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Pulmonary hypertension associated with bronchopulmonary dysplasia

Pulmonary hypertension associated with bronchopulmonary dysplasia
Literature review current through: Jan 2024.
This topic last updated: Oct 04, 2023.

INTRODUCTION — Pulmonary hypertension (PH), a condition characterized by elevated pulmonary artery pressure (PAP), is usually associated with underlying cardiac or lung disease in children. In particular, PH develops in a subset of infants with bronchopulmonary dysplasia (BPD) [1-3]. Infants with BPD who develop PH often require supplemental respiratory support and have longer initial hospitalizations, higher medical costs, and higher mortality in the first two years of life compared with those with BPD and without PH [4]. They are also at increased risk for death, especially when undergoing general anesthesia [5,6]. With supportive medical management, the condition often improves over time, so that many affected infants may have few or no long-term effects.

This topic review will provide an overview of screening, diagnosis, and management of PH in infants with BPD. Related topic reviews include:

Other types of PH in infants and children, including PH due to congenital heart disease or idiopathic PH:

(See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis".)

(See "Pulmonary hypertension in children: Management and prognosis".)

Clinical features and management of BPD:

(See "Bronchopulmonary dysplasia (BPD): Clinical features and diagnosis".)

(See "Bronchopulmonary dysplasia (BPD): Management and outcome".)

(See "Complications and long-term pulmonary outcomes of bronchopulmonary dysplasia".)

DEFINITIONS

Bronchopulmonary dysplasia (BPD) — Clinically, BPD is defined as a need for supplemental oxygen and/or respiratory support for at least 28 days [7] or continued support at 36 weeks postmenstrual age in a preterm neonate (born <32 weeks gestational age) (table 1) [8]. (See "Bronchopulmonary dysplasia (BPD): Clinical features and diagnosis", section on 'Definitions and severity of BPD'.)

Pulmonary hypertension (PH) — For full-term infants >3 months old, the definition of PH is the same as in adults: mean pulmonary artery pressure (PAP) ≥20 mmHg at sea level [9]. Earlier guidelines used a slightly higher cutoff of ≥25 mmHg [10]. A definition specific to preterm infants is not available. However, any definition should be interpreted in view of the clinical context, including the age of the patient (young infants tend to have higher PAP) and conditions under which pulmonary pressures are measured. PH associated with BPD is classified within group 3 by the World Symposium on Pulmonary Hypertension [11]. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis", section on 'Definition'.)

EPIDEMIOLOGY AND NATURAL HISTORY — Between 20 and 40 percent of infants with BPD develop PH at some point during their initial hospital course, and PH is an important risk factor for morbidity and mortality in this population [1-3,12,13]. This PH typically develops during the first few months of life and has been associated with more severe BPD symptomatology [1]; it is distinct from the delayed transition from fetal circulation seen in some preterm and full-term neonates within the first several weeks of life [14]. As an example, in one series of infants with extremely low birth weight (birth weight <1000 g), approximately 7 percent developed PH by four weeks of age and 20 percent developed PH by hospital discharge [15]. The Pediatric Pulmonary Hypertension Network (PPHNet) registry reported that the incidence of PH related to BPD is highest among Black children, but this may be related to a higher rate of preterm birth among Black mothers [16].

Infants surviving the initial stages of PH often experience improvement or resolution of the PH due to catch-up lung growth and development [17,18]. Nonetheless, mortality rates in BPD infants with PH are substantial, ranging from 14 to 38 percent in retrospective studies [1,2,12,19-21] and 12 percent in one prospective study [15]. In one study of patients with BPD and PH treated during the surfactant era, 90 percent of those who survived subsequently had improvement in their PH (median follow-up 9.8 months), but only 20 percent had full resolution of PH [19]. Evidence suggests that there may be a subpopulation of infants with BPD who have chronic PH that can last for years [14,22].

Studies of school-age children with a prior history of BPD have not observed persistence or recurrence of PH, even under hypoxic conditions [23,24]. In another study, children with a history of PH were found to have subclinical right ventricular dysfunction at seven years of age; the long-term consequences of this are unknown [25]. However, one study of asymptomatic young adults born prematurely reported evidence of early pulmonary vascular disease including elevated pulmonary pressures, a less compliant pulmonary vascular bed, and right ventricular dysfunction [26].

PHYSIOLOGY AND PATHOGENESIS — Early disruption of angiogenesis leads to dysmorphic pulmonary vasculature, which causes both PH and impaired alveolar development [15]. This explains the frequent association between PH and BPD and also their shared risk factors (eg, extreme prematurity). In infants with BPD, mechanisms that contribute to the development of PH include:

Abnormal pulmonary vascular bed – PH in infants with BPD is characterized by an absolute reduction in the size and complexity of the pulmonary vascular bed, increased resting tone of pulmonary artery smooth muscle, and increased reactivity of the arteries to a variety of stimuli [27]. More current therapies aim to reduce pulmonary artery reactivity and promote vascular remodeling, which reduces resting pulmonary artery tone. However, the pulmonary capillary bed may remain underdeveloped, and the long-term effects of this physiology on the course of PH in BPD patients are unclear.

Oxygen toxicity and barotrauma – The effects of oxygen toxicity and ventilator-induced barotrauma and volutrauma on the immature lung can also interfere with alveolar development, with reduced numbers of alveoli and intra-acinar arteries. The consequences of these events may include impaired production of nitric oxide and vascular endothelial growth factor as well as increased expression of endoglin, all of which are involved in angiogenesis [28-30].

Alveolar hypoxia – Paradoxically, chronic or intermittent alveolar hypoxia and acidosis cause acute vasoconstriction and produce further structural change within the affected pulmonary arteries, including endothelial cell injury, intimal proliferation, medial hypertrophy, and extension of muscle into the arterial wall. Normal values on oximetry do not rule out the possibility that there are regions of alveolar hypoxia.

Cardiac dysfunction – Left ventricular diastolic dysfunction (which may be caused by systemic hypertension and steroid use), increased left ventricular diastolic pressure, left ventricular inflow obstruction, and left ventricular outflow obstruction can all contribute to the PH [31].

Pulmonary vein stenosis (PVS) – Preterm infants can develop PH secondary to PVS, which typically develops after the first few months of life. PVS can coexist with BPD or can develop in preterm infants who have only minimal lung disease; the pathobiology of this is not understood but may be a function of environmental or epigenetic factors [32,33]. PVS is poorly responsive to typical PH-directed pharmacotherapy and is associated with high mortality [32,34]. The possibility that necrotizing enterocolitis (NEC) may be a risk factor for PVS was raised by a study in which 50 percent of infants with PVS had a history of NEC during their hospital course; these infants had NEC at a mean age of 4.5 weeks, with PVS diagnosed at a mean age of 20 weeks [35].

RISK FACTORS — In an infant with BPD, predictors of risk for developing PH include [1,13-15,19,36]:

More severe BPD

Extreme prematurity

Very low birth weight (<1500 g)

Prolonged mechanical ventilation

Prolonged oxygen therapy

Cardiovascular anatomic abnormalities, such as pulmonary vein stenosis (PVS), patent ductus arteriosus (PDA), and aorta-pulmonary collaterals

Oligohydramnios or chorioamnionitis

Placental anomalies

Intrauterine growth retardation

Epigenetic or genetic factors

PH in the infant with BPD can be exacerbated by structural abnormalities and decreased surface area of the BPD lung, persistent ventilation-perfusion mismatch, poor gas exchange (intermittent hypoxemia and/or hypercarbia) [37], and poor airway clearance. Indeed, any factors that hinder lung growth and recovery from BPD may increase the risk and severity of PH or precipitate a PH crisis. Factors that contribute to the development of BPD may also contribute to the development or severity of PH in preterm infants; these factors include positive pressure ventilation, use of high concentrations of supplemental oxygen, chronic aspiration due to swallowing dysfunction and/or gastroesophageal reflux, and suboptimal nutrition [2].

In infants with chronic PH, factors that may precipitate an acute worsening of the disorder (PH crisis) may include viral or bacterial infections, acute aspiration, or general anesthesia [38]. (See 'Acute pulmonary hypertension crisis' below.)

SCREENING — Screening for PH in infants with BPD is recommended by expert consensus panels [39,40]. However, the optimal timing for screening is uncertain. Early identification of PH is useful to optimize therapy and minimize risks. If pulmonary vascular disease is identified at seven days of age, it is weakly associated with PH at 36 weeks postmenstrual age (positive predictive value 21 percent; negative predictive value 91 percent) [21]. However, early screening (eg, before 28 days of age) can also miss many late-developing cases of PH in extremely low birth weight infants [15]. Therefore, we suggest a combination of universal screening for infants with BPD and earlier screening for selected infants with risk factors or symptoms of PH, as outlined in the following sections (algorithm 1).

Universal screening for infants with bronchopulmonary dysplasia — We suggest screening for PH with echocardiography in all infants with BPD [10,39]. An echocardiogram should be performed at the time the formal diagnosis of BPD is made, which is typically at 36 weeks postmenstrual age. Practice varies regarding whether to perform routine echocardiographic screening for infants with mild BPD (eg, those who are breathing room air by 36 weeks postmenstrual age) and no other risk factors.

Earlier echocardiography for selected patients — Performing echocardiography at a younger age is recommended for infants with symptoms or important risk factors for PH, including [39]:

Severe hypoxemic respiratory failure shortly after birth, suggesting persistent pulmonary hypertension of the newborn

Need for ventilator support at postnatal day 7

Need for respiratory support disproportionate to lung disease

Recurrent or severe episodes of hypoxemia

Persistent hypercarbia (partial pressure of carbon dioxide [PaCO2] >60 mmHg)

Unexplained poor somatic growth

It is especially important to screen high-risk infants if they are scheduled for a procedure with anesthesia because PH is associated with increased risk of complications during anesthesia, typically during anesthesia induction and emergence. (See 'Acute pulmonary hypertension crisis' below.)

The most commonly used definitions for the diagnosis of BPD include a criterion of >36 weeks postmenstrual age [41]. Therefore, if PH is diagnosed in younger infants, the etiologies include antecedents of BPD, underlying congenital heart disease, or pulmonary vascular disease. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis", section on 'Common types of pulmonary hypertension in children' and "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

Follow-up — If clinically significant PH is noted on the initial echocardiogram, serial echocardiography (eg, monthly) is recommended until the PH has resolved or is consistently improving (algorithm 1) [42]. (See 'Monitoring' below.)

If the initial echocardiogram is negative, repeat screening may be warranted for infants with ongoing severe lung disease, such as those with persistent hypercarbia and/or difficulty weaning from the ventilator [39]. Repeat screening is also appropriate if the initial screening was performed during the first month of life since PH often develops after 28 days of age among extremely low birth weight infants [15].

EVALUATION — Echocardiography is often used to screen for and monitor progression of PH in infants with BPD [15]. Cardiac catheterization is the gold standard for diagnosis of PH and determining the severity but is performed for only selected cases. Measurements of brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) serum levels are not sufficient to diagnose or exclude PH, but serial measurements can be a useful component of assessing the patient's clinical course and monitoring response to treatment [39]. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis", section on 'Evaluation' and 'Monitoring' below.)

Echocardiography — Echocardiography is the initial test of choice to estimate pulmonary artery pressure (PAP) and make a provisional diagnosis of PH [43]. It should be performed in infants with BPD [39] or those at high risk for developing PH, as outlined above. If clinically significant PH is noted, serial echocardiography (eg, monthly) is recommended until resolution is assured. Institutional protocols for diagnosing and evaluating PH in preterm infants by echocardiography are recommended to improve the identification of this disorder [44]. (See 'Screening' above and 'Follow-up' above.)

Echocardiography includes the following [39,45]:

Estimation of PAP – In the absence of structural heart disease involving the right ventricular outflow tract or the pulmonary arteries, right ventricular systolic pressure and, by extension, systolic PAP (sPAP) can be estimated using tricuspid regurgitant (TR) jet velocity in combination with other echocardiographic findings. Measurement of the systolic gradient across a patent ductus arteriosus (PDA) to estimate sPAP eliminates the concern regarding right-sided anatomic lesions that elevate right ventricular pressure. Other echocardiographic parameters that may be helpful include pulmonary systolic time intervals, left pulmonary artery flow, and tricuspid annular plane systolic excursion [45,46]. Predominantly right-to-left shunting across the PDA suggests suprasystemic sPAP. Systemic systolic blood pressure (sBP) is measured simultaneously to allow for comparison.

The estimated sPAP can be used to categorize the severity of the PH [39]:

Mild PH – sPAP 1/3 to 1/2 of systemic sBP

Moderate PH – sPAP 1/2 to 2/3 of systemic sBP

Severe PH – sPAP >2/3 systemic sBP with severe flattening or posterior bowing of the interventricular septum

A TR jet is not detected in as many as 20 to 40 percent of infants, which can limit the ability to quantify the severity of PH on echocardiogram [45,47]. In the absence of a TR jet, sPAP can be roughly estimated by septal position [19].

Assessment of right and left ventricular function. Right ventricular dysfunction may be associated with higher mortality [48].

Identification of structural abnormalities – Structural changes secondary to PH may be noted (eg, right ventricular hypertrophy, right atrial enlargement); however, these findings alone lack sufficient sensitivity and specificity to make the diagnosis. In addition, it is important to identify other structural lesions (eg, PDA, ventricular septal defects, and other congenital heart lesions) since these may contribute to PH risk and management decisions.

As a result, infants with shunt lesions may require cardiac catheterization to evaluate for PH and determine the need for a device or surgical closure of the shunt. (See 'Cardiac catheterization' below.)

Pulmonary vein stenosis (PVS) – PVS can evolve over time and should be assessed in infants with severe or worsening PH; the median age of diagnosis is 6.5 months of age [32]. All four pulmonary veins may not be visualized on every echocardiogram. If the echocardiogram is inconclusive, but there remains a strong clinical suspicion for PVS, further evaluation with contrast computed tomography may be warranted [32,49,50].

Echocardiography has the advantage of being noninvasive and therefore does not require anesthesia. It provides an estimate of right ventricular pressure and additional information such as an assessment of ventricular function and identifying structural abnormalities. Its main disadvantage compared with cardiac catheterization is that it is less accurate in measuring PAP. This was illustrated in a retrospective study of 25 children with PH secondary to chronic lung disease (including 17 patients with BPD) who underwent both echocardiography and cardiac catheterization, though not simultaneously [47]. In this study, TR jet velocity could be measured in only 61 percent of infants. When this parameter could be measured, the presence or absence of PH was correctly identified in 80 percent of studies, although echocardiography performed poorly in discriminating between mild and severe PH. Special considerations for preterm infants with BPD are that lung hyperinflation may make echocardiography interpretation challenging and that PVS can be missed.

Cardiac catheterization — Cardiac catheterization provides definitive information about PH and is therefore the gold standard for making the diagnosis but should be used selectively because of its invasive nature. Candidates for catheterization include [43]:

Selected infants in whom the echocardiographic evaluation was unable to determine the severity of PH and for whom the clinical suspicion for severe disease is high.

Infants with severe PH who fail to respond to conservative or single-agent therapy and are candidates for long-term targeted PH pharmacotherapy [14,39,40], especially for those with clinical deterioration and echocardiographic evidence of increasing PH or decreasing ventricular function. In this case, catheterization may help to determine the utility of the pharmacotherapy since some infants with BPD and PH may not respond [51]. Practice varies regarding the use of catheterization for this group of patients: Some centers routinely perform cardiac catheterization before initiating targeted PH pharmacotherapy, whereas others initiate targeted PH monotherapy (eg, sildenafil) without catheterization, based on echocardiographic and clinical data.

Infants with a known or suspected shunt lesion (PDA, ventricular septal defect, or atrial septal defect), in which case, the catheterization can be used to direct therapy. In infants with these shunts, the catheterization helps to distinguish between volume overload (due to the shunt) and pressure overload (due to the PH). In addition, the catheterization provides an opportunity for therapeutic closure of the PDA or atrial septal defect and/or evaluation for surgical closure of the shunt. A significant shunt with volume overload reduces lung compliance and may impede growth and recovery from the PH.

Infants who are being treated with targeted PH pharmacotherapy but are not responding well or are experiencing adverse effects.

Given the risks associated with anesthesia and cardiac catheterization in children with PH, it is strongly recommended that catheterization be performed only in tertiary care centers with experience in treating preterm infants and children with severe PH [6,38].

The goals of cardiac catheterization are to determine the severity of the PH and determine the magnitude of associated structural or functional abnormalities, such as left ventricular diastolic dysfunction, systemic collaterals, PVS, left-sided obstructive lesions, or intracardiac shunts that may be contributing to the PH [38,43]. Cardiac catheterization for evaluation of PH in infants and children is discussed in greater detail separately. The benefits of cardiac catheterization must be weighed against the risks of the procedure, especially since these infants are fragile. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis", section on 'Cardiac catheterization'.)

Other — Noninvasive modalities that have been used to diagnose and evaluate PH in the child with BPD include computed tomography and cardiac magnetic resonance imaging [43,49]. Computed tomography scans or computed tomography angiography may be helpful to assess severity of parenchymal disease and evaluate vascular structures [14,50]. Magnetic resonance imaging is not widely used but may be used to help assess morphology and function, including septal curvature and pulmonary artery size, and to identify contributors to the PH, including PVS [52,53].

DIAGNOSIS — In an infant with BPD, a presumptive diagnosis of PH can be established on the basis of echocardiography showing quantitatively or qualitatively elevated right ventricular pressure, as described above (algorithm 1) (see 'Echocardiography' above). Definitive diagnosis of PH requires cardiac catheterization. However, because this test is invasive, it is often used selectively (see 'Cardiac catheterization' above). The diagnosis of PH is confirmed if mean pulmonary artery pressure (PAP) is ≥20 mmHg. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis", section on 'Diagnosis'.)

REFERRALS — Infants with BPD and PH should be managed by a multidisciplinary team that includes intensivists (neonatologists and/or pediatric intensivists) and specialists in BPD (typically, a pulmonologist or neonatologist) and PH (typically, a pulmonologist or cardiologist) [40]. In particular, a PH specialist should ideally be involved before initiating targeted PH pharmacotherapy.

MANAGEMENT — The main goals of management of PH in infants with BPD are to optimize treatment of the chronic lung disease to improve gas exchange, avoid hypoxic vasoconstriction, prevent further lung injury, and optimize lung growth.

Supportive medical therapy — Many patients with mild or moderate BPD-associated PH can be managed with supportive medical therapy alone (algorithm 1). This includes:

Use of supplemental oxygen as needed to maintain oxygen saturations between 92 and 95 percent to maximize lung growth and reduce pulmonary artery pressure (PAP) [38-40,54]. Although there are no specific data for management of PH in the setting of retinopathy of prematurity, target saturations may be needed to adjust for infants with immature retinal vasculature to minimize risk for retinopathy of prematurity. (See "Complications and long-term pulmonary outcomes of bronchopulmonary dysplasia", section on 'Oxygen therapy' and "Neonatal target oxygen levels for preterm infants".)

For infants who require respiratory support, use of strategies to minimize barotrauma. (See "Bronchopulmonary dysplasia (BPD): Management and outcome", section on 'Mechanical ventilation'.)

Other measures to maximize lung growth, including adequate nutrition and avoidance of respiratory infection and aspiration. (See "Complications and long-term pulmonary outcomes of bronchopulmonary dysplasia", section on 'General measures'.)

Diagnosis and management of underlying cardiovascular or upper airway defects [39].

Vigilance for situations in which life-threatening PH crises may occur, specifically with acute respiratory infections or the induction of or emergence from anesthesia [3,55]. (See 'Acute pulmonary hypertension crisis' below.)

The general principles are similar to those for infants and children with other forms of PH (eg, familial PH, idiopathic PH, PH associated with congenital heart disease) and are discussed in a separate topic review. (See "Pulmonary hypertension in children: Management and prognosis", section on 'Supportive medical therapy'.)

Acute pulmonary hypertension crisis — Acute PH crisis is a potentially fatal complication of PH. It is characterized by a rapid rise in pulmonary vascular resistance leading to acute right heart failure, and inadequate cardiac output. Acute PH crisis can be triggered by multiple causes including surgery/anesthesia (eg, for cardiac catheterization), acute lung disease (eg, pneumonia and/or viral infections), fever, hypoxia, or hypovolemia. Transient acute crises with hypoxemia also may be triggered by defecation or breath-holding (with associated acute hypoventilation). Avoiding these triggers is an important component of PH management. An acute PH crisis may resolve with treatment of the triggering event and is not necessarily an indication for a change in targeted PH pharmacotherapy.

An anesthesiology consult should be obtained prior to any surgery or anesthesia in an infant or child with BPD with a history of PH since these children are at risk for a PH crisis and death during any anesthetic procedure [5,38].

Inhaled nitric oxide (iNO) is often used for treatment of acute PH crises [39,40]. It is weaned after stabilization, often by transitioning to a long-term medication such as sildenafil. (See 'Targeted pulmonary hypertension pharmacotherapy' below.)

Targeted pulmonary hypertension pharmacotherapy — For sustained moderate or severe BPD-associated PH that does not respond to the above measures, targeted PH pharmacotherapy can be considered (algorithm 1). The use of these drugs in this population is not well studied. There are no published trials that formally examine the effect of PH-specific therapies on infants or children with BPD [9]. Infants who are candidates for pharmacotherapy should only be managed by a team with special expertise in this disorder since management decisions may be complex. As an example, targeted PH therapy may be detrimental in patients with certain cardiovascular anomalies (eg, pulmonary veno-occlusive disease, left ventricular dysfunction, large intracardiac shunts, or collateral vessels) [56].

Sildenafil is the agent used most commonly to treat BPD-associated PH (table 2) [57,58]. Sildenafil is an enterally administered selective type 5 phosphodiesterase (PDE5) inhibitor. Evidence supporting the efficacy of sildenafil for treatment of BPD-associated PH is limited to small, uncontrolled, retrospective, single-center studies that demonstrated improvements in respiratory requirements and echocardiographic markers of PH [59-62]. Indirect evidence comes from clinical trials in children with other forms of PH (eg, familial, idiopathic, or congenital heart disease-associated PH) [63,64]. This is discussed in greater detail separately. (See "Pulmonary hypertension in children: Management and prognosis", section on 'Phosphodiesterase type 5 inhibitors'.)

Adverse events reported in studies of sildenafil in infants with BPD include transient hypotension, episodes of hypoxemia secondary to ventilation-perfusion mismatch, and recurrent priapism [59,60]. Concerns have been raised about the safety of sildenafil in children, but an emerging consensus supports its use in carefully selected infants and children with PH, with close monitoring [65,66]. In some centers, tadalafil is used, but there are no published data for its use in this clinical context.

Other drugs that may be useful for management of PH associated with BPD include bosentan, inhaled iloprost, intravenous epoprostenol, and treprostinil [67].

Pharmacologic management is similar to that for infants with other types of PH, except that calcium channel blockers are rarely used in the BPD population because of increased risks in young infants and acute vasoreactivity testing (outside of a cardiac catheterization procedure) is not used to determine medication selection. A detailed discussion of these drugs is beyond the scope of this topic, but their use in other forms of pediatric PH is discussed separately. (See "Pulmonary hypertension in children: Management and prognosis", section on 'Targeted pulmonary hypertension therapy'.)

Monitoring — If PH is diagnosed, we suggest monthly follow-up echocardiograms until the abnormal findings normalize or stabilize [10,42]. More frequent follow-up echocardiograms should also be considered in children with BPD and a history of PH who experience an acute and persistent pulmonary exacerbation or those treated with PH-directed pharmacotherapy. Although studies are limited, serial measurements of serum brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) may also be used to monitor the patient's clinical course and response to treatment. The relative benefit of measuring BNP versus NT-proBNP is unclear [68].

Management after hospital discharge

Follow-up — Follow-up after hospital discharge will generally involve outpatient visits to a respiratory specialist (often a pulmonologist or neonatologist) for management of BPD, with the goal of optimizing ongoing lung growth and development, and avoiding triggers that may worsen the BPD or cause an acute PH crisis. Patients with significant PH should also be seen by a PH specialist (often a cardiologist or pulmonologist) and be evaluated by serial echocardiograms to facilitate weaning and management of pharmaceutical agents. Weaning of PH therapies should be undertaken by the PH specialist.

Expert follow-up is particularly important during the first few months after discharge and during respiratory viral season. All measures should be taken to prevent respiratory infection, including:

Avoidance of exposure

Prophylaxis against respiratory syncytial virus (RSV) (See "Respiratory syncytial virus infection: Prevention in infants and children".)

Immunizations against influenza, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and pneumococcus (following guidelines for high-risk patients). (See "Seasonal influenza in children: Prevention with vaccines" and "Pneumococcal vaccination in children".)

If the patient has an acute deterioration of cardiorespiratory function, the possibility of an acute PH crisis should be considered; evaluation may include echocardiogram, BNP, or NT-proBNP. Triggers for an acute PH crisis or worsening of previously resolved PH include anesthesia and acute respiratory infections. Elective procedures requiring anesthesia should be postponed until the PH has completely resolved, if possible.

Respiratory support — Respiratory support of infants with BPD and PH may range from none (room air only), to supplemental oxygen, to home mechanical ventilation. In general, respiratory support is not weaned until the patient has been successfully weaned off of PH medications, and the PH has resolved or is markedly improved, because hypoxia is a pulmonary vasoconstrictor. When weaning respiratory support, serial echocardiograms may be helpful to monitor for recurrence of PH.

Environment — Any environmental exposures that could worsen PH or lung disease should be avoided, such as aspiration, secondhand smoke, secondhand vape exposure, and exposure to infections. Immunoprophylaxis for respiratory syncytial virus, SARS-CoV-2, and influenza is strongly recommended. Environments with higher infection risks, such as daycare, should be limited if possible.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bronchopulmonary dysplasia" and "Society guideline links: Congenital heart disease in infants and children" and "Society guideline links: Pulmonary hypertension in children".)

SUMMARY AND RECOMMENDATIONS

Epidemiology and natural history – Between 20 and 40 percent of infants with bronchopulmonary dysplasia (BPD) develop pulmonary hypertension (PH) at some point during their initial hospital course. Infants surviving the initial stages of PH often experience improvement or resolution of the PH due to catch-up lung growth and development. Nonetheless, PH is an important risk factor for morbidity and mortality in this population. (See 'Epidemiology and natural history' above.)

Risk factors – The risk for PH is highest in very premature and very low birth weight infants, as well as those with cardiovascular anomalies. The risk is also related to the severity of BPD, prolonged mechanical ventilation, and oxygen therapy. (See 'Risk factors' above.)

Screening – All infants with moderate or severe BPD should be screened for PH using echocardiography. For most infants, the initial echocardiogram should be performed at the time that the formal diagnosis of BPD is made, which is typically at 36 weeks postmenstrual age or at the time of hospital discharge, whichever comes first. Earlier screening should be performed for selected infants with symptoms or important risk factors for PH, such as need for ventilator support at one week of age or recurrent or severe hypoxemia (algorithm 1). (See 'Screening' above.)

Diagnosis – A presumptive diagnosis of PH can be established on the basis of echocardiography showing quantitatively or qualitatively elevated right ventricular pressure. Definitive diagnosis of PH requires cardiac catheterization. However, because this test is invasive and carries anesthesia risks, it is used selectively. (See 'Diagnosis' above and 'Cardiac catheterization' above.)

Management

Supportive therapy – The main goals of management of PH in infants with BPD are to optimize treatment of the chronic lung disease to improve gas exchange, avoid hypoxic pulmonary vasoconstriction, prevent further lung injury, and optimize lung growth. Many patients with BPD-associated PH can be managed with supportive medical therapy alone, including supplemental oxygen to maintain oxygen saturations between 92 and 95 percent, and diagnosis and management of underlying cardiovascular or upper airway defects. (See 'Supportive medical therapy' above.)

Acute PH crises – Life-threatening PH crises may be triggered by acute respiratory infections or by general anesthesia. An anesthesia consult should be obtained prior to any surgery or anesthesia in an infant or child with BPD with a history of PH. (See 'Acute pulmonary hypertension crisis' above.)

Targeted pharmacotherapy – Infants with sustained moderate or severe BPD-associated PH that does not respond to medical management are candidates for targeted PH pharmacotherapy, most commonly with sildenafil (table 2). PH-directed pharmacotherapy should only be managed by a team with special expertise in this disorder since these drugs are frequently used off-label, may have some serious adverse effects, and may be detrimental in patients with certain cardiovascular anomalies. (See 'Targeted pulmonary hypertension pharmacotherapy' above.)

  1. Kim DH, Kim HS, Choi CW, et al. Risk factors for pulmonary artery hypertension in preterm infants with moderate or severe bronchopulmonary dysplasia. Neonatology 2012; 101:40.
  2. An HS, Bae EJ, Kim GB, et al. Pulmonary hypertension in preterm infants with bronchopulmonary dysplasia. Korean Circ J 2010; 40:131.
  3. Farquhar M, Fitzgerald DA. Pulmonary hypertension in chronic neonatal lung disease. Paediatr Respir Rev 2010; 11:149.
  4. Stuart BD, Sekar P, Coulson JD, et al. Health-care utilization and respiratory morbidities in preterm infants with pulmonary hypertension. J Perinatol 2013; 33:543.
  5. Sanabria-Carretero P, Ochoa-Osorio C, Martín-Vega A, et al. [Anesthesia-related cardiac arrest in children. Data from a tertiary referral hospital registry]. Rev Esp Anestesiol Reanim 2013; 60:424.
  6. Bernier ML, Jacob AI, Collaco JM, et al. Perioperative events in children with pulmonary hypertension undergoing non-cardiac procedures. Pulm Circ 2018; 8:2045893217738143.
  7. Higgins RD, Jobe AH, Koso-Thomas M, et al. Bronchopulmonary Dysplasia: Executive Summary of a Workshop. J Pediatr 2018; 197:300.
  8. Jensen EA, Dysart K, Gantz MG, et al. The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based Approach. Am J Respir Crit Care Med 2019; 200:751.
  9. Rosenzweig EB, Abman SH, Adatia I, et al. Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management. Eur Respir J 2019; 53.
  10. Abman SH, Hansmann G, Archer SL, et al. Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation 2015; 132:2037.
  11. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019; 53.
  12. Slaughter JL, Pakrashi T, Jones DE, et al. Echocardiographic detection of pulmonary hypertension in extremely low birth weight infants with bronchopulmonary dysplasia requiring prolonged positive pressure ventilation. J Perinatol 2011; 31:635.
  13. Check J, Gotteiner N, Liu X, et al. Fetal growth restriction and pulmonary hypertension in premature infants with bronchopulmonary dysplasia. J Perinatol 2013; 33:553.
  14. Malloy KW, Austin ED. Pulmonary hypertension in the child with bronchopulmonary dysplasia. Pediatr Pulmonol 2021; 56:3546.
  15. Bhat R, Salas AA, Foster C, et al. Prospective analysis of pulmonary hypertension in extremely low birth weight infants. Pediatrics 2012; 129:e682.
  16. Ong MS, Abman S, Austin ED, et al. Racial and Ethnic Differences in Pediatric Pulmonary Hypertension: An Analysis of the Pediatric Pulmonary Hypertension Network Registry. J Pediatr 2019; 211:63.
  17. Tomashefski JF Jr, Oppermann HC, Vawter GF, Reid LM. Bronchopulmonary dysplasia: a morphometric study with emphasis on the pulmonary vasculature. Pediatr Pathol 1984; 2:469.
  18. Subhedar NV, Shaw NJ. Changes in pulmonary arterial pressure in preterm infants with chronic lung disease. Arch Dis Child Fetal Neonatal Ed 2000; 82:F243.
  19. Khemani E, McElhinney DB, Rhein L, et al. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics 2007; 120:1260.
  20. Kumar VH, Hutchison AA, Lakshminrusimha S, et al. Characteristics of pulmonary hypertension in preterm neonates. J Perinatol 2007; 27:214.
  21. Mourani PM, Sontag MK, Younoszai A, et al. Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med 2015; 191:87.
  22. Abman SH, Mullen MP, Sleeper LA, et al. Characterisation of paediatric pulmonary hypertensive vascular disease from the PPHNet Registry. Eur Respir J 2022; 59.
  23. Korhonen P, Hyödynmaa E, Lautamatti V, et al. Cardiovascular findings in very low birthweight schoolchildren with and without bronchopulmonary dysplasia. Early Hum Dev 2005; 81:497.
  24. Joshi S, Wilson DG, Kotecha S, et al. Cardiovascular function in children who had chronic lung disease of prematurity. Arch Dis Child Fetal Neonatal Ed 2014; 99:F373.
  25. Kwon HW, Kim HS, An HS, et al. Long-Term Outcomes of Pulmonary Hypertension in Preterm Infants with Bronchopulmonary Dysplasia. Neonatology 2016; 110:181.
  26. Goss KN, Beshish AG, Barton GP, et al. Early Pulmonary Vascular Disease in Young Adults Born Preterm. Am J Respir Crit Care Med 2018; 198:1549.
  27. Ivy DD, Abman SH, Barst RJ, et al. Pediatric pulmonary hypertension. J Am Coll Cardiol 2013; 62:D117.
  28. Abman SH. The dysmorphic pulmonary circulation in bronchopulmonary dysplasia: a growing story. Am J Respir Crit Care Med 2008; 178:114.
  29. Kinsella JP, Abman SH. Inhaled nitric oxide in the premature newborn. J Pediatr 2007; 151:10.
  30. Balasubramaniam V, Mervis CF, Maxey AM, et al. Hyperoxia reduces bone marrow, circulating, and lung endothelial progenitor cells in the developing lung: implications for the pathogenesis of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2007; 292:L1073.
  31. Mourani PM, Ivy DD, Rosenberg AA, et al. Left ventricular diastolic dysfunction in bronchopulmonary dysplasia. J Pediatr 2008; 152:291.
  32. Mahgoub L, Kaddoura T, Kameny AR, et al. Pulmonary vein stenosis of ex-premature infants with pulmonary hypertension and bronchopulmonary dysplasia, epidemiology, and survival from a multicenter cohort. Pediatr Pulmonol 2017; 52:1063.
  33. Drossner DM, Kim DW, Maher KO, Mahle WT. Pulmonary vein stenosis: prematurity and associated conditions. Pediatrics 2008; 122:e656.
  34. Laux D, Rocchisani MA, Boudjemline Y, et al. Pulmonary Hypertension in the Preterm Infant with Chronic Lung Disease can be Caused by Pulmonary Vein Stenosis: A Must-Know Entity. Pediatr Cardiol 2016; 37:313.
  35. Heching HJ, Turner M, Farkouh-Karoleski C, Krishnan U. Pulmonary vein stenosis and necrotising enterocolitis: is there a possible link with necrotising enterocolitis? Arch Dis Child Fetal Neonatal Ed 2014; 99:F282.
  36. del Cerro MJ, Sabaté Rotés A, Cartón A, et al. Pulmonary hypertension in bronchopulmonary dysplasia: clinical findings, cardiovascular anomalies and outcomes. Pediatr Pulmonol 2014; 49:49.
  37. Cerro MJ, Abman S, Diaz G, et al. A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011. Pulm Circ 2011; 1:286.
  38. Collaco JM, Romer LH, Stuart BD, et al. Frontiers in pulmonary hypertension in infants and children with bronchopulmonary dysplasia. Pediatr Pulmonol 2012; 47:1042.
  39. Krishnan U, Feinstein JA, Adatia I, et al. Evaluation and Management of Pulmonary Hypertension in Children with Bronchopulmonary Dysplasia. J Pediatr 2017; 188:24.
  40. Abman SH, Collaco JM, Shepherd EG, et al. Interdisciplinary Care of Children with Severe Bronchopulmonary Dysplasia. J Pediatr 2017; 181:12.
  41. Pérez-Tarazona S, Marset G, Part M, et al. Definitions of Bronchopulmonary Dysplasia: Which One Should We Use? J Pediatr 2022; 251:67.
  42. Abman SH. Monitoring cardiovascular function in infants with chronic lung disease of prematurity. Arch Dis Child Fetal Neonatal Ed 2002; 87:F15.
  43. Levy PT, Jain A, Nawaytou H, et al. Risk Assessment and Monitoring of Chronic Pulmonary Hypertension in Premature Infants. J Pediatr 2020; 217:199.
  44. Carlton EF, Sontag MK, Younoszai A, et al. Reliability of Echocardiographic Indicators of Pulmonary Vascular Disease in Preterm Infants at Risk for Bronchopulmonary Dysplasia. J Pediatr 2017; 186:29.
  45. Nagiub M, Lee S, Guglani L. Echocardiographic assessment of pulmonary hypertension in infants with bronchopulmonary dysplasia: systematic review of literature and a proposed algorithm for assessment. Echocardiography 2015; 32:819.
  46. Benatar A, Clarke J, Silverman M. Pulmonary hypertension in infants with chronic lung disease: non-invasive evaluation and short term effect of oxygen treatment. Arch Dis Child Fetal Neonatal Ed 1995; 72:F14.
  47. Mourani PM, Sontag MK, Younoszai A, et al. Clinical utility of echocardiography for the diagnosis and management of pulmonary vascular disease in young children with chronic lung disease. Pediatrics 2008; 121:317.
  48. Altit G, Bhombal S, Feinstein J, et al. Diminished right ventricular function at diagnosis of pulmonary hypertension is associated with mortality in bronchopulmonary dysplasia. Pulm Circ 2019; 9:2045894019878598.
  49. Latus H, Kuehne T, Beerbaum P, et al. Cardiac MR and CT imaging in children with suspected or confirmed pulmonary hypertension/pulmonary hypertensive 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; 102 Suppl 2:ii30.
  50. O'Callaghan B, Zablah JE, Weinman JP, et al. Computed tomographic parenchymal lung findings in premature infants with pulmonary vein stenosis. Pediatr Radiol 2023; 53:1874.
  51. Kumar VHS. Diagnostic Approach to Pulmonary Hypertension in Premature Neonates. Children (Basel) 2017; 4.
  52. Critser PJ, Higano NS, Tkach JA, et al. Cardiac Magnetic Resonance Imaging Evaluation of Neonatal Bronchopulmonary Dysplasia-associated Pulmonary Hypertension. Am J Respir Crit Care Med 2020; 201:73.
  53. Critser PJ, Higano NS, Lang SM, et al. Cardiovascular magnetic resonance imaging derived septal curvature in neonates with bronchopulmonary dysplasia associated pulmonary hypertension. J Cardiovasc Magn Reson 2020; 22:50.
  54. Allen J, Zwerdling R, Ehrenkranz R, et al. Statement on the care of the child with chronic lung disease of infancy and childhood. Am J Respir Crit Care Med 2003; 168:356.
  55. Carmosino MJ, Friesen RH, Doran A, Ivy DD. Perioperative complications in children with pulmonary hypertension undergoing noncardiac surgery or cardiac catheterization. Anesth Analg 2007; 104:521.
  56. Baker CD, Abman SH, Mourani PM. Pulmonary Hypertension in Preterm Infants with Bronchopulmonary Dysplasia. Pediatr Allergy Immunol Pulmonol 2014; 27:8.
  57. Wardle AJ, Wardle R, Luyt K, Tulloh R. The utility of sildenafil in pulmonary hypertension: a focus on bronchopulmonary dysplasia. Arch Dis Child 2013; 98:613.
  58. Backes CH, Reagan PB, Smith CV, et al. Sildenafil Treatment of Infants With Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension. Hosp Pediatr 2016; 6:27.
  59. Mourani PM, Sontag MK, Ivy DD, Abman SH. Effects of long-term sildenafil treatment for pulmonary hypertension in infants with chronic lung disease. J Pediatr 2009; 154:379.
  60. Trottier-Boucher MN, Lapointe A, Malo J, et al. Sildenafil for the Treatment of Pulmonary Arterial Hypertension in Infants with Bronchopulmonary Dysplasia. Pediatr Cardiol 2015; 36:1255.
  61. Tan K, Krishnamurthy MB, O'Heney JL, et al. Sildenafil therapy in bronchopulmonary dysplasia-associated pulmonary hypertension: a retrospective study of efficacy and safety. Eur J Pediatr 2015; 174:1109.
  62. Kadmon G, Schiller O, Dagan T, et al. Pulmonary hypertension specific treatment in infants with bronchopulmonary dysplasia. Pediatr Pulmonol 2017; 52:77.
  63. Barst RJ, Ivy DD, Gaitan G, et al. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation 2012; 125:324.
  64. Barst RJ, Beghetti M, Pulido T, et al. STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension. Circulation 2014; 129:1914.
  65. Abman SH, Kinsella JP, Rosenzweig EB, et al. Implications of the U.S. Food and Drug Administration warning against the use of sildenafil for the treatment of pediatric pulmonary hypertension. Am J Respir Crit Care Med 2013; 187:572.
  66. European Medicines Agency. Assessment report for Revatio. International non-proprietary name: sildenafil. Procedure No. EMEA/H/C/000638/II/0028. London, UK: European Medicines Agency; 2011. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000638/WC500107804.pdf (Accessed on June 27, 2014).
  67. Krishnan U, Krishnan S, Gewitz M. Treatment of pulmonary hypertension in children with chronic lung disease with newer oral therapies. Pediatr Cardiol 2008; 29:1082.
  68. Xiong T, Kulkarni M, Gokulakrishnan G, et al. Natriuretic peptides in bronchopulmonary dysplasia: a systematic review. J Perinatol 2020; 40:607.
Topic 115896 Version 16.0

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