recent developments in the pathophysiology and treatment of persistent pulmonary hypertension of the...

THE JOURNAL OF

PEDIATRICS J U N E 1 9 9 5 Volume 126 Number 6

MEDICAL PROGRESS

Recent developments in the pathophysiology and treatment of persistent pulmonary hypertension of the newborn

John P, Kinsella, MD, and Steven H. A b m a n , MD

From the Department of Pediatrics, Divisions of Neonatology and Pulmonary Medicine, Children's Hospital and the University of Colorado School of Medicine, Denver, Colorado

Persistent pulmonary hypertension of the newborn is a complex disorder associated with a wide array of cardiopulmonary diseases, which are characterized by marked pulmonary hypertension and altered vasoreactivity, leading to right-to-left shunting of blood across the patent ductus arteriosus and foramen ovale. 1-3 Extrapulmonary shunting associated with high pulmonary vascular resistance in severe PPHN can cause critical hypoxemia, which is often poorly responsive to inspired oxygen or pharmacologic vasodilation. 4 However, the syndrome of PPHN is often associated with severe parenchymal lung disease (e.g., lung hypoplasia, meconium aspiration pneumonitis, bacterial pneumonia, and surfactant deficiency), which causes intrapulmonary shunting and further complicates the clinical course and response to treatment. Moreover, disturbances in cardiac performance, hypovolemia, and decreased systemic vascular resistance may compromise the tenuous balance between the systemic and pulmonary circulation in PPHN. Thus effective therapy for neonatal hypoxemic respiratory failure complicated by extrapulmonary venoarterial admixture requires vigilant attention to all aspects of these cardiopulmonary interactions (Fig. 1).

Submitted for publication Aug. 8, 1994; accepted Feb. 10, 1995. Reprint requests: John P. Kinsella, MD, Division of Neonatology, Box B-070, Children's Hospital, 1056 E. 19kh Ave., Denver, CO 80218-1088. THE JOURNAL OF PEDIATRICS 1995;126:853-64 Copyright © 1995 by Mosby-Year Book, Inc. 0022-3476/95/$3.00 + 0 9/18/64030

Treatment of PPHN has been limited by the lack of vasodilator agents with selective pulmonary vascular effects and by the ineffectiveness of therapies for severe parenchymal lung disease and systemic hemodynamic collapse (e.g., bacterial sepsis syndromes). The treatment of PPHN has been influenced by recent insights into fetal and transitional pulmonary vasoregulation, newer approaches to management of severe parenchymal lung disease in newborn infants, and the potential role of inhaled nitric oxide as a selective pulmonary vasodilator. We will review (1) recent develop

CDH Congenital diaphragmatic hernia ECMO Extracorporeal membrane oxygenation ET Endothelin HFOV High-frequency oscillatory ventilation HMD Hyaline membrane disease NO Nitric oxide PPHN Persistent pulmonary hypertension of ~e

newborn

merits in vascular biology concerning the endothelial- derived products NO and endothelin and (2) the potential applications (and limitations) of inhalational NO in the management of PPHN.

F E T A L A N D T R A N S I T I O N A L P U L M O N A R Y V A S O R E G U L A T I O N

The fetal circulation is characterized by high pulmonary vascular resistance; pulmonary blood flow accounts for less than 10% of combined ventricular output in the late-gesta-

8 5 3

8 $ 4 Kinsella and Abman The Journal of Pediatrics June 1995

PULMONARY

VASCULAR

(structural changes; altered reactivity to dilator and constrictor stimuli)

t PVR J SVR

1 t right-to-left shunting

at PDA and FO /

hypoxia, hypercarbia, acidosis

1 LUNG

lung volume

compliance

t intrapulmonary shunt

HEART

(RV pressure overload, hypotension, and

LV dysfunction)

Fig. 1. Cardiopulmonary interactions in PPHN. PVR, Pulmonary vascular resistance; SVR, systemic vascular resistance; PDA, patent ductus arteriosus; FO, foramen ovale; RV, fight venla'icular; LV, left ventricular.

tion ovine fetus. 5 Mechanisms responsible for maintaining high fetal pulmonary vascular resistance and causing sustained pulmonary vasodilation at birth are incompletely un- derstood; however, studies in fetal and transitional pulmonary vasoregulation have led to increased understanding of the normal physiologic control of pulmonary vascular resistance. Fetal and neonatal pulmonary vascular tone is mod- ulated through a balance between vasoconstrictor and vasodilator stimuli, including mechanical factors (e.g., lung volume) and endogenous mediators (Table). Among multiple vasoactive mediators involved in perinatal pulmonary vasoregulation, recent interest has focused on endothelin. Endothelin type 1 is a vasoactive peptide produced by vascular endothelium that is unique in its ability to cause potent and sustained vasoconstriction. 6 In the late-gestation ovine fetal lung, brief infusions of ET-1 cause transient vasodilation; however, with prolonged infusion, pulmonary vascular resistance increases. 7 Similar to the effects of other vasoac- five mediators, the effects of ET-1 on pulmonary vascular resistance are also tone dependent, causing pulmonary vasoconstriction in the ventilated lung. 8 The effects of endothelin on pulmonary vascular resistance in the normal fetus are mediated through distinct receptor subtypes, 9 two of which have been identified. The ETA receptor has been localized to the vascular smooth muscle cell, 1° and the ETB receptor is present on the vascular endothelial cell. 11

In the late-gestation ovine feats, intrapulmonary infusions

of BQ 123 (a selective ETA receptor antagonist) caused sustained reductions in pulmonary vascular resistance, which suggests that endogenous endothelin formation contributes to basal pulmonary vascular tone in the fetus. In contrast, selective ETB receptor stimulation (sarafotoxin $6c) causes pulmonary vasodilation through endothelial cell NO release. Similarly, inhibition of endogenous NO formation attenuates the dilator response to exogenous ET-1.12 It is likely that endogenous production of ET-1 by vascular endothelium pri- marily causes pulmonary vasoconstriction by its action on the A receptor of the vascular smooth muscle cell. 13

It is possible that endothelin contributes to the altered vasoreactivity in the pulmonary circulation of patients with PPHN. Severe hypoxia stimulates endothelin secretion and gene expression in vitro, 14 and the pulmonary vasoconstriction associated with compression of the ducats arteriosus in the late-gestation ovine fetus is caused in part by endothelin stimulation of the pulmonary vascular smooth muscle cell. 15 Moreover, circulating ET-1 levels in human neonates with PPHN are markedly elevated, correlate with disease severity, and decline with resolution of the PPHN.16 Understand- ing the role of endothelin in the functional and structural changes characterizing PPHN will be a critical component in studies of this complex disorder.

The vasoconstrictor effects of endothelin are offset by dilator substances produced by the pulmonary vascular endothelium, including the recently described endothelium-de-

The Journal of Pediatrics Kinsella and Abman 8 5 5 Volume 126, Number 6

Table. Factors that modulate pulmonary vascular resistance in the near-term and term transitional and neonatal pulmonary circulation

Lowers PVR Increases PVR

Endogenous mediators and mechanisms Oxygen Nitric oxide PGI2, E2, D2 Adenosine, ATP, magnesium Bradykinin Atrial natriuretic factor Alkalosis K + channel activation Histamine Vagal nerve stimulation Acetylcholine [3-Adrenergic stimulation

Mechanical factors Lung inflation Vascular cell structural changes Interstitial fluid and pressure changes Shear stress

Endogenous mediators and mechanisms Hypoxia Acidosis Endothelin- 1 LeukoVienes Thromboxanes Platelet activating factor Ca ++ channel activation a-Adrenergic stimulation PGF2~

Mechanical factors Overinflation or uuderinflation Excessive muscularization, vascular remodeling Altered mechanical properties of smooth muscle Pulmonary hypoplasia Alveolar capillary dysplasia Pulmonary thromboemboli Main pulmonary artery distention Ventricular dysfunction, venous hypertension

PVR, Pulmonary vascular resistance; PGI2, E2, D2, prostaglandins I2, E2, and 1)2; ATP, adenosine triphosphate; PGF2e~, prostaglandin F2~.

rived relaxing factor, NO. The pharmacologic activity of ni- trovasodilators derives from the release of NO, and NO was recognized as a potent vascular smooth muscle relaxant as early as 1979.17 In 1987 investigators from two separate

laboratories reported that the endothelium-derived relaxing factor was NO or an NO-containing substance, is, 19 Recent reports have described the physiologic role of NO in fetal and transitional pulmonary vasoregulafion. NO modulates basal pulmonary vascular tone in the late-gestation fetus; pharmacologic NO blockade inhibits endothelium-dependent pulmonary vasodilafion and attenuates the rise in pulmonary blood flow at delivery, implicating endogenous NO formation in postnatal adaptation after birth. 2° Increased fetal oxygen tension augments endogenous NO releaseY, 22 and the increase in pulmonary blood flow in response to rhythmic distention of the lung and high inspired oxygen concentrations are mediated in part by endogenous NO release. 23 However, in these studies the pulmonary circulation was structurally normal. Studies using a model of PPHN in which marked structural pulmonary vascular changes are induced by prolonged fetal ductus arteriosus compression demonstrated that the structurally abnormal pulmonary circulation was also functionally abnormal. 24, 25 Despite the progressive loss of endothelium-dependent (acetylcholine) vasodilation with prolonged ductus compression in this model, the response to endothelium-independent (ANP, NO) vasodilafion was intact. 24

Exogenous (inhaled) NO causes potent, sustained, and selective pulmonary vasodilation in the late-gestation ovine fetus.26 On the basis of the long-term ambient levels consid-

ered to be safe for adults by regulatory agencies in the United States, 27 studies were performed in near-term lambs with the

use of inhaled NO at doses of 5, 10, and 20 ppm. Inhaled NO caused a dose-dependent increase in pulmonary blood flow in newborn lambs undergoing mechanical ventilation. In- haled NO at 20 ppm did not decrease coronary arterial or cerebral blood flow in this model.

Roberts et a lY studied the effects of inhaled NO on pulmonary hemodynamics in newborn lambs whose lungs were mechanically ventilated; inhaled NO reversed hypoxic pulmonary vasoconstriction, and maximum vasodilation occurred at doses of greater than 80 ppm. They also found that the vasodilation caused by inhaled NO during hypoxia was

not attenuated by respiratory acidosis in this model. Berger et al. 29 investigated the effects of inhaled NO on pulmonary

vasodilation during the course of group B streptococcal sepsis in piglets; inhaled NO at 150 ppm for 30 minutes caused marked pulmonary vasodilation but was associated with physiologically significant increases in methemoglobin concentrations. Corroborating studies in other animal models support the observations that inhaled NO is a selective pulmonary vasodilator at low doses (-<20 ppm). 30"31

C L I N I C A L T R I A L S O F I N H A L E D N O IN I N F A N T S W I T H P P t l N

Recent studies have demonstrated that inhaled NO causes marked improvement in oxygenation in many newborn infants with PPHN. Roberts et ;tl.33 reported that brief (30 minutes) inhalation of NO at 80 ppm improved oxygenation in patients with PPHN, but this response was sustained in

8 5 6 Kinsella and Abman The Journai of Pediatrics June 1995

only one patient after NO was discontinued. In another re- port, rapid improvement in oxygenation in neonates with severe PPHN was demonstrated with the use of doses of 20 ppm NO for 4 hours, after which the dose was decreased to 6 ppm for the duration of treatment34; this strategy resulted in sustained improvement in oxygenation. In a subsequent study, this low-dose NO strategy was used in an additional nine patients with severe PPHN, including two patients with congenital diaphragmatic hernia. 35 The management incor- porated the use of high-frequency oscillatory ventilation to achieve optimal lung inflation during the use of NO. Eight patients had resolution of the underlying PPHN, but one patient with overwhelming sepsis, despite an initial improvement in oxygenation, subsequently required treatment with extracorporeal membrane oxygenation for hemodynamic support. In these pilot studies, we found that 13 of 15 infants with severe PPHN recovered without the need for ECMO. 36 Inhaled NO may also be a useful adjunctive therapy in patients who require early decannulation because of severe complications during ECMO (before reactive pulmonary hypertension has resolved). We have succesfully employed NO in such infants for as long as 21 days after ECMO, at doses as low as 0.35 ppm.

The efficacy of low dose NO (-<20 ppm) in causing acute improvement in oxygenation in patients with severe PPHN has been corroborated in a recent study by Finer et al. 37 These investigators measured the improvement in oxygenation associated with doses of NO ranging from 5 to 80 ppm and found that the acute improvement in oxygenation in PPHN was similar at all doses of NO studied. They also found that oxygen levels increased in patients who did not have extrapulmonary shunting as indicated by echocardiography, which suggests that NO could acutely improve oxygenation in some cases of neonatal hypoxemic respiratory failure without severe PPHN.

M A N A G E M E N T S T R A T E G I E S IN P P H N

Increasing clinical experience with inhaled NO in PPHN has led to improved understanding of the potential role of this potent and selective pulmonary vasodilator. Although con- sensus on diagnostic criteria is lacking, 38 for the purposes of this discussion PPHN is defined as severe neonatal hyoxemic respiratory failure associated with extrapulmonary right-to- left shunting of blood across the foramen ovale or patent ductus arteriosus or both. Patients with idiopathic PPHN have severe pulmonary hypertension without apparent parenchymal lung disease. In idiopathic PPHN (i.e., without significant lung disease) the pulmonary management should be directed at minimizing overzealous mechanical ventilation and avoiding lung overinflation. Selective pulmonary vasodilation with inhaled NO may cause marked improvement in oxygenation in patients with idiopathic PPHN.

However, myriad pathophysiologic disturbances can cause pulmonary hypertension. PPHN frequently compficates the course of more common causes of neonatal respiratory distress, which are marked by severe lung disease (e.g., lung hypoplasia, meconium aspiration, pneumonitis, and surfactant deficiency). Disturbances in cardiac performance can cause further clinical deterioration. 39 Recognizing the rela- tive roles of the pulmonary vascular, pulmonary parenchy- real, and cardiac components contributing to hypoxemic respiratory failure is vital in an assessment of the effects of new therapies in PPHN.

Rudolph, 4° Geggel and Reid, 41 and others have described classifications of PPHN based predominantly on structural abnormalities of the lung and the pulmonary vascular smooth muscle. Severe PPHN has been associated with (1) under- development of the pulmonary circulation (e.g., congenital diaphragmatic hernia), (2) maldevelopment with excessive muscularization of pulmonary arteries, and (3) maladaptation or failure of the pulmonary vascular resistance to decline after birth in an otherwise structurally normal pulmonary vascular bed. As pathologic classifications, these descrip- tions are important, but the clinical manifestations of severe neonatal hypoxemic respiratory failure are infrequently at- tributable to a single pathophysiologic or structural classification. It is likely that all cases reflect some measure of "maladaptation" related to the multisystem involvement of this disorder. A limitation of such classifications is exempli- fied in the syndrome of meconium aspiration. The clinical manifestations of this disease may reflect severe reactive pulmonary hypertension, but the pulmonary parenchymal disease may be variable. Progressive deterioration in oxygenation may be the result of disturbances in cardiac, hemodynamic, or pulmonary function. For example, the chest radiograph may be initially marked by patchy parahilar con- solidation associated with aspiration of particulate rneconium, but subsequent progression of diffuse parenchy- real disease may complicate the clinical course (perhaps related to a "secondary-" surfactant deficiency or surfactant inactivation).42, 43 A subset of patients with this syndrome has predominantly large airways disease associated with aspiration of particulate meconium, leading to the "check valve" type of obstruction, focal overinflation, and air leak. Moreover, decreased cardiac performance and reduced left ventricular output can decrease systemic vascular resistance. exacerbating the right-to-left shunting of blood at the ductus arteriosus.

Another disease category in which severe hypoxemia may be caused by multiple factors is congenital diaphragmatic hernia. In infants with CDH, increased pulmonary vascular resistance is related to the small cross-sectional area of pulmonary vessels causing a fixed component of high pulmonary vascular resistance, and altered pulmonary vasoreac-


11 O0

80

60 Pa02 ,

40-

20

0 I IMV + NO [ HFOV ] I I I I I I I I I I I

0 10 20 30 40 50 60 70 80 90 100 TIME (minutes)

Fig. 9 Role of intrapulmonary shunting in severe PPHN: effects of inhaled NO and HFOV in a patient with PPHN and severe parenchymal lung disease. Before treatment with inhaled NO (20 ppm), echocardiography demonstrated right-to-left shunting at the patent ductus arteriosus (PDA R ---) L). After 30 minutes of NO therapy during conventional mechanical ventilation, the extrapulmonary shunting had reversed (PDA L ~ R); however, improvement in oxygenation was insuffi- cient. This response to inhaled NO demonstrated the contribution of intrapulmonary shunting in this patient, who responded well to lung recruitment using HFOV. Pa02, Partial pressure of oxygen, arterial; IMV, intermittent mandatory ventilation.

tivity leads to reactive pulmonary hypertension. In some patients with CDH, left ventricular mass is diminished, 44, 45 which may also contribute to pulmonary hypertension and decreased left ventficular output. Moreover, lung immaturity, underinflation, and susceptibility to lung injury during mechanical ventilation further complicate the management of patients with CDH. In these settings, therapies that target only a single pathophysiologic component of the syndrome will often be ineffective.

Alternative approaches to mechanical ventilation of the newborn infant with PPHN have attracted considerable interest. Alkalosis induced by mechanical hyperventilation has decreased pulmonary arterial pressure and improved oxygenation in some patients with PPHN. However, concerns have been raised regarding the potential complications associated with volu-trauma, and sustained hypocapneic alkalosis may have adverse neurologic effects. 46, 47 Wung et ai.48 described an approach to management of PPHN that is characterized by individualized ventilator strategies based on the underlying disease state, minimal use of paralysis, pulmonary vasodilation using tolazoline, and avoidance of hypocapneic alkalosis. A corroborating study using a similar strategy reported survival in five of six infants with PPHN49; however, controlled trials have not been conducted.

Exogenous surfactant therapy is another promising adjunctive treatment for near-term and term neonates with severe hypoxemic respiratory failure. There is evidence that surfactant deficiency contributes to decreased lung compliance and atelectasis in some patients with PPHN. 5°-52 Recent

studies have suggested that exogenous suffactant therapy can cause sustained clinical improvement in term infants with pneumonia and meconium aspiration syndrome, 53 and can reduce the duration of ECMO. 54 A multicenter trial to study the role of surfactant treatment in term neonates with severe respiratory failure is ongoing.

Considering the important role of parenchymal lung disease in many cases of PPHN, one might not expect pharmacologic pulmonary vasodilation alone to cause sustained clinical improvement. The effects of inhaled NO may be suboptimal when lung volume is decreased in association with pulmonary parenchymal disease. 55 Atelectasis and air space disease (pneumonia, pulmonary edema) will decrease effective delivery of this inhalational agent to its site of action in terminal lung units. In PPHN associated with heter- ogeneous (patchy) parenchymal lung disease, inhaled NO may be effective in achieving optimal ventilation-perfusion matching by preferentially causing vasodilation in lung units that are well ventilated. The effects of inhaled NO on ventilation-perfusion matching appear to be optimal at low doses (<20 ppm). 56, 57 However, in cases complicated by homoge- neous (diffuse) parenchymal lung disease and underinflation, pulmonary hypertension may be exacerbated because of the adverse mechanical effects of underinflation on pulmonary vascular resistance, resulting in functional hypoplasia. In this setting, effective treatment of the underlying lung disease is essential (and sometimes sufficient) to cause resolution of the accompanying pulmonary hypertension.

In cases complicated by severe lung disease, inhaled NO

8 5 8 Kinsella and Abman The Journal of Pediatrics June 1995

A 1 oo

80

40

( H o u r s )

Fig. 3. A, Independent and combined effects of inhaled NO and HFOV on PaQ in a patient with congenital diaphragmatic hernia and PPHN. Although this patient had an initial response to inhaled NO during conventional mechanical ventilation (CMV), this response was not sustained. Oxygenation did not improve during 1 hour of HFOV, but marked improvements in lung volume were noted on chest radiograph. After adequate lung inflation was achieved, there was a marked and sustained improvement in oxygenation in response to inhaled NO therapy. B, Radiographic changes in lung inflation associated with HFOV. Marked improvement in oxygenation with inhaled NO occurred only after adequate lung inflation was achieved with HFOV.

alone will likely be ineffective without optimal pulmonary

management and adequate alveolar recruitment. We employed high-frequency oscillatory ventilation to achieve optimal lung inflation and to cause minimal lung injury from

tidal volume mechanical breaths (Fig. 2). When HFOV has been used with a strategy designed to recruit atelectatic lung and sustain lung volume, it has been more efficacious than conventional mechanical ventilation in severe neonatal hy-


poxemic respiratory failure. 58 HFOV allows for effective alveolar ventilation and recruitment while reducing the potential parenchymal and airway injury associated with large phasic pressure and lung volume changes. 59 High end- inspiratory lung volume (such as occurs during conventional ventilation) has been implicated in the development of pulmonary edema and lung injury. 6° However, the strategy employed during HFOV is critically important for optimal lung inflation and minimal risk of adverse cardiopulmonary interactions.61, 62 If a strategy that does not adequately recruit and sustain lung volume is used, HFOV treatment will often be ineffective. 63 Because of marked attenuation of airway pressure across the endotracheal tube and airways during HFOV, the proximal airway pressure measurements do not accurately reflect the pressure transmitted to the lung. 64 Therefore the conventional indexes of severity of illness (oxygenation index, ventilation index) may not be applica- ble during HFOV. An effective strategy during HFOV often requires stepwise increases in mean airway pressure (3 to 5 cm H20 increments) and pressure amplitude until improvement in oxygenation occurs, with rapid reduction in airway pressure in response to improved oxygenation and lung volume. Airway pressure is poorly transmitted to the pleural space in the underinflated and poorly compliant lung. How- ever, as lung inflation and compliance improve, ventilator support must be reduced to avoid injury.

Because of the diverse nature of diseases complicating PPHN, there is no single approach to mechanical ventilation. Ventilator adjustments must be made with attention to radiographic changes of the accompanying lung disease and to hemodynamic status. Although the optimal roles for HFOV and NO are unclear, some patients appear to benefit from combination treatment without adverse effects. 65 In patients with severe PPHN and parenchymal lung disease or pulmonary hypoplasia (CDH), optimal management may include HFOV to recruit and maintain lung volume, thus promoting effective delivery of the inhalational vasodilator NO (Fig. 3).

Serial echocardiographic measurements may prove useful during NO treatment to determine the effects of therapy on extrapulmonary shunting. The cause of suboptimal or transient improvement in oxygenation associated with inhaled NO therapy may be difficult to interpret without adequate assessment of the severity of extrapulmonary shunting. In- haled NO may eliminate the extrapulmonary right-to-left shunting (as measured with echocardiography) but not result in adequate improvement in oxygenation. In this setting the primary pathophysiologic disturbance is likely caused by severe intrapulmonary shunting, and effective alveolar recruitment is essential.

In some patients the effects of inhaled NO may be time dependent, with gradual improvement in oxygenation for a

period of several hours. The rate of response to inhaled NO is likely dependent on several factors, including the nature of the underlying lung disease, the presence of circulating vasoconstrictor agents, cardiac performance, and structural changes in the pulmonary vasculamre. Although some patients have rapid improvement in oxygenation with NO therapy, others have a slower, gradual response (Fig. 4).

Potential mechanisms for suboptimal NO responses and loss of NO responsiveness require further study. Serial echocardiographic determinations of cardiac performance may yield predictors for refractory cardiac dysfunction and may indicate the need for the cardiac support provided by ECMO. Cfi'culating vasoconstrictor substances could potentially abate the vasodilatory effects of inhaled NO. More- over, both structural and functional (e.g., decreased soluble guanylate cyclase activity) changes in the pulmonary vascular smooth muscle cell may alter responsiveness to exogenous NO. It is also possible that the combination of other agents with inhaled NO (e.g., the phospodiesterase inhibitor dipyridamole) could augment pulmonary vascular cyclic guanosine monophosphate concentrations and allow for more effective vasodilation at lower doses of NO. 66-6s

N I T R I C O X I D E IN THE P R E M A T U R E I N F A N T ' S P U L M O N A R Y C I R C U L A T I O N

The fetus is characterized by both structural and functional pulmonary immaturity, including surfactant deficiency. Pul- monary immaturity and hyaline membrane disease lead to respiratory failure after premature delivery, and exogenous surfactant therapy can decrease the severity of the respiratory insufficiency. 69 However, exogenous surfactant therapy re- sults in suboptimal responses in up to 50% of human neonates thought to have HMD, 7° which suggests that other problems of prematurity (e.g., structural lung immaturity or altered vascular responses to dilator stimuli) or complications of mechanical ventilation contribute to respiratory failure.

In some experimental models of HMD, pulmonary vascular resistance falls in response to mechanical ventilation alone, and surfactant therapy does not change the direction or magnitude of sytemic-to-pulmonary shunting across the patent ductus ar ter iosus . 71' 72 However, progressive deterioration after surfactant therapy occurs in a subset of premature human neonates with HMD, leading to severe pulmonary hypertension with right-to-left shunting across the ductus arteriosus. 7376 Recent studies have shown that the association of pulmonary hypertension with severe HMD leads to increased mortality rates despite surfactant therapy.77

We recently reported that endogenous NO production modulates basal pulmonary vascular tone as early as 115 days of gestational age (term = 147 days) in the ovine fetus

8 6 0 Kinsella and Abman The Journal of" Pediatrics June 1995

250

225

200

175

Pa02 1so

125

100

75

5O

25

0

0 30 60 90 120 150 180 210 240

TIME (minutes} Fig. 4. Variability in time-dependent responses to inhaled NO in PPHN: Change in PaO2 for three patients with severe PPHN treated with inhaled NO. Note variability in responses and time-dependent improvement in oxygenation. All patients recovered without the need for ECMO. (Mean baseline PaO2 = 19 +_ 3; FIO2 at 4-hour time point = 0.96.)

OI

70

60

50

40

30

20

10

0

i

0 6 12

NO TIME (hours)

Fig. 5. Response to inhaled NO in premature infants with severe hypoxemic respiratory failure: Oxygenation index (O/) is shown for three premature infants (26 to 28 weeks of gestation). All patients had sustained improvement in oxygenation during inhaled NO therapy, but the most rapid improvement in oxygenation occurred in patients with extrapulmonary shunting at the foramen ovale and ductus arteriousus (patients O and ~).

and contributes to the increase in pulmonary blood flow after extremely premature delivery. 78 In addition, inhaled NO caused marked increases in pulmonary blood flow after NO synthase inhibition, demonstrating marked responsiveness of the vascular smooth muscle cell to NO very early in ges-

tation. We also found that during tidal-volume mechanical ventilation with high inspired oxygen concentrations after delivery of extremely premature lambs, altered pulmonary vasoregulation leads to increased pulmonary vascular resistance, decreased pulmonary blood flow, and worsening gas


exchange despite a good initial response to exogenous surfactant. The pulmonary hypertension associated with severe HMD in the extremely premature lamb is responsive to exogenous NO. Continuous treatment with low-dose NO attenuates the decline in gas exchange and pulmonary perfusion during prolonged mechanical ventilation. 79

These findings have potential implications for the clinical management of severe respiratory failue in premature infants. The immature pulmonary circulation is responsive to inhaled NO, which suggests a potential therapeutic role in the management of the preterm infant with pulmonary tay- pertension. It is possible that the early use of low-dose inhaled NO could play a role in the management of the premature subject with severe respiratory failure unresponsive to exogenous surfactant therapy, s° by improving ventilation- perfusion matching and reducing pulmonary vascular resistance (Fig. 5). However, little is known of the potential pulmonary and systemic toxic effects that could occur in the premature subject exposed to inhalafional NO, and studies designed to carefully assess such effects are essential before routine clinical application.

T O X I C I T Y

The clinical studies described above were designed to in- vestigate the hemodynamic effects of inhaled NO within "nontoxic" concentrations, but concerns remain regarding potential toxic effects, including methemoglobinemia and lung injury caused by NO2, peroxynitrite, and hydroxyl radical formation, a, s2 Although tittle evidence exists for NO toxicity at low concentrations in adult animals, s3s5 further studies in the neonatal lung are needed. Of particular concern are the potential effects of NO on inhibition of DNA synthesis and deamination of DNA. s6, s7 Moreover, long-term exposure to high concentrations of NO may cause down-regulation of endogenous NO synthesis, ss However, inhaled NO may also have a protective effect by attenuating the increases in capilla'y permeability associated with oxidant-induced acute lung injury, s9

The effects of inhaled NO may not be limited to the pulmonary vasculature. Preliminary evidence suggests that NO at high doses may modify the inflammatory response of alveolar macrophages, 9° and the possibility- exists that circulating NO-adducts could have adverse extrapulmonary effects including neurotoxic effects in the developing brain. 91

Another potentially important effect of NO inhalation is the prolongation in bleeding time at doses of 30 to 300 ppm. 92 Endogenous NO inhibits platelet adhesion to the vascular endothelium, and this effect may be related to the formation of stable S-nitroso-proteins. %, 94 However, in a small study of premature infants treated with inhaled NO, no change in bleeding time occurred. 95 Moreover, as with most therapeutic agents, the complications associated with NO are

fikely dose dependent, and NO should be used in the lowest effective dose. However, the safe and effective application of inhalational nitric oxide therapy to neonates with severe cardiopulmonary failure must also take into account decreased antioxidant host defenses in the immature lung and the potential risk of surfactant inactivation. 96 Controlled clinical trials are ongoing to clarify the potential toxic effects of this new therapy, including NO-induced target cell toxic effects, pulmonary inflammatory cell function, and pathologic consequences of long-term exposure. 97

S U M M A R Y

Successful management of severe PPHN depends on the application of appropriate strategies to manage the cardiopulmonary interactions that characterize this syndrome. Manifestations of PPHN often involve dysfunctional pulmonary vasoregulation, with suprasystemic pulmonary vascular resistance causing extrapulmonary shunting, pulmonary parenchymal disease causing intrapulmonary shunting, and systemic hemodynamic deterioration. Inhaled NO can cause marked improvement in oxygenation when optimal lung inflation is achieved and systemic blood volume and vascular resistance are adequate. Although concern has been expressed regarding potential increases in costs associated with this new therapy, 9s we have found that the successful application of inhaled NO in PPHN has reduced costs of hospitalization and duration of hospital stay by approxi- mately 50% and 40%, respectively. However, inhaled NO alone is unlikely to cause sustained improvement in oxygenation in neonatal hypoxernic respiratory failure associated with severe parenchymal lung disease without extrapulmonary shunting. Inhaled NO may be an important tool in the management of severe PPHN when its application is limited to patients with severe extrapulmonary shunting and vigilant attention is given to changes in the clinical course.

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