Artery Disease

Muscle Disorder

In all groups, a 5 mm large gastrocnemius muscle biopsy will be performed and the samples immediately managed in experimental laboratory.

Gastrocnemius muscle biopsy

In Vivo Analysis of Muscle Stem Cells in Chronic and Acute Lower Limb Ischemia (MyostemIschemia)

In Vivo Analysis of Muscle Stem Cell Vascular Niche in Patients Presenting Chronic and Acute Lower Limb Ischemia (MyostemIschemia)

Number of SC, capillaries, distance to each others, fiber type, number and diameter of muscle fibers

Number of induced myotubes, shape of myotubes, presence of myonuclei (Score 0: Normal, 1: Dystrophic) during cell culture:

Number of induced vessels in a co-culture system (SC/HUVECs)

Ability to induce muscle regeneration, revascularisation, and SC original pool renewal:
Measurements performed at day 0, 5, 7, 14, 21 days after SC transplantation and tibias anterior lesion
Evolution of the number of SC per 100 myofibers
Evolution of the number of capillaries per 100 myofibers
Evolution of the myofibers diameter
Surface of necrosis

Institut National de la Santé Et de la Recherche Médicale, France

All muscle biopsies are immediately labeled and routed to the lab where technicians and assessors are blinded.

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.

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.

Acute Kidney Injury

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.

Nitric Oxide

This is the placebo group. Nitrogen will be added instead of nitric oxide.

Placebo

This is the clinical trial that we previously performed in collaboration with Xijing Hospital.

The first preliminary data analysis of the NCT01802619 has been presented at the section "Late Breaking Trial" of the American Heart Association in Orlando,Florida,November 2015.

Massachusetts General Hospital

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

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.

Incidence of Acute Kidney injury according to KDIGO criteria.

Difference in AKI severity between the two groups using following KDIGO stages.

To study the incidence of acute renal failure requiring RRT

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).

Assessment of organ dysfunction through the evaluation of SOFA score

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.

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).

Difference of duration of mechanical ventilation

Difference between groups of ICU-LOS defined as number of days spent in an ICU bed.

Difference between groups of hospital LOS defined as number of days spent in a hospital bed.

Renal biomarkers to evaluate renal tubular injury.

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.

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).

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.

Evaluation of the overall intrahospital mortality and at 28 6 weeks 90 days and 1 year after surgery

Blood methemoglobin levels will be measured to evaluate the oxidation of oxyhemoglobin in the two groups until 48h after surgery.

Difference between groups of incidence of non fatal stroke will be assessed by at 6 weeks after cardiac surgery.

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.

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.

Differences between the two groups of transfusions with plasma and stored or autologous red blood cells (RBCs) recovered using intraoperative cell salvage devices.

Post-operative infections (e.g., pneumonia, wound infection, endocarditis, central line infection, urinary tract infection, sepsis).

Cardiac arrhythmias and other non-cardiac post-operative complications (e.g., hepatobiliary disorders, pneumothorax, pleural effusion, vascular disorders).

Lorenzo Berra, MD

Lorenzo Berra, MD, Assistant Professor, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School

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)

metformin 2000 mg + pioglitazone 15-45 mg

metformin 2000 mg + glibenclamide 5-15 mg or metformin 2000 mg + gliclazide 30-120 mg or metformin 2000 mg + glimepiride 2-6 mg

Type 2 Diabetes Mellitus

Cardiovascular Disease

participants randomised to this arm will add pioglitazone 15 mg/die to therapy with metformin (2 gr/die)

add-on pioglitazone

participants randomized to this arm will add a sulphonylurea (glibenclamide 5 mg/die; gliclazide 30 mg/die or glimepiride 2 mg/die)to monotherapy with metformin (2 gr/die)

add-on sulphonylurea

Ospedale Locatelli di Piario

Hospitaal of Treviglio

Hospital of Lanciano

Ospedale Casa Sollievo della Sofferenza

ASL 4 - Chiavarese

ASL 64

Presidio Ospedaliero Atri

"Maggiore" Hospital

Inrca - Irccs

San Donato Hospital

University of Bari

Ospedali Riuniti di Bergamo

Policlinico S. Orsola Malpigli

Presidio Ospedaliero A.S.RE.Molise

"Garibaldi di Nesima" Hospital

"Mater Domini" University

M. Bufalini Hospital

Arcispedale "S.Anna"

University of Ferrara

University of Florence

Ospedali Riuniti

University of Genova

San Salvatore Hospital

ASL Latina

Santa Maria Goretti Hospital

"Cittadella della Salute" Hospital

ASL 6

Hospital of Massa

Matera Hospital

"Ospedali Riuniti Papardo-Piemonte" Hospital

University of Messina

Istituto Scientifico San Raffaele

Niguarda Cà Grande Hospital

"Federico II"University of Naples

"Federico II" University

Second University

Complesso Sociosanitario dei Colli

University of Padua

University of Palermo

University of Parma

University of Perugia

Civil Hospital

Ospedale Gugliemo da Saliceto

University of Pisa

Spedali Riuniti di Pistoia

Praia a Mare Hospital

Operative Unit of Diabetologia - ASL 4

University of Ravenna

Ospedale Infermi

Ospedale Pertini

Policlinico di Tor Vergata

Sant'Andrea Hospital

University of Siena

"San Matteo degli Infermi" Hospital

"Molinette" Hospital

Azienda Ospedaliero Universitaria " S.Maria della Misericordia "

Hopital of Gallarate

"G. Fracastoro" Civil Hospital

Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents.Intervention Trial

Effects on Incidence of Cardiovascular Events of the Addition of Pioglitazone as Compared With a Sulphonylurea in Type 2 Diabetic Patients Inadequately Controlled With Metformin.

intermittent claudication/edema

In Vivo Analysis of Muscle Stem Cells in Chronic and Acute Lower Limb Ischemia (MyostemIschemia)

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

Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents.Intervention Trial

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