Clinical trial NCT03748082: Effects of Nitric Oxide on the Endothelium During Hemolysis.
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.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Endothelial Dysfunction
Hemolysis Intravascular
Cardiovascular Diseases
Cardiovascular Risk Factor
Keywords: Cardiac Surgery
Cardiopulmonary Bypass
Reactive Hyperemia Index
Nitric Oxide
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Spina, Stefano, M.D., Massachusetts General Hospital
name: Marrazzo, Francesco, M.D., Massachusetts General Hospital
name: Zadek, Francesco, M.D., Massachusetts General Hospital
name: Jennifer En-Sian Ho M.D., Massachusetts General Hospital
name: Naomi M Hamburg, M.D., Boston University
First posted: 2018-11-20
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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

Primary outcomes:
measure: Reactive Hyperemia Index (RHI)
timeFrame: The test will be performed perioperatively before anesthesia induction and at 24 hours after CPB during ICU admission.
Secondary outcomes:
Other outcomes:
measure: Endothelial Nitric Oxide Synthase (eNOS) enzymatic activity
timeFrame: Endothelial Cells will be collected perioperatively before anesthesia induction and at 24 hours after CPB during ICU admission.
measure: Pulmonary vascular resistances (PVR)
timeFrame: PVR will be measured every 6 hours after surgery for 24 hours after cardiopulmonary bypass start.
measure: Systemic vascular resistances (SVR)
timeFrame: SVR will be measured every 6 hours after surgery for 24 hours after cardiopulmonary bypass start.
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
Study officials:
References:
citation: Lei C, Berra L, Rezoagli E, Yu B, Dong H, Yu S, Hou L, Chen M, Chen W, Wang H, Zheng Q, Shen J, Jin Z, Chen T, Zhao R, Christie E, Sabbisetti VS, Nordio F, Bonventre JV, Xiong L, Zapol WM. Nitric Oxide Decreases Acute Kidney Injury and Stage 3 Chronic Kidney Disease after Cardiac Surgery. Am J Respir Crit Care Med. 2018 Nov 15;198(10):1279-1287. doi: 10.1164/rccm.201710-2150OC.
citation: Rezoagli E, Ichinose F, Strelow S, Roy N, Shelton K, Matsumine R, Chen L, Bittner EA, Bloch DB, Zapol WM, Berra L. Pulmonary and Systemic Vascular Resistances After Cardiopulmonary Bypass: Role of Hemolysis. J Cardiothorac Vasc Anesth. 2017 Apr;31(2):505-515. doi: 10.1053/j.jvca.2016.06.009. Epub 2016 Jun 8.
citation: Tabit CE, Shenouda SM, Holbrook M, Fetterman JL, Kiani S, Frame AA, Kluge MA, Held A, Dohadwala MM, Gokce N, Farb MG, Rosenzweig J, Ruderman N, Vita JA, Hamburg NM. Protein kinase C-beta contributes to impaired endothelial insulin signaling in humans with diabetes mellitus. Circulation. 2013 Jan 1;127(1):86-95. doi: 10.1161/CIRCULATIONAHA.112.127514. Epub 2012 Nov 30.
citation: Hamburg NM, Keyes MJ, Larson MG, Vasan RS, Schnabel R, Pryde MM, Mitchell GF, Sheffy J, Vita JA, Benjamin EJ. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation. 2008 May 13;117(19):2467-74. doi: 10.1161/CIRCULATIONAHA.107.748574. Epub 2008 May 5.