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Abstract
Background : The aim of the study was to compare the effect of two different regimens of milrinone in pediatric patients with pulmonary artery hypertension (PAH) undergoing corrective procedure.
Materials and Methods : This randomized prospective study included 100 pediatric patients undergoing corrective cardiac surgeries. Group E: Milrinone was started as infusion 0.5 μg/kg/min without a loading dose after induction of anesthesia and continued as infusion 0.5–0.75 μg/kg/min in the pediatric cardiac surgical intensive care unit (PSICU). Group L: Milrinone was started as a loading dose 50 μg/kg over 10 min before weaning from cardiopulmonary bypass (CPB) followed by infusion 0.5–0.75 μg/kg/min in the PSICU. We compared heart rate, mean arterial blood pressure, central venous pressure, cardiac index (CI), mean pulmonary arterial pressure (MPAP), serum lactate level, urine output, vasoactive inotropic score, mechanical ventilation duration, and intensive care unit (ICU)- and hospital length of stay between the groups.
Results : There was an increase in mean arterial blood pressure, CI, and urine output in Group E compared to Group L (P < 0.05). MPAP, serum lactate level, and requirement of inotropes and vasopressors were lower in Group E compared to Group L (P < 0.05). Mechanical ventilation duration, ICU, and hospital length of stay were shorter in Group E than Group L (P < 0.05).
Conclusions : Early use of milrinone in patients with PAH undergoing corrective cardiac surgeries improved CI and mean arterial pressure, decreased MPAP, improved urine output, decreased serum lactate level, and decreased requirement of inotropes and vasopressors after weaning from CPB compared to the milrinone bolus group.
Keywords: Hemodynamic, milrinone, pediatric cardiac surgeries, pediatric patients, pulmonary artery hypertension
How to cite this article: Introduction 
Pulmonary artery hypertension (PAH) is a pathological hemodynamic condition defined as an increase in mean pulmonary arterial pressure (MPAP) ≥25 mmHg at rest, assessed using the gold standard investigation by right heart catheterization.[1] Pulmonary hypertension could be a complication of cardiac or pulmonary disease or a primary disorder of small pulmonary arteries. Pulmonary hypertension in congenital heart disease is commonly secondary to left-to-right shunt defects or left heart obstructive disease-causing postcapillary hypertension. Common defects include ventricular septal defect (VSD), atrial septal defect (ASD), and patent ductus arteriosus. Milrinone is a intravenously active selective phosphodiesterase III inhibitor that increases the intracellular concentration of cyclic adenosine monophosphate in vascular smooth muscle cells and cardiomyocytes.[2] It is used as an effective medication for patients with preexisting pulmonary hypertension or depressed postoperative cardiac function as it has positive inotropic, vasodilatory, and lusitropic effects. Therefore, it produces relaxation of the vascular smooth muscle and improves both systolic and diastolic cardiac function. It reduces systemic as well as pulmonary vascular resistance. Its usage has become a first-line choice for patients with various extents of pulmonary hypertension. Milrinone is a drug commonly used to support cardiac output after congenital heart surgery in neonates, infants, and children.[3]
The aim of this study is to assess the effect of two regimens of milrinone infusion in pediatric patients with PAH undergoing corrective procedure.
Materials and Methods After obtaining informed consent and approval of the ethics committee (UNMICRC/C. ANESTHE/2019/01) of our institute, a randomized study was conducted including 100 pediatric patients undergoing corrective congenital cardiac surgeries. The inclusion criteria included pediatric patients having age from 2 to 10 years and congenital heart diseases with PAH (MPAP ≥25 mmHg) diagnosed with two-dimensional echocardiography, primary corrective surgery, large VSD, large ASD, patients having VSD and ASD both, and ASA Class III or IV. In our study, we have included patients operated by a single surgeon only to avoid surgical bias. Exclusion criteria included revision surgery due to any cause, preoperative low cardiac output syndrome, preexisting renal failure, preexisting thrombocytopenia, and allergy to study medication. The allocation into two equal groups (n = 50 each) was done using random numbers generated through excel.
Anesthetic technique
The patients have been given midazolam 0.5 mg/kg orally 30 min before surgery in the preparation room to decrease separation anxiety. Before induction of anesthesia noninvasive monitors (electrocardiography, pulse oximeter, and noninvasive blood pressure) were attached. Induction of anesthesia was done for all patients by administration of intravenous ketamine (1–2 mg/kg), followed by fentanyl (4–5 μg/kg) and vecuronium (0.1–0.2 mg/kg). After tracheal intubation, anesthesia was maintained with oxygen (50%–100%), and sevoflurane (1%–3%) in addition to bolus doses of fentanyl (1–2 μg/kg). The end-tidal CO2 was maintained between 30 and 35 mmHg. After induction, invasive monitoring such as arterial line and central venous line was inserted. Transesophageal echocardiography probe was placed to confirm the preoperative echocardiography findings and for proper de-airing before weaning from cardiopulmonary bypass (CPB). CPB circuit was primed with an average of 650 ml of a combination of Plasmalyte, 20% albumin, and whole blood to achieve a hematocrit around 30%. All procedures were done under CPB and with aortic cross-clamping. The patients were classified randomly into two groups:
• Group E (early milrinone group): Milrinone was started as infusion at the rate of 0.5 μg/kg/min without a loading dose after induction of anesthesia and continued postoperatively (0.5–0.75 μg/kg/min) in the pediatric cardiac surgical intensive care unit (PSICU). The perfusionists were informed at the beginning of administration of milrinone to observe the mean arterial blood pressure during CPB
• Group L (late milrinone group): Milrinone was started as a loading dose 50 μg/kg over 10 min before weaning from CPB and continued as infusion at the rate of 0.5–0.75 μg/kg/min postoperatively in the PSICU.
During and after weaning from CPB, the oxygen concentration was kept 50%–100%. After surgery, all patients were transferred to the PSICU and maintained ventilated mechanically on oxygen: air 50% and positive end-expiratory pressure 3–5 cm H2O if needed. In intensive care unit (ICU) patients were given injection frusemide 1–2 mg/kg/day to maintain adequate urine output.
Patient monitoring
For all patients, the following variables were closely monitored: the heart rate, mean arterial pressure (MAP), central venous pressure, pharmacological support (epinephrine, norepinephrine, and vasopressin), lactate level, urine output, and arterial blood gases. The readings were recorded at the following time points – T1: 15 min after weaning from CPB; T2: at the end of surgery; T3: 6 h after ICU admission; T4: 24 h after ICU admission; and T5: 48 h after ICU admission. MPAP and cardiac index (CI) were measured with two-dimensional echocardiography at the following time points: T2: at the end of surgery; T4: 24 h after ICU admission; and T5: 48 h after ICU admission. Continuous-wave (CW) Doppler of the tricuspid regurgitation (TR) trace is used to measure the difference in pressures between the right ventricle and right atrium. The simplified Bernoulli equation (P = 4 [TRmax]2) is used to calculate this pressure difference using peak TR velocity. This method correlates well with pulmonary artery systolic pressure on right heart catheterization.[4],[5] A coaxial TR jet is identified in parasternal long-axis (RV inflow), parasternal short-axis, or apical four-chamber view with the help of color Doppler. CW Doppler is used with a sweep speed of 100 mm/s to achieve a satisfactory envelope. The peak velocity of the envelope is then measured (TRmax). Mean PAP can be approximated from the systolic PAP (SPAP) using the following formula:
MPAP = 0.61 × SPAP + 2 mmHg.[6] CI was measured by two-dimensional echocardiography using modified Simpson's rule to calculate the cardiac output (stroke volume and heart rate) and dividing the cardiac output over the body surface area.
We have noted inotropic and vasopressor requirements in both the study groups apart from milrinone infusion after weaning from CPB and calculated maximal vasoactive-inotropic score (vasoactive inotropic score [VIS] max) which is the highest doses of vasoactive and inotropic medications administered during the first 24 h postsurgery. VIS was calculated with this formula: VIS = Dopamine dose (μg/kg/min) + dobutamine (μg/kg/min) + 100 × epinephrine dose (μg/kg/min) + 100 × norepinephrine dose (μg/kg/min) + 50 × levosimendan dose (μg/kg/min) + 10 × milrinone dose (μg/kg/min) + 10,000 × vasopressin dose (unit/kg/min).[7] The data were retrieved from the ICU critical care information system.
Outcomes
The primary outcome was the postoperative hemodynamic stability and it was assessed by heart rate, arterial blood pressure, central venous pressure, oxygen saturation, MPAP, CI, urine output, and serum lactate level. The secondary outcome was the safety of the study medications, which was assessed by the occurrence of any adverse events.
Statistical analysis
Collected data were analyzed using IBM, SPSS version 20.0 software (SPSS Inc., Chicago, IL, USA). These data were presented as mean ± standard deviation or proportion according to their distribution characteristics. Categorical variables were described using counts and percentages as appropriate. Paired Student's t-test was used to compare continuous variables. The Chi-square test was used for categorical variables. P < 0.05 was considered to be statistically significant.
Results All included patients completed the study. There were no significant differences regarding the demographic data, type of congenital cardiac lesions, preoperative echocardiography data, CPB time, aortic cross-clamp time, and total surgical time in both the study groups (P > 0.05) [Table 1].
[Table 2] shows the comparison of different hemodynamic parameters of both the study groups. There was no significant change in heart rate in both the groups (P > 0.05). The mean arterial blood pressure was higher in Group E compared to Group L at all time points (T1-T5) and it was statistically significant (P < 0.05).
Central venous pressure was lower in Group E compared to Group L at all time points and it was also statistically significant (P < 0.05). Urine output was statistically higher in Group E compared to Group L (P < 0.05). Serum lactate level was statistically lower in Group E compared to Group L (P < 0.05). We have measured CI and MPAP with help of 2D echocardiography at three different time points – T2: at the end of surgery, T4: 24 h after admission to ICU, and T5: 48 h after admission to ICU.
[Table 3] shows that during postoperative period, CI was higher in Group E compared to Group L and it was statistically significant (P < 0.05). MPAP was lower in Group E compared to Group L during postoperative course and it was statistically significant (P < 0.05).
[Table 4] shows inotrope and vasopressor requirements in both the study groups. The total milrinone dose required before weaning from CPB is higher in Group E compared to Group L (P < 0.05). However, the difference in the total milrinone dose required was insignificant after weaning from CPB (P = 0.27) or in the ICU (P = 0.70). [Table 4] shows that the total number of patients who required epinephrine was higher in Group L compared to Group E (P = 0.015) and the total dose requirement was also higher in Group L compared to Group E (P < 0.05). The number of patients who required vasopressors such as norepinephrine and vasopressin was also higher and statistically significant in Group L compared to Group E (P < 0.05). [Table 5] shows that the duration of mechanical ventilation was shorter in the patient's Group E than Group L (P = 0.032). The ICU and hospital length of stay were shorter in the patient's Group E than Group L (P = 0.042 and P = 0.018, respectively).
Discussion This study compared two different regimens of milrinone administration in pediatric patients with PAH undergoing corrective procedures. Patients required less inotropes and vasopressors in the early milrinone group compared to the late milrinone group. Early milrinone was infused without the bolus dose to avoid the possible problems such as hypotension related to bolus administration, and we found clinically that the early milrinone is more effective than the late milrinone with the bolus dose. The total milrinone dose given before weaning from CPB was higher in patients in the early milrinone group, and this may be related to the improvement of outcomes with early milrinone administration. The reasons for better hemodynamics in group E may be due to (a) larger overall dose of milrinone, (b) better perfusion during CPB, and (c) anti-inflammatory properties of milrinone.[8],[9],[10]
One study showed that infusion of milrinone at the beginning of CPB has a potent vasodilator effect and may be associated with improving tissue perfusion as indicated by lower serum lactate levels, higher urine output, and normal mixed venous oxygenation than administration of milrinone after CPB[11] and that could be explained by a study done by Möllhoff et al.[12] They showed that milrinone improved tissue perfusion and the postoperative oxygen transport to the tissue after cardiac surgery as a result of the increased cardiac output and vasodilatation associated with milrinone and the same results were shown by another study.[13]
A similar study in pediatric patients undergoing congenital cardiac surgery showed that early milrinone increased the mean arterial blood pressure, central venous oxygen saturation, and urine output and was associated with decreased serum lactate level.[14] The good results with early uses of milrinone at the beginning of CPB may be related to the increased level of milrinone in the blood and its effect on the tissue perfusion during and after CPB[15] and other studies showed the same results.[3],[13],[16]
A retrospective analysis of high-risk patients who received milrinone before CPB initiation were weaned easily from CPB and associated with a significant decrease in the pulmonary artery pressure and significant improvement of ventricular function.[17],[18] Another study showed that the plasma concentration of milrinone after continuous infusion without a bolus reached the same level after 1 h as the concentration in patients who received continuous infusion initiated by a loading dose.[19]
Study limitations
There are some limitations to this study. The major limitation of this study is not measuring the plasma levels of milrinone, which would have given greater insight into pharmacokinetics of bolus versus infusion regimen both during CPB and post-CPB. We have not measured the plasma level of milrinone because of unavailability of the kit in the laboratory. Additional inotrope administration could have affected hemodynamics as well. Another limitation is population of the study, which was relatively small.
Conclusion Milrinone administration after induction of anesthesia and during CPB in patients with PAH undergoing corrective surgeries improved CI, improved MAP, decreased MPAP, improved urine output, and decreased serum lactate level. Furthermore, early use of milrinone decreased the requirement of inotropes and vasopressors after weaning from CPB compared to the milrinone bolus group; however, early use of milrinone led to higher total milrinone dose administration.
Acknowledgments
The authors thank all staff nurses in the operative rooms and pediatric cardiac surgical ICU for their efforts and help during the study. The authors appreciate Mrs. Himani Pandya who did the statistical analysis for the study.
Financial support and sponsorship
This study was financially supported by the U.N. Mehta Institute of Cardiology and Research Centre.
Conflicts of interest
There are no conflicts of interest.
References 
Correspondence Address:
Dr. Mrugesh Prajapati
Associate Professor, Department of Cardiac Anesthesia, U.N. Mehta Institute of Cardiology and Research Center (Affiliated to B. J. Medical College), New Civil Hospital Campus, Asarwa, Ahmedabad - 380 016, Gujarat
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/apc.apc_230_21
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