Effect of Brief Nebulization of Milrinone on Pulmonary Arterial Pressure Before Cardiopulmonary Bypass on Mitral Valve Surgery Patients
Condition: Pulmonary Hypertension; Mitral Regurgitation
MeSH terms: Hypertension, Pulmonary; Hypertension; Mitral Valve Insufficiency
Study type: Interventional
Phase: Phase 3

Summary: 
      Our main hypothesis is that inhalation of milrinone can reduce the elevated pulmonary
      arterial pressure due to severe mitral valve regurgitation without compromising systemic
      hemodynamics. Therefore, the effects of a brief inhaled milrinone (IH) on pulmonary artery
      pressure are determined and compared to those of intravenous milrinone (IV) in severe mitral
      regurgitation patients undergoing mitral valve surgery.
    

Detailed description: 
      Perioperative pulmonary hypertension (PHT), an independent risk factor for cardiac surgery,
      1,2 is frequently associated with chronic mitral valve regurgitation and tends to produce
      right ventricular (RV) dysfunction. Worsening PHT, which is sensitive to any increase in the
      RV afterload, reduces the right coronary perfusion pressure, exacerbates RV dysfunction, and
      compromise the left ventricular (LV) preload and systemic perfusion pressure. 3,4 Although
      intravenous (IV) milrinone is preferred for treating PHT due to its beneficial effects in
      enhancing myocardial contractability without increasing the heart rate-related myocardial
      oxygen consumption, 5-7 its frequent association with systemic vasodilation requires
      additional vasoconstrictor therapy for maintaining the optimal perfusion pressure.8-10
      Selective pulmonary vasodilation, which reduces the RV afterload without systemic arterial
      vasodilation, is important for managing PHT and the accompanying RV dysfunction.11 A study
      reported that nebulized and inhaled (IH) milrinone ( 1 mg/ml) produced dose-dependent
      selective pulmonary vasodilatation in postoperative PHT in the intensive care unit.12 If IH
      milrinone during the pre-cardiopulmonary bypass (CPB) period produces selective pulmonary
      vasodilation in patients with PHT undergoing mitral valve surgery, it would be a beneficial
      option for managing intraoperative PHT.

      Our main hypothesis is that a brief inhaled milrinone could reduce the pulmonary arterial
      pressure without the systemic side effects better than intravenous milrinone in elevated
      pulmonary artery pressure patients. The aim of this study is to determine the effects of
      hemodynamic before and after administering IH and to compare them to those of IV milrinone in
      patients with elevated pulmonary artery pressure due to severe mitral regurgitation
      undergoing mitral valve surgery.

      Materials and Methods Experimental Groups Adult patients with PHT (systolic PAP > 50 mmHg
      estimated by the velocity of tricuspid valve regurgitation in preoperative transthoracic
      echocardiography) undergoing mitral valve surgery for chronic mitral regurgitation are
      enrolled in this study after obtaining approval from the institutional research board and
      providing written informed consent.

      Preoperative exclusion criteria include preoperative supraventricular tachycardia (SVT),
      atrial fibrillation, atrial flutter, multiple ventricular ectopic contractions, continuous
      inotropic support, LV ejection fraction (EF) < 30%, emergent surgery, obstructive
      cardiomyopathy, bleeding diatheses, bronchial asthma and had biochemical evidence of hepatic
      disease or renal impairment.

      The pharmacist implements the randomization process for grouping the patients by giving the
      enrolled patients, a patient identification number (PIN). Then, the patients are stratified
      by their PIN in a 1:1 ratio to receive IH (Primacor, Sanofi-Synthelabo Canada Inc., Markham,
      ON, Canada) (Group IH) or IV (Group IV) milrinone. The investigators are blinded to the
      allocation of the study group.

      Anesthesia and Patient Monitoring When the patient arrived in the operating room, continuous
      monitoring of a five-lead ECG (lead II and V5), the bispectral index (BIS), pulse oximetry,
      and invasive arterial pressure via the radial artery are started. Patients are given
      midazolam 1.5-2 mg intravenously in the patient holding area. Anesthesia is induced with
      propofol 1-1.5 mg/kg, fentanyl 10-15 μg/kg, and rocuronium 0.9 mg/kg. Target controlled
      infusion (TCI) and a TCI infusor (Diprifusor™ TCI system; Fresenius, Waltham, MA, USA) are
      used to administer propofol for anesthetic induction and maintenance, and the infusion dose
      is titrated to achieve a propofol effect-site concentration of 2-2.5 μg/ml. Additional
      fentanyl at 10-30 μg/kg/h and rocuronium at 20-30 mg/h are administered to maintain
      anesthesia, and the propofol concentration is adjusted to maintain a BIS score of 40-60.
      After tracheal intubation, volume-controlled ventilation of oxygen with air (FiO2 0.6, flow
      rate 100 ml/kg/min) is started with a tidal volume of 10 ml/kg, respiration rate of
      12-14/min, inspiration:expiration ratio of 1:2, and peak airway pressure lower than 25 cmH2O.
      Then, the respiration rate is adjusted to maintain an end-tidal CO2 of 35-40 mmHg.

      An introducer and a pulmonary artery catheter (Oximetrix™ Opticath catheter; Abbot
      Laboratories, North Chicago, IL, USA) are placed in the right internal jugular vein. A
      transesophageal echocardiography (TEE) probe is placed, and intraoperative TEE is used to
      monitor ventricular and valvular function throughout the operation. The LV EF is measured
      using a modification of Simpson's method from the midesophageal 4 or 2 chamber view of
      two-dimensional TEE images as appropriate.

      During and after anesthesia induction and obtaining vascular access for hemodynamic
      monitoring, synthetic hydroxyethylstarch (Voluven™; Fresenius Kabi, Bad Homberg, Germany) is
      administered as needed to maintain stable hemodynamics, and bolus phenylephrine 50-100 μg is
      administered intravenously to treat any refractory hypotension (MAP < 60 mmHg) persisting for
      more than 1 min with intravascular volume administration.

      After delivering the study drugs and collecting data, CPB with moderate hypothermia (rectal
      temperature 28-30ºC) via crystalloid cardioplegia is used during the surgical procedure. The
      MAP was maintained at 50-80 mmHg by adjusting the pump flow and administering 50 μg boluses
      of phenylephrine during the CPB period.

      The IV milrinone infusion (0.5 μg/kg/min) is started at the release of the aortic cross-clamp
      and a continuous infusion of norepinephrine is started at a rectal temperature of 35ºC as
      needed; its dosage is titrated to wean the patient from CPB and to maintain the optimal
      hemodynamics during the post-CPB period in both groups.

      Delivery of the Study Drug After performing the sternotomy and achieving stable hemodynamics,
      but before the initiation of CPB, the study drugs are administered; IH milirinone and IV
      placebo (0.9% normal saline 0.05 ml/kg) or IH placebo (distilled water) and an IV bolus of
      milrinone (50 μg/kg) are administered in Group IH and IV, respectively. Milrinone is used at
      its commercial concentration (1.0 mg/ml) for both inhalation and IV administration. The
      reservoir of a nebulizer (MiniHeart™; Westmed, Tucson, AZ, USA) in the inspiratory limb of
      the ventilator circuit (90 cm proximal to the Y-piece) is filled with milrinone or placebo.
      The milrinone or placebo in the reservoir is nebulized with a fixed operating flow at 2 L/min
      of O2 (as per the manufacturer's recommendation) and delivered over 10 min at a ventilator
      flow rate of 100 ml/kg/min to avoid rebreathing the expiratory flow, which may produce
      contamination or interaction between the nebulized milrinone and CO2 absorbent (Fig. 1). The
      aerosol size and delivery rate of the nebulized drug are assumed to be 1.0-2.5 μm and 45-65
      μL per gas flow, respectively, according to the manufacturer's manual for the nebulizer.
      Excess inspiratory gas flow from the nebulizer was compensated for by adjustment of minute
      ventilation settings on the ventilator, keeping minute ventilation constant. Inspiratory
      oxygen fraction (FiO2) is kept constant throughout the procedure. If MAP decreases below 60
      mmHg, inhalation of the study drug is stopped and the patient excluded from the study.

      Hemodynamic Data The following data are obtained before and 10 min after completely
      administering the study drug: mean arterial pressure (MAP), mean pulmonary arterial pressure
      (MPAP), central venous pressure (CVP), pulmonary arterial occlusion pressure (PAOP), the
      transpulmonary pressure gradient (TPG= mean PAP-PAOP), thermodilution cardiac output (CO),
      systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), arterial O2 tension
      (PaO2), mixed venous O2 saturation (SvO2), and TEE measured EF.

      Statistical Analysis Intergroup comparisons of the changes in SVR, PVR, the PVR/SVR ratio,
      and TPG are used to identify selective pulmonary vasodilation. The data before and after
      administration are compared using paired t-test. If the data do not pass a normality test,
      the Wilcoxon signed-rank test was used. Intergroup data are compared using the t-test. The
      need for bolus phenylephrine due to hypotension in the pre-CPB period or during CPB is
      compared using Fisher's exact test. Statistical significance is assumed at p<0.05.
    

Intervention name(s): inhaled milrinone; intravenous milrinone
Intervention type(s): Drug; Drug
Intervention description(s): After performing the sternotomy and achieving stable hemodynamics, but before the initiation of CPB, inhaled milirinone and intravenous placebo (0.9% normal saline 0.05 ml/kg) are administered; After performing the sternotomy and achieving stable hemodynamics, but before the initiation of CPB, inhaled placebo (distilled water) and an intravenous bolus of milrinone (50 μg/kg) are administered
Other intervention name(s): Primacor, Sanofi-Synthelabo Canada Inc., Markham, ON, Canada; Primacor, Sanofi-Synthelabo Canada Inc., Markham, ON, Canada
Intervention MeSH terms: Milrinone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: inhaled milrinone; pulmonary hypertension; mitral regurgitation; mitral valve surgery