Pulmonary Hypertension and Right Ventricular Function
Learning modules on Pulmonary Hypertension and Important sections:
Table of content (clickable):
Abnormal PA pressure defined (> 3 months of age):
Normal PA pressure usually around sPAP: 15 mmHg and dPAP: 5 mmHg (mean of 10) after 3 months of age
Mean PAP ≥ 20 mmHg (measured by cath but can be estimated by echocardiography using the pulmonary insufficiency jet)
Highly suspect increased PA pressure if systolic PAP ≥ 40 mmHg, estimated by echocardiography
Usually through a tricuspid regurgitant jet velocity estimating a RV-RA gradient and assuming RA pressure between 0-5 mmHg (although may underestimate RA pressure in the context of RV diastolic dysfunction)
In the presence of a PDA or VSD shunt - may use velocity gradient to estimate systolic PA pressure, by evaluating the directionality and systemic systolic blood pressure at the time of echocardiography.
R to L post-tricuspid shunt systolic velocity gradient: systolic systemic BP + gradient = estimation of systolic pulmonary arterial pressure
L to R post-tricuspid shunt systolic velocity gradient: systolic systemic BP - gradient = estimation of systolic pulmonary arterial pressure
Caveats:
PDA/VSD may not satisfy fully the assumptions of the Bernoulli equation.
In the context of unrestrictive post-tricuspid shunt, the systolic PA pressure will be, by definition, close to systemic as:
An unrestrictive left to right ventricular septal defect will transmit flow and pressure in systole in the pulmonary vascular bed and sPAP will approximate systemic systolic blood pressure by pressure transmission from the left ventricle into the right ventricle,
An unrestrictive left to right patent ductus arteriosus septal defect will transmit flow and pressure in systole and diastole in the pulmonary vascular bed and sPAP will approximate systemic systolic blood pressure by pressure transmission from the aorta to the pulmonary artery.
One may have increased pulmonary pressure due to a left to right shunt (pressure and/or flow transmission). This may not mean that there is underlying increase pulmonary vascular resistance as: Pressure factors Flow x Resistance. As such, an infant with a large left to right ductus arteriosus (or VSD) will have by definition equalization of pressure on both sides of the ductus (two connected compartments will equalize in pressure). This will lead to septal motion flattening (and increased eccentricity index) secondary to increase pulmonary arterial pressure by systemic pressure transmission. Once the shunt is removed, PA pressure may normalize and underlying pulmonary vasculature may be with adequate pulmonary vascular resistance.
We assume that echocardiography-estimated RV systolic peak pressure approximates systolic pulmonary arterial pressure in the absence of structural cardiac anomaly
First 3 months: PVR dropping and PA pressures should be < systemic (if systemic within normal for age).
Important resources:
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."
"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."
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)"
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).
"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".
Pre-capillary pulmonary hypertension official definition by catheterization (Pulmonary Arterial Hypertension) - click here for reference:
mPAP > 20 mm Hg
Pulmonary arterial wedge pressure or LV end-diastolic pressure ≤ 15 mm Hg
PVR index ≥ 3 Woods unit ×m2
Diastolic transpulmonary gradient ≥ 7 mm Hg
From: Changes in systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) during gestation. (Lakshminrusimha and Saugstad, 2016).
Systemic HTN = abnormal high BP in systemic compartment. Similarly, pulmonary hypertension (PH) = ”Abnormally” High pressure in PA
Etiologies of systemic hypertension: idiopathic, renal, cancer, steroids, etc.
One must identify the cause to tailor treatment
PH is a symptom of underlying process: Congenital heart, BPD, HIV, Pulmonary Embolus, Mitral Regurgitation, PPHN…
Similary to systemic HTN, one must identify cause to tailor treatment in a case of PH.
Etiologies have different pathophysiology and management:
Hypoplastic pulmonary vasculature (TOF-MAPCA, pulmonary hypoplasia)
High PVR, such as in acute PH of newborns (ie: PPHN) with disturbed transition to extra-uterine life
Pulmonary Embolus, pulmonary thromboembolic diseases
Congenital heart defect, such as Large PDA or Aortic to PA window: equalization of pressure during Systole and Diastole between Aorta and PA, pulmonary vasculature is exposed to excessive pressure and volume = PA has pressure similar than Aorta (depending on restrictive of PDA) = PH.
Post-Capillary, such as in: obstruction of pulmonary veins, severe mitral regurgitation, LV disease with poor drainage of venous return and backflow in pulmonary circulation
Tricuspid regurgitation jet velocity gradient
During systole, tricuspid valve is closed (prevents backflow in RA)
As RV pressure starts rising and RV dilates, the annulus dilates and coaptation of valve becomes less competent. TR appears: blood flow from high pressure RV to low pressure RA generates a velocity of low.
Measuring speed using Doppler allows to estimate the “gradient” (difference) between RV and RA chamber at peak of systole
Simplified Bernoulli equation tells you that :
Pressure difference between the 2 cavities = 4 x velocity2
True if the opening of jet is a narrow point.
Assuming RA pressure – 0-5mmHg (will increase with diastolic RV dysfunction)
TR = 5.45 m/s à 119 mmHg at peak of systole à RV-RA gradient of 119 mmHg
Assuming RA pressure about 5 mmHg: estimate of systolic PAP = 119+5 = 124 mmHg
Continuous-wave (CW) Doppler captures the velocity of flow across the entire line of interrogation (versus Pulsed-Wave (PW) Doppler captures the velocity of flow at the selected interrogation cursor).
TR obtained from the PLAX view and estimating RV-RA gradient of 33.6 mmHg - Providing an estimate of RV peak systolic pressure at 39 mmHg
TR obtained from the Apical view and estimating RV-RA gradient of 92 mmHg - Providing an estimate of RV peak systolic pressure at 97 mmHg (assuming RA pressure at 5 mmHg - likely underestimated in the context of RV failure leading to increased RA pressure)
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.
Significant RV failure and dilation in the context of severe pulmonary hypertension.
Various degree of septal flattening or bowing in systole
Significant septal bowing in systole indicating a supra-systemic right ventricle:
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.
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 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
- Assessment of RV volumes and ejection fraction
- RV global and regional function
Case of acute pulmonary hypertension of the newborn (PPHN):
Parasternal long axis indicating underfilled LV (from low pulmonary vascular flow) and dilated RV outflow tract.
Sweep in parasternal short axis indicating almost pancaking of left ventricle. RV is dilated and septum is bowing at times in systole into the LV cavity at mid-papillary level. LV is underfilled due to the persistence of increased pulmonary vascular resistance.
RV function is preserved despite increased pulmonary afterload. TR appears (mild) due to RV strain.
RV peak systolic pressure is estimated using the TR jet peak velocity. RV-RA gradient of 58 mmHg (based on modified Bernouilli equation; 4 x 3.81 x 3.81). Assuming a RA pressure of about 5 mmHg, estimated peak systolic RV pressure of 63 mmHg. Assuming normal cardiac anatomy, systolic Pulmonary Arterial Pressure estimated at 63 mmhg. This patient had a systolic blood pressure (systemic) of 45 mmHg. Hence, supra-systemic pulmonary pressures.
LV end-systolic eccentricity index as a way to quantify septal deformation
Eccentricity index (RV-LV Interaction: D1/D2) (Normal < 1.23)
RV/LV ratio (marker of RV dilation: D3/D2) (Normal < 1.00)
References:
Jone JG, Ivy D, Frontiers in Pediatrics - November 2014 , Volume 2, Article 124
Nagiub M, Echocardiography 2015;32:819–833
The following image is from the above article. The article outlines:
Systolic septal flattening recognized at EIs ≥ 1.15.
High inter-observer agreement for EIs.
Quantitative parameters of RV systolic function were impaired only at EIs ≥ 1.3.
Reference: Echocardiography 2016;33:910–915
From King ME et al. Circulation 1983. - "Marked exaggeration of this configurational change occurred in patients with right ventricular systolic hypertension (right ventricular systolic pressure greater than 50% systemic pressure), with progressive loss of curvature from end-diastole (0.45 ± 0.05) to end-systole (0.19 ± 0.06)."
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)
Pulmonary insufficiency - CW-Doppler
Same concept as TR
Pulmonary valve is closed during diastole
If RV/PA dilation à PV annulus dilate, valve becomes less competent à Pulm Ins.
Early Insufficiency jet speed gives you estimate of mean PA pressure; end diastolic of diastolic PA pressure
Diastolic pulm pressure (DPAP) estimated from pulm regurgitation jet from velocity of end-diastolic PI velocity
DPAP = 4 (end-diastolic PI velocity)2 + estimated RA pressure*
mPAP = 4 (early diastolic PI velocity)2 + estimated RA pressure*
*estimated RA pressure = RV end-diastolic pressure
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
From: Steven A. Goldstein MD; Echo in Pulmonary HTN, ASE - Georgetown University Medical Center MedStar Heart Institute
Normal profile
Mid-systolic notching from suspected high PVR. This is caused by the recoil of blood flow during systole from the pulmonary artery capacitance. Here the PAAT/RVET is 34/203 = 0.17 (<0.3)
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).
Right Ventricle Output
Right ventricular output should be evaluated in the context of pulmonary hypertension as a measure of RV performance. Here it is estimated at 112 mL/kg/min using the VTI of the PW-Doppler of the RVOT and the RVOT diameter. Normal 150 mL/kg/min and above.
PV stenosis suspected if mean gradient ≥ 4 mmHg on echo
Right to left patent ductus arteriosus in the context of supra-systemic pulmonary pressure.
CW-Doppler of the Right to Left PDA - Peak systolic gradient indicates that the PA pressure is 46 mmHg above the aortic pressure.
RV-LV cross-talk - Inter-Atrial shunt:
•LA-RA assessment of PFO/Atrial shunting reflects end-diastolic pressure relationships (influenced by MR-TR)
•With severe PH – RV diastolic dysfunction, increased RV end-diastolic pressures and bidirectional, eventually R to L shunt (and retrograde flow in hepatic veins with diastolic dysfunction).
Ventricular Septal Defect:
Relationship between LV and RV
Restrictive L to R with peak gradient of 20 means that LV pressure is 20 points > RV pressure when Aortic / Pulmonary valves open. If systolic BP is 60, sPAP is 40 (60 – 20 = 40)
If large and unrestrictive – will expose RV and pulmonary circulation (unless pulmonary stenosis) to systemic systolic pressures (and increases Qp:Qs)
Relationship between Aorta and PA
If large and L à R: expose pulmonary circulation to systemic pressures in systole/diastole
If restrictive and bidirectional: isosystemic PA pressures
Right to left: Suprasystemic PA pressures
When restrictive, may estimate PA pressures with Bernouilli equation (with caveat that PDA tubular and not a narrow point - hence, there may be some velocity attenuation through the course of the ductus)
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.
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:
Ensure appropriate ventilation, but avoid hypocapnia (cerebral vasoconstriction)
Surfactant for RDS or Meconium Aspiration Syndrome
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).
Sedation/Analgesia may be indicated to avoid reactive increase in PVR
Oxygen should be administered to aim 90-95% saturation. Oxygen is a pulmonary vasodilator but also toxic when exposed in excess.
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
Despite optimization of status, still high PVR and hypoxic:
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
Wean if not working; Wean once phenotype changes/resolves (implies reassessments)
Increasing data that vasopressors like vasopressin and norepinephrine may improve the PVR/SVR ratio in acute PH
PGE may be considered once PDA becomes restrictive as a pop-off for the RV (if there is RV failure), see below.
Hydrocortisone should be considered in certain situations
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.
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
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."
Common Pulmonary Vasodilators:
New avenues under investigation for pulmonary arterial vasodilation
"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."
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."

Presentation on Acute Pulmonary Hypertension at BINS 2024



An Interdisciplinary Consensus Approach to Pulmonary Hypertension in Developmental Lung Disorders
Nidhy P. Varghese, Eric D. Austin, Csaba Galambos, Mary P. Mullen, Delphine Yung, R. Paul Guillerman, Sara O. Vargas, Catherine M. Avitabile, Corey A. Chartan, Nahir Cortes-Santiago, Michaela Ibach, Emma O. Jackson, Jill Ann Jarrell, Roberta L. Keller, Usha S. Krishnan, Kalyani R. Patel, Jennifer Pogoriler, Elise C. Whalen, Kathryn Wikenheiser-Brokamp, Natalie M. Villafranco, Steven H. Abman European Respiratory Journal Jan 2024, 2400639; DOI: 10.1183/13993003.00639-2024

Table of Echocardiography Metrics for Pulmonary Hypertension
Interesting article on Treprostinil pharmacokinetic review: https://pubmed.ncbi.nlm.nih.gov/27286723/
Embracing the challenges of neonatal and paediatric pulmonary hypertension
