Date of Initial Publication: May 2026  

Contact Authors: William Corder and Sergei Roumiantsev

Contributing Authors: Maame Arhin; Shehla Siddiqui; Stephanie Grayson; Amy Lembeck, Jason Stoller; Osvaldo Mercado ; Sam Garber; Crystal Bass; Amy Cohen; Novisi Arthur; Kelle Matthews; Brendan Carty; Laken Tedrow; Kelsie Ellis; Sarvin Ghavam ; Mary Haggerty; Molly May; Dolapo Avungbeto; Tami Stuart; Kristin Coletti; Anna O’Brien; Rodney Littlejohn; Megan Sheakoski; Taylor Wild; Jennifer Maher; Kelsie Ellis; Eric Will; Hannah Chalal; Maky Fraga; Andrea Jones; Taylor Wild; Ana Arias-Oliveras; Aimee Cunningham; Mark Ogino; Purvi Jethva  

Abstract

Background: Persistent pulmonary hypertension of the newborn (PPHN) remains a significant cause of neonatal morbidity and mortality and is characterized by failure of the normal postnatal decrease in pulmonary vascular resistance, resulting in hypoxemia and hemodynamic instability. Despite advances in neonatal care, significant variation persists in diagnostic approaches, ventilatory management, cardiovascular support, and the use of pulmonary vasodilator therapies. 

Objective: To develop multidisciplinary, evidence-informed, and consensus-driven recommendations to guide the diagnosis, monitoring, stabilization, and management of infants with PPHN using a physiology-based and echocardiography-informed framework. 

Methods: A multidisciplinary expert panel performed an in-depth review of the published literature, critically appraised the available evidence, and integrated these data with institutional practices and clinical expertise. Consensus was achieved through structured discussion and iterative multidisciplinary expert review focused on key domains including diagnostic evaluation, ventilatory management and oxygenation targets, hemodynamic support, pulmonary vasodilation, the role of echocardiography and cardiac ultrasound modalities, and referral for advanced therapies, including extracorporeal membrane oxygenation (ECMO). 

Results: The panel developed structured recommendations emphasizing early recognition, targeted monitoring, judicious ventilation and oxygen strategies, cautious volume administration and vasoactive support, echocardiography-guided use of pulmonary vasodilators, and timely referral for advanced support. Areas with limited evidence or incomplete consensus were explicitly identified to support informed clinical decision-making and to highlight priorities for future research and quality-improvement efforts. 

Conclusions: These consensus recommendations provide a practical, physiology-guided framework for the management of PPHN, with the goal of reducing practice variability, supporting bedside decision-making, and optimizing clinical outcomes, while acknowledging the need for individualized care and ongoing investigation in areas with limited evidence. 

Consensus Goals

The goals of this multidisciplinary consensus effort are to: 

• Critically appraise the PPHN literature, identifying areas of strong evidence and ongoing uncertainty.  
• Provide evidence-informed, consensus-driven recommendations to guide diagnosis and management.  
• Standardize core management principles while preserving flexibility for patient-specific physiology and clinical context.  
• Promote early recognition and accurate diagnosis using clinical assessment, physiologic monitoring, and timely echocardiography.  
• Support physiology-guided, echocardiography-informed management across ventilation, oxygenation, hemodynamics, and pulmonary vasodilation.  
• Define the roles of echocardiography, TnECHO, and cardiac POCUS in diagnosis, phenotyping, and longitudinal care.  
• Reduce practice variability and avoid potentially harmful interventions.  
• Facilitate timely escalation and referral for advanced therapies, including iNO, High Frequency Ventilation, and ECMO.  
• Highlight evidence gaps to support individualized care and guide future research and quality improvement. 

Background

Persistent pulmonary hypertension of the newborn (PPHN) is a complex cardiopulmonary disorder resulting from the failure of the normal postnatal transition of the pulmonary circulation. Elevated pulmonary vascular resistance leads to right-to-left shunting at the ductal and atrial levels, impaired pulmonary blood flow, hypoxemia, and variable degrees of cardiac dysfunction. PPHN may occur as an isolated condition or in association with parenchymal lung disease, infection, meconium aspiration, or maladaptive cardiovascular physiology. 

Management of PPHN requires careful integration of respiratory, cardiovascular, and hemodynamic strategies. Early recognition and stabilization are essential to minimize hypoxemia, prevent worsening pulmonary vasoconstriction, and preserve end-organ perfusion. However, approaches to ventilation, oxygenation targets, sedation, volume administration, vasoactive support, and pulmonary vasodilation vary widely across institutions and providers.

Echocardiography plays a central role in confirming the diagnosis of PPHN, excluding structural congenital heart disease, assessing ventricular function, and defining shunt physiology. Increasing availability of targeted neonatal echocardiography has further enabled real-time, physiology-based management, though its role must be clearly distinguished from comprehensive diagnostic echocardiography and cardiac point-of-care ultrasound.

Despite existing guidelines and clinical pathways, significant uncertainty remains regarding optimal thresholds for escalation of care, sequencing of vasoactive and pulmonary vasodilator therapies, and timing of referral for ECMO. This consensus document was developed to synthesize current evidence and expert opinion into a cohesive framework that supports bedside decision-making, explicitly identifies evidence gaps, and promotes a shared mental model for managing neonates with PPHN. 

Literature Search

Table 1. Pulmonary Optimization Strategies in Neonatal PPHN

Table 2. Inhaled Nitric Oxide (iNO) Therapy in Term and Near-Term Neonates With PPHN / Hypoxic Respiratory Failure 

Table 3. Pharmacologic and Hemodynamic Adjuncts in Neonatal Persistent Pulmonary Hypertension (PPHN)  

Literature Summary

A literature review demonstrates that contemporary management of persistent pulmonary hypertension of the newborn (PPHN) is supported by randomized trials, observational studies, and physiology-driven expert consensus. Across studies, consistent themes include early pulmonary optimization, targeted pulmonary vasodilation, and hemodynamic stabilization guided by disease phenotype.  

• Early surfactant therapy improves oxygenation and reduces progression to extracorporeal membrane oxygenation (ECMO), particularly in neonates with parenchymal lung disease. Multicenter data further support combined surfactant and inhaled nitric oxide (iNO), which accelerates oxygenation and reduces death or ECMO compared with iNO alone. An “open lung” strategy with adequate mean airway pressure and lung-protective ventilation remains foundational to optimize response to pulmonary vasodilation.  
• Optimal oxygenation and ventilation targets are guided primarily by physiologic data. Both hypoxemia and hyperoxemia are detrimental; hyperoxia does not further reduce pulmonary vascular resistance and may impair responsiveness to iNO. Observational data demonstrate frequent hyperoxemia during iNO therapy, supporting careful oxygen titration. Avoidance of hypocapnia and maintenance of near-normal pH are consistently recommended given their effects on pulmonary vascular tone and cerebral perfusion.  
• Inhaled nitric oxide is supported by high-quality evidence demonstrating improved oxygenation and reduced ECMO utilization, establishing it as first-line pulmonary vasodilator therapy in term and near-term neonates. However, incomplete, or absent response identifies a higher-risk subgroup requiring reassessment and escalation.  
• Vasoactive selection should be physiology driven. Dopamine may increase pulmonary vascular resistance, particularly in hypoxemic states, whereas epinephrine provides more favorable support for cardiac output and systemic perfusion. Contemporary evidence supports prioritizing agents that preserve the balance between systemic and pulmonary circulation, including epinephrine and vasopressin.  
• Hypotension in PPHN most commonly reflects ventricular dysfunction rather than hypovolemia, supporting a physiology-based approach that limits unnecessary volume administration. Maintenance of adequate systemic blood pressure is critical to support right ventricular and coronary perfusion. Vasopressin has demonstrated improvements in both oxygenation and systemic perfusion, though hyponatremia is a common adverse effect.  
• Milrinone improves pulmonary vascular resistance and ventricular performance in neonates with left or biventricular dysfunction, though hypotension may limit use. Hydrocortisone improves hemodynamics in refractory shock without clear adverse outcome signals.  
• Prostaglandin E₁ (alprostadil) may benefit selected neonates by maintaining ductal patency to decompress a pressure-loaded right ventricle and preserve systemic blood flow, though evidence is limited and adverse effects require monitoring.  
• Emerging evidence supports a transition from uniform treatment strategies to a phenotype-based approach guided by echocardiography. PPHN represents a spectrum of hemodynamic states, including precapillary pulmonary hypertension, postcapillary physiology due to left ventricular dysfunction, and biventricular failure, thus requires targeted therapy. This approach improves alignment between treatment and underlying pathophysiology and may reduce harmful or ineffective interventions.  
• In iNO-refractory PPHN, adjunctive pulmonary vasodilators, including sildenafil, prostacyclin analogs (treprostinil and epoprostenol), and endothelin receptor antagonists (bosentan), improve oxygenation and pulmonary pressures, though high-quality outcome data remain limited. These therapies are best used in specialized centers with pulmonary hypertension expertise and access to ECMO.  

Overall, the literature supports a multimodal, physiology-driven approach integrating pulmonary optimization, targeted vasodilation, and hemodynamic support. While high-quality evidence supports foundational therapies such as surfactant and iNO, many adjunctive strategies rely on lower-level evidence, reinforcing the importance of individualized, echocardiography-guided care and early escalation when response is inadequate. 

Persistent Pulmonary Hypertension of the Newborn (PPHN) 

Multidisciplinary Consensus Statement  

Scope, Purpose, and Definitions

Purpose: Provide a structured, physiology-based framework for diagnosis, stabilization, and management of PPHN in term and near-term neonates, including escalation and referral pathways. 

Population: Neonates ≥ 34 weeks gestation with suspected or confirmed PPHN. 

Guiding Principles: 

• Early recognition and prompt stabilization 
• Echocardiography-guided, phenotype-directed management focused on optimizing systemic perfusion and cardiac function  
• Lung protective ventilation with adequate recruitment 
• Maintenance of physiologic stability by avoiding extremes in systemic blood pressure, oxygenation, carbon dioxide levels, and acid–base status 
• Timely referral for escalation to advanced therapies 

Definitions: 

Initial Recognition, Diagnosis, and Stabilization

Clinical Recognition and Monitoring

• Strong Recommendation: Pre- and post-ductal SpO₂ should be monitored in neonates with hypoxemic respiratory failure. Measurements should be obtained from the right hand (pre-ductal) and either foot (post-ductal). 
• Clinical guidance: A pre- to post-ductal SpO₂ gradient >5–10% supports right-to-left shunting consistent with PPHN physiology. 
• Conditional Recommendation: Pre-ductal SpO₂ should guide oxygen titration and escalation decisions; post-ductal SpO₂ should inform shunt physiology but not serve as the sole therapeutic target. 

Diagnostic Evaluation

• Strong Recommendation: Chest radiography should be obtained early to assess lung inflation and identify parenchymal lung disease contributing to hypoxemia. Idiopathic PPHN may demonstrate relatively clear lung fields, pulmonary vascular oligemia, and normal or mildly increased lung volumes, whereas secondary PPHN is commonly associated with meconium aspiration syndrome, pneumonia, or respiratory distress syndrome. 
• Strong Recommendation: Echocardiography is the diagnostic gold standard for PPHN and should be obtained urgently (goal: prior to or within 6-12 hours of diagnosis or iNO initiation) to exclude congenital heart disease, define shunt direction, estimate pulmonary pressures, and assess ventricular function, particularly left ventricular systolic performance prior to initiation of pulmonary vasodilators. 
• Conditional Recommendation: If echocardiography cannot be obtained within approximately 6-12 hours, clinical status worsens, or critical congenital heart disease is suspected, escalation of diagnostic evaluation, consultation, or transfer should be considered. 
• Clinical Guidance: Routine hyperoxia testing is not recommended due to limited diagnostic utility and potential for clinical instability. If performed, 100% oxygen may be administered for 10 minutes with measurement of pre-ductal PaO₂ from the right radial artery; a PaO₂ < 100 mmHg suggests hypoxemia is less likely due to isolated PPHN and should raise concern for critical congenital heart disease. 
• Clinical Guidance: Hyperoxia testing may precipitate clinical decompensation and should prompt readiness for prostaglandin initiation in ductal-dependent lesions. 
• Strong Recommendation: Initial laboratory evaluation should include arterial blood gas analysis, serum lactate, and electrolytes (including ionized calcium and potassium when available). Complete blood count and blood cultures should be obtained when infection is suspected. 

Vascular Access 

• Strong Recommendation: Central venous access should be obtained to facilitate vasoactive and sedative medication administration; a double-lumen umbilical venous catheter is preferred when feasible. 
• Strong Recommendation: Arterial access is recommended for continuous blood pressure monitoring and frequent blood sampling, with prioritization of the right upper extremity when feasible. 

Sedation and Neuromuscular Blockade

• Strong Recommendation: Sedation should follow CHOP institutional pathways to minimize agitation, hypoxemia, ventilator dyssynchrony, and increases in pulmonary vascular resistance. 

• Conditional Recommendation: Adequate sedation should be ensured prior to escalation of ventilator settings or initiation of pulmonary vasodilator therapy.
• Clinical Guidance: Routine neuromuscular blockade is not recommended. 
• Clinical Guidance: Short-term neuromuscular blockade may be considered in neonates with worsening hypoxemia or cardiorespiratory instability despite adequate sedation. 
• Conditional Recommendation: Continuous neuromuscular blockade may be considered if transient paralysis results in clear and sustained improvement, with frequent reassessment and attempts at weaning. 
• Conditional Recommendation: Ensure adequate sedation before starting neuromuscular blockade. 
• Evidence Gap: Optimal thresholds and duration for neuromuscular blockade and standardized approaches to sedation depth in neonates with evolving PPHN. 

Ventilator Management and Oxygenation Targets 

Lung-Directed Therapies 

• Strong Recommendation: Surfactant therapy should be considered in neonates with hypoxemic respiratory failure and an oxygenation index >15–20, particularly in the presence of parenchymal lung disease; early administration is preferred. 

Ventilation Strategy

• Strong Recommendation: Volume-targeted conventional mechanical ventilation should be used as the initial ventilatory strategy when feasible to provide consistent tidal volumes and reduce the risk of volutrauma. 
• Conditional Recommendation: Escalation to High Frequency Oscillatory Ventilation (HFOV) may be appropriate when oxygenation or ventilation remains inadequate despite optimization of conventional ventilation, particularly with rising oxygenation index, mean airway pressure ≥ 12–14 cmH₂O, or peak inspiratory pressure > 28 cmH₂O to achieve desirable tidal volumes. 
• Clinical Guidance: Ventilation strategy may be modified based on the presence or absence of parenchymal lung disease and institutional expertise. 
• Clinical Guidance: High Frequency Jet Ventilation (HFJV) may be considered in selected cases with significant parenchymal lung disease or air leak. Use should be guided by local HFJV protocols and RT expertise, with confirmation of institutional compatibility and setup for concurrent iNO delivery.   

Physiologic Targets

• Strong Recommendation: Ventilation should target lung-protective physiologic parameters, including lung inflation approximating 9 posterior ribs on chest radiograph. 
• Conditional Recommendation: Target arterial blood gas parameters include PaCO₂ 45–55 mmHg, PaO₂ 60–100 mmHg, and arterial pH 7.30–7.40. 
• Strong Recommendation: Intentional hypocapnia and extreme hypercapnia should be avoided given the risk of adverse effects on cerebral blood flow, pulmonary vascular tone, and neurologic outcomes. 

Oxygen Saturation Targets

• Strong Recommendation: Target pre-ductal oxygen saturation of 93–97% should guide oxygen titration and ventilator adjustments. 
• Conditional Recommendation: Post-ductal oxygen saturation should be monitored to assess differential shunting but should not independently guide therapeutic decisions. 
• Evidence Gap: Thresholds for transition from conventional ventilation to HFOV and upper limits of acceptable PaCO₂ in neonates with concomitant neurologic risk. 

Hemodynamic Support and Management of Hypotension

Background and Rationale 

Hypotension in PPHN most commonly reflects impaired cardiac output or ventricular dysfunction rather than hypovolemia. Management should prioritize adequate systemic oxygen delivery while avoiding interventions that increase right ventricular afterload, exacerbate right-to-left shunting, or precipitate ventricular failure. 

Hemodynamic Goals

• Strong Recommendation: Management of hypotension in PPHN should prioritize systemic oxygen delivery rather than normalization of blood pressure alone. 
• Conditional Recommendation: A target mean arterial pressure (MAP) of 45–55 mmHg is appropriate for most term neonates with PPHN. 
• Conditional Recommendation: Permissive hypotension may be acceptable when markers of systemic oxygen delivery are reassuring, including normal or improving serum lactate, adequate urine output, and reassuring echocardiographic assessment of cardiac output. 
• Strong Recommendation: Pharmacologic hypertension should be avoided, as excessive systemic vasoconstriction may increase right ventricular afterload and worsen right ventricular failure. 

Volume Management

• Strong Recommendation: True hypovolemia is uncommon in PPHN. 
• Strong Recommendation: Unnecessary volume expansion should be avoided due to the risk of worsening right ventricular failure and increasing right-to-left shunting. 
• Conditional Recommendation: If volume expansion is considered, cautious boluses of 5–10 mL/kg of crystalloid fluids should be administered over 10–30 minutes. 
• Clinical Guidance: Repeat volume boluses should only be given in the setting of clear hemodynamic responsiveness and should primarily serve as a bridge to initiation of inotropic support. 

Acid-Base Management and Sodium Bicarbonate

• Strong Recommendation: Arterial pH should be maintained within the target range of 7.30–7.40 to support myocardial performance and limit pulmonary vasoconstriction.  
• Conditional Recommendation: Severe metabolic acidosis (pH < 7.10) may increase pulmonary vascular resistance or worsen cardiac function and impair a neonates responsiveness to inotropic agents. 
• Conditional Recommendation: When pH falls < 7.10, sodium bicarbonate may be considered, particularly in the presence of cardiac dysfunction, with proactive attention to adequate ventilation given the potential for rising CO₂. 
• Clinical Guidance: When used, sodium bicarbonate should be administered at 1–2 mEq/kg/dose over approximately 60 minutes. 
• Strong Recommendation: Routine or aggressive use of sodium bicarbonate is not recommended. 

Vasoactive and Inotropic Therapy 

General Principles

• Strong Recommendation: Vasoactive therapy should be individualized based on echocardiographic assessment of ventricular function and systemic perfusion. 
• Conditional Recommendation: Choice and sequencing of vasoactive agents should account for effects on pulmonary vascular resistance, right ventricular afterload, and myocardial performance. 

Initial Vasoactive Agent

• Strong Recommendation: Epinephrine is recommended as the preferred initial vasoactive agent in hypotensive neonates with PPHN, given its combined inotropic and chronotropic effects. 
• Conditional Recommendation: Epinephrine should be initiated at low doses (0.03 mcg/kg/min) and titrated based on clinical response. Clinicians should recognize that norepinephrine, dopamine, and epinephrine demonstrate dose-dependent increases in pulmonary arterial pressure, most pronounced with dopamine, and dosing should therefore be balanced against potential effects on pulmonary vascular resistance. 

Adjunctive Therapies

• Strong Recommendation: Hydrocortisone should be considered in neonates requiring escalating doses of catecholamines or demonstrating inadequate response to epinephrine. 
• Clinical Guidance: The need for a hydrocortisone loading dose remains uncertain and may be individualized based on illness severity and institutional practice. 
• Strong Recommendation: Vasopressin may be added for persistent hypotension as a non-catecholamine vasopressor that preserves pulmonary and cerebral blood flow. 
• Conditional Recommendation: Close monitoring of serum sodium is recommended during vasopressin therapy due to the risk of hyponatremia; fluid restriction or sodium supplementation may be required. 
• Clinical Guidance: Preemptive use of isotonic, sodium-containing infusions may reduce the risk of hyponatremia during vasopressin therapy. 
• Clinical Guidance: Norepinephrine may be considered in refractory hypotension, recognizing limited evidence in PPHN and potential risk in right ventricular failure. 
• Strong Recommendation: Dopamine is not preferred due to its potential to increase pulmonary vascular resistance; if used, doses should be limited to ≤ 5-10 mcg/kg/min. 

Suggested Vasoactive Sequence (Conditional Recommendation)

• Initiate low-dose epinephrine (0.03 mcg/kg/min) and titrate in increments of 0.01-0.02 mcg/kg/min every 3-5 minutes to a maximum recommended dose of 0.1 mcg/kg/min. Escalation of epinephrine beyond 0.1 mcg/kg/min should be avoided. 
• Initiate hydrocortisone early if epinephrine requirements escalate or response is inadequate. We currently recommend hydrocortisone 1mg/kg/dose every 6 hours for 48 hours (may extend duration if clinically indicated) 
• Initiate vasopressin for persistent hypotension despite catecholamine and hydrocortisone support. Initiate vasopressin at 12 milli-units/kg/hr (0.2 milli-units/kg/min) and titrate in increments of 6-12 mU/kg/hr every 15 minutes to a maximum recommended dose of 72 mU/kg/hr. 
• Consider norepinephrine if hypotension remains refractory or if vasopressin therapy extends beyond 48–72 hours. Initiate norepinephrine at  0.02 mcg/kg/min and titrate in increments of 0.01 mcg/kg/min every 3-5 minutes  to a maximum recommended dose of 0.5 mcg/kg/min. 

Special Considerations

• Conditional Recommendation: During vasopressin therapy, frequent serum sodium monitoring is recommended. 
• Clinical Guidance: Where applicable, alignment with congenital diaphragmatic hernia (CDH) management guidelines may be appropriate, particularly with respect to hydrocortisone and vasopressin dosing strategies. 
• Evidence Gap: Routine use and loading dose requirements for hydrocortisone, optimal sodium monitoring strategies during vasopressin therapy (serum versus urinary), and the ideal duration of vasopressin infusion. 

Pulmonary Vasodilation and Cardiac Dysfunction

Background and Rationale

Cardiac dysfunction frequently coexists with persistent pulmonary hypertension of the newborn (PPHN) and contributes to hypoxemia, hypotension, and poor response to pulmonary vasodilator therapy. Effective management requires early assessment of ventricular performance and thoughtful integration of pulmonary vasodilation strategies that reduce right ventricular afterload while preserving left ventricular filling and output. 

Initial Evaluation and Echocardiography

• Strong Recommendation: Echocardiography should be obtained as soon as possible in neonates with suspected PPHN, particularly in neonates ≥ 34 weeks gestation with significant hypoxemia or a pre- to post-ductal saturation gradient. 
• Strong Recommendation: Echocardiographic assessment should include evaluation of right and left ventricular systolic function, shunt direction and magnitude, and estimation of pulmonary artery pressure. 
• Conditional Recommendation: Echocardiographic assessment of left ventricular systolic performance should guide the safe initiation and continuation of pulmonary vasodilator therapies. 

Inhaled Nitric Oxide (iNO)

• Strong Recommendation: Inhaled nitric oxide should be initiated at a dose of 20 ppm in neonates with suspected or confirmed PPHN and preserved left ventricular systolic function. 
• Strong Recommendation: If iNO is initiated prior to echocardiographic assessment and severe left ventricular dysfunction is subsequently identified, discontinuation of iNO is recommended. 
• Strong Recommendation: Clinical and oxygenation response should be assessed within 30-60 minutes of iNO initiation. 
• Conditional Recommendation: When possible, CHOP NIICU Pathway for iNO should be utilized to guide management, including weaning of iNO and FiO2. 
• Strong Recommendation: Neonates who do not demonstrate a meaningful clinical or oxygenation response within 30-60 minutes should be reassessed for lung recruitment, ventricular dysfunction, and alternative diagnoses. Discontinuation of iNO should be considered. 
• Clinical Guidance: Clinical response to iNO can be defined by several parameters, including an increase in PaO2 ≥ 20 mmHg or SpO2 ≥ 5%. 
• Strong Recommendation: Routine escalation of iNO above 20 ppm is not recommended due to limited additional efficacy and increased risk of adverse effects, including methemoglobinemia. 
• Clinical Guidance: Temporary escalation of iNO up to 40 ppm may be considered during transport to an ECMO-capable center. 

Prostaglandin E₁ (Alprostadil) 

• Strong Recommendation: Prostaglandin E₁ may be used to maintain ductal patency in select neonates with right ventricular dysfunction. 
• Conditional Recommendation: Initiation of prostaglandin therapy may be considered in the setting of a restrictive or closing ductus arteriosus with evidence of right ventricular pressure overload. 
• Conditional Recommendation: Prostaglandin E₁ should be initiated at 0.01 mcg/kg/min and titrated to the lowest effective dose, with a suggested maximum dose of 0.1 mcg/kg/min. 
• Clinical Guidance: Common adverse effects include transient apnea, hypotension, flushing, and fever. Dose adjustment is not required for renal or hepatic dysfunction. 

Milrinone

• Strong Recommendation: Milrinone should be considered in neonates with left or biventricular dysfunction to improve myocardial contractility and lusitropy. 
• Conditional Recommendation: Milrinone should be initiated at 0.25 mcg/kg/min without a loading dose and titrated in increments of 0.125–0.25 mcg/kg/min based on echocardiographic findings and clinical response, to a suggested maximum of 1 mcg/kg/min. 
• Clinical Guidance: Hypotension is a known adverse effect. Dose titrations should be adjusted cautiously, particularly in the setting of renal dysfunction. 

Integration with Systemic Vasoactive Support 

• Strong Recommendation: Pulmonary vasodilator therapy should be integrated with systemic vasoactive support to maintain adequate coronary and systemic perfusion. 
• Conditional Recommendation: In neonates with combined pulmonary hypertension and systemic hypotension, initiation or escalation of inotropic support should precede or accompany pulmonary vasodilation. 

Early Transfer and Escalation of Care

• Strong Recommendation: Early transfer to an ECMO-capable center should be considered for neonates with refractory hypoxemia or hemodynamic instability despite optimized ventilation, oxygenation, and first-line pulmonary vasodilator therapy. 
• Conditional Recommendation: Lack of response to iNO, progressive ventricular dysfunction, or escalating vasoactive requirements should prompt early consultation and transfer planning. 

Management of iNO Non-Responders and Partial Responders 

Neonates with persistent hypoxemia despite optimized lung recruitment and an adequate trial of inhaled nitric oxide (iNO) (i.e., non-responders or partial responders) may require escalation to adjunctive pulmonary vasodilator therapies. These therapies should only be initiated in an ECMO-capable center and in close consultation with a Pulmonary Hypertension Cardiology team, given the limited neonatal evidence base, potential for systemic adverse effects, and frequent need for rapid escalation to extracorporeal support. 

• Strong Recommendation: Escalation beyond iNO should occur exclusively in ECMO-capable centers with expertise in neonatal pulmonary hypertension. 
• Conditional Recommendation: Prior to escalation, confirm adequate lung recruitment, reassess ventricular function and shunt physiology by echocardiography, and optimize systemic perfusion. 

Prostacyclin Analogs 

• Conditional Recommendation: Inhaled prostacyclin (PGI₂) analogs (e.g., epoprostenol, iloprost) may be considered as adjunctive therapy in neonates with PPHN refractory to iNO. 
• Strong Recommendation: Systemic prostacyclin therapy (e.g., epoprostenol, treprostinil) should be reserved for centers with neonatal pulmonary hypertension expertise due to risks of systemic hypotension and ventilation-perfusion mismatch. 
• Conditional Recommendation: Available evidence in neonates is limited to case series and retrospective cohorts demonstrating transient improvements in oxygenation without consistent adverse effects; randomized controlled trial data are lacking. 

Phosphodiesterase-5 Inhibition and Endothelin Receptor Antagonism

• Conditional Recommendation: For neonates who are partial responders to iNO and able to tolerate enteral therapy, enteral sildenafil is generally preferred as the initial adjunctive agent. 
• Conditional Recommendation: Bosentan may be considered as an additional enteral agent in selected cases; available data suggest that enteral sildenafil and bosentan may demonstrate clinical benefit within 2-6 hours of initiation. 
• Clinical Guidance: Enteral therapy should be used cautiously in neonates with poor gut perfusion or evolving hemodynamic instability. 
• Conditional Recommendation: In neonates who are strictly NPO with normal coagulation parameters and platelet counts, IV epoprostenol may be prioritized for rapid pulmonary vasodilation and stabilization, with subsequent transition to treprostinil for longer-term management. 
• Conditional Recommendation: In the presence of coagulopathy, persistent uncontrolled bleeding, or thrombocytopenia, IV sildenafil may be considered as an alternative systemic pulmonary vasodilator. 
• Strong Recommendation: Selection, sequencing, and titration of adjunctive pulmonary vasodilators should be individualized and guided by the Pulmonary Hypertension Cardiology team. 

Table 5. Adjunctive Pulmonary Vasodilator Therapies for iNO Non-Responders (ECMO-Capable Centers Only) 

• Evidence Gap: Optimal sequencing and combination of adjunctive pulmonary vasodilators, comparative efficacy among agents in neonates, and criteria for transition from pharmacologic escalation to ECMO support. 

Role of Echocardiography, TnECHO, and Cardiac POCUS 

Background and Rationale

Echocardiography plays a central role in the diagnosis, phenotyping, and longitudinal management of persistent pulmonary hypertension of the newborn (PPHN). Multiple imaging modalities -including comprehensive echocardiography performed by pediatric cardiology, targeted neonatal echocardiography (TnECHO), and cardiac point-of-care ultrasound (POCUS) -serve complementary but distinct purposes. Clear delineation of scope and intent for each modality is essential to ensure accurate diagnosis, safe initiation of therapies, and physiology-guided management while avoiding misapplication beyond training or capability. 

Initial Imaging Approach

• Strong Recommendation: A comprehensive echocardiogram should be performed early in neonates with suspected PPHN to exclude structural congenital heart disease, establish baseline cardiopulmonary physiology, and guide initiation of pulmonary vasodilator therapy. 
• Strong Recommendation: Formal echocardiography performed by pediatric cardiology remains the gold standard for definitive structural assessment. 
• Conditional Recommendation: When immediate access to formal echocardiography is limited, escalation of care, consultation, or transfer should be considered in neonates with clinical instability or diagnostic uncertainty. 

Role of Cardiac POCUS

• Strong Recommendation: Cardiac POCUS should be used as a focused bedside tool to answer specific binary clinical questions. 
• Conditional Recommendation: Appropriate applications of cardiac POCUS include confirmation of central line position, detection of pericardial effusion, gross qualitative assessment of global systolic function, and assessment of significant volume depletion. 
• Strong Recommendation: Cardiac POCUS should not be used as a primary diagnostic or management tool for PPHN, given limitations in assessing complex shunt physiology, pulmonary pressures, and ventricular interactions. 
• Clinical Guidance: Institutions should ensure that cardiac POCUS use is aligned with provider training, credentialing, and quality assurance processes. 

Role of Targeted Neonatal Echocardiography (TnECHO)

• Strong Recommendation: Targeted neonatal echocardiography performed by appropriately trained neonatologists may be used to provide quantitative and functional assessment of cardiac performance and pulmonary hemodynamics. 
• Conditional Recommendation: TnECHO is not a substitute for comprehensive structural evaluation by pediatric cardiology but may complement formal echocardiography by enabling serial, physiology-guided assessment. 
• Clinical Guidance: Availability and scope of TnECHO should be guided by institutional expertise, training standards, and collaborative practice models with pediatric cardiology. 

Key Echocardiographic Parameters in PPHN

• Strong Recommendation: Echocardiographic assessment in PPHN should include evaluation of right ventricular function, pulmonary artery pressure estimation, shunt physiology, left ventricular systolic function, and volume status. 
• Conditional Recommendation: Commonly used parameters may include: 
  • Right ventricular function: TAPSE, fractional area change (FAC), and longitudinal strain 
  • Pulmonary artery pressure estimation: tricuspid regurgitant jet velocity, interventricular septal flattening, eccentricity index, pulmonary artery acceleration time (PAAT), PAAT/RVET ratio, and pulmonary insufficiency jet velocity 
  • Shunt assessment: patent ductus arteriosus (size, direction, velocity) and patent foramen ovale flow direction 
  • Left ventricular function: fractional shortening, ejection fraction, and left ventricular strain 
  • Volume assessment: left ventricular cavity size, systolic performance, and inferior vena cava collapsibility 

Echocardiographic Phenotypes and Clinical Implications

• Strong Recommendation: Echocardiographic phenotyping should be used to guide targeted management strategies in PPHN. 
• Conditional Recommendation: Common phenotypes include: 
  • Precapillary PPHN: Elevated pulmonary pressures with right ventricular dysfunction and right-to-left shunting, typically supporting pulmonary vasodilator therapy and right ventricular support. 
  • PPHN with left ventricular dysfunction (postcapillary pulmonary hypertension): Depressed LV systolic function with pulmonary venous congestion, favoring inotropic support and avoidance of excessive preload or vasodilation. 
  • PPHN with restrictive or closed ductus arteriosus: Elevated right ventricular pressures with limited ductal shunting, prompting consideration of prostaglandin E₁ to reduce RV afterload. 
  • PPHN with pulmonary over circulation: Large left-to-right ductal shunt with left atrial and ventricular volume overload, favoring diuretics, fluid restriction, and avoidance of excessive oxygen. 

Echo-Guided Management Integration

• Strong Recommendation: Echocardiographic findings should directly inform ventilation, vasoactive, and pulmonary vasodilator strategies. 
• Conditional Recommendation: Changes in ventricular function, shunt direction, or pulmonary pressure estimates should prompt reassessment of current therapies and adjustment of management. 

Timing and Frequency of Echocardiography

• Strong Recommendation: An initial echocardiogram should be obtained at the time of diagnosis of suspected PPHN. 
• Conditional Recommendation: Repeat echocardiography should be guided by clinical change, escalation or de-escalation of therapy, lack of response to pulmonary vasodilators, or planned weaning of inhaled nitric oxide. 
• Strong Recommendation: A pre-discharge echocardiogram, ideally obtained off respiratory support, is recommended by pediatric cardiology to confirm resolution of pulmonary hypertension and guide outpatient follow-up. 
• Evidence Gap: Minimum echocardiographic requirements in resource-limited settings, optimal timing for repeat echocardiography following initiation of pulmonary vasodilators, and routine necessity of pre-discharge echocardiography in all neonates. 

Referral for Advanced Therapies and ECMO

Background and Rationale

Decisions regarding referral for inhaled nitric oxide (iNO), advanced ventilatory strategies, and extracorporeal membrane oxygenation (ECMO) in neonates with persistent pulmonary hypertension of the newborn (PPHN) should be proactive and trajectory based. Referral evaluation is distinct from indications for cannulation and should occur while additional stabilization strategies remain available and transport can be performed safely.

Terminology and Conceptual Framework

• The term referral should be used to describe early consultation and transfer to a higher level of care, whereas cannulation should be reserved for the decision to initiate ECMO support. 
• Early referral allows access to advanced therapies, multidisciplinary expertise, and ECMO evaluation before irreversible decompensation occurs.

Referral for Advanced Respiratory and Cardiovascular Support

• Strong Recommendation: Neonates should be referred to centers with iNO and High Frequency Ventilation (HFV) capabilities when escalating respiratory support raises concern for evolving PPHN. 
• Conditional Recommendation: For level II NICUs, early referrals to ECMO capable centers are encouraged when advanced respiratory or vasoactive support is anticipated to avoid sequential or double transfers. 
• Conditional Recommendation: For level III NICUs, referral to an ECMO-capable center should be considered when escalation of ventilatory, vasoactive, or pulmonary vasodilator therapy fails to produce sustained clinical improvement. 

Referral to an ECMO-Capable Center

• Strong Recommendation: Referral to an ECMO-capable center should occur while additional stabilization options remain available and before the development of refractory hypoxemia or circulatory collapse.
• Conditional Recommendation: Clinical trajectories that may prompt ECMO referral include: 
  • Persistent hypoxemia despite optimized conventional and High Frequency Ventilation with iNO 
  • Mean airway pressure > 18 cmH₂O with inadequate improvement after 4-6 hours 
  • Persistent systemic hypotension despite treatment with two vasoactive agents and initiation of hydrocortisone therapy 
  • Oxygenation Index exceeding 25 over 4-6 hours despite implemented changes.  
• Strong Recommendation: Initiation of a second pulmonary vasodilator at a non-ECMO center is not recommended. 

Contraindications and Eligibility Considerations

• Conditional Recommendation: Potential contraindications should be reviewed in consultation with the ECMO medical and surgical teams prior to transfer whenever feasible. 
• Conditional Recommendation: Relative contraindications may include birth weight < 2 kg, significant congenital or chromosomal anomalies, complex congenital heart disease (particularly single-ventricle physiology, which should prompt referral to a cardiac intensive care unit), and lack of response to postnatal resuscitation. 
• Strong Recommendation: Absolute contraindications include gestational age < 32 weeks, grade III or higher intracranial hemorrhage, and known trisomy 13 or trisomy 18 prior to cannulation. 

ECMO Cannulation Considerations (Conditional Recommendation)

Conditional Recommendation: The following considerations are intended to support multidisciplinary decision-making rather than mandate cannulation: 

• Inability to maintain pre-ductal oxygen saturation > 85% or post-ductal PaO₂ > 30 mmHg despite maximal medical management 
• Respiratory acidosis unresponsive to optimized ventilatory support 
• Refractory systemic hypotension despite fluid resuscitation and vasoactive infusions 
• Severe ventricular dysfunction on echocardiography unresponsive to medical therapies 
• Evidence of inadequate oxygen delivery, including persistent metabolic acidosis or rising serum lactate 
• Inability to wean FiO₂ below approximately 80% during the first week of life despite optimized lung-directed and pulmonary vasodilator therapies 

Mode of ECMO Support

• Strong Recommendation: Veno-venous (VV) ECMO should be prioritized whenever feasible in neonates with PPHN, as it provides effective gas exchange while preserving pulsatile cardiac output. 
• Conditional Recommendation: Veno-arterial (VA) ECMO may be required in the presence of severe cardiac dysfunction, inadequate systemic perfusion, or inability to achieve adequate support with VV-ECMO. 

ECMO Related Evidence Gap

Optimal timing thresholds for referral versus cannulation, the role of additional pulmonary vasodilators prior to ECMO in select centers, and precise oxygenation or ventilation thresholds that should trigger cannulation.

Figure 1. Initial Recognition and Diagnostic Evaluation of Suspected PPHN 

Strong Recommendation: Pre- and post-ductal SpO₂ monitoring and early echocardiography. 
Conditional Recommendation: SpO₂ gradient > 5–10% suggests right to left shunting. 

Figure 2. Ventilation and Oxygenation Strategy in PPHN 

Strong Recommendation: Lung protective ventilation with goal preductal SpO₂ 93–97%. 
Conditional Recommendation: HFOV escalation based on oxygenation and pressure requirements. 

Figure 3. Hemodynamic Support and Hypotension Management  

Strong Recommendation: Prioritize oxygen delivery over blood pressure normalization. 
Conditional Recommendation: Stepwise vasoactive escalation guided by perfusion. 

Figure 4. Cardiac Phenotype-Guided Escalation Pathway in Persistent Pulmonary Hypertension of the Newborn (PPHN)

Strong Recommendation: Echocardiographic phenotype should guide escalation strategy rather than reflexive pharmacologic intensification. 
Conditional Recommendation: Ventricular interaction and dominant dysfunction pattern determine whether pulmonary vasodilation, inotropy, preload optimization, or early ECMO consultation is prioritized. 

Consideration: Mixed or evolving physiology warrants early involvement of Pulmonary Hypertension Cardiology and ECMO teams. 

Figure 5. Referral and ECMO Evaluation Pathway 

Strong Recommendation: Early referral to an ECMO-capable center for refractory hypoxemia despite optimal ventilation and iNO. 
Conditional Recommendation: ECMO modality selection guided by degree of cardiac dysfunction; VA-ECMO reserved for severe hemodynamic compromise. 

One page summary:

Further Goals:

• Continue to add evidence-based recommendation with evolving evidence 
• Reassess data on use of adjuvant pulmonary vasodilators based on our experience and published data  
• Monitor compliance with current guideline recommendations 

QI Metrics: 

• Change in response to “near and no consensus” responses since implementation of guideline at 6 month intervals  
• Time from recognition of hypoxemic respiratory failure to first ECHO 
• % of patients treated with surfactant prior to transfer 
• Use of epinephrine as a first line therapy in management of hypotension  
• Use of vasopressin in PPHN patients with hypotension, requiring at least 2 vasopressors (including hydrocortisone)   
• Reduction in use of dopamine as the first line therapy for management of hypotension in patient with PPHN 

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The Neonatology Consensus Statements (“Statements”) are based on a consensus of medical practitioners at The Children’s Hospital of Philadelphia (“CHOP”) and are current at the time of publication. These Statements are intended to be a guide for practitioners and may need to be adapted for each specific patient based on the practitioner’s professional judgment, consideration of any unique circumstances, the needs of each patient and their family, and/or the availability of various resources at the health care institution where the patient is located. 

Accordingly, these Statements are not intended to constitute medical advice or treatment, or to create a doctor-patient relationship between/among CHOP, its physicians and the individual patients in question. CHOP does not represent or warrant that the Statements are in every respect accurate or complete, or that one or more of them apply to a particular patient or medical condition. CHOP is not responsible for any errors or omissions in the Statements, or for any outcomes a patient might experience where a clinician consulted one or more such Statements in connection with providing care for that patient. If you use a printed version of a Statement, please ensure that you are using the most current version.