Study design and Ethical statement:
This study is a double-blind clinical trial. The study was permitted by the Anesthesiology and Pain Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran (IR.AJUMS.REC.1399.654). The written informed agreement was achieved from all patients participating in the trial. The samples are all patients who underwent open-heart surgery in the Golestan hospital, Ahvaz, Iran. From October 2020 to July 2021 that meets suitability criteria.
Participant
Thirty-two patients candidates for open-heart surgery were selected. The inclusion criteria were as follows: (1) age 20 to 70 years, (2) on pump cardiac surgery; (3) pulmonary arterial pressure more than 40 mmHg that was evaluated by transthoracic and transesophageal echocardiography. The exclusion criteria included the following: (1) Patients were indisposed to the participant or were incompetent to communicate, (2) Redo surgery, (3) emergency surgery, (4) history of chronic obstructive pulmonary disease (COPD), (5) history of severe hepatic or renal dysfunction, (6) hemoptysis. Consort flow diagram
Randomization and Blindness:
The patients were randomized using the simple incidental method, after recognizing appropriate individuals, they were randomly distributed a three-digit exclusive code using the random table. The final digit on the right concludes the patient group. If the figure is 0, 1, 2, 3, 4 it was located in the nebulized milrinone (Group A, N=16), and if the figure is 5, 6, 7, 8, 9 it was situated in the intravenous milrinone (Group B, N=16).To ensure that, the patients, the surgeon, and the investigators were unaware of the treatment group before the study begins and they were uninformed of the type of administration of the drug and the surgeries performed by the same surgeon.
Sample size:
Based on a previous study (12), the prevalence (P) of this disorder is estimated to be 0.1. Therefore, according to the accuracy of the study (d = 0.1), the significance level of 95% in this study and the error level (alpha) of the average are considered 0.05. Z with 95% confidence is 1.96 the prevalence equation of sample size detection 16 samples were selected in each group.
Standardized anesthesia
Premedication was managed according to local practices (0.1mg/kg of Morphine and 0.025 mg/kg of Diazepam as IM). Standard monitoring was performed after entering the operating room, such as electrocardiogram, heart rate (HR), non-invasive blood pressure (NIBP), invasive blood pressure (by radial artery cannulation), and pulse oximetry (SpO2). The anesthesia procedure, the surgeon, and the cardiopulmonary bypass technique was intended to be identical for all patients. General anesthesia was induced with 0.1–0.2 mg/kg of midazolam (Caspian Tamin, Iran), 0.5–1 μg/kg of sufentanil (Aburaihan, Iran), 0.1 mg/kg of Etomidate (Lipuro, B. Braun, India), and 0.5 mg/ kg of cisatracurium (Rosamed, Iran). Additionally, isoflurane 1% (Piramal Critical Care, USA) in 50% oxygen, 0.1 μg/kg/h of sufentanil, 0.1 mg/kg/h of midazolam, and 0.1 mg/kg/h of cisatracurium were used to maintain general anesthesia. End-tidal co2 was retained in the range of 30-40 mmHg, and arterial pH was maintained at 7.4 ± 0.02 for all patients in both groups. After induction of anesthesia, pulmonary artery catheters are inserted from the right internal jugular vein.
Intervention
After surgical repair of the cardiac defect and the opening of the cross-clamp of the aorta, and before weaning off from CPB; Group A patients received nebulized milrinone (Milrinone Lactate 1 mg·ml−1; Pharmaceutical Partners of Canada Inc., Richmond Hill) through a jet nebulizer (Ref 8901; Salter Labs, Arvin, CA) attached to the inspiratory limb of the ventilator with a bypass flow of oxygen at 10 L/min (50-80 μg kg−1) close the endotracheal tube, dissolved in 5mL normal saline. Patients in group B received intravenous bolus milrinone 50 μg kg−1, followed by continuous administration of 0.5 μg kg−1 min−1, started immediately before trying to weaning off from CPB. After administration of the drug (nebulized or IV) weaning off from CPB was started. This process was based on the CVP protocol. (13) Before CPB weaning off, dobutamine was infused at a dose of 5 μg kg−1 min−1 that was augmented up to 10μg kg−1 min−1 according to patient response. Epinephrine infusion was added up to a dose of 0.05 μg kg−1 min−1 that was augmented up to 0.1μg kg−1 min−1 according to patient response if the mean arterial blood pressure during weaning off CPB did not exceed 50 mmHg. After surgery, all patients were transferred to the cardiovascular intensive care unit (CV ICU) sedated and on controlled mechanical ventilation. Patients were extubated when the weaning criteria emerged.
Data collection
The measured hemodynamic parameters included heart rate (HR), cardiac output (CO), cardiac index (CI), stork volume (SV), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), central venous pressure (CVP), mean pulmonary artery pressure (MPAP), Systemic vascular resistance (SVR) pulmonary vascular resistance(PVR) and MAP/M PAP ratio was calculated using the standard method, after induction of anesthesia as baseline (T1), 10, 30 and 60 minutes after the termination of cardiopulmonary bypass ( CPB ) (T2, T3, and T4).
Statistical analysis
All Patient characteristics data were expressed as mean ± standard deviation (SD) and percentages. Evaluations of hemodynamic variables between groups were accomplished with the Student t-test for normally distributed variables. To evaluate variations over time within each group were used one-way analysis of variance (ANOVA) on repeated measurements. Two-way analysis of covariance (ANCOVA) determined for baseline values (T1) was used to compare groups at T2, T3, and T4. Statistical analyses were done with the computer software IBM SPSS Statistics for Windows, Version 19.0 (Armonk, NY: IBM Corp). P-value less than 0.05 was considered as statistical significance.