Neonatal fellow University of Iowa University of Iowa Iowa City, Iowa, United States
Background: Milrinone, a PDE-3 inhibitor, is a commonly used adjunct therapy to improve oxygenation in acute pulmonary hypertension or prevent a low cardiac output state in left ventricular dysfunction. Severe hypotension, however, has been reported in term infants with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia, which may relate to impaired renal clearance. Extremely preterm neonates have physiological differences which may impact pharmacokinetics and the risk of toxicity.
Objective: To assess risk factors for adverse reaction during milrinone treatment among preterms ≤28 weeks in the first 4 postnatal weeks.
Design/Methods: A retrospective cohort study was conducted of neonatal admissions at University of Iowa [2018 to 2020]. Infants 22-28+6 weeks gestational age (GA) who received milrinone at ≤28 days were included. Clinical data including demographics, milrinone indication, co-treatments and acute illness severity measures before and after treatment were collected. The primary outcome was low mean blood pressure (MBP<GA) >1h during infusion. Univariate analysis was used to compare hypotensive to normotensive patients. Serial data was analyzed using repeat measures ANOVA.
Results: 38 patients were screened and 33 fulfilled inclusion criteria (7 hypotensive, 26 controls). Demographics, indication and illness severity were similar between groups. Diastolic BP became lower (p=0.03 vs group) in the hypotensive group beginning 3h after milrinone and declined over time (p=0.01[PJM1] ). Systolic BP was non-significantly lower.[Fig 1] The only variable associated with hypotension was co-infusion of continuous vecuronium (p=0.01), and not primary indication for treatment.[Table 1] Although hypotension was associated with escalation of cardiovascular therapy (p=0.008), treatment was discontinued for only 1 patient, there was no difference in oxygenation, urine output or morbidity. The risk of death was higher in the hypotensive group, all of whom were co-treated with vecuronium.[Table 2] Conclusion(s): Though generally well tolerated, 20% of this cohort of extreme preterms experienced a sustained decline in BP beginning 3-4h following milrinone initiation, which was associated with co-infusion of vecuronium infusion. Plausible mechanisms include vasoparesis [i.e. prevention of vascular adaptation to PDE-3 inhibition] or compromised renal solute excretion [i.e. impaired clearance of both milrinone and active vecuronium metabolites]. Judicious co-infusion of these two agents should be considered and further pharmacological study is needed.
Figure 1. Blood pressure trend following Milrinone infusion. Hourly systolic blood pressures and diastolic blood pressures during first 18 hours following milrinone infusion are shown with hypotensive group in green line versus non-hypotensive group in blue. Values are mean ± SEM. [*] marked p < 0.05 and [+] marked p<0.1. Statistical significance between the two groups was determined using repeat measures ANOVA. Diastolic BP became lower (p=0.03) in the hypotensive group beginning 3h after milrinone and declined over time (p=0.01). Systolic BP was non-significantly lower.
Authors/Institutions: Trassanee Chatmethakul, University of Iowa, Iowa City, Iowa, United States; Adrianne R. Bischoff, University of Iowa, Coralville, Iowa, United States; Patrick J. McNamara, University of Iowa, Iowa city, Iowa, United States; Regan E. Giesinger, University of Iowa, Iowa City, Iowa, United States