Effect of Brief Nebulization of Milrinone on Pulmonary Arterial Pressure Before Cardiopulmonary Bypass on Mitral Valve Surgery Patients
Effect of Brief Nebulization of Milrinone on Pulmonary Arterial Pressure Before Cardiopulmonary Bypass on Mitral Valve Surgery Patients
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.
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.
Inclusion Criteria:

 -  patients undergoing mitral valve surgery for chronic mitral regurgitation

 -  estimated pulmonary hypertension (systolic PAP > 50 mmHg estimated by the velocity of
 tricuspid valve regurgitation in preoperative transthoracic echocardiography)

 -  patients who agreed to participate in this study and signed written informed consent

 Exclusion Criteria:

 -  preoperative supraventricular tachycardia (SVT),

 -  atrial fibrillation,

 -  atrial flutter,

 -  multiple ventricular ectopic contractions,

 -  continuous inotropic support,

 -  LV ejection fraction (EF) < 30%,

 -  emergent surgery,

 -  obstructive cardiomyopathy,

 -  bronchial asthma

 -  biochemical evidence of hepatic disease or renal impairment