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The role of bedside functional echocardiography in the assessment and management of pulmonary hypertension

Open AccessPublished:June 13, 2022DOI:https://doi.org/10.1016/j.siny.2022.101366

      Abstract

      Pulmonary hypertension is an emergency in neonatal intensive care units with high morbidity and mortality. Its timely assessment and management is crucial for intact survival. Over the last couple of decades, there have been significant advances in management and techniques, which have resulted in improved survival. The use of neonatologist-performed echocardiography (NPE) is now increasingly utilized on neonatal intensive care units to understand the pathophysiology of the disease and to direct the treatment to the underlying cause. Its use is now established not only in cases of congenital diaphragmatic hernia and in the newborn with refractory hypoxemia, but also in other conditions such as bronchopulmonary dysplasia and the premature infant with difficulty in oxygenation. The use of NPE, however, requires the availability of trained personnel, equipment, and a close working relationship with pediatric cardiology.

      Keywords

      1. Background

      Pulmonary hypertension (PH) of the newborn is characterized by increased pulmonary vascular resistance with pulmonary-to-systemic shunting of deoxygenated blood resulting in severe hypoxemic respiratory failure (HRF) [
      • Puthiyachirakkal M.
      • Mhanna M.J.
      Pathophysiology, management, and outcome of persistent pulmonary hypertension of the newborn: a clinical review.
      ]. Broadly, PH can be classified under three categories - abnormally constricted pulmonary vasculature secondary to parenchymal diseases (maladaptation), hypoplastic pulmonary vasculature (underdevelopment) and normal parenchyma with remodelled pulmonary vasculature (maldevelopment) with various conditions contributing to it (Table 1). The commonest cause of PH in the newborn period is persistent pulmonary hypertension of the newborn (PPHN), which is erroneously also called persistent fetal circulation [PFC], which occurs from a failure of the lung circulation to achieve or sustain the normal drop in pulmonary vascular resistance (PVR) at birth [
      • Dakshinamurti S.
      ,
      • Mathew B.
      • Lakshminrusimha S.
      ]. PPHN affects 0.2% of all live births and is a significant contributor to the mortality and morbidity in term and late preterm infants.
      Table 1Etiologies of PPHN/PH.
      1. Maladaption of pulmonary vasculature (abnormal, ‘reactive’ pulmonary vasoconstriction)Parenchymal lung diseases-meconium aspiration syndrome (MAS), respiratory distress syndrome (RDS), hypoventilation, and pneumonia

      In response to certain stimuli, such as hypothermia, sepsis, stress, hypercapnia, hypoxemia, acidosis, and hyperviscosity

      Exposure to maternal medications- (maternal SSRI use)
      2. Maldevelopment of pulmonary vasculature (remodelling of pulmonary vasculature)In utero closure of ductus arteriosus (for example maternal cyclooxygenase inhibitor use)

      Pulmonary hyperperfusion in congenital heart disease with large left-to-right shunt

      Infants with fetal growth restriction
      3. Underdevelopment of pulmonary vasculature (hypoplastic pulmonary vessels; decreased cross-sectional area)Congenital diaphragmatic hernia

      Pulmonary hypoplasia (premature prolonged rupture of membranes, oligohydramnios etc.
      PPHN results in impaired oxygenation, right ventricular failure, and pulmonary-to-systemic shunting. In the premature infant, where the pulmonary vasculature is either maladapted, maldeveloped, or underdeveloped, the mechanisms are similar, and the pulmonary hypertension is usually secondary to pulmonary vascular immaturity. The incidence of acute PH in preterm infants is not clearly defined, but its prevalence could be higher than in term infants, as the lung parenchymal disease is more common because of immaturity of the lung [
      • Kumar V.H.
      • Hutchison A.A.
      • Lakshminrusimha S.
      • Morin F.C.
      • Wynn R.J.
      • Ryan R.M.
      Characteristics of pulmonary hypertension in preterm neonates.
      ]. Late-onset pulmonary hypertension, on the other hand, results from maldevelopment of the pulmonary circulation and is seen with severe bronchopulmonary dysplasia (BPD). The prevalence of PH in infants with severe BPD is under recognised with higher mortality compared to those without BPD [
      • Berkelhamer S.K.
      • Mestan K.K.
      • Steinhorn R.
      An update on the diagnosis and management of bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension.
      ].
      NPE or bedside/point of care functional echocardiography (fECHO) has gained recent global interest. It has become an integral part of neonatal practice in many centers [
      • El-Khuffash A.F.
      • McNamara P.J.
      Neonatologist-performed functional echocardiography in the neonatal intensive care unit.
      ,
      • Poon W.B.
      • Wong K.Y.
      Neonatologist-performed point-of-care functional echocardiography in the neonatal intensive care unit.
      ]. Guidance on assessment and management of PH by NPE has been published [
      • de Boode W.P.
      • Singh Y.
      • Molnar Z.
      • Schubert U.
      • Savoia M.
      • Sehgal A.
      • et al.
      Application of Neonatologist Performed Echocardiography in the assessment and management of persistent pulmonary hypertension of the newborn.
      ]. When there is a clinical suspicion of PPHN and structural heart disease has been ruled out, fECHO assessment is recommended. NPE is an important tool for confirming the diagnosis and grading of PPHN, objective selection of specific therapies, and titrating and monitoring response to treatment. Specific protocols are available for assessing PH related to bronchopulmonary dysplasia [
      • Arjaans S.
      • Zwart E.A.H.
      • Roofthooft M.
      • Kooi E.M.W.
      • Bos A.F.
      • Berger R.M.F.
      Pulmonary hypertension in extremely preterm infants: a call to standardize echocardiographic screening and follow-up policy.
      ,
      • Savoia M.
      • Morassutti F.R.
      • Castriotta L.
      • Pavoni D.
      • Mourani P.M.
      • Freschi P.
      • et al.
      Pulmonary hypertension in a neonatologist-performed echocardiographic follow-up of bronchopulmonary dysplasia.
      ], late onset sepsis [
      • Deshpande S.
      • Suryawanshi P.
      • Holkar S.
      • Singh Y.
      • Yengkhom R.
      • Klimek J.
      • et al.
      Pulmonary hypertension in late onset neonatal sepsis using functional echocardiography: a prospective study.
      ], and congenital diaphragmatic hernia [
      • Patel N.
      • Massolo A.C.
      • Kipfmueller F.
      Congenital diaphragmatic hernia-associated cardiac dysfunction.
      ,
      • Kinsella J.P.
      • Steinhorn R.H.
      • Mullen M.P.
      • Hopper R.K.
      • Keller R.L.
      • Ivy D.D.
      • et al.
      The left ventricle in congenital diaphragmatic hernia: implications for the management of pulmonary hypertension.
      ]. The aim of this article is to provide guidance to neonatologists undertaking fECHO examinations of newborn infants suspected of having PH to assist with diagnosis and management.

      2. Hemodynamic manifestations of PPHN

      The principal role of NPE in PH is to identify key features of PPHN, which include high pulmonary arterial pressure (PAP), increased pulmonary vascular resistance (PVR), and right-to-left shunting across the ductus arteriosus and/or inter-atrial shunting. There can be right ventricular (RV) systolic and diastolic dysfunction secondary to increased afterload, decrease in RV stroke volume, and RV filling. There is decreased pulmonary blood flow with ventilation-perfusion mismatch, leading to decreased left ventricle (LV) preload and, in turn, reduced LV stroke volume causing systemic hypotension. With progressive elevation of PVR, the RV dilates and bulges into the left ventricle, reducing the LV cavity size and its preload.
      In severe PPHN with RV dysfunction, the ductus arteriosus works as a conduit with right-to-left shunting. This helps in offloading the RV and helps in maintaining post-ductal systemic perfusion, causing peripheral cyanosis and differential saturations [
      • Dakshinamurti S.
      ,
      • Storme L.
      • Aubry E.
      • Rakza T.
      • Houeijeh A.
      • Debarge V.
      • Tourneux P.
      • et al.
      ].

      3. ECHO assessment of PPHN

      A bedside diagnosis of PPHN can be made based on labile saturations, a wide pre- and post-ductal saturation difference >5% and low PaO2; however, confirmation of diagnosis requires an NPE assessment. NPE in PH is useful in multiple ways, such as making the diagnosis and assessing the severity of PH, determining the need for specific monitoring, the choice of inotrope, and titration of pulmonary vasodilator therapy. A comprehensive echocardiographic assessment is essential in a case with suspected PH as no single echocardiographic parameter can reliably diagnose PH in isolation and should therefore be interpreted with caution. Table 2 summarizes the echocardiographic parameters used for assessment of PH in a systematic way.
      Table 2Echocardiographic assessment of Pulmonary Hypertension.
      NoECHO parameterViewImage AcquisitionCommentECHO image
      Step 1: Rule out congenital heart disease and other potential associated conditions
      1Situs view

      Great arteries arising from ventricles

      Venous return
      Subcostal

      Subcostal

      PSAX

      Suprasternal/crab view
      Situs view

      Visualise great vessels arising from both ventricles and crossing each other

      Visualise all four veins draining to LA
      Confirmation of Situs solitus

      Rule out transposition of great vessels

      Rule out Total anomalous pulmonary venous connection (TAPVC)
      Step 2: Is there PPHN and how severe it is?
      22.1 Estimation of Pulmonary artery pressures
      2.1.1 Peak TR velocity (TRV)

      PASP ∼ RVSP

      RVSP = 4 x (Vmax TR)2 + RAP

      (RAP = 3–5 mmHg)
      A4C

      PLAX (inflow)

      PSAX

      Subcostal

      Modified PSAX and A4C
      Peak TRV measured by CW Doppler across the tricuspid valve.

      Ensure the CW Doppler to flow angle is correctly aligned.

      Measure from a complete TR envelope. Choose the highest velocity.

      Eccentric jets can lead to incomplete Doppler envelopes and underestimation of TR velocity.

      Velocity can be under estimated in severe/free TR and should be stated in the report.

      A TRV <2.5 m/s is considered normal.
      The angle of insonation should be < 20° to achieve a reliable measurement.

      Even small errors in the absolute measurement of TRV can result in significant changes to the estimate of RVSP.

      Limitation: i)Not reliable in presence of right ventricular failure or right ventricular outflow tract obstruction or presence of valvular incompetence. ii) TR cannot always be observed and maybe absent in 15–40% of patients with PPHN.




      2.1.2 Peak PR velocity

      MPAP = 4x (Vmax PR)2 + RVdP

      (RVdP; right ventricular diastolic pressure

      RVdP = 2–5 mmHg)
      PLAX (outflow)

      PSAX

      Subcostal
      A CW Doppler measurement through the pulmonary valve in line with the PR jet.

      The peak (early/beginning of diastole) PR velocity (PRVBD) value is measured.

      An early PR velocity >2.2 m/s is considered a marker of raised mean PAP.
      PR cannot always be observed in patients with PPHN.

      This may have additional value when TRV cannot be used or relied upon.

      Limitation: Not reliable in presence of valvular incompetence.
      2.1.3IVS configuration/LV Eccentricity index. (LVsEI)PSAX

      PSAX
      Measure from PSAX view at mid LV level between papillary muscle and tips of mitral valve leaflets. End systole is taken as the frame with the smallest LV cavity; end diastole is measured on the peak of the R-wave.

      Interpretation based on shape:

      O shaped is <50% of LVP

      D shaped is 50–100%

      Crescent shaped is >100%

      LVsEI: The ratio of the minor axis dimensions as shown in the image (D2/D1) measured at end systole and end diastole.

      D1 = left ventricular diameter perpendicular to the septum; D2 = left ventricular diameter parallel to the septum
      LV diastolic EI is more a marker of volume overloaded right ventricle; for clinical conditions such as PPHN, pressure overload predominates, and hence the usefulness of the systolic EI.

      Left ventricular eccentricity index >1.1 is considered abnormal.

      Limitations: i)Off-axis PSAX images may cause artefactual eccentricity

      ii) RV pressure and volume overload can lead to an abnormal shape and function of the interventricular septum, resulting in flattening.




      Peak transductal right-to-left velocity

      SPAP = 4x (VmaxDA)2+ SSAP
      Ductal view

      Subcostal

      PSAX
      PW or CW doppler of transductal right-to-left blood flow can be used to estimate SPAP, when it lasts ≥30% of the heart cycle, by measuring its peak velocityA ductal right-to-left or bidirectional shunt is observed in 73–91% of the patients with PPHN.

      Measurement of PAP via ductal flow is often not reliable. Assessment of the direction of transductal blood flow is more useful and will indicate the relation between pulmonary and systemic pressures.
      2.2 Pulmonary vascular resistance:
      PVR = 

      PAAT/RVET ratio
      1.PLAX (outflow)

      2.PSAX

      3.Subcostal
      PAAT is validated as a feasible and reproducible, non-invasive echocardiographic imaging marker, for detection of pulmonary vascular disease and PH in neonates and children

      PAAT cutoff value of <90 ms reliably detects pulmonary vascular disease, <40 ms detects pulmonary vascular disease in its most severe form of PH.

      The normal PAAT:RVET ratio is ∼0.31 or greater.

      PAAT:RVET <0.23 is indicative of increased PAP.
      It is only a surrogate marker and does not give estimation of PAH

      TRV/VTI(RVOT)PLAX (outflow)

      PSAX
      PVR can be estimated by calculating the TRV: VTI ratio, which is the ratio between TRV and the VTI of blood flow through the RVOT using pulsed-wave doppler.

      TRV:VTI ratio have been shown to correlate well with PVR in children and a cut off value of 0.14 provided high predictive values
      Paucity of data in neonates
      Pulmonary artery compliance

      CdynPA = [(Ds-Dd)/(Dd x SPAP)] x 104
      PLAX (outflow)

      PSAX
      Dynamic pulmonary artery compliance (CdynPA) can be calculated by measuring pulmonary diameter in systole (Ds) and diastole (Dd) and analyzing the TR jet to calculate SPAP.

      Lower CdynPA is found in children with PH.
      Paucity of data in neonates
      2.3 Assessing direction of Shunts-PDA, PFO
      Transductal shunt -PDADuctal view

      Subcostal

      PSAX
      In 73–91% of patients with PPHN, a transductal right-to-left or bidirectional shunt can be observed. A bidirectional shunt with a systolic right-to-left duration ≥30% of the total heart cycle is considered non-physiologic and likely to represent PPHN.

      An exclusive right-to-left transductal shunt in patients with PPHN is associated with an increased risk of mortality.
      Measurement of pulmonary artery pressure via ductal flow is often not reliable.
      Interatrial - PFOSubcostalAn atrial bidirectional or right-to-left shunt is detected in 73–100% of PPHN patients. Also, left-to-right shunting over the interatrial septum is possible, since in PPHN diastolic pulmonary artery pressure is generally sub-systemic with suprasystemic SPAP.

      3Step 3: Is there associated right or left or bi- ventricular dysfunction?
      3.1 Objective assessment of RV function:
      3.1.1 Fractional area change (FAC)A4C

      2-D
      RV dimensions measured in 2-D by manual tracing of the endocardial border of the right ventricle.

      Trabeculations should be included within the cavity while tracing the area.

      RV-FAC = Area at the end of diastole (cm2) - area at the end of systole (cm2)/Area at the end of diastole (cm2).
      Normal values range from 25 to 45%

      Median RV-FAC value of 19% is considered abnormal and associated with need for ECMO or death;

      RV-FAC ≤ 33% is a major criterion in cardiomyopathy/dysplasia/akinesia or dyskinesia and RV-FAC> 33% and <40% is a minor criterion Cardiomyopathy/Dysplasia/akinesia or dyskinesia
      3.1.2 Tricuspid annular plane systolic excursion (TAPSE)A4CTo assess RV longitudinal function & obtained from the 4-chamber view using the M-Mode with the cursor aligned along the direction of the lateral annulus

      TAPSE is both angle and load dependent.
      Normal value in babies 1500–2500 g is 0.45 ± 0.03 cm, &

      In babies 2500–3600 g is 0.8 ± 0.16 cm.

      Diminished values below 4 mm are predictive of the need for ECMO and death in infants with PPHN
      3.1.3 MPI via TDIA4C

      Tissue Doppler or pulsed wave Doppler
      MPI is an index of global RV performance.

      The isovolumic contraction time (IVCT), isovolumic relaxation time (IVRT) and ejection time intervals can be measured using

      MPI = (IVET + IVRT)/RVET

      IVET; isovolumic ejection time; IVRT; isovolumic relaxation time; RVET; right ventricular ejection time

      Tissue Doppler is preferred as it is derived from a single sample
      Normal MPI in term infants is 0.42 (0.15).

      RV MPI in term infants decreases from 0.42 (0.14) on day 1 of life to 0.29 (0.09) after PDA closure and 0.22 (0.09) on 28th day of life

      MPI >0.43 by pulsed wave Doppler or >0.54 by tissue Doppler indicates RV dysfunction

      Tissue Doppler values > 0.64 are associated with worse prognosis
      3.2 Objective assessment of LV function:
      3.2.1 LV DimensionsPLAX or PSAXLV Dimension measured by 2-dimensional M-mode echocardiography at the level of the papillary muscles in PLAX or PSAX.

      Following measurements are taken:

      Left-ventricular end-diastolic dimension (LVEDD),

      Left-ventricular end-systolic dimension (LVESD),

      Interventricular septal thickness at end diastole (IVSd) and end systole (IVSs)

      Left ventricular posterior wall thickness at end diastole (LVPWd) and end systole (LVPWs)
      Refer to z-scores for various assessments corrected for weight/body surface area
      3.2.2 Shortening fraction(FS%)PLAX

      PSAX
      Measured by 2D or M-mode.: Shortening fraction(FS%) is a measure of global LV systolic function

      FS% = (LVEDD-LVESD) X 100

      LVEDD
      Normal values 26–40%

      Values below 25% suggest reduced LV function

      In presence of paradoxical septal movement, FS should not be calculated
      3.2.3 LV ejection fraction (EF)A4C

      2-D measurements
      Biplane Simpson's method:

      End diastole (LV EDD) & end-systole (LV ESD).

      The papillary muscles should be excluded from the cavity in the tracing.

      Ejection fraction (EF) = (EDV- ESV)/EDV
      EF >55% - normal

      EF 41–55% - slightly reduced

      EF 31–40%- moderately reduced, &

      EF < 30% markedly reduced
      3.2.4 Tissue Doppler Imaging (TDI) Technique for RV TEI indexA4CTDI of the right ventricular lateral wall with the sampling gate positioned at the junction of tricuspid annulus allows assessment of systolic and diastolic velocities.

      Peak systolic (s′), early and late diastolic (e′ and a′) myocardial velocities can be easily obtained.

      MPI can be calculated to assess diastolic function from IVCT, IVRT & ET
      Reduced systolic and diastolic TDI velocities have been found in neonates with PH.

      Reduced early diastolic velocity on days 1 and 2 of life predicted early respiratory outcome in infants with congenital diaphragmatic hernia
      3.2.5 Speckled tracking Echocardiography (STE)A4C

      A3C

      A2C
      Longitudinal shortening is the main deformation of the right

      Ventricle & is the most robust parameter in describing systolic right ventricular function.

      Diastolic measurements of early and late myocardial movements can be obtained
      In term infants reduced global systolic peak strain of the RV is associated with progression to death or need for ECMO.
      A4C- Apical four chamber; PLAX- Parasternal long axis; PSAX- Parasternal short axis; A3C - Apical three chamber; A2C - Apical two chamber.
      IVCT – Isovolumetric contraction time; IVRT - Isovolumetric relaxation time; ET – Ejection time.

      3.1 A stepwise approach for echocardiographic assessment of PH

      3.1.1 Step 1: rule out congenital heart disease and other potential associated conditions [
      • McLaughlin V.v.
      • Archer S.L.
      • Badesch D.B.
      • Barst R.J.
      • Farber H.W.
      • Lindner J.R.
      • et al.
      ACCF/AHA 2009 expert consensus document on pulmonary hypertension. A report of the American college of cardiology foundation task force on expert consensus documents and the American heart association developed in collaboration with the American college of chest physicians; American thoracic society, inc.; and the pulmonary hypertension association.
      ] [Table 2, section 1]

      Many cyanotic heart conditions may mimic PPHN, and it is important to rule out specific cardiac conditions [
      • Ricci M.
      • Elliott M.
      • Cohen G.A.
      • Catalan G.
      • Stark J.
      • de Leval M.R.
      • et al.
      Management of pulmonary venous obstruction after correction of TAPVC: risk factors for adverse outcome.
      ] where vasodilating therapies (e.g., inhaled nitric oxide) are contraindicated. The recommendation is for the first echocardiogram to be done by an expert pediatric cardiologist prior to an NPE fECHO assessment. If the first screening echocardiogram is done by a neonatologist, he/she should systematically look for situs solitus, exclude transposition of the great vessels, demonstrate good chamber sizes to rule out any hypoplastic chambers, look for ventricular septal defects (VSD), and demonstrate that all pulmonary veins enter the left atrium (LA). A high index of clinical suspicion is needed for diagnosing a Vein of Galen malformation, which may present as PPHN. The echocardiographic findings will incllude supra-normal superior vena cava (SVC) flows in the absence of other causes and can be confirmed clinically by auscultating the head for the presence of a bruit [
      • Tiwary S.
      • Geethanath R.M.
      • Abu-Harb M.
      Vein of Galen malformation presenting as persistent pulmonary hypertension of newborn (PPHN).
      ,
      • Tran C.
      • Nagpal A.
      Vein of Galen malformation masquerading as pulmonary hypertension.
      ].

      3.1.2 Step 2: is there PH and how severe it is [Table 2, section 2]?

      ECHO diagnosis and assessment of the severity of PH can be classified in three broad categories:
      • 1.
        Estimation of pulmonary artery pressures
      • 2.
        Assessment of pulmonary vascular resistance
      • 3.
        Assessing direction of Shunts-PDA, PFO

      3.2 Estimation of pulmonary artery pressures using various echocardiographic indices

      3.2.1 Measurement of tricuspid regurgitation (TR) or peak TR velocity

      The traditional echocardiographic approach to estimating pulmonary artery systolic pressure (PASP) uses a derivation of right ventricular systolic pressure (RVSP) from the tricuspid regurgitation (TR) velocity measured by performing a continuous wave (CW) spectral Doppler in an apical four chamber view [
      • Berger M.
      • Haimowitz A.
      • van Tosh A.
      • Berdoff R.L.
      • Goldberg E.
      Quantitative assessment of pulmonary hypertension in patients with tricuspid regurgitation using continuous wave Doppler ultrasound.
      ]. Many patients will have a degree of TR, which is often compensated by a normally functioning right ventricle, even with elevated PVR. The modified Bernoulli equation states that the pressure gradient between either side of a fixed obstruction with no significant length is proportional to the velocity of the flow across that obstruction and calculated as shown Table 2.1.1. Generally, a velocity of ≥2.5 m/s is significant (in the absence of pulmonary stenosis and a normal PV confirmed). TR cannot always be observed and is present in approximately 60–85% of patients with PH [
      • Skinner J.R.
      • Hunter S.
      • Hey E.N.
      Haemodynamic features at presentation in persistent pulmonary hypertension of the newborn and outcome.
      ]. In the presence of RV dysfunction, the pulmonary pressures can be underestimated.

      3.2.2 Assessment of PH using pulmonary regurgitant jet (Table 2.1.2)

      The pulmonary regurgitation jet across the PV can be utilized to calculate mean pulmonary artery pressure (mPAP). PR velocity >2.2 m/s is considered a marker of elevated mean PAP.

      3.2.3 interventricular septal (IVS) flattening

      IVS position and shape of the left ventricle can be visually assessed and categorized into normal curvature (O-shaped), flat septum (D-shaped), or crescent shaped (bowing into the LV).
      O-shaped LV suggests RV pressure <50% of LV.
      D-shaped LV suggests RV pressure 50–100% of LV.
      Crescent shaped LV suggests RV pressure >100% of LV.

      3.2.4 Calculating left ventricle systolic eccentricity index (LVsEI)

      The LVsEI is calculated as the ratio of LV dimension parallel and perpendicular to the septum. The normal LVsEI is typically 1.0, and it increases >1.0 in PH, as it allows for IVS flattening and bowing into the LV. The serial measurement of the LVEI over time may allow monitoring of the progression of the right ventricular pressure [
      • Abraham S.
      • Weismann C.G.
      Left ventricular end-systolic eccentricity index for assessment of pulmonary hypertension in infants.
      ].

      3.3 Assessment of pulmonary vascular resistance (Table 2.2)

      3.3.1 Pulmonary artery acceleration time to right ventricular ejection time. [
      • Gately C.
      • Patel H.
      Time to peak velocity in the main pulmonary artery as a marker of persistent pulmonary hypertension in neonates.
      ]

      Surrogate method for assessing PVR is by calculating the ratio of pulmonary artery acceleration time (PAT) to right ventricular systolic ejection time (RVET) intervals. This index has recently been validated as a feasible and reproducible non-invasive echocardiographic imaging marker for detection of PVR and PH [
      • Jain A.
      • Mohamed A.
      • Jankov R.P.
      • Kavanagh B.
      • McNamara P.J.
      • Mertens L.
      Use of echocardiography to characterize and time circulatory changes associated with normal postnatal adaptation in human neonates.
      ]. The normal value is approximately 0.31 or greater; a ratio less than 0.23 indicates increased PAP.

      3.3.2 Pulmonary Doppler flow envelope pattern

      Visual inspection of the shape of the Doppler flow envelope pattern across the right ventricle outflow tract is a sensitive predictor of PH in children and infants. The mid-systolic notch, also referred to as the “flying W,” is associated with elevated PVR and PAP. This is only sensitive if the RV function is normal. In right heart dysfunction the Doppler trace will not reflect the severity of PVR.

      3.3.3 TRV/vti(rvot)

      PVR can also be estimated by calculating the TRV:VTI ratio, which is the ratio between TRV and the VTI of blood flow through the RVOT using pulsed-wave Doppler; however, limited data are available in neonates.

      3.4 Assessing directions of shunts-PDA, PFO (Table 2.3)

      Right-to-left or bidirectional shunting is observed in 73–91% of patients with PPHN. The proportion of right-to-left blood flow can be used to estimate systolic PAP when it lasts greater than or equal to 30% of the cardiac cycle. A right-to-left ductal shunt may be able to predict mortality (83% vs. 28%, p = 0.043) [
      • Breinig S.
      • Dulac Y.
      • Berthomieu L.
      • Marcoux M.
      PO-0490 echocardiographic predictors of outcome in persistent pulmonary hypertension in newborn (pphn): a prospective study.
      ].
      Elevated right atrial pressures can be identified by a bulging inter-atrial septum into the left atrium in 2D imaging. Elevated RA pressures may reflect impaired RV diastolic function secondary to elevated pulmonary arterial pressures in the setting of PH.

      3.4.1 Step 3: is there associated right- or left- or bi-ventricular dysfunction?(Table 3.1 and 3.2)

      Global myocardial function of the heart may be affected in infants with PH [
      • Sehgal A.
      • Athikarisamy S.E.
      • Adamopoulos M.
      Global myocardial function is compromised in infants with pulmonary hypertension.
      ].

      3.4.2 Assessment of right ventricular (RV) function

      RV function in PH can be assessed by measuring the fractional area change (FAC), myocardial performance index (MPI), and tricuspid annular plane systolic excursion (TAPSE). Other advanced modalities, such as tissue Doppler imaging, can be utilized to assess systolic function on the right ventricle free wall and the interventricular septum.

      3.4.3 Fractional area change (FAC)

      FAC is a ratio of systolic-to-diastolic area, which is a surrogate of RV systolic function similar to LV ejection fraction (EF). Normal values range from 25% to 45%, with values increasing with postnatal age and are higher in preterm than term infants. Median RV-FAC values of 19% are associated with the need for extracorporeal membrane oxygenation (ECMO) or death.

      3.4.4 Tricuspid annular plane systolic excursion (TAPSE) [
      • Chikkabyrappa S.M.
      • Critser P.
      • Roane J.
      • Buddhe S.
      • Tretter J.T.
      Tripartite assessment of right ventricular systolic function in persistent pulmonary hypertension of the newborn.
      ]

      TAPSE provides a useful measure of RV contractile reserve, as it measures the systolic movement of the base of the RV free wall at the level of the tricuspid annulus. TAPSE assesses the shortening of longitudinal fibers of the RV and is validated by correlation with techniques estimating right ventricle global systolic function. The normal TAPSE value in babies 1500–2500 g is 0.45 ± 0.03 cm, and in babies 2500–3600 g it is 0.8 ± 0.16 cm. Diminished values below 4 mm are predictive of the need for ECMO and death in infants with PPHN [
      • Núñez-Gil I.J.
      • Rubio M.D.
      • Cartón A.J.
      • López-Romero P.
      • Deiros L.
      • García-Guereta L.
      • et al.
      Determinación de valores normalizados del desplazamiento sistólico del plano del anillo tricuspídeo (TAPSE) en 405 niños y adolescentes españoles.
      ,
      • Koestenberger M.
      • Nagel B.
      • Ravekes W.
      • Avian A.
      • Heinzl B.
      • Cvirn G.
      • et al.
      Reference values of tricuspid annular peak systolic velocity in healthy pediatric patients, calculation of Z score, and comparison to tricuspid annular plane systolic excursion.
      ].

      3.4.5 Myocardial performance index (MPI) [
      • Patel N.
      • Mills J.F.
      • Cheung M.M.H.
      Use of the myocardial performance index to assess right ventricular function in infants with pulmonary hypertension.
      ,
      L. D, A.G. D.
      ]

      MPI (also called the Tei index) is a good measure of biventricular myocardial performance and diastolic function, which is computed utilizing isovolumetric contraction and relaxation times, and ejection time derived from pulsed wave (PW) Doppler or tissue Doppler. In PH, increased right ventricular afterload results in RV dysfunction, and there may be prolonged isovolumetric phases, resulting in higher MPI. The normal RV MPI in term infants decreases from 0.42 (0.14) on day 1 to 0.29 (0.09) after PDA closure and 0.22 (0.09) on day 28 day.

      3.4.6 Left ventricular (LV) systolic function

      LV Dimension is measured by 2D M-mode echocardiography at the level of the papillary muscles. Diameters and thickness are generally corrected for body surface area (BSA), and normal ranges are assessed according to values published by Kampmann et al. [
      • Kampmann C.
      • Emschermann T.
      • Stopfkuchen H.
      • Wiethoff C.M.
      • Wenzel A.
      • Stolz G.
      • et al.
      Normal values of M mode echocardiographic measurements of more than 2000 healthy infants and children in central Europe.
      ].

      3.4.7 LV fractional shortening (FS or SF %)

      Normally SF% ranges from 25 to 45% in healthy newborns. The use of SF can be limited by septal flattening or paradoxical motion of the interventricular septum secondary to a hypertrophied and relatively high-pressure RV. In this case, measurement of LV ejection fraction (LV EF) using the biplane Simpson's method is acceptable and widely practiced.

      3.4.8 LV ejection fraction (EF): ejection fraction is a measure of global LV systolic function

      The end-diastolic and end-systolic volumes (EDV, ESV) are calculated using 2D echocardiography. LV EF is calculated using biplane Simpson's method.

      4. Advance echocardiographic parameters

      Tissue Doppler imaging (TDI) and Speckle tracking are advanced assessment techniques, which utilize the assessment of tissue (myocardial) motion. TDI assessments can be done at RV free wall, interventricular septum, and LV free wall loci. The peak systolic (s’) and diastolic (e’ & a’) velocities, isovolumetric contraction and relaxation times, and Tei index can be calculated. These can help in assessing the myocardial systolic and diastolic function, which are pre-load independent. Speckle tracking, on other hand, assesses the segmental and global myocardial function, but its use in pulmonary hypertension is currently limited to research pending further studies on diagnostic utility and outcome.

      5. Cardiac catheterization

      The gold standard for the diagnosis of PH is cardiac catheterization. However, it is an invasive procedure and the risks must be weighed against the benefits in a sick and fragile infant. The advantages of cardiac catheterization include direct measurement of PAP and PVR, assessment of anatomic shunts, detection of left ventricular diastolic dysfunction, and the diagnosis of pulmonary vein stenosis. It also provides an opportunity to perform interventional procedures.

      6. Specific considerations

      6.1 Bronchopulmonary dysplasia (BPD) associated pulmonary hypertension

      A screening ECHO for PH is recommended at 36 weeks’ postmenstrual age in extremely preterm infants with BPD, which may find PH in about 14% of patients [
      • Mourani P.M.
      • Sontag M.K.
      • Younoszai A.
      • Miller J.I.
      • Kinsella J.P.
      • Baker C.D.
      • et al.
      Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia.
      ]. Criteria used to diagnose PH in BPD are described above; however, most common and clinically relevant is septal wall flattening, which has the highest sensitivity with good inter-rater and intra-rater agreement [
      • McCrary A.W.
      • Barker P.C.A.
      • Torok R.D.
      • Spears T.G.
      • Li J.S.
      • Hornik C.P.
      • et al.
      Agreement of an echocardiogram-based diagnosis of pulmonary hypertension in infants at risk for bronchopulmonary dysplasia among masked reviewers.
      ]. An American Academy of Pediatrics (AAP) survey found that 38% of neonatologists have an institutional screening protocol and a m ajority screens at 36 weeks.(33, 34) Advanced ECHO imaging techniques, such as speckled tracking, can be utilized to assess LV function in BPD [
      • Czernik C.
      • Rhode S.
      • Helfer S.
      • Schmalisch G.
      • Bührer C.
      • Schmitz L.
      Development of left ventricular longitudinal speckle tracking echocardiography in very low birth weight infants with and without bronchopulmonary dysplasia during the neonatal period.
      ]. Differences in eccentricity index and systolic:diastolic ratio in extremely low birth weight infants with BPD can also predict the risk of pulmonary hypertension [
      • McCrary A.W.
      • Malowitz J.R.
      • Hornick C.P.
      • Hill K.D.
      • Cotten C.M.
      • Tatum G.H.
      • et al.
      Differences in eccentricity index and systolic-diastolic ratio in extremely low-birth-weight infants with bronchopulmonary dysplasia at risk of pulmonary hypertension.
      ].

      6.2 PH related to congenital diaphragmatic hernia (CDH) [
      • Altit G.
      • Bhombal S.
      • van Meurs K.
      • Tacy T.A.
      Diminished cardiac performance and left ventricular dimensions in neonates with congenital diaphragmatic hernia.
      ]

      About 40% of newborns with CDH may be born with either LV dysfunction or biventricular dysfunction because of ventricular interdependence [
      • Massolo A.C.
      • Paria A.
      • Hunter L.
      • Finlay E.
      • Davis C.F.
      • Patel N.
      Ventricular dysfunction, interdependence, and mechanical dispersion in newborn infants with congenital diaphragmatic hernia.
      ]. Association of ventricular dysfunction and ventricular performance is not only a predictor for disease severity but also mortality and the need for ECMO [
      • Patel N.
      • Lally P.A.
      • Kipfmueller F.
      • Massolo A.C.
      • Luco M.
      • van Meurs K.P.
      • et al.
      Ventricular dysfunction is a critical determinant of mortality in congenital diaphragmatic hernia.
      ,
      • Patel N.
      • Massolo A.C.
      • Paria A.
      • Stenhouse E.J.
      • Hunter L.
      • Finlay E.
      • et al.
      Early postnatal ventricular dysfunction is associated with disease severity in patients with congenital diaphragmatic hernia.
      ]. The role of timed echocardiographic assessment with pre-defined criteria for assessing the degree of PH and biventricular dysfunction helps in the management of CDH and the timing of CDH repair, as well as the management of acute postoperative clinical decompensation from pulmonary hypertensive crisis.

      7. Utility of NPE in the management of PPHN

      7.1 Decision making based on blood pressure (BP) and scardiac dysfunction

      7.1.1 Normal BP and good cardiac function

      Consider a selective pulmonary vasodilator such as inhaled nitric oxide (iNO), if available, otherwise intravenous (IV) or oral sildenafil can be used. If BP starts dropping, consider fluid boluses. Many centers prefer to start dopamine up to 10 mcg/kg/min [
      • Nakwan N.
      • Chaiwiriyawong P.
      An international survey on persistent pulmonary hypertension of the newborn: a need for an evidence-based management.
      ], but there is evidence suggesting that Dopamine, particularly in the context of hypoxemia, might increase PVR and should be avoided. Dopamine is used to increase the BP with the idea that increasing SVR may reverse the shunt. SVR is more easily monitored by invasive BP techniques, but we are not able to monitor PVR at all times, hence it is difficult to evaluate the response. Low dose epinephrine or norepinephrine in situations e are widely used, especially in sepsis (where peripheral vascular resistance is low) and the use of vasopressin is also on rise. Hydrocortisone can also be used.

      7.1.2 Normal BP but cardiac dysfunction on echo

      Consider low dose epinephrine or dobutamine to optimize cardiac function and iNO once stable. However, if the BP drops, avoid IV sildenafil as it may worsen hypotension. Cardiac dysfunction needs optimization with epinephrine and milrinone [
      • Patel N.
      Use of milrinone to treat cardiac dysfunction in infants with pulmonary hypertension secondary to congenital diaphragmatic hernia: a review of six patients.
      ], provided BP improves. In severe cases, early consideration of ECMO should be considered.

      7.2 Decision making based on shunting via PDA and PFO

      7.2.1 Left-to-right shunting across PDA and PFO

      Conservative and supportive management as no or minimal PPHN.

      7.2.2 Right-to-left shunting at PFO and left-to-right across the PDA

      It is always abnormal, and it might suggest ductal-dependent pulmonary circulation or supra-systemic pulmonary pressures, so one can safely start prostaglandins pending confirmation from the cardiologist about the presence of any structural abnormality.

      7.2.3 Right-to-left shutting at the PDA but left-to-right at PFO

      This could suggest a different physiology of LV dysfunction along with pulmonary hypertension. Here, one needs to support the heart with milrinone and or epinephrine and possibly prostaglandins. In this situation, iNO is relatively contraindicated, as it might worsen pulmonary venous hypertension.

      7.2.4 Right-to-left shutting at the PDA and PFO

      This means supra-systemic pulmonary hypertension, hence iNO, sildenafil, and other pulmonary vasodilators with inotropes (if cardiac dysfunction) should be used to optimize pulmonary and systemic hemodynamics.

      8. Pitfalls

      There may be several reasons why the level of agreement between the estimated pressures derived by echocardiography and those measured invasively are poor. Errors may occur in accurate measurement of the peak TRV signal. This can result in both overestimation and underestimation if the quality of the Doppler signals is poor or inaccurate because of suboptimal Doppler alignment from eccentric jets. When estimating right ventricular systolic pressure (RVSP) from the TRV using the Bernoulli equation, the TRV is squared and multiplied by 4, so even small errors in the absolute measurement of TRV can result in significant changes to the estimate of RVSP.
      In patients with severe free-flowing TR, the correlation between TRV and RVSP is poor and should not be performed. Absence of TR is also insufficient to exclude the presence of PH. Many echo assessments depend upon the integrity of RV function, and thus in the presence of RV dysfunction, the measured values underestimate the severity of PHT, and this should be considered in clinical decision making.
      The echo assessments should always utilize ECG guided systolic and diastolic time points, otherwise it can compound the errors and reduce reproducibility. The decisions should be made taking into account clinical parameters supplemented with fECHO measurements but should not override clinical decision making.

      9. Conclusions

      Bedside fECHO is now considered an essential tool for diagnosis and management of moderate to severe pulmonary hypertension in term and preterm infants. This requires a systematic evaluation of pulmonary pressures, pulmonary vascular resistance, fetal shunts, and cardiac function. The treatment can thus be directed to match the underlying pathophysiology and assess responses to treatment with timely escalation to ECMO when indicated, by performing serial echocardiography in non-responders. On the other hand, it also helps in titrating the therapy and defining timing for surgery. The use of NPE, however, requires structured training and should be reserved for experienced hands to minimize pitfalls and iatrogenic harm.
      Practice points:
      • 1.
        Neonatologist performed echocardiography (NPE) is essential for the management of infants with moderate to severe pulmonary hypertension on the neonatal intensive care units.
      • 2.
        The first echocardiography assessment should include segmental sequential analysis to exclude cyanotic congenital heart disease.
      • 3.
        Subsequent NPE assessments should be undertaken by well-trained clinicians to serially assess pulmonary pressures, pulmonary vascular resistance, foetal shunts and cardiac function to guide management and titrate inotropes and pulmonary vasodilators.
      • 4.
        NPE can also be used to facilitate early identification of infants with progressive or refractory pulmonary hypertension for consideration of transfer to ECMO centre.
      Future Research:
      • 1.
        Echocardiography biomarkers to predict outcomes in infants with pulmonary hypertension associated with congenital diaphragmatic hernia.
      • 2.
        Transitional circulation in infants with severe intra-uterine growth retardation and difficulty in oxygenation
      • 3.
        Echocardiography guided management of chronic pulmonary hypertension in infants with broncho-pulmonary dysplasia (BPD)
      (see Fig. 1).
      Fig. 1
      Fig. 1Echo-based management approach.
      (a) Echocardiography and blood pressure assessment to guide management of pulmonary hypertension
      (b) Echocardiography and assessment of PDA and inter-atrial shunts to guide management of pulmonary hypertension
      BP – Blood pressure; Echo – Echocardiography; iNO- inhaled nitric oxide; HIE – Hypoxic ischemic encephalopathy; PVR – pulmonary vascular resistance.

      Declaration of competing interest

      None

      Acknowledgments

      Open Access funding provided by the Qatar National Library .

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