Keywords

Introduction

Pulmonary hypertension (PH) is defined as a mean pulmonary artery pressure (PAP) of greater than or equal to 25 mmHg. This simple definition belies the complexity and variety of pathophysiologic situations that can cause PH in critically ill pediatric patients. Moreover, pulmonary vascular dysfunction can complicate the course of patients before the definition of PH is satisfied. This chapter will provide a brief overview of the disease processes associated with PH, review the key pathophysiologic principles, and describe a general therapeutic approach, with an emphasis on the critical care setting.

Clinical Classification and Etiology

Over the past 40 years, clinical classification schemes have evolved in order to keep pace with the expanding number of disease processes identified to be associated with PH. The initial classification endorsed by the World Health Organization in 1973 divided PH into only two categories – primary and secondary PH. The most recent classification, which followed the 5th World Symposium on PH in 2013, divided PH into 5 groups, with 28 subgroups (Table 15.1) [1].

Table 15.1 Clinical classification of pulmonary hypertension1
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The prevalence of PH in pediatric patients is not known precisely. A French registry estimated the prevalence of PH to be 3.7 cases/million [2]. In that cohort, the majority (60 %) had idiopathic PH, 24 % had PH associated with congenital heart disease, and 10 % had familial PH [2]. An earlier report from the UK Pulmonary Hypertension Service for Children from 2001 to 2006 described 216 children with PH [3]. In that cohort, 28 % of the patients had idiopathic PH, 31 % had Eisenmenger physiology, 30 % had postoperative PH, 19 % had PH associated with lung disease, 9 % had PH associated with miscellaneous disorders including HIV, bone marrow transplant and metabolic disease, 6 % had connective tissue disease, and 5 % had PH associated with complex un-operated or palliated congenital heart disease [3].

In the neonatal population, persistent pulmonary hypertension of the newborn (PPHN) warrants particular attention. The incidence of PPHN has been estimated to be approximately 2 per 1,000 live births [4]. PPHN may occur as a primary disorder of the fetal pulmonary circulation, or may be secondary to pathologic processes that cause a maladaptive transition from the fetal to neonatal circulation, such as sepsis, meconium aspiration or surfactant deficiency, or diseases that result in abnormalities of lung development, such as congenital diaphragmatic hernia [5]. Furthermore, PH is also associated with chronic lung disorders, including bronchopulmonary dysplasia [6–9].

It is important to recognize that patients may have significant pulmonary vascular disease without resting PAPs that meet the definition of PH [10]. For example, patients with congenital cardiac defects resulting in either increased pulmonary blood flow or impaired pulmonary venous drainage are prone to episodes of acute reactive pulmonary vasoconstriction, even when baseline PAPs are normal, that can result in catastrophic cardiopulmonary collapse, particularly in the postoperative period after exposure to cardiopulmonary bypass [11, 12]. In addition, certain disease processes can create pulmonary vascular disease in patients without preexisting abnormalities. For example, acute lung injury (ALI) is associated with pulmonary vascular endothelial injury, that can lead to vascular obstruction from intravascular thrombi, segmental atelectasis, and/or increased hypoxic pulmonary vasoconstriction [13, 14]. In some patients this can progress to PH and right ventricular failure [13–16]. In a cohort of 23 children with ALI, Katz and colleagues found that PAP, pulmonary vascular resistance (PVR), and intrapulmonary shunt fractions were higher in non-survivors than in survivors [17]. More recently, Bull and colleagues evaluated the transpulmonary gradient (PAP – pulmonary capillary wedge pressure) and the PVR index in 475 and 470 (respectively) adult patients with ALI, and found that pulmonary vascular dysfunction was common and independently associated with poor outcome [18].

Diagnosis

Invasive and noninvasive techniques are used in order to diagnose, classify, and manage PH. Indwelling pulmonary artery catheters provide the most direct information, allowing for measurements of vascular pressures and cardiac output, and calculations of PVR. However, these catheters are used infrequently in critically ill pediatric patients, owing to size limitations and a lack of evidence that justifies their routine use.

Standard noninvasive studies include ECG and transthoracic echocardiography. The chief finding of interest on an ECG is evidence of right ventricular hypertrophy, although studies of patients with known PH have demonstrated that ECG alone lacks adequate sensitivity and specificity [19, 20].

The important data that may be obtained by echocardiography are: an estimate of systolic pulmonary arterial pressure (sPAP), right and left ventricular function, and cardiac anatomy, including determinations of chamber sizes, valvular function, and intracardiac shunts. In general, the sPAP is considered equivalent to the right ventricular systolic pressure (RVSP), unless there is right ventricular outflow tract obstruction or pulmonary valve stenosis. With the use of Doppler echocardiography, RVSP is estimated by determining the velocity of flow across the tricuspid valve during systole (tricuspid regurgitation jet, TR jet). A modification of the Bernoulli equation is used to estimate the RVSP, as follows: RVSP = 4ν2 + RAP, where ν is the velocity of the TR jet in meters per second, and RAP is the right atrial pressure that is ether standardized or estimated by echocardiography. Multiple studies have validated estimates of sPAP determined by echocardiography using right-heart catheterization as confirmation [21–29]. In the absence of a measurable TR jet, parameters related to right ventricular outflow patterns and time intervals could be assessed by Doppler echocardiography with demonstrated accuracy compared to right-heart catheterization [30–33]. Recently, Arkles and colleagues found that the shape of the right ventricular Doppler envelope predicted hemodynamics and right heart function in adult PH patients [34]. The same group in an earlier study demonstrated that another echocardiographic estimate of right heart function, the tricuspid annular plane systolic excursion (TAPSE), was reflective of RV function when compared to right heart catheterization, and predicted survival in a cohort of 63 adult PH patients [35].

Cardiac catheterization remains the “gold standard” for the diagnosis of pulmonary hypertension. In addition to measuring PAP and PVR, cardiac catheterization can assess for intracardiac and extracardiac shunts, evaluate the pulmonary vascular anatomy (such as assessments of pulmonary venous abnormalities), and measure intracardiac pressures and cardiac output. Furthermore, pulmonary vascular reactivity testing is essential in selecting appropriate therapy. Indeed, children who are responsive to acute vasodilator testing (evoked by short acting agents such as inhaled nitric oxide (iNO) or iloprost, and intravenous epoprostenol or adenosine) which is defined as a ≥20 % decrease in PAP without a decrease in cardiac output, have been shown to have improved survival [36]. In addition, responsiveness to acute vasodilator testing predicts a favorable response to long-term therapies, such as calcium channel blockers [37, 38]. Conversely, calcium channel blockers may be deleterious for patients not responsive to vasodilator therapy, which exemplifies the value of this information [39, 40]. However, the timing of cardiac catheterization is often less clear. Indeed, catheterization may not be safe in critically ill patients suffering from severe acute PH.

Other diagnostic modalities include V/Q scan, CT scan, and MRI. Thromboembolic disease may present with pulmonary hypertension, and can be evaluated by V/Q scan. Several studies found that V/Q scanning was highly sensitive and specific in differentiating between idiopathic pulmonary hypertension and thromboembolic disease [41–43]. Contrast enhanced CT scan and/or MRI can help identify causes of pulmonary hypertension. Thromboembolic disease may be visualized by both modalities [44]. In addition, both imaging techniques can help identify other pulmonary pathology, such as interstitial disease, masses or vasculitis [45]. Findings on CT scan, such as pulmonary artery size, may contribute to the diagnosis of pulmonary hypertension, but do not replace Doppler echocardiography [46–49]. MRI can better delineate the cardiac anatomy, particularly chamber sizes and wall thickness, and MRI measurements can detect PH [50–52]. However, like CT, it is not clear that MRI offers significant advantages for diagnosis compared to Doppler echocardiography.

Pathophysiology

The pathophysiology of PH is multifactorial, complex, and incompletely understood. Various etiologies are associated with different particular mechanisms of disease, and a unifying construct has not been identified. However, several pathways common to a number of etiologies have been elucidated.

Hemodynamics and Morphology

From a hemodynamic standpoint, the morbidity and mortality associated with PH relates to increased right ventricular afterload. Over some period of time, compensatory mechanisms fail leading to right heart failure and death. It is important to note that the tempo of this clinical sequence varies across etiologies and individual patients. For example, right ventricular failure can develop rapidly in an infant following cardiac surgery (i.e. postoperative pulmonary hypertensive crisis) or may progress over years in other patients (e.g. Eisenmenger’s).

Although right ventricular failure is a common potential endpoint for patients with PH, the location of the disease within the pulmonary vasculature depends upon the particular etiology. This is important when considering available therapies, since therapies appropriate for one group of patients may be deleterious for another. For example, iNO may be effective for patients suffering from acute pulmonary arteriolar constriction (e.g. pulmonary arterial hypertension (PAH); or PH owing to lung diseases and/or hypoxia), but may be entirely ineffective or even harmful in patients with pulmonary veno-occlusive disease or left heart failure [53–55].

Among the various PH groups, the mechanisms that result in increased right ventricular afterload are best understood in PAH. However, left heart disease is a common cause of PH, at least in adults [56]. In these patients, elevations in PAP relate to the transmission of elevated left atrial pressures. PVR may be normal. Although subsets of patients with left heart disease develop PAH, the associated mechanisms are less well understood and specific therapies for these patients have not been adequately studied [57–60]. Likewise, the pulmonary vascular changes associated with pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis, and congenital cardiac defects associated with pulmonary venous obstruction are less well studied, but the initial elevations in PAP relate to the backward transmission of pressure across the pulmonary vasculature, a situation that is not likely to benefit from pharmacologic pulmonary arteriolar dilation [61–63].

In PAH, increased right ventricular afterload relates to increased PVR and decreased compliance [64, 65]. Traditionally, hemodynamic assessments focused on measuring PAP and calculating PVR in PH patients, but more recent data have demonstrated value in measuring pulmonary vascular impedance, which combines resistance and compliance [66–68]. Increased PVR and decreased compliance in PAH relates to several basic mechanisms: increased pulmonary vascular reactivity, sustained pulmonary vasoconstriction, vascular remodeling, and luminal obstruction, due to in situ thrombosis and/or obstructive neointimal and plexiform lesions. In 1958, Heath and Edwards first described the histopathology of pulmonary vascular changes associated with congenital cardiac defects, and devised a six grade classification [69]. In their classification, changes progress from medial hypertrophy (Grade I) to intimal hyperplasia (Grade II), lumen occlusion (Grade III), arterial dilatation (Grade IV), angiomatoid formation (Grade V) and fibrinoid necrosis (Grade VI). Rabinovitch and colleagues followed with a morphometric classification system, based on lung biopsies taken from patients (aged 2 days to 30 years, with a median age of 1 year) with congenital cardiac defects [70]. This morphometric analysis showed progression of disturbed arterial growth and remodeling of the pulmonary vascular bed that correlated with the aberrant hemodynamic state of the pulmonary circulation. These changes were characterized by: (i) abnormal extension of vascular smooth muscle into small peripheral pulmonary arteries and mild medial hypertrophy of normally muscular arteries (Grade A), (ii) severe medial hypertrophy of normally muscular arteries (Grade B) and (ii) decreased pulmonary arterial number (Grade C) (Fig. 15.1). These vascular changes tend to progress in a stepwise fashion, and in severe disease obliterate portions of the pulmonary circulation at the level of the distal precapillary resistance arterioles. It is recognized that this sequence represents a pathologic framework, but that significant heterogeneity exists in terms of the precise pathology of PAH [71]. Furthermore, the degree to which these changes are reversible remains unclear, but likely depends in part upon the etiology, and may be influenced by age [72]. For example, in a seminal study, Rabinovitch and colleagues demonstrated that age at surgery, lung morphometric analysis, and the Heath-Edwards system grade predicted the reversibility of structural and functional pulmonary vascular changes secondary to congenital cardiac defects with increased pulmonary blood flow after surgical repair [73]. In addition, it must be remembered that even early reversible pulmonary vascular disease can contribute to morbidity and mortality. An important study by Celermajer and colleagues, for example, demonstrated that children with increased pulmonary blood flow due to intracardiac shunting had a selective impairment of endothelium-dependent pulmonary vascular relaxation, before their baseline PAP or PVR increased significantly [10].

Fig. 15.1
figure 1

Examples of morphometric analysis done on lung biopsies taken from a patient with a small ventricular septal defect (a) and a patient with an atrioventricular septal defect and pulmonary hypertension (b). A cross section from arteries at the same level are shown (Elastic Van Geison stain, magnification × 100). The wall thickness is increased in the patient with pulmonary hypertension (b). Arrows indicate wall thickness and external diameter (Reprinted from Rabinovitch et al. [70]. With permission from Wolter Kluwers Health.)

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In addition, extravascular forces also influence PAP and pulmonary vascular impedance. The relationship between intravascular pressures and alveolar pressures are well described [74, 75]. Pulmonary vessels are termed extra-alveolar, corner, or intra-alveolar. Extra-alveolar and corner vessels increase their size with lung expansion, due to radial traction placed on their walls by the lung parenchyma. Intra-alveolar vessels, however, are directly associated with alveoli and thus are subject to compression with alveolar expansion. This results in the classic U-shaped curve describing the relationship between PVR and lung inflation, wherein PVR is lowest at functional residual capacity, but increased with under- and over-inflation of the lung (Fig. 15.2). West further characterized this relationship by dividing the lung into three theoretical zones, which move down the lung from the apex to the base, in an upright subject. These zones are based on the relationship between pulmonary artery pressure (PAP), or inflow pressure, alveolar pressure (Pav), and pulmonary venous pressure (Pven), or outflow pressure. In theory, no blood flows to zone I because Pav exceeds PAP, or Pav > PAP > Pven. In this zone, intra-alveolar vessels are collapsed. Clinically, zone I conditions are negligible in a healthy lung, as pulmonary blood flow does occur at the apex. The fact that extra-alveolar and corner vessels are patent in this zone may help maintain blood flow. In Zone II, PAP exceeds Pav and blood flow occurs independent of outflow pressures, or PAP > Pav > Pven. In this zone, blood flow increases down the lung, since PAP, but not Pav, is influenced by gravity. In Zone III, blood flow is dictated by the normal relationship of PAP to Pven, or inflow pressure minus outflow pressure. In this zone, blood flow does not change dramatically down the lung as it does in zone II because gravity affects PAP and Pven equally, or PAP > Pven > Pav. Subsequently, an additional zone, zone IV, has been described where pulmonary blood flow decreases at the extreme base of the lung. This is due to the impact of the weight of the lung on the extra-alveolar and corner vessels, which causes compression thereby increasing resistance to flow; furthermore, the decrease in ventilation that occurs at the base results in areas of relative hypoxia with resultant hypoxic pulmonary vasoconstriction.

Fig. 15.2
figure 2

A schematic of some endothelial derived factors. These factors may cause decreased (relaxation) and/or increased (constriction) smooth muscle cell contraction. PLA2 phospholipase A2, PGI2 prostaglandin I2, AA arachidonic acid, TXA2 thromboxane A2, ECE endothelin converting enzyme, L-Arg L-arginine, L-Cit L-citrulline, NOS nitric oxide synthase, ET-1 endothelin-1, ETA endothelin A receptor, ETB endothelin B receptor, NO nitric oxide, sGC soluble guanylate cyclase, GTP guanosine-5′-triphosphate, cGMP guanosine-3′-5′cyclic monophosphate, GMP guanosine monophosphate, AC adenylate cyclase, ATP adenosine-5′-triphosphate, cAMP adenosine-3′-5′-monophosphate, PDE phosphodiesterase (type 5 shown), PLC phospholipase C, IP3 inositol 1,4,5-trisphosphate, DAG diacylglycerol, Ca2+ calcium

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Under normal conditions, pulmonary blood flow is largely determined by zone III conditions. It is important to stress that these zones are conceptual and that in disease states a number of factors in addition to gravity influence V/Q matching; in addition, critically ill patients are rarely upright, but rather are supine or prone [76]. Particularly pertinent to pediatric critical care are the effects of positive pressure ventilation with high levels of peak end expiratory pressure. Increased alveolar pressure, may expand zone II and allow zone I conditions to be realized, resulting in mismatching of ventilation and perfusion and intrapulmonary shunting with hypoxia and hypercapnia. Likewise, pathology such as pneumothorax, hemothorax, pleural effusion, pneumonia and pulmonary edema, along with other conditions, can increase zone IV conditions within the lung. Finally, hypotension from multiple etiologies, such as hemorrhage, can expand zone I and zone II conditions.

Pulmonary Vascular Endothelium

It is now accepted that increased pulmonary vasoconstriction and impaired relaxation in PH is mediated in large part by aberrant endothelial function, wherein endogenous vasodilators, such as nitric oxide (NO) and prostacyclin (PGI2), are decreased while endogenous vasoconstrictors, such as endothelin (ET-1) and serotonin (5-HT), are increased (Fig. 15.2) [77–82]. Indeed, the majority of approved therapies for PH target these endothelial-derived factors or their signaling pathways in some way (Fig. 15.3).

Fig. 15.3
figure 3

A schematic of the sites of action of some endothelial and smooth muscle cell based therapies. Arrows indicate activation and (T) indicate inhibition

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NO is produced in the vascular endothelium by the enzyme endothelial NO synthase (eNOS), from the precursor L-arginine. Once formed, NO diffuses into the adjacent smooth muscle cell and activates soluble guanylate cyclase (sGC), producing cGMP. cGMP results in smooth muscle cell relaxation through protein kinase G (PKG). cGMP is broken down by a family of phosphodiesterases (PDE), with PDE5 being prominent in the pulmonary vasculature (Fig. 15.2).

Arachidonic acid metabolism within vascular endothelial cells, results in the production of PGI2 and thromboxane (TXA2). PGI2 activates adenylate cyclase, resulting in increased cAMP production, activation of protein kinase A, and subsequent vasodilation, whereas TXA2 results in vasoconstriction via phospholipase C signaling (Fig. 15.2). PGI2 also binds to platelet receptors, which inhibits their activation.

ET-1 is a 21 amino acid polypeptide also produced by vascular endothelial cells [83]. The vasoactive properties of ET-1 are complex [84–88]. However, its most striking property is its sustained hypertensive action. The hemodynamic effects of ET-1 are mediated by at least two distinct receptor populations, ETA and ETB [89, 90]. The ETA receptors are located on vascular smooth muscle cells, and mediate vasoconstriction, whereas the ETB receptors are located on endothelial and smooth muscle cells, and thus may mediate both vasodilation and vasoconstriction, respectively (Fig. 15.2). In addition, ETB receptors are involved in the clearance of ET-1.

An important area of active research is focused on understanding the mechanisms responsible for endothelial injury or dysfunction in PH. Some important mechanisms include: alterations in mechanical forces (such as increased pulmonary blood flow associated with congenital cardiac defects, or altered flow velocities that are associated with areas of luminal narrowing) that result in increased vascular wall shear stress, hypoxia, oxidative stress, and inflammation [91–99]. Additional factors that contribute to endothelial injury in some patients include, infection, such as HIV and Schistosomiasis, as well as injury from drugs or toxins [100–102].

Moreover, it is known that endothelial derived factors, such as NO, PGI2, and ET-1, are integral to processes beyond the regulation of vascular smooth muscle cell tone. Nitric oxide and PGI2 are key regulators of vascular homeostasis, having antithrombotic and antiproliferative properties, in addition to their effects on vascular tone. Conversely, the mitogenic properties of ET-1 are well described. Indeed, endothelial injury or dysfunction likely contributes to alterations in inflammatory cascades, growth factors, and transcriptional factors that are increasingly recognized as key mediators of the vascular remodeling associated with PH [99].

Pulmonary Vascular Smooth Muscle

Considerable efforts have been made to understand the processes responsible for smooth muscle cell hypertrophy and proliferation that accompany PH. It is clear that a complex interplay exists between endothelial and smooth muscle cells. Some known mechanisms include: increased pericyte differentiation, smooth muscle cell migration, endothelial cell transdifferentiation, smooth muscle cell proliferation, smooth muscle cell hypertrophy, and inflammation [103, 104]. The extracellular matrix and matrix metalloproteinases (MMPs) are known to participate in these processes, with a cascade that involves the release of mitogens, such as basic fibroblast growth factor [105–107]. Multiple putative mechanisms and mediators are currently under investigation, many of which involve abnormalities in apoptosis with some sharing features with neoplastic processes [108]. In addition, genetic abnormalities participate in the development of PH in some patients, most prominently, mutations in bone morphogenetic protein receptor 2 (BMPR2) [109–114].

Management Strategies and Therapeutic Options

The basic elements of PH management include: the prevention and/or treatment of active pulmonary vasoconstriction, the support of right ventricle function and, when possible, treatment of the underlying disease. The ultimate treatment would involve the regression of advanced pulmonary vascular structural remodeling, but to date this remains an unattained goal.

In the critical care setting, avoidance, recognition and treatment of pulmonary hypertensive crises are paramount. Pulmonary hypertensive crises are most commonly observed in susceptible patients after cardiac surgery, but can occur in a number of settings. These life-threatening events involve: acute elevations in pulmonary vascular impedance, that cause an increase in right ventricular afterload, right ventricular ischemia, and decreased cardiac output [115, 116]. Decreased cardiac output results from the associated increase in right ventricular end diastolic volume that shifts the intraventricular septum to the left, decreasing left ventricular end diastolic volume and stroke volume. Decreased cardiac output results in decreased systemic oxygen delivery and metabolic acidosis. In addition, decreased pulmonary blood flow increases dead space ventilation. Distention of the pulmonary arteries and perivascular edema produce large and small airway obstruction, respectively, which further impairs ventilation-perfusion matching and decreases lung compliance. In fact, the decrease in lung compliance can be so dramatic that chest wall movement is impaired, even with manual ventilation. A cycle of worsening hypoxemia, hypercapnia, and acidosis (metabolic and/or respiratory) that results in further increases pulmonary vascular impedance develops that ultimately ends with right heart failure and death if left untreated (Fig. 15.4) [117–121].

Fig. 15.4
figure 4

A schematic of a pulmonary hypertensive crisis. An acute increase in pulmonary arterial pressure (PAP) results in a decrease in pulmonary blood flow (PBF) and airway obstruction due to distention of pulmonary arteries proximal to the maximally constricted resistance arterioles and perivascular edema. This results in an increase in dead space ventilation and ventilation-perfusion (V/Q) mismatch, both of which contribute to respiratory acidosis. In addition, right ventricular end-diastolic pressure (RVEDP) and volume (RVEDV) increase, which can result in failure of the right ventricle (RV) and movement of the intraventricular septum leftward, with compromise of left ventricular filling (decreased left ventricular end-diastolic volume (LVEDV)). This can impair cardiac output, resulting in metabolic acidosis. The resultant hypoxia (via hypoxic pulmonary vasoconstriction) and respiratory and metabolic acidosis can further increase PAP, causing a downward cycle

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Prevention and/or Treatment of Active Pulmonary Vasoconstriction

Increased pulmonary vascular reactivity is an early feature of PH, which manifests clinically as augmented pulmonary vasoconstriction in response to such stimuli as hypoxia, acidosis, catecholamine-mediated α1-adrenergic stimulation associated with pain and/or agitation, and increases in intrathoracic pressure [121–123].

In critical care settings, acute PH is often first treated with pain control, sedation, oxygenation, and alkalinization. Indeed, recently published clinical practice guidelines for the hemodynamic support of pediatric and neonatal septic shock, specifically addressed the risk of elevated PAP/PVR and right heart failure in neonates with sepsis, and the potential need for metabolic and respiratory alkalinization as a part of the initial resuscitative strategy [124]. Decreasing oxygen tension and decreases in pH elicit pulmonary vasoconstriction. Alveolar hypoxia constricts pulmonary arterioles, diverting blood flow away from hypoxic lung segments, toward well-oxygenated segments, thus enhancing ventilation-perfusion matching. This response to hypoxia is unique to the pulmonary vasculature. Indeed, in all other vascular beds hypoxia is a potent vasodilator. The exact mechanism of hypoxic pulmonary vasoconstriction remains incompletely understood, but likely involves changes in the local concentration of reactive oxygen species that in turn regulate voltage-gated potassium channels and calcium channels [125]. Acidosis potentiates hypoxic pulmonary vasoconstriction, while alkalosis reduces it [126]. The exact mechanism of pH-mediated pulmonary vascular reactivity also remains incompletely understood, but appears to be independent of PaCO2. Recent data suggest that potassium channels play an important role in mediating these responses as well [127].

Vasodilator Therapy

The most widely used therapies for PH work by altering one of three endothelial signaling cascades: NO-cGMP, PGI2, and ET-1. Figure 15.3 is a simplified depiction of the various sites of action of the therapies. In the critical care setting, augmentation of NO-cGMP signaling is most common, but the use of PGI2 analogs is increasing. For the treatment of chronic PH, combination therapy is often required, and in fact may also be necessary in severe PH in the critical care setting [128–132]. Calcium channel blockers have demonstrated efficacy in the chronic treatment of subsets of PH patients, although their use may be decreasing [37, 40]. However, in the acute care setting the effects on the systemic circulation are of great concern, particularly in the face of right heart failure, and thus they are rarely used [133].

NO-cGMP Cascade

Inhaled NO (iNO) is the best-studied and most widely used agent for acute selective pulmonary vasodilation. When delivered by inhalation, NO diffuses across the alveolus into the smooth muscle of the accompanying capillary, resulting in relaxation. NO then diffuses into the blood vessel where it is rapidly inactivated by its interaction with hemoglobin. In this way, the effects of iNO are relatively confined to the pulmonary circulation and to ventilated areas of the lung, thus optimizing VQ matching. In large trials, iNO was found to decrease the need for extracorporeal life support in neonates with PPHN and hypoxic respiratory failure, and these data led to its FDA approval [134–136]. Despite this initial indication, iNO is used to treat many other forms of PH and for diagnostic purposes. For example, several studies have investigated the use of iNO in pediatric patients undergoing cardiac surgery [12, 137–140]. These studies indicated that iNO was effective in lowering PAP and PVR in the postoperative period, but the data were less clear about the impact on outcome [141]. Likewise, investigators have examined the utility of iNO in the particular situations of bidirectional cavopulmonary connections and after Fontan completion [142–144]. In these patients, iNO decreased central venous pressure and transpulmonary gradient, and increased oxygen saturations. In addition, the pulmonary vascular response to iNO has been studied as a part of the assessment for operability in patients with PH associated with congenital heart disease [145–148]. These studies found that the combination of 100 % oxygen and iNO (80 ppm) produced maximal pulmonary vasodilation and was more predictive than either treatment alone for postoperative outcome [145–148].

Sildenafil is a PDE5 inhibitor and, as such, its mechanism of action is to augment NO-cGMP signaling by inhibiting the degradation of cGMP. Increased cGMP results in pulmonary vascular relaxation. It should be noted, however, that sildenafil has both pulmonary and systemic effects. In addition, the effects of PDE5 inhibition may not be restricted to the vasculature. For example, a recent study found that PDE5 was upregulated in the hypertrophied right ventricle and that PDE5 inhibition improved contractility [149]. Several studies have demonstrated the efficacy of sildenafil for the treatment of chronic PH [150–154]. Despite limited data, the use of sildenafil in infants and children with PH after cardiac surgery is increasing. Three small studies found that enteral sildenafil facilitated weaning from iNO in pediatric patients with congenital heart disease undergoing therapy for postoperative PH [155–157]. Two studies examined the effects of intravenous sildenafil in pediatric patients after cardiac surgery [158, 159]. Both studies found that intravenous sildenafil decreased PAP and PVR either to a greater extent than iNO or synergistically, but that its use was associated with increased intrapulmonary shunting and decreased systemic arterial pressures.

The administration of additional substrate for NOS with arginine and citrulline is another approach that has been taken to augment the NO-cGMP cascade, with some success [160–167].

Prostanoids

Higenbottam and colleagues, first described the long-term use of intravenous PGI2 for the treatment of PH almost 30years ago [168]. Despite the many recent advances in therapy, intravenous PGI2, epoprostenol, remains the best-proven and most effective therapy for chronic PH [169–173]. Complications associated with long-term epoprostenol are well known and include: thrombosis and infection secondary to the required indwelling central venous catheter, the need for dose escalation over time, and life threatening rebound PH with abrupt discontinuation of the infusion.

Given the success of chronic intravenous epoprostenol therapy, recent efforts have focused on developing additional agents and delivery approaches, in large part in order to address the complications and limitations associated with chronic intravenous infusions. In order to achieve selective pulmonary vascular relaxation, various investigations have focused on delivering prostanoids via the inhalational route [174–176]. This route (in large part due to the potential for selective pulmonary vascular relaxation) is particularly useful in the intensive care setting. Iloprost is a PGI2 analog that is FDA approved for administration by nebulization. Ivy and colleagues studied iloprost in 22 children with PH [177]. They found that inhaled iloprost decreased PAP to a degree equivalent to iNO with oxygen. Likewise, Rimensberger and colleagues administered inhaled iloprost and iNO, alone and in combination, to 15 children with PH secondary to congenital cardiac defects [178]. Both agents decreased the PVR:SVR ratio to a similar degree, and there was no added benefit from a combination of the treatments. Furthermore, in an interesting study by Limsuwan and colleagues done in Thailand, which has relatively less access to iNO, inhaled iloprost decreased mean PAP and increased systemic saturations without decreasing systemic blood pressure in eight children suffering from acute increases in PAP after repair of congenital heart disease [179].

Other dosing strategies for prostanoids include subcutaneous and oral routes of administration, although these are less likely to be useful in critically ill children [180–185]. In children, an important impediment to the use of subcutaneous treprostinil relates to pain at the site of injection, but nonetheless it has been used successfully in these patients [186, 187].

Endothelin-1

Unlike augmentation of the NO-cGMP and prostanoid cascades, inhibition of ET-1 signaling does not reliably cause acute pulmonary vascular relaxation, and thus ET receptor antagonists are considered chronic therapies. However, in a small study that included seven infants that had undergone surgical repair of left-to-right intracardiac shunts, Schulze-Neick and colleagues demonstrated that an intravenous infusion of a selective ETA-receptor antagonist resulted in an acute decrease in PVR [188]. Notably, the addition of iNO had no effect, and the decrease in PVR correlated with left atrial ET-1 levels. But, currently, intravenous ET receptor antagonists are restricted to experimental settings.

Presently, the most common ET receptor antagonist is bosentan, an oral dual ET receptor antagonist. A number of studies have demonstrated the efficacy of bosentan in patients with chronic PAH, including children [189–192]. Bosentan is a sulfonamide-based agent metabolized by cytochrome P450 enzymes and thus monitoring liver function is important due to potential hepatic toxicity [193, 194]. Newer agents include selective ETA-receptor antagonists [195–198].

The Support of Right Ventricular Function

Mortality from PH is most directly related to right ventricular function. The therapies outlined above may improve right ventricular function to the extent that they decrease right ventricular afterload, although emerging data suggest that some of these therapies, such as PDE5 inhibition and ET-1 receptor antagonism, may also enhance or impair (respectively) contractility of the hypertrophied right ventricle [149, 199]. However, in addition to afterload reduction, other therapies that support the right ventricle may be necessary, especially in acute care settings.

Under conditions of increased afterload, the contractility of right ventricular cardiomyocytes increases initially, due to changes in sarcomere length-tension relationships, increased Ca+2 sensitivity, and alterations in force-frequency relationships [200, 201]. In addition, the time course over which right ventricular afterload increases with the state of the right ventricle (in particular, right ventricular mass) together influence the degree to which the right ventricle can compensate [202]. For example, patients with Eisenmenger’s syndrome tolerate elevated right ventricular afterload far better than patients with normal right ventricles who suffer an acute pulmonary embolism [200, 203].

Nonetheless, over some period of time (acutely or chronically) compensatory mechanisms fail, leading to elevations in right ventricular end-diastolic volume and decreased output. Due to ventricular interdependence, increases in right ventricular end-diastolic volume result directly in decreased left ventricular filling and decreased systemic output [204]. In fact, diastolic ventricular interactions, with decreases in left ventricular end-diastolic volumes, have been demonstrated to be more closely related to stroke volume than PAP in patients with PAH [205]. It is also important to recognize that right and left ventricular contractility are directly related. The ventricles share muscle fibers, the interventricular septum, and the pericardial space. Based on studies that used electrically isolated right heart preparations and experimental aortic constriction, it is estimated that 20–40 % of right ventricular systolic pressure is due to left ventricular contraction [206–208]. In addition, right coronary artery perfusion is dependent, in large part, on the pressure gradient between the aortic root and right ventricle.

Taken together, then, the principles of right ventricular support are: a reduction in right ventricular afterload (i.e. a reduction in pulmonary vascular impedance), optimization of right ventricular volume, augmentation of right ventricular contractility, and maintenance of left ventricular contractility and systemic vascular resistance. Importantly, this strategy requires adequate left ventricular function. The physiology associated with PH due to left heart failure, is quite different. Left heart failure is associated with elevations in left ventricular end-diastolic volume and pressure, the reverse situation of right heart failure due to PAH. Moreover, in this situation decreased right ventricular afterload and/or increased systemic vascular resistance could result in clinical deterioration, with pulmonary edema or impaired cardiac output [53, 54, 209]. Interestingly, however, sildenafil has been shown to increase cardiac output in patients with PH secondary to left heart failure, presumably due to reductions in pulmonary and systemic vascular resistance [210, 211].

The optimization of right ventricular volume presents a significant clinical challenge, as the proper management is dependent on the particular situation [212–217]. Although volume loading may be necessary in some situations, excessive volume may provoke adverse diastolic ventricular interactions. Management aimed at decreasing right ventricular volume (e.g. diuretics) may be necessary [217, 218].

Inotropes are often necessary in order to augment right ventricular contractility, however it remains unclear if one agent is superior. Although dopamine has been shown to increase cardiac output in patients with PH, Liet and colleagues found that dopamine increased the PVR to systemic vascular resistance ratio in preterm infants with a widely patent ductus arteriosus [219, 220]. Based on animal studies, epinephrine may have a superior hemodynamic profile in the setting of PH compared to dopamine, including a decrease in the PVR to systemic vascular resistance ratio, but direct clinical evidence is sparse [221]. Dobutamine, at low doses, may result in a reduction in PVR, while increasing right ventricular contractility. Several clinical studies have demonstrated the efficacy of dobutamine in adult patients with PH [222–224]. Likewise, milrinone, a PDE3 inhibitor and inodilator that augments ventricular contractility while decreasing PVR and systemic vascular resistance, has been shown to improve right ventricular output in adult patients with PH [225–227]. The decrease in systemic vascular resistance may not be desirable and thus may need to be addressed by the addition of a vasopressor. Finally, the drug levosimendan, which is a Ca2+ sensitizing agent and PDE3 inhibitor, holds great promise. Levosimendan has been shown to decrease PVR and improve right ventricular output in adult patients with RV failure secondary to a number of conditions including PH [228–232].

The role of vasopressors is to increase systemic vascular resistance in order to augment right ventricular output through an elevation in left ventricular systolic pressure, and to maintain right coronary perfusion. Norepinephrine has been validated as a useful agent in a number of animal studies [233, 234]. Tourneux and colleagues demonstrated that norepinephrine increased left ventricular output, systemic arterial pressure, and pulmonary blood flow, while decreasing the pulmonary to systemic pressure ratio in 18 newborns with PPHN [235]. Phenylephrine has been shown to increase right coronary blood flow in the setting of increased right ventricular pressures, but may also increase PVR [236, 237]. Vasopressin, a systemic vasoconstrictor and pulmonary vasodilator, has been advocated in the treatment of right ventricular failure secondary to PH, with several positive clinical studies [238–243].

Finally, atrial septostomy as a part of management for chronic pulmonary hypertension has been advocated in order to allow for decompression of the right ventricle due to right-to-left shunting [231, 244–249]. Severe hypoxemia with this approach remains a concern. Recently, Labombarda and colleagues described favorable results with the placement of a Potts anastomosis (descending aorta to left pulmonary artery) in two children with severe idiopathic PH, thereby directing desaturated blood to the lower body [250].

Treatment of Underlying Disease

The ability to impact the course of PH by treating associated conditions is highly variable. Early repair of congenital cardiac defects represents the most successful effort to alter the natural history of PH [73, 122, 251, 252]. Likewise, PH related to treatable left heart disease would be expected to resolve in most cases, depending on the timing of the repair. However, treatment for other associated conditions may not decrease the incidence of PH. For example, PH can develop with Schistosomiasis and HIV infection despite treatment [253, 254]. The reversal of PH associated with portal hypertension after liver transplant has been described, but not in large series [255, 256]. Likewise, the reversal of PH associated with systemic lupus erythematosus after hematopoietic stem cell transplantation has been described, but only as case reports [257]. The use of steroids has been successful in the treatment of some patients with autoimmune disease, mixed connective tissue disease, POEMS syndrome, Langerhans’ cell granulomatosis, and sarcoidosis [133, 258–261]. Advances in the management of sickle cell disease may decrease the incidence of associated PH, but definitive studies are lacking [262].

Subsets of newborns with PPHN are often treatable, and can ultimately survive without PH [263]. Several reports have described the reversal of PH after tonsillectomy or adenoidectomy for the treatment of obstructive sleep apnea [264, 265, 266]. In addition, PH related to high altitude can be reversed when patients move to sea level [267]. Home oxygen therapy is a relatively common treatment for pediatric patients with PH or at risk for developing PH. But, the data are conflicting about whether oxygen therapy alters the disease course, likely due to differences between the diseases that are studied [268, 269]. Finally, an increasing number of metabolic conditions have been found to be associated with PH. For example, the association between thyroid disorders and PH is now well established, and in fact therapy has been shown to reverse PH in these patients [270].

Future Directions

Right heart failure due to elevated pulmonary vascular impedance is the ultimate cause of mortality in most patients with PH. The majority of patients with advanced disease do not respond to acute pulmonary vasodilators, and yet most available therapies either augment pathways that cause vasodilation or inhibit pathways that cause vasoconstriction. Taken together it can be seen that an approach aimed at promoting the regression of structural pulmonary vascular remodeling may be a fundamentally more effective paradigm for patients with PH not associated with treatable conditions or with advanced PH. For critically ill patients with impending right heart failure, novel therapies may yet promote acute pulmonary vascular relaxation in patients that do not respond to the currently available treatments, by targeting new pathways within endothelial and/or smooth muscle cells.

Novel therapies in various stages of development include: direct sGC activators, eNOS couplers, antioxidants, cell-based therapy, vasoactive intestinal peptide, adrenomedullin, Rho-kinase inhibitors, tyrosine kinase inhibitors, statins, peroxisome proliferator–activated receptor agonists, elastase inhibitors, epidermal growth factor receptor inhibitors, and dichloroacetate.

Conclusions

Neonates, infants, and children may present to critical care settings primarily due to PH, or PH may complicate the course of another illness. A basic understanding of pulmonary vascular biology, the pathobiology and pathophysiology of PH, and the therapeutic approach is essential for intensive care physicians caring for these vulnerable patients. Early attention to right heart function is absolutely essential.