246 - Transitions in Novel Hemodynamic Phenotypes Impact Clinical Severity in Neonates with Congenital Diaphragmatic Hernia

Publication Number: 4242.246

John Wren, University of Iowa Stead Family Children's Hospital, Iowa City, IA, United States; Rachael M. Hyland, Iowa, Iowa City, IA, United States; Patrick McNamara, University of Iowa, Iowa city, IA, United States

Background: Congenital diaphragmatic hernia (CDH) is associated with significant morbidity and mortality. This is despite an increased focus on targeted and judicious use of key medications including prostaglandins (PGE) and inhaled nitric oxide (iNO) which, if used indiscriminately, can iatrogenically worsen outcomes in a subset of neonates with CDH via flow-mediated pulmonary over-circulation. Heterogeneity in CDH cardiovascular disease is illustrated by the concept of echocardiogram-defined hemodynamic phenotypes, of which three were originally proposed: (1) no/mild pulmonary hypertension (PH), (2) pre-capillary PH, and (3) post-capillary PH. With increasing use and duration of PGE and associated risk for pulmonary over-circulation, we hypothesize the development of two additional phenotypes over time: (4) flow-mediated PH and (5) mixed PH. Despite growing clinical adoption of these as-yet hypothetical phenotypes, little consideration has been given to their dynamic nature over time.

Objective: To assess the natural history of hemodynamic phenotypes within CDH longitudinally and their impact on key clinical outcomes.

Design/Methods: All neonates with CDH from 2018-2025 who received an echo in the first 24 hours and at least one other at 24-72 hours, pre-operatively, and post-operative repair, were retrospectively included. An echo-based algorithm (Fig. 1) was developed and used to classify each patient into 1 of 5 hemodynamic phenotypes which were then assessed against pre-selected clinical outcomes.

Results: 29 neonates, at a high PGE use center (19/29, 66%), were identified of whom 26 (90%) exhibited > 1 phenotypic transition overall and specifically to a flow-mediated or mixed PH phenotype in 18/29 (62%, Fig. 1). Transition to a mixed PH phenotype at 24-72 hours was associated with mortality (Table 1). The continued use of PGE and iNO post-operatively was associated with the flow-mediated PH phenotype and prolonged mechanical ventilation. The development of either a flow-mediated or mixed PH phenotype was associated with delayed surgical repair and prolonged hospitalization (Table 2).

Conclusion(s): Hemodynamic phenotypes transition frequently in neonates with CDH, underscoring the need for frequent reassessments as different management approaches are required for each. We identified two novel hemodynamic phenotypes: flow-mediated and mixed PH, associated with delayed repair/prolonged hospitalization and mortality, respectively. Further work and awareness of the potential progression to these phenotypes and their impact on outcomes is needed.

Figure 1. Hemodynamic phenotypes in neonates with congenital diaphragmatic hernia (CDH).
(A) Sankey diagram depicting individual hemodynamic phenotypes and their transitions over time and their relation to survival to discharge. For the first two timepoints, the first targeted neonatal echocardiogram (TNE) <24 hours and the first TNE between 24-72 hours was included. The last TNE prior to operative diaphragm repair and the first TNE post-repair was included for the last two time points. (B-D) Algorithm of phenotype classification employed at each timepoint based on the applicable TNE. Predominant ventricular systolic dysfunction was determined via a comparison of left (LV) and right ventricular (RV) echocardiography measures including ejection fraction by Simpon's biplane, LV s' and tricuspid annular plane systolic excursion (TAPSE), RV s', and RV fractional area change, respectively. Patent ductus arteriosus (PDA) shunt direction was determined quantitatively via percent left-to-right (LR) by velocity time integral (VTI). Atrial shunt direction was subjectively categorized. Flow reversal in the descending aorta, a recognized marker of ductal steal/pulmonary over-circulation in preterm neonates, was only considered present if it was present throughout diastole (holodiastolic). PH, pulmonary hypertension; Pr LR, predominant left-to-right; bid, bidirectional; Pr RL, predominant right-to-left; RL, right-to-left; RVSp, estimated right ventricular systolic pressure (+ right atrial pressure); sEI, systolic eccentricity index; iNO, inhaled nitric oxide; PGE, prostaglandin E infusion; DAo, descending aorta.

Table 1. Clinical, demographic, and outcome data between hemodynamic phenotypes at each time point.
Hemodynamic phenotypes were delineated via a standardized algorithm seen in Figure 1. Data are expressed as the mean (standard deviation) except where indicated. Blank/shaded columns indicate no TNEs fit into that phenotype at that time point. Statistical analysis via Kruskal-Willis for the <24 hour, 24-72 hours, and pre-operative time point and Mann-Whitney for the post-operative time point was utilized for continuous variables and Fisher's exact test was utilized for categorical variables. P < 0.05 was considered statistically significant. a,b denote statistical significance between matched subgroups by Dunn's multiple comparisons test. PH, pulmonary hypertension, TNE, targeted neonatal echocardiography; VIS, vasoactive inotrope score; iNO, inhaled nitric oxide; PGE, prostaglandin infusion; PDA, patent ductus arteriosus; ECLS, extracorporeal life support.

Table 2. Clinical outcomes between neonates with congenital diaphragmatic hernia (CDH) who did or did not develop at least one period of a flow-mediated or mixed pulmonary hypertension (PH) phenotype.
Hemodynamic phenotypes were delineated via a standardized algorithm seen in Figure 1. Data are presented as the mean (standard deviation) unless otherwise indicated. PH, pulmonary hypertension; ECLS, extracorporeal life support. Statistical analysis via Mann-Whitney test. P < 0.05 considered statistically significant.