Pulmonary Hypertension and Right Ventricular Function

Synchrony of Airway and Vascular Development
Airway and vascular development occur in tandem. This synchronous evolution ensures functional matching of ventilation and perfusion. From the canalicular stage onward, alveolar structures progressively mature with an expanding surface area for gas exchange. Postnatally, alveolar and vascular maturation continues, critical for full respiratory function.

Transition to Extra-Uterine Life
At birth, a rapid physiological shift must occur. In utero, pulmonary vascular resistance (PVR) is high, and oxygenation occurs via the placenta. Oxygenated blood from the umbilical vein enters the right atrium and preferentially passes through the foramen ovale to the left atrium and aorta. The pulmonary blood flow in a foetus is very low. In this stage, the circulation and oxygenation are primarily handled by the placenta. There is very low pulmonary blood flow (3% of total cardiac output in early pregnancy, and up to 20% towards end of pregnancy). This is because the foetal pulmonary arteries have a very reduced lumen and extremely high resistance. Approximately one-third of the venous return (preload) to the right atrium is shunted through the foramen ovale into the left atrium, preferentially directing the more oxygenated blood toward the left ventricle and subsequently the cerebral circulation, including the brain. A significant portion (two-thirds) of the blood from the right ventricle and pulmonary artery is shunted through the widely open ductus arteriosus to the descending aorta, avoiding the high-resistance pulmonary circulation. In fetal life, pulmonary vascular resistance (PVR) is high, systemic vascular resistance (SVR) is low due to placental circulation, and the pulmonary and systemic circuits function in parallel. As a result, right and left ventricular systolic pressures are equalized via the ductus arteriosus, and pulmonary arterial and aortic pressures are similarly matched due to this shared outflow tract. Several extrinsic factors can significantly affect the pulmonary development: skeletal, diaphragmatic, oligohydramnios, polyhydramnios, abdominal defect (i.e. omphalocele), creating setups of adverse pulmonary and pulmonary vascular development.

After birth: At birth, when the umbilical cord is cut, the newborn's lungs must abruptly take over oxygenation. This transition involves a dramatic restructuring and opening of the pulmonary arterioles to accommodate the entire cardiac output. Pulmonary vascular resistance (PVR) drops sharply in the first minutes of life, continuing to decrease over days and weeks. PVR is inversely proportional to the fourth power of the vessel's radius, meaning even small increases in vessel diameter lead to significant drops in resistance. This critical shift in circulation is prepared for during the last month of pregnancy, with PVR gradually decreasing. Indeed, there is already some slight decrease in PVR in the last month of gestation, outlining the importance of avoiding induced prematurity, when possible. 

• Clamping of the umbilical cord stops placental circulation. The systemic vascular resistance will increase. 

• Initiation of breathing expands the lungs. The lungs are expanding brutally like a parachute opening. The mechanical stretch will contribute to the stretching/opening of the pulmonary vasculature 

• Increased oxygen tension and mechanical expansion reduce PVR. The oxygen tension in the blood increases, which is a pulmonary vasodiator that will trigger cascades within the endothelium of the pulmonary vasculature. The endothelium has the role of messaging to smooth muscle cells surrounding arterioles to not constrict (by secreting vasodilators: nitric oxyde, prostacyclins). Endothelin receptors trigger vasodilation and vasoconstriction (Endothelic is an extremely potent vasoconstrictor)

• Pulmonary blood flow increases dramatically. Suddenly, the pulmonary circulation has to accomodate the same output as the systemic output (Qp=Qs). Contrary to the systemic vasculature, the lungs  is a single organ that will accomodate the entire output, while on the systemic circulation there is fractionated output to each organs.

• During the last month of pregnancy, the foetal pulmonary circulation prepares for birth by progressively decreasing its vascular resistance. At the moment of birth, under the impulse of respiration and the effect of oxygen, there is a dramatic drop in pulmonary vascular resistance within minutes, allowing the pulmonary arteries to open considerably. This enables the lungs to take on their full function of ensuring oxygenation.
  
  

Hemodynamic Shifts
Poiseuille’s Law describes how small increases in vessel diameter lead to large drops in resistance (resistance ∝ 1/radius⁴). The pulmonary arterioles dilate significantly after birth, facilitating the shift from fetal parallel to postnatal serial circulation. Animal studies confirm that within 5 minutes of birth, PVR falls rapidly. Oxygen and lung expansion trigger endothelial NO production and prostacyclin release, promoting vasodilation. In ~2 per 1,000 live births, this transition fails. PPHN (persistent pulmonary hypertension of the newborn / acute PH) results from delayed or impaired pulmonary vasodilation due to various triggers (inflammation, hypoxia, meconium aspiration). Histologically, these neonates show thickened vascular walls and reduced luminal diameter. Endothelial cells fail to spread along the vessel wall, impeding vasodilation.

The pulmonary circulation adapts to physiological needs:

• During exercise: increases from ~5 to 40 L/min.

• In response to hypoxia or shunts: must handle increased flow demands.

This adaptability underscores the importance of proper vascular remodeling during fetal and postnatal life. Failure in this remodeling, especially in preterm infants or those with congenital heart disease, can set the stage for lifelong pulmonary hypertension.

The pulmonary circulation is unique because it must handle 100% of the systemic blood flow. It has remarkable adaptability to manage significant variations in blood flow, from 5 litres per minute at rest to 40 litres per minute during exertion. This adaptation occurs through two primary mechanisms:

• Vascular Recruitment and Distension:

  • The lung has "West zones" based on varying pressures. In adults, Zone 1 (the apex), alveolar pressure is high, potentially compressing arterioles and limiting circulation. In Zone 2, arterial pressure is higher than alveolar pressure, which is higher than venous pressure, but alveoli still compress veins, hindering flow. Most physiological gas exchange occurs in Zone 3 (the base), where there's an optimal balance between pressure and flow, with sufficiently open capillaries.

  • When blood flow increases, the pulmonary venous pressure rises, leading to the recruitment of previously unused vascular territories in the lung (Zones 1 and 2). This "vascular redistribution" towards the apices helps accommodate the increased flow without a proportional increase in pressure.

  • These mechanisms are likely true for the newborn as well but the differential distribution may be different due to the pulmonary particularities of the newborn, and the dependencies based on gravity. 

Endothelial Function:

• • The endothelial cells lining the blood vessels are crucial for adapting to flow changes. They are the "first line" responders to changes in blood flow, sensing shear forces on their surface.

  • To maintain stable pressures despite increased flow, endothelial cells release vasodilating substances, such as nitric oxide (NO) and prostacyclins. NO is a potent vasodilator, produced from L-arginine, which activates cyclic GMP. Prostacyclins also cause vasodilation by activating cyclic AMP in underlying smooth muscle cells.

  • Conversely, when less flow is needed, endothelial cells can release vasoconstrictors like endothelin, the most potent vasoconstrictor known. This creates a constant balance between vasodilation (e.g., during effort) and vasoconstriction (e.g., returning to rest).

  • The endothelium acts as a "guardian," controlling the contraction of the underlying smooth muscle cells.

PH develops when the delicate balance of pulmonary circulation is disrupted, often leading to structural changes in the blood vessels. Endothelial dysfunction is a central feature in the progression of PH. In a healthy state, the endothelium primarily promotes vasodilation. However, when the endothelium is altered or damaged (e.g., by prolonged high blood flow in shunts), its protective function diminishes. This can lead to an excess of vasoconstriction, and even some drugs that are normally vasodilators can paradoxically cause vasoconstriction if the endothelium is dysfunctional.

• When NO is no longer adequately produced, smooth muscle cells, whose natural tendency is to contract and proliferate, do so unchecked. NO also has anti-proliferative and anti-platelet effects, so its absence exacerbates the problem.

• Platelets may aggregate at damaged vessel sites, releasing further vasoconstricting substances, creating a "snowball effect" of increased muscle tone and proliferation.

Vascular Remodeling: This is the process of structural change in the pulmonary arterioles. Initially, as an adaptation to increased pressure, the vessel wall may undergo hypertrophy to limit parietal tension. However, if the endothelial dysfunction persists, the endothelial cells themselves can begin to proliferate abnormally and develop intimal fibrosis, progressively reducing the vessel's lumen. This proliferation can be so extensive that it completely obstructs the vessel, turning the normally compliant pulmonary bed into a "concrete wall" against which the right ventricle must eject blood. This often leads to right heart failure, the ultimate cause of death in advanced PH.

Genetic Factors: Genetics play a significant role in susceptibility to PH.

• A mutation in the BMPR2 gene is found in about 70% of adult patients with familial forms of PH. The BMPR2 protein is crucial because it acts similarly to nitric oxide, inhibiting the proliferation of smooth muscle cells and regulating endothelial apoptosis (programmed cell death). When this gene is mutated, the beneficial BMPR2 molecule cannot act, leading to uncontrolled proliferation of smooth muscle cells and a loss of the apoptotic regulation of endothelial cells. Patients with a BMPR2 mutation may not necessarily develop PH unless there's an additional "superimposed event," such as a congenital heart defect, exposure to toxins, or a respiratory pathology. Only 10-15% of PAH will have an identification of a genetic condition. Only a minority of BMPR2 mutation carrier will express a phenotype of pulmonary hypertension, which creates ethical challenges for the screening and monitoring. Having a mutation does not imply that a pathological condition will occur.  

• A critical aspect is that PH leads endothelial cells to become resistant to apoptosis, a characteristic likened to tumor cells. This resistance allows them to proliferate uncontrollably within the vascular lumen, leading to occlusion.

Classification and Types of Pulmonary Hypertension

The classification of PH has evolved, with the 2018 Nice congress standardizing it into five main groups:

• Group 1: Pulmonary Arterial Hypertension (PAH)

  • This group involves direct pathological changes to the pulmonary arteries themselves. It includes:

    • Idiopathic PAH: No identifiable cause.

    • Heritable/Genetic PAH: Associated with gene mutations, notably BMPR2. See genetics below.

    • Drug- or Toxin-Induced PAH.

    • PAH Associated with Congenital Heart Disease (CHD) with shunts: This is a significant category in children. Shunts create an abnormal connection between the systemic and pulmonary circulations, leading to excessive blood flow into the lungs (hyperdebit). This increased flow and shear stress on the endothelium eventually lead to irreversible vascular remodeling. Early surgical closure of large shunts (e.g., VSDs before 4-6 months) is crucial to prevent irreversible damage.

    • It is a bit of a misnomer because all the etiologies of PH will lead to an increase in the arterial compartment pressure. However, these conditions are considered pre-capillary etiologies leading to the high pulmonary arterial pressure. 

• Group 2: PH due to Left Heart Disease (Post-Capillary PH)

  • This type results from problems in the left side of the heart (e.g., mitral valve stenosis, left ventricular dysfunction) that increase pressure in the left atrium and pulmonary capillaries.

  • In this group, the pulmonary arterial lesions are always reversible. The arterial pressure increases simply because the blood is "stuck" upstream, not due to intrinsic arterial wall disease. Pressures typically normalize weeks to months after the underlying cardiac issue is corrected surgically. However, these patients are still at high risk for PH crises post-operatively due to their highly muscular pulmonary arterioles.

• Group 3: PH due to Chronic Lung Disease and/or Hypoxemia

  • This group is becoming increasingly common, especially in very premature infants who develop bronchopulmonary dysplasia (BPD).

  • PH in BPD is linked to incomplete lung maturation and persistent hypoxemia/V-Q mismatch, CO2 clearance, airway disease, pulmonary fibrosis/scaring/inflammation. There is possibly a component of Groupe 2 disease in this condition with concerns with lympatics, pulmonary veins and LV diastolic issues. Even brief, repeated episodes of desaturation can cause pulmonary arterioles to constrict, perpetuating PH.

  • Early and meticulous oxygen monitoring and optimization of ventilation are critical. If treated early, these children can often normalize their pulmonary pressures and be weaned off vasodilators. However, late diagnosis and inadequate management can lead to fixed, irreversible PH with hypoplastic and hypovascularized lungs.

• Group 4: Chronic Thromboembolic PH (CTEPH)

  • This form is rare in children but should not be missed!

• Group 5: PH with Unclear and/or Multifactorial Mechanisms

Persistent Pulmonary Hypertension of the Newborn (PPHN): This is a specific type of PH seen in neonates, where the pulmonary arterioles fail to open adequately after birth, often due to delayed vascular maturation and/or abnormal absence of a drop in pulmonary vascular resistances (or not sufficient drop). While typically resolving in a few days with oxygen and vasodilators, if it does not improve, it warrants aggressive investigation for other more severe underlying PH forms, alveolar-capillary dysplasia (FOXF1), surfactant deficiencies, pulmonary veno-occlusive disease, TBX4-related acute PH, mitochondrial and metabolic disorders, etc. These conditions carry a more challenging prognosis. It is called PPHN. The term “pulmonary hypertension” (hyper=high, tension=blood pressure) may be somewhat misleading in the neonatal context. While these patients are labeled as having elevated pulmonary arterial pressures, many in fact have iso-systemic pulmonary pressures but supra-systemic pulmonary vascular resistance (PVR). A more accurate descriptor might be “failure of PVR to fall after birth.” It is physiologically normal for many asymptomatic newborns to have near-systemic pulmonary pressures and PVR during the first 24–72 hours of life as they undergo cardiovascular transition. These infants are asymptomatic, well saturated. In contrast, neonates with acute pulmonary hypertension or persistent pulmonary hypertension of the newborn (PPHN) often present with hypoxemia due to right-to-left shunting across persistent fetal channels—namely the ductus arteriosus and foramen ovale, if they remain patent. Some may have ductal closure (in utero or early post-birth) and will not have the classical pre/post saturation differences. Some may have a component of abnormally high PVR and a congenital heart defect (example: dTGA with acute PH leading to reversed differential saturation). The clinical presentation can vary significantly depending on multiple factors, including the severity of PVR elevation, the right ventricle’s capacity to handle increased afterload, and the presence and size of shunts that can decompress the circulation. For instance, a large PDA may serve as a “pop-off” to reduce RV pressure, whereas a restrictive PDA may not. Similarly, a generous interatrial communication may allow right-to-left shunting that increases hypoxemia but helps preserve LV preload and, consequently, systemic output. The interaction between shunt directionality, RV performance, and systemic hemodynamics creates a spectrum of phenotypes in neonatal pulmonary hypertension.

Diagnosis of Pulmonary Hypertension

Diagnosing PH can be challenging because its clinical signs are often non-specific and subtle, especially in children. Common symptoms include dyspnea (shortness of breath), fatigue (e.g., refusing to climb stairs, asking to be carried), and chest pain. The source stresses that pediatricians should be more vigilant and refer children who refuse sports or complain of chest pain for evaluation.

Key diagnostic tools include:

• Echocardiography: This is the primary evaluative method. It can provide indirect signs of right ventricular strain (e.g., septal flattening/bowing) and direct measurements of systolic, diastolic, and mean pulmonary arterial pressures. It also helps assess cardiac output and detect associated congenital heart defects. It is evaluated under "real-life" circumstances, often free of concomitant confounder (anesthesia / sedation). 

• Cardiac Catheterization: While not used for initial diagnosis, catheterization is essential for confirming PH, measuring pulmonary vascular resistance, assessing the QP/QS ratio (pulmonary to systemic flow ratio), and performing pharmacodynamic tests. These tests determine the reversibility of PH in response to vasodilators, which is crucial for guiding treatment and prognosis.

• Other diagnostic aids:

  • Electrocardiogram (ECG): May show right heart strain, but often non-specific, especially in newborns who naturally have right ventricular predominance.

  • Chest X-ray: Can show cardiomegaly and increased vascular markings (with high Qp:Qs from a shunt) or a small heart with reduced vascular markings (idiopathic PAH), along with an enlarged main pulmonary artery.

  • Etiological workup: Once PH is diagnosed, a comprehensive search for underlying causes is performed, including chest CT for respiratory causes, abdominal ultrasound, ENT evaluation for conditions like epistaxis, and rheumatological assessment for connective tissue diseases. Genetic testing is recommended for all cases of idiopathic PAH.

Management and Treatment of Pulmonary Hypertension

Treatment strategies for PH have advanced significantly, leading to improved survival rates. PH must be treated based on the underlying etiology / grouping of the PH. Each etiology may have a different approach and important elements to consider. As such, a PPHN patient will not be treated the same way as a BPD-PH, or large VSD patient. Similarly, a patient with thromboembolic disorder will not be managed the same way as a patient with pulmonary vein stenosis.

General Recommendations in Pulmonary Arterial Hypertension:

• Correct iron deficiency (in both children and adults).

• Avoid intense physical exertion due to the risk of sudden cardiac death.

• Prevent infections (especially respiratory) through vaccinations, as infections can worsen PH.

• Avoid altitudes above 1500 meters, which can cause hypoxic vasoconstriction.

• Discuss contraception early with adolescent girls, as pregnancy carries a high vital risk.

Specific Pharmacological Treatments: 

These treatments target specific molecular pathways involved in PH in order to achieve pulmonary arterial vasodilation and remodelling. They may not be suitable for all the causes of PH (i.e. Group 2). The three main pathways are:

• Nitric Oxide (NO) Pathway: Enhances vasodilation. Medications include inhaled NO and phosphodiesterase inhibitors (e.g., sildenafil, tadalafil). Riociguat is a stimulator of soluble guanylate cyclase

• Endothelin Pathway: Blocks the effects of endothelin, a potent vasoconstrictor. Endothelin receptor antagonists (ERAs) are used (e.g., bosentan, ambrisentan).

• Prostacyclin Pathway: Promotes vasodilation and anti-proliferative effects. Prostacyclin analogues are administered (e.g., epoprostenol, treprostinil, selexipag).

• Calcium Channel Blockers: Reserved for a very small group of patients who show a positive response to acute vasoreactivity tests during catheterization; these patients generally have a good prognosis. Calcium channel blockers are NOT recommended before the age of 1 year old. 

Oxygen Therapy: This is specifically recommended for PH associated with chronic respiratory diseases (Group 3), based on oximetry, to prevent chronic hypoxemia and reduce vasoconstriction. It is not generally recommended for other groups.

Anticoagulants: Not routinely recommended in children with PH. Their use is debated in adults.

Surgical and Interventional Strategies:

• Shunt Closure: For patients with congenital heart disease and significant shunts, early surgical correction is paramount to prevent irreversible pulmonary vascular damage.

• Potts Anastomosis: For severe, intractable PAH (idiopathic or non-operable shunts), a surgical communication between the aorta and pulmonary artery (Potts anastomosis) can be created. This procedure decompresses the right ventricle and can significantly improve the quality of life by diverting blood from the high-pressure pulmonary circulation. It's considered an alternative before lung transplantation. However, these patients may develop significant collaterals and some centers will refuse to transplant a patient with a Potts shunt. 

• Lung Transplantation: This is a last resort for end-stage PH when other treatments fail. Challenges include the scarcity of pediatric lung donors and the significant morbidity associated with transplantation. The goal of medical therapy is to delay or ideally avoid the need for transplantation.

The prognosis for PH has dramatically improved with the advent of modern treatments. Survival rates for children with PH have increased from an average of 10 months prior to treatments to 85-95% at 3 years and 85% at 5 years with current therapies. These treatments allow many children to reach adolescence and adulthood, potentially making transplantation an easier option if needed later in life. Despite improved survival, the quality of life is not perfect, with about 70% of patients experiencing adverse events within 5 years. The aim of treatment is to maintain patients in a "low-risk" state, with good right ventricular function and favorable hemodynamic parameters. Modern treatments have been shown to reduce intimal proliferation and stimulate the release of endothelial progenitor cells, which are believed to help regenerate damaged vessels.

Future Research and Therapeutic Avenues: Several promising areas of research that aim to go beyond mere vasodilation and address the underlying cellular and genetic mechanisms of PH:

• New Therapeutic Pathways: Exploring targets beyond the current three main pathways, including inflammation and epigenetics.

• Gene Therapy: Activating deficient genes (e.g., BMPR2) to restore normal cellular function.

• Immunology and Inflammation: Targeting the inflammatory components of PH, potentially drawing on advances in cancer research like CAR-T cell therapy, to repair damaged pulmonary arterioles.

• Regenerative Medicine: Investigating the use of progenitor cells and micro-particles to restore vessel structure and function.

• The speaker expresses optimism that future research will enable PH to be treated as effectively as common illnesses like angina, by restoring cellular balance and repairing damaged vessels.

Reference: HTAP by Maryline Lévy - Youtube Link.

Echocardiographic Probability of Pulmonary Hypertension (PH) after 3 months of age at sea-level by TRJ based on sPAP

Important resources:

• Mourani PM, Sontag MK, Younoszai A, Miller JI, Kinsella JP, Baker CD, Poindexter BB, Ingram DA, Abman SH. Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2015 Jan 1;191(1):87-95. doi: 10.1164/rccm.201409-1594OC. PMID: 25389562; PMCID: PMC4299632.

  • This study used this definition for suspicion of PH by echocardiography: "The primary criteria for PH were met by any of the following findings: an estimated right ventricular systolic pressure (RVSP) greater than 40 mm Hg, RVSP/systemic systolic blood pressure greater than 0.5, any cardiac shunt with bidirectional or right-to-left flow, or any degree of ventricular septal wall flattening."

• Nawaytou H, Hills NK, Clyman RI. Patent ductus arteriosus and the risk of bronchopulmonary dysplasia-associated pulmonary hypertension. Pediatr Res. 2023 Feb 17. doi: 10.1038/s41390-023-02522-4. Epub ahead of print. PMID: 36804505.

  • "An echocardiogram was considered positive for PH if the tricuspid regurgitant jet velocity was >2.9 m/s (RV-RA of 33.6 mmHg), the PDA systolic flow velocity estimated a peak systolic pulmonary artery pressure >35 mmHg, or if systolic septal flattening was present (based on end-systolic eccentricity index >1.0)."

  • "The PH was considered to be flow-associated PH, due to the presence of a left-to-right PDA shunt (in the absence of a VSD), if there was left-to-right flow through the PDA in both systole and diastole and the echocardiographic signs of PH disappeared following ductus closure." 

  • "An echocardiogram was classified as positive for PVD if it met the above criteria for PH in the absence of a PDA or VSD shunts. If a PDA or VSD shunt was present, the echocardiogram was only classified as positive for PVD if it met the above criteria for PH and there was bidirectional or right-to-left flow through the PDA or VSD, or left-to-right flow through a moderate/large PDA without holodiastolic flow reversal in the abdominal aorta."

• Faqih SA, Noto-Kadou-Kaza B, Abouamrane LM, Mtiou N, El Khayat S, Zamd M, Medkouri G, Benghanem MG, Ramdani B. Pulmonary hypertension: prevalence and risk factors. Int J Cardiol Heart Vasc. 2016 May 9;11:87-89. doi: 10.1016/j.ijcha.2016.05.012. PMID: 28616531; PMCID: PMC5462628.

  • In the adult literature using echocardiography to evaluate pulmonary arterial pressure: "A value greater than or equal to 35 mm Hg is considered PAH and classified as follows: mild PAH (35–50 mm Hg), moderate PAH (50–70 mm Hg), and severe pulmonary hypertension (> 70 mm Hg)"

• Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P, Ferrari P, Ferreira DS, Ghofrani HA, Giannakoulas G, Kiely DG, Mayer E, Meszaros G, Nagavci B, Olsson KM, Pepke-Zaba J, Quint JK, Rådegran G, Simonneau G, Sitbon O, Tonia T, Toshner M, Vachiery JL, Vonk Noordegraaf A, Delcroix M, Rosenkranz S; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022 Oct 11;43(38):3618-3731. doi: 10.1093/eurheartj/ehac237. Erratum in: Eur Heart J. 2023 Feb 23;: PMID: 36017548.

  • Probably of PH by echocardiography recommended in the adult population:

    • High probability: 

      • TRJ > 3.4 m/s (46 mmHg of RV-RA gradient)

      •  TRJ between 2.9 (33.6 mmHg) and 3.4 m/s with at least one of: 

        • LV end-systolic eccentricity index >1.1

        • RV/LV basal diameter ratio >1.0

        • Tricuspid annular plane systolic excursion (TAPSE)/sPAP <0.55 mm/mmHg, 

        • RVOT acceleration time (PAAT) <105 ms or midsystolic notching, 

        • Early diastolic pulmonic insufficiency velocity >2.2 m/s, 

        • Increased pulmonary artery diameter >25 mm, 

        • Estimated right atrial pressure ≥15 mmHg,

        • Right atrial area >18 cm2. 

    • Intermediate probability 

      • TRJ 2.9 to 3.4 m/s without other indices listed above 

      • TRJ is ≤2.8 m/s and at least one indirect indices listed above is present. 

    • Low probability 

      • TRJ ≤2.8 m/s with no other indices (listed above).

• Koestenberger M, Apitz C, Abdul-Khaliq H, Hansmann G. Transthoracic echocardiography for the evaluation of children and adolescents with suspected or confirmed pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and D6PK. Heart. 2016 May;102 Suppl 2:ii14-22. doi: 10.1136/heartjnl-2014-307200. PMID: 27053693.

  • "Usually TR velocity (TRV) values >3.4 m/s, corresponding to a PASP >50 mm Hg at rest, make PAH highly likely in adults." - This cut-off was established when definition for PAS was considered to be mPAP >25 mmHg. This definition has now been reviewed for a mPAP >20mmHg. As such, we locally use a value of TRV corresponding to a PASP > 40 mmHg (TRV 35 + expected RA pressure of 5 mmHg = 40 mmhg) as our local cut-off for "Echocardiographically-suspected PH".

References: 

• Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P, Ferrari P, Ferreira DS, Ghofrani HA, Giannakoulas G, Kiely DG, Mayer E, Meszaros G, Nagavci B, Olsson KM, Pepke-Zaba J, Quint JK, Rådegran G, Simonneau G, Sitbon O, Tonia T, Toshner M, Vachiery JL, Vonk Noordegraaf A, Delcroix M, Rosenkranz S; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022 Oct 11;43(38):3618-3731. doi: 10.1093/eurheartj/ehac237. Erratum in: Eur Heart J. 2023 Apr 17;44(15):1312. doi: 10.1093/eurheartj/ehad005. PMID: 36017548.

• Hypertension Artérielle Pulmonaire - Dr Laurent Savale - Protocole National de Diagnostic et de Soins - Pulmotension 2020

Hemodynamic Measures Obtained During Right Heart Catheterization (adolescent/adult values)

ᵃ Derived from blood sample taken from the pulmonary artery; compartmental oximetry to exclude an intracardiac shunt is recommended when SvO₂ >75%.
ᵇ PVR = (mPAP – PAWP) / CO
ᶜ TPR = mPAP / CO
ᵈ PAC = SV / (sPAP – dPAP)

Here the systemic blood pressure is based on adults. These valuses must be adapted to the child or neonate.

Reference: 

Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P, Ferrari P, Ferreira DS, Ghofrani HA, Giannakoulas G, Kiely DG, Mayer E, Meszaros G, Nagavci B, Olsson KM, Pepke-Zaba J, Quint JK, Rådegran G, Simonneau G, Sitbon O, Tonia T, Toshner M, Vachiery JL, Vonk Noordegraaf A, Delcroix M, Rosenkranz S; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022 Oct 11;43(38):3618-3731. doi: 10.1093/eurheartj/ehac237. Erratum in: Eur Heart J. 2023 Apr 17;44(15):1312. doi: 10.1093/eurheartj/ehad005. PMID: 36017548.

Transitional drop in pulmonary vascular resistance

The transitional bidirectionality at the atrial level occurs because left and right atrial pressures are transiently similar. As the right ventricle (RV) adapts to the now low-resistance pulmonary circulation, it undergoes remodeling—becoming thinner-walled, less muscular, and developing a lower end-diastolic pressure. In contrast, the left ventricle (LV), which now supports the systemic circulation, develops a slightly higher end-diastolic pressure. This pressure is transmitted to the left atrium, which is now well-filled by pulmonary venous return, further promoting a left-to-right shunting pattern. The foramen ovale (FO) closes through a combination of functional and anatomical processes that occur after birth. The reversal of the pressure gradient causes the septum primum (a flap-like structure) to be pushed against the septum secundum, effectively sealing the foramen ovale—this is referred to as functional closure. Over time, fibrous tissue fuses the septum primum and septum secundum, resulting in anatomical closure and the formation of the fossa ovalis. In approximately 75–80% of individuals, this process is complete within the first year of life. In up to 25% of the population, the FO remains patent (PFO), though it is usually asymptomatic unless associated with conditions such as cryptogenic stroke or paradoxical embolism. 

Similarly, the ductus arteriosus (DA) remains patent in fetal life due to circulating prostaglandins from the placenta, as well as local prostaglandin production by specialized ductal endothelial cells—particularly active at lower gestational ages. The ductus is also highly sensitive to oxygen, which promotes constriction. With advancing gestational maturity, there is progressive thickening and increased sensitivity of the smooth muscle tissue surrounding the ductus. After birth, the closure of the DA occurs in two phases: functional and anatomical. As the newborn begins to breathe, oxygen tension (PaO₂) rises, triggering smooth muscle constriction of the ductus. Concurrently, the low-resistance placental circulation is removed, increasing systemic vascular resistance (SVR), while pulmonary vascular resistance (PVR) decreases as the lungs expand. These changes reverse the pressure and resistance gradients across the ductus—initially from right-to-left, then bidirectional as PVR approximates SVR, and eventually left-to-right as PVR falls well below SVR. Ductal flow diminishes significantly when PVR and SVR become comparable. Increased oxygen levels and decreased circulating prostaglandin E2 (PGE2), no longer maintained by the placenta, further promote ductal constriction, leading to functional closure. In term infants, this typically occurs within 12 to 24 hours after birth. Following functional closure, the DA undergoes intimal proliferation, smooth muscle migration, and fibrosis, resulting in permanent anatomical closure and formation of the ligamentum arteriosum, usually within 2–3 weeks in healthy term infants.

Echocardiography assessment in PH

Examples of Tricuspid Regurgitant Jet

Here are some examples of TRJ velocity with the full curve. Remember to consider the "chin" and not the "beard" when evaluating the peak velocity. Considering that TRJ provides a systolic Right Ventricular to Right Atrial GRADIENT, to derive the estimated RV systolic pressure, one may need to assume the right atrial pressure (which may increase in the context of RV diastolic dysfunction). Typically, most centers use the assumption of a 0-5 mmHg RA pressure. However, it's important to note that this may be much higher in the context of RA dilatation, IVC/subhepatic vein dilatation, and/or a right-to-left/bidirectional inter-atrial shunt.

When obtaining the TR jet, one must always probe all the views in order to evaluate the directionality of the jet. The line of interrogation should be placed in line with the direction of the jet in order to obtain the best alignment and not underestimate the velocity of the jet. A full envelopped should be achieved in order to obtain the most reliable RV-RA gradient (using the modified Bernouilli equation to convert the velocity in mmHg). See below two examples of a TRJ in the parasternal long axis view, and in the apical view. 

Septal position in systole: septal flattening or bowing in systole

As pressure rises on RV side (or pressure decreases on LV side), it can become iso-systemic (same as pressure on the LV compartment) or supra-systemic (higher pressure than on RV side).

Because there is a shared wall:

Isosystemic (>2/3 systemic) = Flat Interventricular septum at peak of contraction - D-Shape LV

Supra-systemic = Bowing septum into the LV cavity

With persistent increased afterload, RV hypertrophies and dilate

Reminder that septal motion in systole is reflective of the relationship between the right and left ventricles. As such, systolic pressure in the RV may be higher than the systolic pressure in the LV for various reasons:

• RV with high systolic pressure > LV with normal systolic pressure

• RV with high systolic pressure > LV with high systolic pressure

• RV with normal systolic pressure > LV with abnormally low systolic pressure

• RV with high systolic pressure > LV with abnormally low systolic pressure

• RV with abnormally low systolic pressure > LV with abnorally low (even lower than RV) systolic pressure.

Significant septal bowing in systole indicating a supra-systemic right ventricle:

Right Ventricular Function metrics by Echocardiography

Echocardiography is a valuable tool for assessing right ventricular (RV) function. Similar to the assessment of left ventricular (LV) function, it involves multiple markers and parameters that offer insights into RV performance. Here is an exhaustive list of markers commonly used to assess RV function by echocardiography:

1. Two-Dimensional Echocardiography (2D):

   - RV size and dimensions

   - RV fractional area change (FAC) - Quantifies changes in RV area during the cardiac cycle

   - RV end-diastolic and end-systolic areas

   - RV wall thickness

   - RV outflow tract (RVOT) diameter

2. M-Mode Echocardiography:

   - Tricuspid annular plane systolic excursion (TAPSE)

3. Tissue Doppler Imaging (TDI) and Doppler Echocardiography:

   - Systolic (S'), early diastolic (E'), and late diastolic (A') velocities of the tricuspid annulus

   - Myocardial Performance Index (Tei Index) based on TDI - Combined systolic and diastolic index of RV performance

   - RV systolic pressure (PASP) estimation by assessment of tricuspid regurgitation velocity or velocity through a small inter-ventricular septal communication.

   - Inter-atrial shunt evaluation

   - Sub-hepatic veins / IVC Doppler / IVC collapsibility / IVC size for appreciation of RA pressure

   - RV-output: stroke distance by velocity time integral of the RV outflow tract, estimation of cardiac output.

    - Assessment of RV filling patterns (E and A wave velocities)

4. Strain Imaging -  Speckle Tracking Echocardiography:

   - RV longitudinal strain (global and segmental)

   - Strain rate measurements

5. 3D Echocardiography:

    - Assessment of RV volumes and ejection fraction

    - RV global and regional function

RV-LV crosstalk

• Often assessed by septal-curvature (shared wall)

• At peak of systole, when both contracted, pulmonary and aortic valve are open à RV equalize with pressure in PA; LV equalize with Aorta.

• Usually LV under higher pressures than RV in systole (contraction)

• LV round and RV crescentic (surrounds LV) in systole

• Flattening only assessed at end systole on cross-sectional view (parasternal short axis)

• Flat in diastole indicative of similar pressure in RV-LV during diastole (ex: volume overload from ASD, severe RV failure with diastolic dysfunction)

PAAT/RVET - Pulmonary artery acceleration time / Right ventricular ejection time

• PW-Doppler of the RVOT – indicates pulmonary arterial flow velocity profile

• Usually parabolic smooth acceleration and deceleration

• With increase afterload – shorter acceleration

• Adjusted by Ejection time to take into consideration heart rate

• Pulmonary artery acceleration time on RV ejection time

• PAAT/RVET (< 0.3 suggestive of PVD; some use cut-off <0.25 or PAAT/RVET>0.4)

• Mid-systolic notch with significant afterload increase due to recoil of pulmonary arterial wall

Here you can contrast the PW-Doppler of a patient with infra-systemic ("normal") pulmonary pressure, showcasing a very parabolic profile (slow acceleration and decelaration in systole). In comparative, a patient with high pulmonary vascular resistances with a Doppler (PW) pattern at the RVOT showcasing mid-systolic notching and rapid acceleration (low PAAT/RVET: 34/203 = 0.17).

Pulmonary Vein Stenosis (PVS) - See Section on PVS

Patent Ductus Arteriosus Pattern - A Window on the Pulmonary Artery to Aorta Relationship 

More in the PDA section

Phenotypes of Acute PH

Acute PH is often implied to be a failure to relax the pulmonary vasculature in the immediate post-natal transition secondary to various cardio-pulmonary insults or stressors. This often yields to "abnormally" high PVR which may cause RV dysfunction, low pulmonary blood flow, hypoxic respiratory failure due to extra-pulmonary right to left shunting. It is often complicated by adverse cardio-pulmonary interactions, ventilation-perfusion mismatch (such as in meconium aspiration syndrome), acidosis, shock and end-organ hypoperfusion.

Acute PH in the newborn may present with diverse cardiovascular phenotypes, each representing a unique and dynamic physiology that requires constant vigilance and customized management. Targeted Neonatal Echocardiography (TNE) can be particularly valuable in deciphering the baby's condition and guiding therapeutic interventions. It’s crucial to remember that medications bring both intended effects and potential side effects. They should be carefully titrated and discontinued as soon as they are no longer required, as prolonged use may have unintended impacts on the body and cardiovascular system.

Tsoi SM, Steurer M, Nawaytou H, Cheung S, Keller RL, Fineman JR. Defining the Typical Course of Persistent Pulmonary Hypertension of the Newborn: When to Think Beyond Reversible Causes. J Pediatr. 2024 Oct;273:114131. doi: 10.1016/j.jpeds.2024.114131. Epub 2024 May 31. PMID: 38823627.

This single-center, retrospective cohort study at UCSF (2015–2020) evaluated newborns ≥35 weeks gestation with a clinical diagnosis of persistent pulmonary hypertension of the newborn (PPHN), excluding those with complex congenital heart disease or congenital diaphragmatic hernia. Infants were grouped by PPHN etiology: perinatal (72%) or fetal developmental (28%). The study compared timing and duration of various therapies, including extracorporeal life support (ECLS), mechanical ventilation, oxygen, iNO, inotropes, and prostaglandin E1. Resolution of PH was faster in the perinatal group, with significantly earlier discontinuation of therapies and echocardiographic resolution. Conclusion: A prolonged course of PPHN into the second week of life suggests a fetal developmental etiology and should prompt further investigation.

Acute PH (Classical "PPHN") with preserved or mildly depressed cardiac function and unrestrictive ductus

These patients often have maintained RV systolic function thanks to the ductus that is "wide open" and allows to "pop-off" the right ventricle in the context of supra-systemic pulmonary vascular resistances, leading to right to left ductal shunting. The baby is blue but at least not gray as they are able to maintain perfusion, at the expense of hypoxemia. There is often low pulmonary venous return, oligemia on the chest radiography. Desaturation is of secondary to right to left atrial shunting (pre-ductal desaturation) and right to left ductal shunting (post-ductal desaturation with differential of saturations). The low pulmonary blood flow leads to decreased LA preload, which favours the right to left atrial shunt. The size of inter-atrial shunt and the relationship between RV and LV end-diastolic pressures dictates the magnitude of the atrial shunt, and the amount of hypoxic blood entering the systemic circulation at that level (making the baby more profoundly desaturated at the pre-ductal level). The wide ductus shunts away the flow from the RV output towards the systemic circulation, decreasing pulmonary blood flow. Qp < Qs, but at least systemic blood flow is maintained (better to have a blue baby than a gray baby with weak pulses and end-organ perfusion compromise). Core strategy should be to promote the fall of PVR in order to reverse the phenotype.  The pre-ductal saturations are dependent on the atrial level shunt, as well as the pulmonary venous saturations (which may be decreased if there is a component of pulmonary parenchymal disease and ventilation perfusion mismatch). 

Management:

1. Ensure appropriate ventilation, but avoid hypocapnia (cerebral vasoconstriction) 

   1. Surfactant for RDS or Meconium Aspiration Syndrome

   2. Appropriate pulmonary recruitment (being aware that increasing MAP can be problematic in terms of cardio-respiratory interactions; high MAP can increase RV afterload and decrease cardiac preload).

2. Sedation/Analgesia may be indicated to avoid reactive increase in PVR 

3. Oxygen should be administered to aim 90-95% saturation. Oxygen is a pulmonary vasodilator but also toxic when exposed in excess. 

   1. Due to right to left shunt, there is a threshold at which FiO2 increase has no impact and excessive O2 may cause lung injury by reactive oxygen species 

4. Despite optimization of status, still high PVR and hypoxic:

   1. iNO is one of the only agent studied in RCT for hypoxic respiratory failure (often with acute PH / PPHN) in the term and near-term newborns

   2. Wean if not working; Wean once phenotype changes/resolves (implies reassessments)

5. Increasing data that vasopressors like vasopressin and norepinephrine may improve the PVR/SVR ratio in acute PH

6. PGE may be considered once PDA becomes restrictive as a pop-off for the RV (if there is RV failure), see below. 

7. Hydrocortisone should be considered in certain situations

   1. We do not recommend necessarily to base on cortisol level - Challenge with cortisol is the aspect of relative adrenal insufficiency. What is the normal values of cortisol in the context of significant stress. We know that some of these babies may have adrenal ischemia, hemorrhage, immaturity or sepsis which may all overwhelm the adrenal function and response. I personally do not rely solely on cortisol values and often consider hydrocortisone in babies with significant hemodynamic derangements. 

   2. Appropriate response to stress essential for maintenance of hemodynamic stability. Glucocorticosteroids  adrenergic receptors in smooth muscles, inhibits NO synthase expression and ↓ reuptake of norepinephrine leading to an increase in vascular tone and support of myocardial function. Effective in increasing BP and decrease inotropic support. No study: improved clinical outcomes with steroids in newborn shock 

   3. Hydrocortisone normalizes PDE-5 activity in pulmonary artery smooth muscle cells from lambs with PPHN

Acute PH (Classical "PPHN") with significantly depressed cardiac function and restrictive ductus

With a closing ductus and supra-systemic pulmonary vascular resistance (PVR), the right ventricle (RV) experiences an increasing afterload that it eventually cannot overcome. The patent ductus arteriosus (PDA) is too small to equalize pressures. Consequently, the RV is forced to maintain output against high PVR, initially causing a marked rise in pulmonary arterial pressures. This elevated afterload results in RV dysfunction and adverse interactions between the RV and left ventricle (LV). These patients are at high risk of progressively impaired left atrial (LA) preload and LV output, as well as progressive drop in  which can lead to profound hypotension and poor systemic perfusion. Eventually, the RV cannot compensate and there is significant drop in RV output, increase in RV end diastolic pressure. This leads to either backflow into the systemic veins (hepatomegaly, retrograde flow in the IVC, subhepatic veins and SVC - which can raise the post-capillary pressure of the cerebral vasculature), or it can lead to increased magnitude of the shunt at the atrial level (depending on the size of the inter-atrial shunt). These patients more "blue" if the volume accross the foramen ovale increases. They become more gray if the foramen ovale is restrictive. For these patients, addressing the elevated PVR must be coupled with cardiac support and potentially re-opening the ductus.

Management:

• Same as previous for high PVR, but here there is also is a component of significant RV systolic +/- diastolic dysfunction. 

  • Consider inotropic support: Dobutamine, Epinephrine

  • Milrinone can lead to significant hypotension. Can be considered if good urine output and normal BP. However, takes time to act, and may have accumulation if poor urine output as it is renally excreted. In our practice we do not use a bolus and we start at a lower dose (0.2 to 0.3 mcg/kg/min)

• PGE should be considered if the duct is restrictive to pop-off the right ventricle (if it is failing). This is ackowledging that it is at the expense of post-ductal hypoxemia. However, better to have perfusion and flow maintained and be "blue", than be gray with poor systemic blood flow. 

Acute PH with a closed duct 

See the section on the premature prenatal closure of the ductus.

Management:

• In this context there PDA is closed and there has been likely pre-natal ductal closure. As such, there is RV remodelling (hypertrophy), which leads to high RV end-diastolic pressure and a significant volume of hypoxic blood entering the systemic circulation at the level of the atrium, leading to pre-ductal desaturation. Pre and post-ductal saturation are the same because there is no duct! The RV may be failing. While these patients may remain with lower saturations for a while because of the R-L shunt at the atrial level, it is important to be patient. Agents like iNO and milrinone may be used to relax the pulmonary vascular bed. Inotropy may be necessary to support the RV function (dobutamine or epinephrine). Occasionally in significant RV hypertrophy, one may consider rate-control (such as esmolol). However, beta-blockers may also have some degree of myocardial depression and one should be particularly cautious in that context. 

LV dysfunction

Many patients with hypoxic-ischemic encephalopathy (HIE) are at risk of left ventricular (LV) dysfunction, which is often multi-factorial in origin. Contributing factors include poor coronary perfusion, myocardial hypoxia, acidosis, electrolyte imbalances (e.g., sodium, potassium, calcium), energy substrate insufficiency (e.g., oxygen, glucose), elevated systemic vascular resistance due to vascular constriction that maintains pressure in the context of low flow, anemia (as seen in cases like fetal-maternal hemorrhage or acute bleeding such as intra-ventricular or subgaleal hemorrhages, placenta previa, or abruptio), kidney injury, adverse cardiopulmonary interactions, and inflammatory conditions (e.g., concomitant sepsis, chorioamnionitis). 

Severe LV dysfunction in these patients can lead to extremely low LV output. In such cases, the right ventricle (RV) may assume a systemic role, providing systemic blood flow, with the ductus arteriosus becoming crucial, similar to a hypoplastic left heart syndrome (HLHS) or coarctation physiology. In this context, inhaled nitric oxide (iNO) should be avoided as it may divert blood from systemic circulation. Pulmonary vasodilators can similarly increase pulmonary flow, risking flash pulmonary edema due to heightened post-capillary congestion from elevated left atrial pressure. Elevated LV end-diastolic pressures often result in a left-to-right shunt at the atrial level, with these patients typically showing "normal" pre-ductal saturations and desirable pre- and post-ductal saturation differences. The pre-ductal saturations are dependent on the atrial level shunt, as well as the pulmonary venous saturations (which may be decreased if there is a component of pulmonary parenchymal disease and ventilation perfusion mismatch). 

If the PDA is small, restrictive, or closed, severe LV dysfunction may manifest as shock with poor perfusion, weak pulses, tachycardia, mottling, prolonged capillary refill, low urine output, and marked acidosis due to impaired end-organ perfusion. Management strategies vary by severity, but significant LV dysfunction may require inotropic support (e.g., epinephrine, dobutamine) and prostaglandin E (PGE) to maintain ductal patency, thereby sustaining systemic blood flow which may depend on RV output. Milrinone should be used with caution if there is poor urinary output as it tends to renally accumulate and can cause hypotension by systemic vascular resistance drop. Milrinone takes a few hours to have effect due to its longer half-life. 

In summary, management of significant LV dysfunction involves:

- Inotropic support (e.g., epinephrine, dobutamine; occasionally milrinone) to strengthen cardiac output.

- Avoiding pulmonary vasodilators to prevent exacerbating systemic steal, especially when a right-to-left ductal shunt is essential for systemic flow.

- Maintaining ductal patency with PGE when systemic circulation relies on RV output to ensure adequate systemic blood flow.

Functional pulmonary valvular atresia/stenosis

Functional pulmonary atresia happens when the RV function is so impacted that the RVO is extremely low, and pulmonary blood flow becomes dependent on the left to right shunt at the level of the ductus. Paradoxically, these patients may have differential of saturation once the RV function improves and output becomes sufficient through the RVOT to have some bidirectional or right to left component to the ductal shunt. These patients are often quite blue with similar saturations pre-post ductal. They have significant volume of hypoxic blood entering at the atrial level (depending on the size of their foramen ovale and RV end-diastolic pressure). They may have significant hepatomegaly. These patients may benefit from PGE to provide pulmonary blood flow, which increases the LA pressure by pulmonary venous return and decreasing the atrial shunt in the Right to Left direction. They also benefit from RV inotropic support and pulmonary vasodilation if the primary cause is high PVR. Some infants with this phenotype have significant RV hypertrophy and only PGE with adequate filling (and sometimes rate control: esmolol and/or sedation-analgesia to avoid fast heart rate) may be sufficient. 

Biventricular dysfunction

In the case of significant biventricular dysfunction, the goal is to provide inotropic support. Here epinephrine and dobutamine are agents to consider. These patients are often hypotensive and hypoxic, they have low LV and RV output. Hydrocortisone may be added to provide some degree of adrenal support in certain cases. 

In all these cases, if medical management fails, one shall consider alternatives such as ECMO (and occasionally removing TH depending on the patient and the local practice).

Acute PH with a closed duct 

See the section on the premature prenatal closure of the ductus.

Management and information:

• In this context there PDA is closed and there has been likely pre-natal ductal closure. As such, there is RV remodelling (hypertrophy), which leads to high RV end-diastolic pressure and a significant volume of hypoxic blood entering the systemic circulation at the level of the atrium, leading to pre-ductal desaturation. Pre and post-ductal saturation are the same because there is no duct! The RV may be failing. While these patients may remain with lower saturations for a while because of the R-L shunt at the atrial level, it is important to be patient. Agents like iNO and milrinone may be used to relax the pulmonary vascular bed. Inotropy may be necessary to support the RV function (dobutamine or epinephrine). Occasionally in significant RV hypertrophy, one may consider rate-control (such as esmolol). However, beta-blockers may also have some degree of myocardial depression and one should be particularly cautious in that context. 

• If the duct has been closed for a long time, it is unlikely that PGE will function as a strategy to re-open it.

  • If the ductus has been closed for an extended period in utero (e.g., weeks), intimal thickening, fibrosis, and remodeling may make it refractory to PGE1. If closure was recent or incomplete, PGE1 may still be theoretically effective in reopening the PDA.

• Milrinone may be considered to help the RV relax if the baby is not hypotensive and has good urine output (because it tends to renaly accumulate and can cause significant systemic vasodilation) - Reference.

• Ishida H, Kawazu Y, Kayatani F, Inamura N. Prognostic factors of premature closure of the ductus arteriosus in utero: a systematic literature review. Cardiology in the Young. 2017;27(4):634-638. doi:10.1017/S1047951116000871

  • "We analysed the data of 116 patients from 39 articles. Of these, 12 (10.3%) died after birth or in utero. Fetal or neonatal death was significantly correlated with fetal hydrops (odds ratio=39.6, 95% confidence interval=4.6–47.8) and complete closure of the ductus arteriosus (odds ratio=5.5, 95% confidence interval=1.2–15.1). Persistent pulmonary hypertension was observed in 33 cases (28.4%), and was also correlated with fetal hydrops (odds ratio=4.2, 95% confidence interval=1.3–4.6) and complete closure of the ductus arteriosus (odds ratio=5.5, 95% confidence interval=1.6–6.0). Interestingly, maternal drug administration was not correlated with the risk of death and persistent pulmonary hypertension."

  • "Persistent pulmonary hypertension of the newborn was observed in 33 cases (28.4%), 14 of which required mechanical ventilation (42.4%), including five patients who received nitric oxide inhalation. Fisher’s exact tests revealed that persistent pulmonary hypertension was significantly correlated with fetal hydrops (p=0.015; odds ratio 4.2, 95% confidence interval 1.3–4.6) and fetal right heart dilatation (p=0.0014; odds ratio 8.6, 95% confidence interval 1.4–22.1), but not with maternal drug administration (p=0.245) and fetal tricuspid regurgitation (p=0.108)." ... "Patients who could survive the perinatal period, regardless of persistent pulmonary hypertension, had no neurological or cardiac complications for at least 1–10 months; however, 11 patients (9.5%) had mild right ventricular hypertrophy or tricuspid regurgitation without any clinical symptoms, as detected by follow-up echocardiography at 1–6 months of age."

Example of an echocardiography in acute pulmonary hypertension of the newborn (PPHN):

Common Pulmonary Vasodilators

Grouping of Pulmonary Hypertesion

Acute vasoreactivity testing from PHA (Click here)

"Interpretation/Positive test: The 2009 ACC/AHA and 2015 ESC/ERS guidelines define a positive study based on a reduction in the mean pulmonary artery pressure of at least 10 mmHg to an absolute mean PA pressure of less than 40 mm Hg with a stable or improved cardiac output. Patients should have normal oxygen saturation prior to starting inhaled nitric oxide so that one can assess the true response on pulmonary vascular tone and not response to improved oxygenation."

"Acute vasoreactivity testing in children is undertaken to assess the response of the pulmonary vascular bed to pulmonary specific vasodilators. Similarly, the current practice in children with IPAH or familial PAH (isolated PVHD) is to use AVT to define the likelihood of response to long-term treatment with CCB therapy and for prognosis. There are 2 definitions of responders to AVT in IPAH or isolated PHVD, including 1) a decrease in mPAP of at least 10 mmHg to below 40 mmHg with a normal or increased increase in cardiac output; and 2) a decrease in mean PAP = 20% and increase or no change in CI and decrease or no change in PVR:SVR. AVT in children with PH associated with congenital heart disease (CHD) is undertaken to assess if the PVR will decrease sufficiently for surgical repair to be undertaken in borderline cases. In general, positive AVT for borderline cases with post tricuspid shunts is defined as decreases in PVRI to < 6-8 WUm2 or PVR:SVR <0.3. However, AVT is only one measure used to define operability and the whole clinical picture, the age of the patient and the type of lesion need to be taken into consideration. AVT may be studied with iNO (20–80 ppm), 100% oxygen, inhaled or intravenous PgI2 analogues, intravenous adenosine or sildenafil."

Apitz C, Hansmann G, Schranz D. Hemodynamic assessment and acute pulmonary vasoreactivity testing in the evaluation of children with pulmonary vascular disease. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK. Heart. 2016 May;102 Suppl 2:ii23-9. doi: 10.1136/heartjnl-2014-307340. PMID: 27053694. 

From this important resource here: https://heart.bmj.com/content/102/Suppl_2/ii23 :

• "Barst criteria, 1986: decrease in mPAP of ≥20%, unchanged or increased cardiac index, and decreased or unchanged PVR to SVR ratio (PVR/SVR); 

• Rich criteria, 1992: decrease in mPAP and PVR of ≥20%; 

• Sitbon criteria, 2005: decrease in mPAP of ≥10 mm Hg reaching an mPAP value of ≤40 mm Hg, and an increased or unchanged cardiac output."

Important References on Pediatric Pulmonary Hypertension

Joshi SR, Atabay EK, Liu J, Ding Y, Briscoe SD, Alexander MJ, Andre P, Kumar R, Li G. Sotatercept analog improves cardiopulmonary remodeling and pulmonary hypertension in experimental left heart failure. Front Cardiovasc Med. 2023 Feb 23;10:1064290. doi: 10.3389/fcvm.2023.1064290. PMID: 36910526; PMCID: PMC9996114.

Anand SC, Furqan M, Tonelli AR, Brady D, Levine A, Rosenzweig EB, Frishman WH, Aronow WS, Lanier GM. Sotatercept: A New Era in Pulmonary Arterial Hypertension. Cardiol Rev. 2025 Jan 7. doi: 10.1097/CRD.0000000000000837. Epub ahead of print. PMID: 39773755.

Sullivan RT, Raj JU, Austin ED. Recent Advances in Pediatric Pulmonary Hypertension: Implications for Diagnosis and Treatment. Clin Ther. 2023 Sep;45(9):901-912. doi: 10.1016/j.clinthera.2023.07.001. Epub 2023 Jul 28. PMID: 37517916.

Interesting article on Treprostinil pharmacokinetic review: https://pubmed.ncbi.nlm.nih.gov/27286723/ 

Safety and Feasibility of Riociguat Therapy for the Treatment of Chronic Pulmonary Arterial Hypertension in Infancy. Giesinger, Regan E. et al. The Journal of Pediatrics, Volume 255, 224 - 229.e1

Table of Echocardiography Metrics for Pulmonary Hypertension