Introduction

Pulmonary hypertension is a physiologic state in which elevated pulmonary vascular pressures cause poor pulmonary blood flow and right ventricular dysfunction leading to gas-exchange problems and abnormal hemodynamics.

Pulmonary hypertension is defined as a resting mean pulmonary artery pressure greater than or equal to 25 mm Hg [1]. While the transpulmonary gradient (pulmonary artery pressure minus left atrial pressure divided by the pulmonary blood flow) measured during cardiac catheterization is the gold standard for precisely measuring pulmonary vascular resistance, bedside echocardiography is the most important tool to detect pulmonary hypertension. Indeed, it is an excellent noninvasive method that provides information on right ventricular hemodynamics (both in systole and diastole) and anatomy that facilitates reliable surveillance. From a practical perspective, right ventricular pressures greater than 50% of systolic blood pressures (in the absence of pre-existing pulmonary disease), a tricuspid valve jet (in patients with tricuspid regurgitation) and right to left shunting across a patent foramen ovale or ductus arteriosus are also indicative of clinically significant pulmonary hypertension.

Content in this topic is referenced in SCORE Pulmonary Hypoplasia/Hypertension

Epidemiology

The true incidence of pulmonary hypertension is poorly defined in the western population but patient registries will hopefully identify the incidence and prevalence of the disease.

The true incidence of pulmonary hypertension is not clearly defined. In the Netherlands, persistent pulmonary hypertension of the newborn (PPHN), defined as the failure of the transition from fetal to normal circulation, was noted to occur with an incidence of 30.1 per million children, while the incidence of all pulmonary hypertension (including congenital heart disease and pulmonary hypertension in older children) was 63.7 per million [2]. The incidence of PPHN in the United States has been estimated to range between 0.43 and 6.82 per thousand (average 1.9 per thousand) in live born neonates admitted to a neonatal intensive care unit[3]. The Pediatric Pulmonary Hypertension Network (PPHNet) aims to capture pediatric pulmonary hypertension patients in the United States and Canada (PPHnet).

Basic Science

The circulation of blood in the fetus is fundamentally different from that of an infant. The change in circulation from in utero to ex utero is termed the transitional circulation. Abnormalities in transitional circulation can lead to pulmonary hypertension.

What is the transitional circulation of the neonate?

The circulation in the newborn undergoes rapid changes as the baby transitions from a liquid in utero environment to an air-filled environment after birth. The reduction in pulmonary vascular resistance (normally high in utero) and the absence of placental blood flow results in an increase in pulmonary blood flow in the infant. Indeed, only 10 to 15% of the cardiac output from the right ventricle reaches the lungs in utero. However, after the first few breaths of air, the majority of cardiac output from the right heart flows through the lower resistance pulmonary circulation [4].

The pulmonary vascular resistance is normally high in utero as a result of low oxygen tension and the reduced production of endogenous pulmonary vasodilators such as nitric oxide (NO) and prostacyclin (PGI₂). However, NO and PGI₂ production increase in the late third trimester in preparation for a need to increase pulmonary blood flow. Upon the first breath and cessation of umbilical blood flow the infant must make rapid changes to adapt to the air filled ex utero environment. Fetal lung fluid is absorbed or expelled which decreases the compression on the alveolar capillary beds. At the same time, oxygen rich air enters the newborn lung and promotes pulmonary vasodilation [5]. The foramen ovale also closes as left heart pressures increase and the ductus arteriosus begins to obliterate in response to increased oxygen tension. The normal pulmonary vascular bed is a low resistance, high capacitance system. Moreover, the pulmonary blood vessels are normally extremely elastic and minimally muscularized which allows for significant increases in pulmonary blood flow without increasing pulmonary pressures.

When does fetal circulation change to normal circulation?

In an otherwise healthy infant, the anatomic changes in the transitional circulation generally occur within the first few days of life. Intra- and extracardiac shunts may remain open for longer periods of time in premature infants. Pulmonary vascular pressures do not reach normal levels until 4-6 weeks of life despite decreasing significantly immediately after birth [5].

Pathophysiology

Major factors increasing pulmonary artery pressures and pulmonary vascular resistance include abnormally muscularized arterioles, decreased capillary bed cross sectional area, abnormal hemodynamics and poorly recruited lungs.

The key components leading to pulmonary hypertension include:

• hyperreactive pulmonary vessels that lead to abnormal vasoconstriction
• highly muscularized arterioles in which the smooth muscle extends into the intra-acinar pulmonary arterioles
• lung hypoplasia (i.e. less vascular cross-sectional area) [6]

Multiple factors affect pulmonary vascular resistance (PVR). These include:

• abnormal transitional changes to the pulmonary vasculature
• altered hemodynamics and pulmonary blood flow
• lung volume and recruitment
• pulmonary vascular smooth muscle tone
• the endothelium
• alveolar/arteriolar development

Abnormal transitional changes
Abnormal transitional changes occur due to several mechanisms including fetal hypoxia, maternal toxic exposure and lung development problems. The intrauterine stress leads to abnormal muscularization in the intra-acinar pulmonary arterioles. These smooth muscle cells not only decrease pulmonary arteriolar diameter but also increase the tendency towards hyper-responsiveness. Both of these factors can lead to increased pulmonary vascular resistance.

Hemodynamics and pulmonary blood flow
The right ventricle is sensitive to changes in afterload and since it is morphologically conditioned to pump blood within a low resistance circuit (through the patent foramen ovale and ductus arteriosus prenatally or through the pulmonary vascular bed postnatally). In severe pulmonary hypertension with a dilated and failing right ventricle, prostaglandin has been used to keep the ductus arteriosus open so that right ventricular function and blood pressure are preserved at the expense of oxygen saturation.

Left ventricular dysfunction in the context of hypoxia may complicate the management of pulmonary hypertension as this produces pulmonary venous hypertension and pulmonary edema (i.e. increased left atrial pressure). The addition of a pulmonary vasodilator like inhaled nitric oxide (iNO) in this context will only exacerbate hypoxia as pulmonary arterial dilation will lead to increased edema. Inotropic medications can help improve ventricular function as well as more effective pulmonary blood flow. Increased pulmonary blood flow will act to recruit poorly perfused arterioles thereby reducing PVR.

Lung volumes and recruitment
Alveolar overdistention with high positive end-expiratory pressure causes compression of the pulmonary capillaries and increases vascular resistance. Conversely, under-inflated alveoli will distort capillaries and prevent effective blood flow leading to increased PVR. Thus, ventilating at the functional residual capacity provides optimal lung volumes without increasing PVR.

Pulmonary vascular tone
The normal response to hypoxia is pulmonary vascular vasoconstriction. This response is mediated by intracellular calcium ion release and is necessary to maintain appropriate ventilation/perfusion (V/Q) matching. In conditions that lead to significant hypoxia, like pneumonia or meconium aspiration, significant increases in PVR will occur. It appears that airway hypoxia is a stronger stimulant for pulmonary vascular vasoconstriction than pulmonary vascular hypoxemia.

Pulmonary vascular endothelium
It is becoming increasingly clear that the pulmonary vascular endothelium plays a vital role in controlling PVR. For example, derangement in nitric oxide synthesis has been identified in some newborns with pulmonary hypertension. Upregulated endothelin-1 (ET-1) levels, a potent vasoconstrictor, have also been found in patients with pulmonary hypertension. Patients with pulmonary hypertension also have up regulation of reactive oxygen species that inactivate nitric oxide which results in vasoconstriction. As such, the pulmonary vascular endothelium has become the preferred target for intervention in moderate to severe pulmonary hypertension[6].

Pulmonary hypoplasia
Hypoplastic lungs are physically small, but also differ histologically from the normal lung with decreased airway branching, fewer alveoli, thicker air-blood interfaces, and a reduced vascular cross-sectional area. In addition, hypoplastic lungs tend to have altered surfactant production, elastin content and epithelial maturation. All of these factors can predispose to the development of pulmonary hypertension [4].

Prenatal causes of pulmonary hypertension include congenital heart disease, congenital diaphragmatic hernia, oligohydramnios, maternal drug exposure [medications that cause antenatal closure of the ductus arteriosus (e.g. aspirin and NSAIDS) and selective serotonin reuptake inhibitors (SSRIs)] and other conditions leading to pulmonary vascular smooth muscle hypertrophy and/or pulmonary hypoplasia. Several other prenatal factors can increase the risk of persistent pulmonary hypertension of the newborn (PPHN) including maternal tobacco smoke, placenta previa and abruption, premature rupture of membranes, oligohydramnios, chronic intrauterine hypoxia and pregnancy-induced hypertension [6].

Postnatal causes of pulmonary hypertension include prematurity, meconium aspiration syndrome, polycythemia (increased blood viscosity), neonatal sepsis, perinatal asphyxia (uncommon), congenital lung lesions (uncommon), omphalocele, surfactant deficiency (respiratory distress syndrome), transient tachypnea of the newborn, and bronchopulmonary dysplasia [5][6].

In otherwise healthy adolescents, undiagnosed ventricular septal defects can lead to severe, late manifestations of Eisenmenger’s complex. Infections such as bacterial or viral pneumonia can also lead to pulmonary hypertension. Chronic thromboembolic disease can become complicated by progressive pulmonary hypertension [1][5].

What biochemical deficiencies are present with common causes of pulmonary hypertension?

Surfactant deficiency has been demonstrated in patients with congenital diaphragmatic hernia and in premature infants with the respiratory distress syndrome. In the meconium aspiration syndrome, surfactant is inactivated by meconium and pulmonary edema fluid that accumulates secondary to alveolar injury. Deficiencies in nitric oxide as well as increases in ET-1 levels have been identified in infants with pulmonary hypertension.

Prevention

Prenatal factors that may decrease pulmonary hypertension include improving lung growth (e.g. treating oligohydramnios, tracheal occlusion for congenital diaphragmatic hernia), decompressing space occupying lesions of the chest (e.g. drain for macrocystic congenital lung lesion), preventing vertically transmitted infections and avoiding meconium aspiration syndrome.

Modifiable prenatal factors include avoidance of certain medications during pregnancy and controlling pregnancy-induced hypertension. In patients with oligohydramnios or space occupying lesions in the chest, amnioinfusion or decompression of the lesion may reduce lung compression and improve lung growth, respectively. Moreover, there is emerging evidence that fetal tracheal occlusion may help to mitigate the consequences of severe pulmonary hypoplasia observed in severe congenital diaphragmatic hernia by promoting lung growth and development.

Decreasing the rate of vertically transmitted infections and neonatal sepsis will also decrease the incidence of persistent pulmonary hypertension of the newborn as this is one of the most common postnatal causes of pulmonary hypertension. Furthermore, the prevention of meconium aspiration with improved suctioning to prevent its migration into small air spaces improves respiratory function and prevents the inactivation of surfactant that can lead to pulmonary hypertension.

Presentation

The signs and symptoms of pulmonary hypertension include hypoxia, right ventricular strain, increased intra- and extracardiac shunting, hypercarbia and poor left ventricular preload leading to hypotension.

The clinical features of pulmonary hypertension include hypoxia, right ventricle strain, increased intra- and extracardiac shunting, hypercarbia and decreased left ventricular preload resulting in hypotension. The presence of these conditions is dictated by the severity of the pulmonary hypertension.

Classical descriptions of patients with persistent pulmonary hypertension of the newborn describe significant hypoxia in the absence of significant radiographic signs of lung disease or congenital heart disease. These patients have a pre/post ductal oxygen saturation difference of greater than five percent that improves with supplemental oxygen administration (indicating a reactive pulmonary vascular bed).

The chest radiograph demonstrates slight hyperinflation and in severe pulmonary hypertension will demonstrate a paucity of vascular markings due to diminished pulmonary blood flow. Echocardiographic evaluation will demonstrate an absence of congenital heart anomalies, a right to left (or bidirectional) shunt through the patent foramen ovale or ductus arteriosus, right ventricular strain, tricuspid regurgitant jets, and a straight or left bowed ventricular septum.

This physiology leads to hypoxemia, hypercarbia (depending on the degree of shunting) and, in cases of associated left ventricular dysfunction, systemic hypotension.

Adolescents with suspected pulmonary hypertension will typically have an associated condition such as pneumonia with associated hypoxia, evidence of right heart strain on electrocardiogram, a prominent right heart on chest radiographs and echocardiographic findings of right ventricular dilatation.

Assessment

The assessment of pulmonary hypertension includes measurement of pre- and postductal oxygen saturation, blood gas analysis, chest radiograph, echocardiogram and right heart catheterization.

The clinical manifestations of pulmonary hypertension will dictate the measures used to assess pulmonary hypertension. It is important to note that oxygen desaturation, differential saturations (right upper versus lower extremity) and profound hypoxemia are not specific to pulmonary hypertension. Chest radiographs are useful to address acute pulmonary causes of oxygen desaturation and hypoxia such as pneumonia or other infections. An ECG demonstrating right heart strain may also be useful.

While its non-invasive nature and portability make an echocardiogram (echo) invaluable, it does come with several limitations. For example, pulmonary vascular pressures are measured indirectly by extrapolating flow and regurgitation through the tricuspid valve, flattening of the ventricular septum and the directionality of the shunt through the ductus arteriosus. Recent evidence suggests that echocardiographic measurements in children should interpreted differently than the same measurements obtained in adults. For example, the inferior vena cava (IVC) compressibility index and the hepatic vein systolic filling fraction (SFF) are useful in determining adult (> 23 yo) right atrial pressures but they do not correlate well in younger patients (< 23 yo). For younger patients, the right atrial volume and IVC maximum diameter (long axis measurement) provides the highest correlation with right atrial pressures.[7] Laboratory data suggestive of right heart strain include an elevated B-natriuretic peptide - especially if there is concomitant heart failure.

Invasive measures include central venous pressure measurements (indicating elevated right atrial pressures) and right heart catheterization, which is the gold standard investigation for the measurement of elevated pulmonary vascular resistance. Cardiac catheterization may be required in adolescents to accurately assess right heart pressures and pulmonary vascular resistance. Other noninvasive modalities such as computerized tomographhy (CT) or magnetic resonance imaging may be helpful in diagnosing the etiology of pulmonary hypertension. A condition called chronic thromboembolic pulmonary hypertension can be diagnosed by contrast CT scan. This is an important entity to distinguish from idiopathic pulmonary hypertension (PHTN) as both can lead to increased pulmonary vascular resistance. In certain situations such as exercise, anemia, pregnancy and sepsis, the PHTN is a result of increased pulmonary blood flow. Elevated pulmonary vascular resistance only occurs with the higher transpulmonary gradients as described above (high pulmonary vascular tone, abnormal endothelium, poorly recruited lungs, and poorly developed alveoli etc.).

Medical Treatment

The medical therapy for pulmonary hypertension includes supplementary oxygen, invasive mechanical ventilation, intravenous fluid and vasopressor support, pulmonary vasodilation and extracorporeal life support.

Pulmonary hypertension treatment involves:

• providing mechanical ventilator support to improve oxygenation, assist lung recruitment and decrease pulmonary shunt
• providing cardiac support with inotropic medications to enhance cardiac function, pulmonary blood flow and oxygen delivery
• decreasing pulmonary vascular resistance through the use of medical adjuncts

Nonpharmacological interventions are aimed at maintaining normal body temperature, electrolyte balance, glucose and intravascular volume. All patients with pulmonary hypertension require optimization of lung function and oxygen delivery, either through the provision of supplemental oxygen or through assisted ventilation (both invasive and noninvasive). Reducing CO₂ by hyperventilation was a classical strategy used to promote alkalosis. Unfortunately, this resulted in lung injury (volu- and barotrauma). Inappropriate ventilatory support may lead to atelectasis with under ventilation while the application of excessive positive pressure leads to alveolar overdistention, both of which contribute increase pulmonary vascular resistance. Thus, ventilatory support which maintains the optimal functional residual capacity is ideal.

Inotropic support may be necessary to augment overall myocardial contractility, supporting the right ventricle as it pumps against increased afterload. Inotropic support may also help to counteract the adverse effects of systemic vasodilation from pulmonary vasodilators (e.g. milrinone and prostanoids). The judicious use of inotropes (e.g. phenylephrine, norepinephrine, epinephrine, and high dose dopamine) is advised since the associated systemic vasoconstriction may also affect the pulmonary vascular bed.

What are the pharmacological strategies used in the management of pulmonary hypertension?

Pharmacological strategies used specifically for pulmonary hypertension target the pulmonary vascular endothelium.

pulmonary hypertension medications and receptor pathways

cGMP and cAMP are the second messengers within the pulmonary vascular endothelium that lead to pulmonary vasodilation. Increased levels of cGMP are produced through the use of inhaled nitric oxide (iNO) which induces soluble guanylate cyclase or through the administration of sildenafil which prevents its degradation by phosphodiesterase 5.

Prostanoids such as prostacyclin (PG12) act on adenylate cyclase to increase conversion of cAMP from adenosine triphosphate (ATP). The degradation of cAMP to adenosine monophosphate can be inhibited through the use of milrinone which inhibits phosphdiesterase 3.

Bosentan, an endothelin 1 receptor antagonist, acts on cell surface receptors on the pulmonary vascular endothelium to prevent the production of endothelin A and B which both mediate vasocontriction.

Inhaled nitric oxide
Inhaled nitric oxide (iNO), an odorless gas, causes pulmonary arterial vasodilation. It activates guanylate cyclase to increase the production of cyclic GMP which in turn leads to relaxation of the smooth muscle of the vascular endothelial cell. The reduction in vascular smooth muscle tone decreases pulmonary vascular resistance (PVR). The usefulness of iNO depends on the underlying cause of pulmonary hypertension. In patients with meconium aspiration syndrome or respiratory distress syndrome, iNO is effective in reducing PVR and the need for extracorporeal life support. Conversely, iNO appears to have little effect on pulmonary hypertension associated with congenital diaphragmatic hernia [4]. The response to iNO is concentration dependent with usual doses ranging from 5 to 40 ppm. Importantly, patients that are unresponsive to lower concentrations of iNO will often derive no benefit from higher concentrations. The administration of high oxygen concentrations have also been linked to suboptimal iNO responses.

While the short half-life of iNO and its direct delivery to the pulmonary vasculature cause no systemic hemodynamic effects, iNO is associated with potential toxicity. For example, inhaled nitric oxide itself is a free radical that can cause cellular damage. When used at doses greater than 5 PPM it produces NO₂ which, when coupled with high O₂ concentrations, may cause cellular injury. iNO also binds to hemoglobin in a dose dependent manner to produce methemoglobin. Finally, iNO is also a costly intervention and routinely adds $3500 to $8100 USD to the daily intensive care unit cost [8].

Sildenafil
Cyclic GMP levels are also increased within the vascular smooth muscle cell by phosphodiesterase-5 (PDE5) inhibitors like sildenafil. PDE5 production is greatest during the late fetal period and eventually falls after birth. Sildenafil relies on hepatic metabolism via the CYP3A4 pathway and, therefore, inhibitors of CYP3A4 will increase plasma sildenafil concentrations (e.g. amiodarone, azalides, fluconazole). Since sildenafil also works on the cGMP pathway the concurrent use of iNO and sildenafil can lead to systemic hypotension.
Whereas iNO is only administered with mechanical ventilation, sildenafil is given orally or intravenously. The off label outpatient use of sildenafil in children with pulmonary hypertension received a Food and Drug Administration (FDA) black box warning due to an observed increase in mortality risk in the STARTS trial. In this study, children >20 kg receiving high doses for longer than three years were at increased risk. While this warning is controversial, it may result in the restricted use of sildanefil in certain populations [9].

Milrinone
Milrinone is a phosphodiesterase-3 (PDE3) inhibitor that is frequently used postoperatively in congenital heart surgery to support patients with low cardiac output syndrome. It works by increasing cAMP levels leading to pulmonary vascular smooth muscle relaxation while also improving biventricular diastolic function. It can also be used as an adjunct to augment pulmonary vasodilation in patients unresponsive to iNO. Milrinone may cause systemic vasodilation and hypotension and thus requires careful titration. It is cleared through the kidneys and consequently its levels increase in renal insufficiency [4].

Prostanoids
Another group of compounds that promote vasodilation include the prostanoids, which are analogues of prostaglandin I₂ (PGI₂). Prostacyclin (sodium epoprostenol) acts on adenylate cyclase and increases cyclic AMP (cAMP) leading to vasodilation. Epoprostenol is a photolabile prostanoid which has been used extensively to decrease pulmonary vascular resistance while only mildly decreasing systemic blood pressure. Higher doses of epoprostenol can increase cardiac output through inotropic effects. Chronic epoprostenol therapy may be an alternative to heart/lung transplantation in the setting of chronic pulmonary hypertension.

Inhaled PGI₂ (iloprost) has been used in mechanically ventilated patients, although its use in this setting may lead to ventilator valve damage. It has also been used in the outpatient setting with frequently administered inhalations (average six times per day) which may not be ideal for children. In adults, inhaled iloprost has shown to decrease pulmonary artery pressure by 4.6 ± 9.3 mmHg associated with improved exercise tolerance.[10] In children, the data is less robust. A retrospective review demonstrated about 65% of pediatric patients either had improvement or stabilization in their pulmonary hypertension. However, several children had to discontinue iloprost due to bronchoconstriction [11]. Other forms of PGI₂ are available for subcutaneous (treprostinil) and oral (beroprost) administration[5].

Endothelin antagonists
Endothelin is a powerful pulmonary vasoconstrictor. Bosentan is an endothelin-1 (ET-1) antagonist which is administered enterally. It works directly on the ET-1 receptor in a pathway independent of the cGMP or cAMP second messenger systems. The use of bosentan in pulmonary hypertension patients has been shown to reduce the oxygenation index within six hours of treatment without rebound hypoxia on cessation of therapy in one clinical study [12]. Monitoring of liver function is required due to the risk of hepatotoxicity[4].

Calcium channel blockers
Calcium channel blockers (CCB) like amlodipine are used more frequently in older children for the outpatient management of pulmonary hypertension. Children under 8 years of age appear to be better responders to CCBs than adults, showing a > 40% response in contrast to ≤ 25% in adults. Ninety-seven percent of children that initially were responders remained as such for the first 5 years after which their response diminished. Children that were initially non-responders that were not placed on prostaglandins had survival rates of 66%, 52% and 35% at 1, 3 and 5 years respectively.[13] Long-term therapy with CCBs in patients with fixed PVRs (i.e. patients with progressive occlusive vascular disease) has been shown to diminish cardiac output and should be avoided.[13]

Tyrosine kinase inhibitors
Another class of medication under investigation is the tyrosine kinase inhibitors (TKI’s) like imatinib. Previous studies have shown that upregulation of platelet derived growth factor (PDGF) leads to vascular remodeling, a key feature in pulmonary hypertension. Imatinib has been shown to decrease pulmonary hypertension through smooth muscle cell apoptosis, normalization of PDGF levels both of which may be helpful in controlling the abnormal muscularization in pulmonary hypertension. However, its clinical use is limited to isolated case reports.[14]

What options are available in cases of refractory pulmonary hypertension?

Patients with pulmonary hypertension refractory to current medical adjuncts may require invasive/operative procedures to maintain adequate cardiorespiratory function. Patients that have an expected two year survival less than 50% may require a lung or heart/lung transplant. In acute situations, extracorporeal life support may be required as a bridge to recovery or transplant while ventricular assist devices may be used in more chronic conditions to help support right heart function.

Those patients suspected of chronic thromboembolic pulmonary hypertension should undergo pulmonary angiography and pulmonary thromboendarterectomy.

Complications

Acute complications of refractory pulmonary hypertension include hypoxia, acidosis and death. Chronic refractory pulmonary hypertension can lead to progressive right heart failure requiring heart and lung transplantation.

The long term consequences of pulmonary hypertension include high rates of neurodevelopmental impairment at eighteen months of age, cerebral palsy, deafness, and blindness. Cor pulmonale develops when the right ventricle remodels and becomes hypertrophied. Long standing right ventricular hypertrophy will lead to diastolic dysfunction of the right heart and elevation in venous pressure causing liver injury. The use of pulmonary antihypertensive medications has increased overall survival for children in pulmonary hypertension. Historically in children, survival without medication was typically less than five years after diagnosis. Currently, several studies have demonstrated seven year survival survival rates of 70% [15][16].

Research and Future Directions

There is intense ongoing research in pediatric pulmonary hypertension management, including use of tyrosine kinase inhibitors, studying effects of vasopressors (e.g. vasopressin) on pulmonary artery pressures, and novel compounds (riociguat - Bayer) that work on soluble guanylate cyclase (sGC), a key protein in nitric oxide mediated vasodilation. The dual endothelin receptor antagonist macitentan works on both endothelin receptor subtypes A and B is currently being studied in children. There are also pediatric pulmonary hypertension registries accruing data to help better define the incidence and prevalence of pulmonary hypertension in North America via the Pediatric Pulmonary Hypertension Network (PPHNet). Clinical trials evaluating pulmonary artery denervation are also ongoing in adults. (ClinicalTrials.gov).

Patient Care Guidelines

The American Heart Association and American Thoracic Society have released a pulmonary hypertension management algorithm for neonates, infants and older children [1].

Perspectives and Commentary

To submit comments about this topic please contact the editors at think@apsapedsurg.org.

Invited commentary from Matthew T. Harting, MD (May, 2016)

Pandya and Puligandla provide an excellent overview of the basic science, pathophysiology, prevention, presentation, assessment, treatment and future directions of pulmonary hypertension. Their review highlights important nuances unique to pulmonary hypertension that arises in the fetal, neonatal and pediatric patient populations. The section on pathophysiology includes compelling discussion of the delicate balance between alveolar over distention and atelectasis - both of which exacerbate pulmonary hypertension. Further, they discuss the critical role of the endothelium, both as a factor in initiation and progression of pulmonary hypertension and an important target for therapy.

The American Heart Association and the American Thoracic Society recently released guidelines for pediatric pulmonary hypertension [1]. This is an exhaustive overview of pediatric pulmonary hypertension including an extensive literature review, insightful discussion and formal scoring of recommendations. This is a must read for anyone involved in the care of pediatric patients with pulmonary hypertension.

Improvements in imaging are driving our ability to diagnose and understand a variety of complex diseases. Although cardiac catheterization remains the gold standard for both diagnosing and defining pulmonary hypertension, ultrasonography continues to improve. Targeted neonatal echocardiography may play a major role in enhancing the level of understanding of pulmonary hypertension as the clinical signs and laboratory values may be nonspecific [17].

Finally, novel therapies must be developed targeting prevention, stabilization or reversal of the vascular consequences known to drive pulmonary hypertension. Several of these including novel soluble guanylate cyclase stimulator/activator compounds and new endothelin receptor antagonists whihc are mentioned within this text. Others including dichloroacetate (a PDK inhibitor), trimetazidine/ranolizine (fatty acid oxidation inhibitors), imatinib (a tyrosine kinase inhibitor), HDAC inhibitors and cell/cell based therapies [18][19] hold significant promise and may change the overall outcome for patients with this very challenging disease.

Glossary

Eisenmenger’s complex - uncorrected heart defect allowing for chronic left to right shunting eventually leads to right ventricular hypertrophy with right to left shunting due to pulmonary hypertension causing cyanosis.

Discussion Questions and Cases

To submit interesting cases which display thoughtful patient management please contact the editors at think@apsapedsurg.org.

What factors can affect pulmonary vascular resistance?

Pulmonary vascular resistance (PVR) can be affected by a number of factors. In the perinatal period, an abnormal transitional circulation (increased pulmonary vasoreactivity, sustained pulmonary vasoconstriction, and vascular remodelling) can lead to increased PVR. Second, inadequate hemodynamics or pulmonary blood flow can also increase PVR. The right ventricle (RV) is very sensitive to increases in afterload and thus the use of prostaglandin E2 has been proposed maintain ductal patency thereby providing a pop off for a failing RV. In this situation, oxygen saturation is sacrificed to maintain systemic perfusion. Furthermore, inotropic support of the heart can increase contractility, cardiac output and pulmonary blood flow. Increased pulmonary blood flow (i.e. perfusion pressure) can help to recruit regions of the pulmonary vascular bed that have limited flow and can ultimately help reduce PVR. Proper assisted ventilation around the functional residual capacity can prevent compression or distortion of the extraalveolar (overdistension) and alveolar (underinflation) capillary beds to also help reduce PVR. One of the most important factors that can affect PVR is the pulmonary vascular endothelium. The endothelium modulates PVR through three main pathways – guanylate cyclase, adenylate cyclase and endothelin. Manipulation of the endothelium represents a major target in the management of patients with elevated PVR.

A newborn is intubated and mechanically ventilated due to respiratory distress. A chest radiograph demonstrates slight hyperinflation but no evidence of infection or parenchymal disease. Echocardiographic evaluation demonstrates normal heart anatomy but evidence of right ventricular dysfunction, bowing of the interventricular septum to the left and almost exclusive right to left shunting through the patent ductus arteriosus suggestive of severe pulmonary hypertension. Blood gas analysis demonstrates significant acidosis and hypoxemia.

What is your general approach to the management of this infant?

The basic tenets of care for this infant are to maintain oxygen delivery and improve pulmonary blood flow. This can be accomplished with nonpharmacological and pharmacological means. Mechanical ventilation with supplemental oxygen should improve delivery of oxygen to the lungs and help with pulmonary vasodilation. Proper sedation will allow better patient - ventilator coordination and potentially prevent further pulmonary hypertensive crises. Judicious volume resuscitation will improve preload and cardiac output. Ventilation around the functional residual capacity will prevent under inflation or overdistension of the alveoli which can both increase pulmonary vascular resistance. Inotropic support will often be required to support the heart and improve contractility - especially in the context of increased central venous pressure due to positive pressure ventilation. Improved contractility will also aid to increase pulmonary blood flow. Re-evaluation with echocardiography is necessary to demonstrate the efficacy of the above mentioned maneuvers.

If the patient continues to demonstrate poor tissue perfusion and evidence of pulmonary hypertension, specific pulmonary vasodilator therapy can be instituted, with echocardiography confirming the response. Inhaled nitric oxide (iNO) is a potent pulmonary vasodilator (through stimulation of guanylate cyclase that increases cGMP) that has almost exclusive local effects. The addition of milrinone (phosphodiesterase-3 inhibitor that increases cAMP within endothelium) can help improve right ventricular diastolic dysfunction while also having some pulmonary vasodilatory effects in synergy with iNO. In the absence of any improvement with iNO or milrinone, other medical adjuncts may be used including prostanoids (inhaled or intravenous – act to increase cAMP by inducing adenylate cyclase) or bosentan, an endothelin-1 antagonist. In the context of unrelenting pulmonary hypertension with persistent acidosis and hypoxemia extracorporeal life support should be considered.

Why should inhaled nitric oxide (iNO) be used with caution in the context of left ventricular dysfunction?

While nitric oxide can improve V/Q mismatch and aid in treating pulmonary hypertension, it can actually further impair gas exchange in the context of left ventricular dysfunction. In this scenario, left atrial pressures are elevated leading to pulmonary venous hypertension and pulmonary edema. The addition of a potent pulmonary arterial vasodilator such as iNO will further exacerbate pulmonary edema by increasing pulmonary blood flow thereby worsening V/Q mismatch and hypoxemia.

Additonal discussion quesrtions in SCORE Pulmonary Hypoplasia/Hypertension conference prep

References