Pulmonary Hypertension and Right Ventricular Function

Table of content (clickable):

Abnormal PA pressure defined (> 3 months of age):

Important resources:

Pre-capillary pulmonary hypertension official definition by catheterization (Pulmonary Arterial Hypertension) - click here for reference:

From: Changes in systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) during gestation. (Lakshminrusimha and Saugstad, 2016).


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.

Simplified Bernoulli equation tells you that :

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:

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

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:

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

Pulmonary insufficiency - CW-Doppler

Same concept as TR


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

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.

Other example of right to left PDA here.

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: 


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:

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:

Acute PH with a closed duct 

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

Management:

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:

Common Pulmonary Vasodilators:

New avenues under investigation for pulmonary arterial vasodilation

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 :

CIR.0000000000000329.pdf

Presentation on Acute Pulmonary Hypertension at BINS 2024

Acute-PH.pdf
PIIS1053249819315645.pdf
PC-1-280.pdf

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 

13993003.00639-2024.full.pdf

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

WSPH 2024 Pediatric task force.pdf

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