Author: Melissa Colizza - Stollery Children’s Hospital - Edmonton, Canada
According to a retrospective analysis by Saengsin et al. from the November 2023 issue of Anesthesia and Analgesia, that compared patients who received milrinone to matched cohorts who did not receive milrinone after Tetralogy of Fallot repair, which of the following outcomes was MOST likely to be observed during the first 72 hours after surgery in patients who received milrinone?
EXPLANATION
Low cardiac output syndrome (LCOS) is a common occurrence in the pediatric cardiac surgical population, with an incidence of 25%-60% reported in the literature. LCOS is a clinical syndrome in which there is an imbalance of oxygen supply and demand to the tissues. Prevention and management often necessitate the use of both pharmacologic and nonpharmacologic strategies to restore oxygen balance. The etiology of post-surgical LCOS is multifactorial, including myocardial ischemia during aortic cross clamping, the effects of cardioplegia, activation of the inflammatory and complement cascades and changes in pulmonary and/or systemic vascular resistance. It is associated with a decrease in cardiac index, accompanied by an increase in systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR). Risk factors include younger age (especially neonates), complex procedures with prolonged cardiopulmonary bypass times, use of large patch materials for repair, and ventriculotomies.
Milrinone is a phosphodiesterase-3 (PDE-3) inhibitor with vasodilatory and inotropic properties. The Prophylactic Intravenous use of Milrinone After Cardiac Operation in Pediatrics
(PRIMACORP) study by Hoffman et al (2003) is a landmark study, as it highlighted the importance of LCOS prevention. The study compared mortality and the development of LCOS (requiring additional pharmacological or other support) within in the first 36 hours after treatment in three groups of patients under six years old following biventricular repair. Patients were randomly assigned to three groups, a high-dose milrinone (75mcg/kg loading dose with an infusion at 0.75 mcg/kg/min), a low-dose milrinone (25mcg/kg loading dose with an infusion at 0.25 mcg/kg/min), or placebo treatment group. LCOS was defined as clinical signs or symptoms of hypoperfusion, with or without a widened arterio-venous oxygen saturation (AVO2) difference or metabolic acidosis. The trial showed a relative risk reduction of 64% for LCOS in the high dose milrinone group when compared to placebo. It also revealed a 5-9% decrease in systolic blood pressure after milrinone loading dose administration. Notably, this trial advanced the use of milrinone as an alternative or adjuvant to other vasoactive agents and has led to its widespread use after pediatric cardiac surgery.
Despite the results of the PRIMACORP study, strategies to prevent and treat LCOS vary widely. While many centers start milrinone intra-operatively and continue post-operatively, dosage and timing of administration differs greatly. Interestingly, milrinone dosage is often lower than that used in the PRIMACORP study, and it is frequently co-administered with other vasoactive agents. A 2015 Cochrane review by Burkhardt et al examined five randomized-controlled trials comparing milrinone to either placebo, levosimendan, or dobutamine. The authors concluded that milrinone could reduce incidence of LCOS versus placebo in the short-term (up to 36 hours), but that there is insufficient evidence to suggest its effectiveness in preventing mortality or LCOS in the pediatric cardiac surgical population, especially when compared to other agents.
A retrospective study from Boston Children’s Hospital by Mills et al (2016) investigated the use of milrinone to reduce SVR in neonates undergoing Stage 1 palliation for hypoplastic left heart syndrome (HLHS). Patients were administered a loading dose of milrinone (25 to 100 mcg/kg titrated to goal SVR at a cardiac index of 2 L/min m2) prior to weaning from cardiopulmonary bypass and an infusion of milrinone (0.25 to 1 mcg/kg/min) upon separation from cardiopulmonary bypass (CPB) which was continued in the cardiac intensive care unit (CICU). Epinephrine was used as the main inotropic agent. The study demonstrated that the milrinone-treated group, after correction for shorter CPB times, had lower SVR, decreased AV-O2 difference and lower lactate levels. This study highlights the physiologic impact of high SVR on the parallel, single-ventricle circulation by demonstrating that lower SVR in conjunction with adequate inotropy leads to improved oxygen delivery (DO2) and is beneficial in this patient population.
More recently, Saengsin et al investigated milrinone use in children less than one year of age undergoing complete Tetralogy of Fallot (TOF) repair. The study included patients with classic TOF or TOF with pulmonary atresia (without major aortopulmonary collateral arteries) between September 2011 and January 2020. Propensity scoring was used to match 212 patients based on anatomical and surgical risks (106 milrinone-treated versus 106 non milrinone-treated). The primary outcome measure was the need for administration of volume (blood products and 5% albumin) during the first 72 hours after surgery. Secondary outcomes included vital signs (heart rate and blood pressure) and indices of cardiac output and oxygen delivery. The dose and timing of milrinone administration were not protocolized. Milrinone-treated patients tended to be younger with lower weights and smaller tricuspid valves, pulmonary valves and main pulmonary arteries, and were more frequently repaired with transannular patches. The study demonstrated that patients treated with milrinone received more fluid boluses than those who did not (66% vs 52%; confidence interval 1%-27%, P=0.036). In addition, the total volume administered during the first 72 postoperative hours was significantly associated with the total amount of milrinone administered. There was no difference in perfusion indices, such as AVO2 difference or serum lactates, nor in ICU or hospital lengths of stay. This study has several limitations. In addition to being a single-center, retrospective study, the dosing of milrinone was not protocolized, and surgeries occurred over a nine-year period when perioperative management strategies may have changed. However, it does provide some physiological insights into the altered physiology after surgical repair of TOF. The right ventricle (RV) in TOF is restrictive due to hypertrophy, use of patch material, a ventriculotomy incision and myocardial edema, which limit its capacitance due to diastolic dysfunction. In turn, this limits RV preload and cardiac output. The restrictive RV requires higher filling pressures to maintain an adequate stroke volume. The vasodilatory properties of milrinone may be counterproductive in this setting, and thus, may lead to an increased need for fluid administration.
The available evidence suggests that neonates undergoing the Stage I palliation are most likely to benefit from milrinone, especially if used with an additional inotrope to target appropriate perfusion indices. Milrinone should be used with caution in patients undergoing TOF repair due to the risk of reducing RV preload or stroke volume and thus cardiac output. There are advantages and drawbacks to each vasoactive agent and usage should be individualized to each patient’s unique physiology with the goal of adequate end organ perfusion.
In summary, based on a recent retrospective study of milrinone use after TOF repair, these patients may be more likely to require increased fluid administration in the early post-operative period. However, milrinone did not appear to improve indices of cardiac output or reduce the length of stay in the intensive care unit.
REFERENCES
Hoffman TM, Wernovsky G, Atz AM, et al. Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Circulation. 2003;107(7):996-1002. doi: 10.1161/01.cir.0000051365.81920.28
Burkhardt BE, Rücker G, Stiller B. Prophylactic milrinone for the prevention of low cardiac output syndrome and mortality in children undergoing surgery for congenital heart disease. Cochrane Database Syst Rev. 2015;(3):CD009515. doi:10.1002/14651858.CD009515.pub2
Mills KI, Kaza AK, Walsh BK, et al. Phosphodiesterase Inhibitor-Based Vasodilation Improves Oxygen Delivery and Clinical Outcomes Following Stage 1 Palliation. J Am Heart Assoc. 2016;5(11): e003554. doi: 10.1161/JAHA.116.003554
Saengsin K, Sperotto F, Lu M, et al. Administration of Milrinone Following Tetralogy of Fallot Repair Increases Postoperative Volume Administration Without Improving Cardiac Output. Anesth Analg. 2023;137(5):1056-1065. doi: 10.1213/ANE.0000000000006662
Bojan M, Pouard P. Hemodynamic Management. In Andropoulos DB. Anesthesia for Congenital Heart Disease. 4th ed. USA: Wiley-Blackwell; 2023: 494-526.
