Pharmacologic Agents for Managing Acute

Pulmonary Hypertension in Preterm Infants:

Mechanisms, Indications, and Considerations

Abstract
Acute pulmonary hypertension (PH) in preterm infants poses significant clinical challenges due to the complex interplay
between the underdeveloped pulmonary and cardiovascular systems. This paper provides a comprehensive overview of
various pharmacologic agents used in managing this condition, highlighting their mechanisms of action, indications, and
limitations. We emphasize the judicious use of inhaled nitric oxide (iNO), discuss alternatives like sildenafil and milrinone,
and explore the roles of vasopressors and inodilators such as vasopressin, norepinephrine, and dobutamine. The goal is to
equip clinicians with a detailed understanding of these agents to optimize therapeutic strategies for this vulnerable
population.

Introduction
Pulmonary hypertension in preterm infants is a critical condition characterized by elevated pulmonary vascular resistance
and subsequent right ventricular dysfunction. Effective management requires a nuanced understanding of various
pharmacologic agents and their specific impacts on the neonatal cardiovascular system. This paper aims to provide a
detailed analysis of these agents, focusing on their mechanisms, appropriate use cases, and potential risks, to guide
clinicians in making informed treatment decisions.

Detailed Analysis of Pharmacologic Agents

Ranked Agents Based on Decreasing Positive Effect on PH

Inhaled Nitric Oxide (iNO)

Evidence: Inhaled nitric oxide (iNO) is well-documented in the literature as a first-line treatment for pulmonary hypertension
in neonates. Clinical trials and observational studies have shown its effectiveness in improving oxygenation and reducing
pulmonary vascular resistance in infants with severe hypoxemia and PH . iNO selectively dilates pulmonary vessels without
significantly affecting systemic blood pressure, making it an ideal agent for managing PH in this population.

Milrinone
Evidence: Milrinone is a phosphodiesterase 3 (PDE-3) inhibitor that increases cyclic AMP, resulting in vasodilation and
improved cardiac output. It has shown promise in reducing pulmonary vascular resistance and improving right ventricular
function in neonates with PH . Although data specific to preterm infants are limited, studies indicate that milrinone can be
effective in managing PH and supporting cardiac function in this population .

Sildenafil
Evidence: Sildenafil has been shown to be beneficial in managing pulmonary hypertension, particularly in term infants with
PPHN. Studies indicate that sildenafil increases cyclic GMP levels, leading to pulmonary vasodilation and improved
oxygenation . While data in preterm infants are less extensive, sildenafil's pharmacologic profile suggests a significant
potential benefit in reducing pulmonary vascular resistance and improving outcomes in PH .

Vasopressin
Evidence: Vasopressin has been used successfully to treat systemic hypotension in preterm neonates. It acts by inducing
systemic vasoconstriction while promoting pulmonary vasodilation through nitric oxide release from endothelial receptors .
Clinical evidence supports its dual role in managing both systemic and pulmonary circulation issues in neonates with PH .

Norepinephrine
Evidence: Norepinephrine supports right ventricular function and reduces pulmonary vascular resistance under hypoxic
conditions, as suggested by neonatal and animal model studies . Its use in preterm infants is supported by limited evidence,
but it has shown potential benefits in managing hypotension and supporting RV function in cases of PH .

Dobutamine
Evidence: Dobutamine acts as an inodilator, providing positive inotropic effects and increasing cardiac output. It is
beneficial in preterm neonates with myocardial dysfunction and low systemic blood flow. Studies have shown that
dobutamine can effectively increase cardiac output without significantly increasing pulmonary vascular resistance, making it
useful in managing PH and supporting systemic circulation .

Prostaglandin E2 (PGE2, Alprostadil)

Evidence: Prostaglandin E2 is used for refractory hypoxemia or compromised systemic blood flow where right ventricular
systolic performance is severely impaired, and the PDA is small or restrictive. Evidence suggests that PGE2 can enhance
systemic blood flow and oxygenation in critical situations, despite its counterintuitive use in preterm infants .

Catecholamines (Dopamine and Epinephrine)

Evidence: Dopamine and epinephrine are commonly used catecholamines that increase both systemic vascular resistance
and pulmonary artery pressure. Studies indicate that these agents can exacerbate pulmonary hypertension by increasing
pulmonary vascular resistance more than systemic arterial pressure . Their use is primarily highlighted to emphasize their
negative effects on PH, as PH and compromised systemic blood flow often occur together.

Conclusion
The management of acute pulmonary hypertension in preterm infants necessitates a comprehensive understanding of
various pharmacologic agents. Each agent presents unique benefits and risks, underscoring the importance of individualized
treatment plans. Judicious use of these medications, guided by a thorough understanding of their mechanisms and
potential complications, can improve outcomes for this vulnerable population.

References
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Pharmacologic Agents for Managing Acute Pulmonary Hypertension in
Preterm Infants: Mechanisms, Indications, and Considerations
Mechanism of
Agent Class Action Indication Considerations/Limitations

iNO Inhaled nitric oxide Vasodilation via Severe Avoid in significant LV

increased NO hypoxemia in dysfunction; use lowest
levels preterm effective dose and duration to
infants with minimize risks of IVH,
PH pulmonary hemorrhage, and
oxidative stress.

Milrinone Phosphodiesterase Vasodilation via Acute PH and Limited efficacy in preterm

3 (PDE-3) inhibitor increased cyclic RV infants due to
AMP dysfunction underdeveloped sarcoplasmic
reticulum; sparse data in
preterm infants.

Sildenafil Phosphodiesterase Increases cGMP Acute PH and Not recommended as an

5 (PDE-5) inhibitor leading to RV alternative to iNO; insufficient
vasodilation dysfunction in study in preterm infants.
term infants

Vasopressin Vasopressor Systemic Hypotension Effective in treating

vasoconstriction; hypotension; acts through
pulmonary endothelial receptors to
vasodilation via release NO in pulmonary
NO release circulation.

Norepinephrine Catecholamine Vasoconstriction; Hypotension, Limited neonatal evidence;

supports RV support of RV may reduce PVR in animal
function under function models.
hypoxic
conditions

Dobutamine Inodilator (α1 and Positive inotropic Myocardial Shown to increase cardiac
β1 receptor effects; increases dysfunction, output in preterm neonates;
agonist) cardiac output low SBF less likely to cause pulmonary
vasoconstriction compared to
other agents.

Prostaglandin Prostaglandin Vasodilation; Refractory Potentially beneficial in cases

E2 (PGE2, alprostadil) maintains PDA hypoxemia, with severe RV dysfunction
compromised and small or restrictive PDA.
SBF

Dopamine Catecholamine Increases Hypotension May increase PAP more than

systemic vascular SAP; greater vasoconstriction
resistance and in the pulmonary vasculature.
PAP

Epinephrine Catecholamine Increases heart Hypotension May cause pulmonary

rate and vasoconstriction at higher
contractility; doses; potentially useful in
vasoconstriction systemic hypotension at lower
doses.