ACE inhibition for severe bronchopulmonary dysplasia - an approach based on physiology

Abstract

Premature infants have a high incidence of bronchopulmonary dysplasia (BPD). Systemic hypertension, arterial thickness and stiffness, and increased systemic afterload may all contribute to BPD pathophysiology by altering left ventricular (LV) function and increasing pulmonary venous congestion by lowering end‐diastolic compliance. This case series studied the usefulness of angiotensin‐converting enzyme (ACE) inhibition by measuring clinical and echocardiographic improvements in six consecutive infants with “severe” BPD unresponsive to conventional therapy. The range of gestation and birthweight were 23–29 weeks and 505–814 g, respectively. All required mechanical ventilation (including high‐frequency oscillation) and all but one were administered postnatal corticosteroids. Other treatments including sildenafil and diuretics made no clinical improvements. Captopril was started for systemic hypertension after cardiac and vascular ultrasounds which were repeated 5 weeks later. A significant reduction in oxygen (55 ± 25 to 29 ± 3%, two‐tailed P = 0.03) and ventilator requirements, and improved cardiovascular parameters were noted. This included a trend toward reduction in aorta intima media thickness [840 ± 94 to 740 ± 83 μm, P = 0.07] and an increased pulsatile diameter [36 ± 14 to 63 ± 25 μm, P = 0.04]). Improvements were observed for both systolic (increased LV output, 188 ± 13 to 208 ± 13 mL/kg/min, P = 0.046 and mean velocity of circumferential fiber shortening, 1.6 ± 0.2 to 2.5 ± 0.3 [circ/sec], P = 0.0004) and diastolic (decreased isovolumic relaxation time, 69.6 ± 8.2 to 59.4 ± 5 msec, P = 0.044) function which was accompanied by increased pulmonary vein flow. Right ventricular output increased accompanied by a significant lowering of pulmonary vascular resistance. These findings suggest that improving respiratory and cardiac indices (especially diastolic function) warrants further exploration of ACE inhibition in BPD infants unresponsive to conventional therapy.

Long-term consequences of prematurity

“…39 In a case series of 6 infants (born at 23-29 weeks of gestation) with hypertension associated with severe chronic lung injury, captopril, an angiotensin-converting enzyme inhibitor, improved respiratory and cardiac indices 5 to 7 weeks after birth. 40 Ischemic heart disease. A populationbased cohort study found that adults ages 30 to 43 who were born preterm (gestational age < 37 weeks) have a 53% increased relative risk of ischemic heart disease compared with a fullterm birth cohort, and those born early term (37 to 38 weeks) have a 19% increased risk.…”

Advances in treating bronchopulmonary dysplasia

“…Infants with severe BPD can experience both systemic and pulmonary hypertension which contributes to their respiratory and cardiovascular morbidity [38]. Infants with severe BPD and pulmonary hypertension are at greater risk of mortality [39].…”

“…The incidence of systemic hypertension has been variously reported to be between 7 and 43% [38]. Infants have increased aorta wall thickness and stiffness [50], hypertrophy of the heart and reduced cardiac function [51].…”

“…Captopril, an angiotensin-converting enzyme (ACE) inhibitor, has been used in neonates with hypertension and is thought to improve endothelial function and nitric oxide release [38]. It, has, however, only been reported to be evaluated in a case series of six infants with severe BPD unresponsive to sildenafil and diuretics, five weeks after commencing treatment with captopril there was a significant reduction in the mean fraction of inspired oxygen (FiO2) (0.55 versus 0.29, p=0.03) and ventilatory requirements with a reduction in aorta intima media thickness [38].…”

Safety, Feasibility, and Impact of Enalapril on Cardiorespiratory Physiology and Health in Preterm Infants with Systemic Hypertension and Left Ventricular Diastolic Dysfunction

“…However, the relationship between the impact on LV function, systemic hypertension, and respiratory morbidity is poorly understood. There is preliminary evidence that Angiotensin Converting Enzyme (ACE) inhibitors may have a positive modulator role on LV diastolic function in neonates [ 13 ]. Since July 2020, infants with systemic hypertension and concern for LV diastolic dysfunction at our institution have received treatment with a long-acting ACE inhibitor, enalapril, according to a standardized protocol and strict serial Targeted Neonatal Echocardiography (TnECHO) monitoring.…”