235 - Hemodynamic profile of neonates receiving sildenafil in addition to therapeutic hypothermia for neonatal encephalopathy

Poster Number: 235
Publication Number: 235.222

Anie Lapointe, CHU Ste-Justine, Montréal, PQ, Canada; Gabriel Altit, McGill University Faculty of Medicine and Health Sciences, Montreal, PQ, Canada; Emmanouil Rampakakis, McGill University Faculty of Medicine and Health Sciences, Montreal, PQ, Canada; Pia Wintermark, McGill University Faculty of Medicine and Health Sciences, Montreal, PQ, Canada

Background: Therapeutic hypothermia (TH) has been shown to improve outcomes of neonates with hypoxic-ischemic encephalopathy (HIE). However, some neonates still die and/or develop brain injury, and complimentary strategies are needed to further improve outcomes. Sildenafil has the potential to prevent brain injury and promote brain repair and may also have an impact on hemodynamic status.

Objective: To compare the hemodynamic profile of neonates with moderate and severe HIE developing brain injury despite TH when exposed to sildenafil vs not.

Design/Methods: We conducted a double-blinded randomized control phase Ib study of near-term and term neonates with moderate or severe HIE developing brain injury despite TH in a single tertiary neonatal intensive care unit. Neonates were randomized to sildenafil (n=7) or placebo (n=3). Intervention (study drug of 2 mg/kg every 12h PO X 14 doses) was initiated after a brain MRI performed on day 2 of life during TH confirmed brain injury. Echocardiography (ECHO) measurements were repeated at the following time-points: DOL 2 (pre-drug initiation), DOL 3 (24 hours after initiation), DOL 4 (after rewarming) and DOL 10 (after cessation of drug). Primary outcome was improvement of left (LV) and right (RV) cardiac function by strain analysis. Generalized linear mixed effect models with repeated measures were used and statistical significance was set to < 0.05.

Results: Demographic data are presented in Table 1. Neonates in the placebo group had higher gestational age at birth (41.2 ± 0.2 vs 39.3 ± 1.6, p=0.02). Cardiorespiratory characteristics over time are presented in Table 2. Creatinine kinase improved in both groups over time (p=0.04) and those with sildenafil were exposed more frequently to inotropes (p=0.02) at the time of each ECHO. Performance of the LV (by peak longitudinal global strain and strain rate; p < 0.001 and p=0.003) and RV (by peak longitudinal strain rate, p=0.04) improved overtime, and more so in the neonates exposed to sildenafil (Table 3). Both groups improved their pulmonary to systemic pressure ratio (p≤0.001) and their biventricular performance over time, as assessed by parameters measured on tissue Doppler imaging.Conclusion(s): In a cohort of neonates with moderate or severe HIE developing brain injury despite TH, sildenafil administration (in addition to TH) improved cardiac function measured by strain analysis, even if incidentally the neonate’s receiving sildenafil presented with more severe cardiac dysfunction before initiation of the study drug. Larger cohorts are needed to replicate these findings.
Table 1. Neonatal characteristicsaEEG: amplitude-integrated electroencephalogram; IQR: interquartile range; MRI: magnetic resonance imaging
P value calculated for comparison by X2 test for categorical data and Wilcoxon Rank Sum test for continuous data
Table 2: Evolution of cardiorespiratory outcomes over timeT1= during therapeutic hypothermia but before randomization; T2= during therapeutic hypothermia and 24h after first dose of sildenafil; T3 = after rewarming and 48 h after the first dose; T4 = at day of life 10, 48 h after sildenafil stop
*[Time] represents the significance of changing values over the different time-points of assessment
**[Group] represents the significance of the difference between the two groups after considering repeated measures over time
FiO2: fractional oxygen administration.