Time Frame: up to 6 weeks ]
    Difference of duration of mechanical ventilation

  8. Intensive care unit length of stay (ICU-LOS) [ Time Frame: up to 6 weeks ]
    Difference between groups of ICU-LOS defined as number of days spent in an ICU bed.

  9. Hospital length of stay (LOS) [ Time Frame: up to 1 year ]
    Difference between groups of hospital LOS defined as number of days spent in a hospital bed.


Other Outcome Measures:
  1. Renal tubular injury [ Time Frame: Up to 6 weeks ]
    Renal biomarkers to evaluate renal tubular injury.

  2. Incidence of AKI related to risk factors [ Time Frame: 7 days ]
    Incidence and severity of AKI related to presence of CKD at baseline, duration of CPB, duration of aortic cross clamp, levels of free Hb, levels of NO consumption, pulmonary pressure at baseline, cardiovascular risks associated with endothelial dysfunction, scheduled procedure and EuroSCORE II.

  3. Incidence of delirium [ Time Frame: 7 days after cardiac surgery ]
    Difference between groups of Incidence of Delirium will be assessed daily in the first 7 days after surgery by using the confusion assessment method for intensive care unit (CAM-ICU).

  4. Score of the Activity of Daily Living [ Time Frame: One year follow up ]
    Analysis of the quality of life up to 1 year after surgery by the Activity of Daily Living evaluation (by Katz Index) and PROMIS global health.

  5. Overall mortality [ Time Frame: up to 1 year ]
    Evaluation of the overall intrahospital mortality and at 28 6 weeks 90 days and 1 year after surgery

  6. Methemoglobin levels in blood [ Time Frame: During and 48 hours after cardiac surgery ]
    Blood methemoglobin levels will be measured to evaluate the oxidation of oxyhemoglobin in the two groups until 48h after surgery.

  7. Incidence of non fatal stroke [ Time Frame: 6 weeks ]
    Difference between groups of incidence of non fatal stroke will be assessed by at 6 weeks after cardiac surgery.

  8. Perioperative and non-perioperative nonfatal myocardial infarction [ Time Frame: 72 hours and 1 year follow up ]
    Incidence of Perioperative and non-perioperative nonfatal myocardial infarction as defined by the third universal definition of MI released in 2012 by the ESC/ACCF/AHA/WHF.

  9. Post operative bleeding [ Time Frame: 24 after surgery ]
    Incidence of postoperative bleeding calculated as the sum of blood loss through thoracic drains from the moment of closure of the chest over a period of 24 hours.

  10. Transfusions [ Time Frame: 7 days surgery ]
    Differences between the two groups of transfusions with plasma and stored or autologous red blood cells (RBCs) recovered using intraoperative cell salvage devices.

  11. Post-operative infections [ Time Frame: 6 weeks ]
    Post-operative infections (e.g., pneumonia, wound infection, endocarditis, central line infection, urinary tract infection, sepsis).

  12. Cardiac and non-cardiac complications [ Time Frame: 6 weeks ]
    Cardiac arrhythmias and other non-cardiac post-operative complications (e.g., hepatobiliary disorders, pneumothorax, pleural effusion, vascular disorders).



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:

  1. Provide written informed consent
  2. Age ≥ 18 years of age
  3. Elective cardiac or aortic surgery with CPB>90 minutes
  4. Stable pre-operative renal function without evidence of plasma creatinine level increase of ≥ 0.3 mg/dL over the prior 3 months and without renal replacement therapy (RRT).
  5. Clinical evidence of endothelial dysfunction assessed by a specifically designed questionnaire.

Exclusion Criteria:

  1. eGFR less than 30 ml/min/1.73 m2
  2. Emergent cardiac surgery.
  3. Life expectancy < 1 year at the time of enrollment.
  4. Hemodynamic instability as defined by a systolic blood pressure <90 mmHg.
  5. Mean pulmonary artery pressure ≥ 40 mm Hg and PVR > 4 Wood Units.
  6. Left ventricular ejection fraction < 30% by echocardiography obtained within three months of enrollment
  7. Administration of one or more Packed Red Blood Cells (RBCs) transfusion in the week prior to enrollment.
  8. X-ray contrast infusion less than 48 hours before surgery.
  9. Evidence of intravascular or extravascular hemolysis from any other origin:

    i. Intravascular: Intrinsic RBCs defects leading to hemolytic anemia (eg, enzyme deficiencies, hemoglobinopathies, membrane defects). 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.

    ii. 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): NCT02836899


Contacts
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Contact: Lorenzo Berra, MD +1 (617) 643 7733 LBERRA@mgh.harvard.edu

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   
Sponsors and Collaborators
Massachusetts General Hospital
Ichinose, Fumito, M.D., Ph.D., Massachusetts General Hospital
Kenneth, Shelton, M.D., Massachusetts General Hospital
Kacmarek, Robert M., Ph.D., Massachusetts General Hospital
Sundt, Thoralf M., M.D., Massachusetts General Hospital
Villavicencio-Theoduloz, Mauricio A., M.D., Massachusetts General Hospital
Thompson, Boyd Taylor, M.D., Massachusetts General Hospital
Bonventre, Joseph V., M.D., Brigham Women Hospital
Shann, Kenneth G., Massachusetts General Hospital
Zapol, Warren M., M.D.
Marrazzo, Francesco, M.D., Massachusetts General Hospital
Spina, Stefano, M.D., Massachusetts General Hospital
Zadek, Francesco, M.D., Massachusetts General Hospital
Rezoagli, Emanuele, M.D., Massachusetts General Hospital
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Lorenzo Berra, MD Massachusetts General Hospital

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Lorenzo Berra, MD, Lorenzo Berra, MD, Assistant Professor, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT02836899     History of Changes
Other Study ID Numbers: MGH K23
K23HL128882-01 ( U.S. NIH Grant/Contract )
First Posted: July 19, 2016    Key Record Dates
Last Update Posted: August 14, 2019
Last Verified: August 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.: Yes
Keywords provided by Lorenzo Berra, MD, Massachusetts General Hospital:
acute kidney injury; nitric oxide; cardiopulmonary bypass; endothelial dysfunction; cardiac surgery
Additional relevant MeSH terms:
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Acute Kidney Injury
Renal Insufficiency
Kidney Diseases
Urologic Diseases
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