Treatment of PPHN

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In general, management of the newborn with PPHN includes the treatment and avoidance of hypothermia, hypoglycemia, hypocalcemia, anemia and hypovolemia; correction of metabolic acidosis; diagnostic studies for sepsis; serial monitoring of arterial blood pressure, pulse oximetery (pre- and post-ductal); and transcutaneous PCo2, especially with the initiation of high frequency oscillatory ventilation (HFOV). Therapy includes aggressive management of systemic hemodynamics with volume and cardiotonic therapy (dobutamine, dopamine, and milrinone), in order to enhance cardiac output and systemic 02 transport. In addition, increasing systemic arterial pressure can improve oxygenation in some cases by reducing right-to-left extrapulmonary shunting. Failure to respond to medical management, as evidenced by failure to sustain improvement in oxygenation with good hemodynamic function, often leads to treatment with extracorporeal membrane oxygenation (ECMO) (82). Although ECMO can be a life-saving therapy, it is costly, labor intensive, and can have severe side effects, such as intracranial hemorrhage. Since arterio-venous ECMO usually involves ligation of the carotid artery, acute and long-term CNS injury remain major concerns.

The goal of mechanical ventilation is to improve oxygenation and to achieve "optimal" lung volume to minimize the adverse effects of high or low lung volumes on PVR, while minimizing the risk for lung injury ("volutrauma"). Mechanical ventilation using inappropriate settings can produce acute lung injury (ventilator-induced lung injury; VILI), causing pulmonary edema, decreased lung compliance and promoting lung inflammation due to increased cytokine production and lung neutrophil accumulation. The development of VILI is an important determinant ofclinical course and eventual outcome ofnewborns with hypoxemic respiratory failure, and postnatal lung injury worsens the degree of pulmonary hypertension (60). Failure to achieve adequate lung volumes (functional residual capacity) contributes to hypoxemia and high PVR in newborns with PPHN. Some newborns with parenchymal lung disease with PPHN physiology improve oxygenation and decrease right-to-left extra-pulmonary shunting with aggressive lung recruitment during high frequency oscillatory ventilation (37) or with an "open lung approach" of higher positive end-expiratory pressure with low tidal volumes, as more commonly utilized in older patients with ARDS (10).

Marked controversy and variability exists between centers regarding the use of hyperventilation to achieve alkalosis in order to improve oxygenation. Past studies have clearly shown that acute hyperventilation can improve Pa02 in neonates with PPHN, providing a diagnostic test and therapeutic strategy. However, there are many issues with the use of hypocarbic alkalosis for prolonged therapy. Depending on the ventilator strategy and underlying lung disease, hyperventilation is likely to increase VILI, and the ability to sustain decreased PVR during prolonged hyperventilation is unproven. Studies suggest that the response to alkalosis is transient, and that alkalosis may paradoxically worsen pulmonary vascular tone, reactivity and permeability edema (23, 43). In addition, prolonged hyperventilation reduces cerebral blood flow and02 delivery to the brain, potentially worsening neurodevelopmental outcome.

Additional therapies, including infusions of sodium bicarbonate, surfactant therapy and the use of intravenous vasodilator therapy, are also highly variable between centers. Although surfactant may improve oxygenation in some lung diseases, such as meconium aspiration and RDS, a multicenter trial failed to show a reduction in ECMO utilization in newborns with PPHN (46). The use of intravenous vasodilator drug therapy, with such agents as tolazoline, magnesium sulfate, PGI2 and sodium nitroprusside, is also controversial due to the nonselective effects of these agents on the systemic circulation. Systemic hypotension worsens right-to-left shunting, may impair 02 delivery and worsen gas exchange in patients with parenchymal lung disease. In addition, the initial response to such agents as tolazoline are often transient, and can have severe adverse effects (e.g., gastrointestinal hemorrhage). Endotracheal administration of vasodilators, including tolazoline and sodium nitroprusside, may cause selective pulmonary vasodilation and minimize systemic hypotension. However, these data are largely limited to animal studies, and evidence is currently lacking that supports the safety and efficacy of this approach in humans.

Pulmonary Artery Pressure Aortic Pressure

Pulmonary Artery Pressure Aortic Pressure

Pre And Post Ductal Sats Pphn

Figure 4. A: Physiologic effects of Inhaled NO in the perinatal lamb. As shown in the upper panel, inhaled NO decreases pulmonary artery pressure (PAP) but not aortic pressure (AoP), and increases pulmonary blood flow (lower panel) during mechanical ventilation with hypoxic gas. B: Low doses of inhaled NO increases oxygenation (as assessed by the arterial to alveolar ratio (a/A 02)) in human newborns with severe PPHN who met ECMO criteria. Improvement in oxygenation was sustained with continuous treatment of inhaled NO, obviating the need for ECMO in these patients (Modified from Refs. 39,40).

Figure 4. A: Physiologic effects of Inhaled NO in the perinatal lamb. As shown in the upper panel, inhaled NO decreases pulmonary artery pressure (PAP) but not aortic pressure (AoP), and increases pulmonary blood flow (lower panel) during mechanical ventilation with hypoxic gas. B: Low doses of inhaled NO increases oxygenation (as assessed by the arterial to alveolar ratio (a/A 02)) in human newborns with severe PPHN who met ECMO criteria. Improvement in oxygenation was sustained with continuous treatment of inhaled NO, obviating the need for ECMO in these patients (Modified from Refs. 39,40).

Inhaled nitric oxide (iNO) therapy at low doses (5-20 ppm) improves oxygenation and decreases the need for ECMO therapy in patients with diverse causes of PPHN (Fig. 4A) (15, 19, 40, 41, 55, 67, 68). Multicenter clinical trials support the use of iNO in near-term (>34 weeks gestation) and term newborns, and the use of iNO in infants <34 weeks gestation remains investigational. Studies support the use of iNO in infants who have hypoxemic respiratory failure with evidence of PPHN, who require mechanical ventilation and high inspired oxygen concentrations. The most common criterion employed has been the oxygenation index (OI; mean airway pressure times Fi02 times 100 divided by Pa02. Although clinical trials commonly allowed for enrollment with OI levels >25, the mean OI at study entry in multicenter trials was ~40. It is unclear whether infants with less severe hypoxemia would benefit from iNO therapy.

The first studies of iNO treatment in term newborns reported initial doses that ranged from 80 ppm to 6-20 ppm (40, 68). In the latter report, rapid improvement in was achieved at low doses (20 ppm) for 4 hours, and this response was sustained with prolonged therapy at 6 ppm (Fig. 4B) (40).

Subsequent multicenter studies confirmed the efficacy of this dosing strategy, and showed that increasing the dose in non-responders did not improve outcomes (Table 2). The available evidence, therefore, supports the use of doses of iNO beginning at 20 ppm in term newborns with PPHN, since this strategy decreased ECMO utilization without an increased incidence of adverse effects. Although brief exposures to higher doses (40-80 ppm) appear to be safe, sustained treatment with 80 ppm NO increases the risk of methemoglobinemia. In our practice, we discontinue iNO if the Fi02 is <0.60 and the Pa02 is >60 without evidence of rebound pulmonary hypertension or a rise in Fi02 >15% after iNO withdrawal. Prolonged need for iNO therapy without resolution of disease should lead to a more extensive evaluation to determine whether previously unsuspected anatomic lung or cardiovascular disease is present (e.g., pulmonary venous stenosis, alveolar capillary dysplasia, severe lung hypoplasia, or others) (22).

Table 2. Summary of Multicenter Randomized Trials of Inhaled NO in Term Newborns with Hypoxemia and PPHN, Showing Reduction of ECMO Utilization


iNO Therapy

P- va lue

ECMO Therapy


























* Retrospective analysis. Data are from the NINOS (ref. 55), CINRGI (ref. 15), and INOSG (ref. 67) trials.

* Retrospective analysis. Data are from the NINOS (ref. 55), CINRGI (ref. 15), and INOSG (ref. 67) trials.

In newborns with severe lung disease, HFOV is frequently used to optimize lung inflation and minimize lung injury. In clinical pilot studies using iNO, the combination of HFOV and iNO caused the greatest improvement in oxygenation in some newborns who had severe PPHN complicated by diffuse parencyhmal lung disease and underinflation (e.g. RDS, pneumonia). A randomized, multicenter trial demonstrated that treatment with HFOV+iNO was often successful in patients who failed to respond to HFOV or iNO alone in severe PPHN, and differences in responses were related to the specific disease associated with the complex disorders of PPHN (41). For patients with PPHN complicated by severe lung disease, response rates for HFOV+iNO were better than HFOV alone or iNO with conventional ventilation. In contrast, for patients without significant parenchymal lung disease, both iNO and HFOV+iNO were more effective than HFOV alone. This response to combined treatment with HFOV+iNO likely reflects both improvement in intrapulmonary shunting in patients with severe lung disease and PPHN (using a strategy designed to recruit and sustain lung volume, rather than to hyperventilate) and augmented NO delivery to its site of action. Although iNO may be an effective treatment for PPHN, it should be considered only as part of an overall clinical strategy that cautiously manages parenchymal lung disease, cardiac performance, and systemic hemodynamics.

Although clinical improvement during inhaled NO therapy occurs with many disorders associated with PPHN, not all neonates with acute hypoxemic respiratory failure and pulmonary hypertension respond to iNO. Several mechanisms may explain the clinical variability in responsiveness to iNO therapy. An inability to deliver NO to the pulmonary circulation due to poor lung inflation is the major cause of poor responsiveness. In some settings, administration of NO with high frequency oscillatory ventilation has improved oxygenation more effectively than during conventional ventilation in the same patient. In addition, poor NO responsiveness may be related to myocardial dysfunction or systemic hypotension, severe pulmonary vascular structural disease, and unsuspected or missed anatomic cardiovascular lesions (e.g., total anomalous pulmonary venous return, coarctation of the aorta, alveolar capillary dysplasia, and others).

Another mechanism of poor responsiveness to inhaled NO may be altered smooth muscle cell responsiveness, and there are emerging therapies that take advantage of our increased understanding of the cellular effects of iNO. Inhibition of cGMP-metabolizing phosphodiesterase (PDE5) activity may increase efficacy of iNO by increasing cGMP concentrations. Recently approved by the FDA for the treatment of male erectile dysfunction, sildenafil is a potent and highly specific PDE5 inhibitor. Intravenous sildenafil was found to be a selective pulmonary vasodilator with efficacy equivalent to inhaled nitric oxide in a piglet model of meconium aspiration (71).

New studies indicate that scavengers of reactive oxygen species such as N-acetylcysteine or superoxide dismutase (SOD) can augment responsiveness to iNO. A single dose of recombinant human SOD significantly enhanced the response to iNO in the ductal ligation lamb model of PPHN (74). Besides administering iNO as an inhalational agent, Moya et al. have recently suggested that treatment with a unique gas, O-nitrosoethanol (ethyl nitrite, ENO), may increase the endogenous pool of S-nitrosothiols in the airway and circulation, thereby providing a new treatment strategy for PPHN (53). In a brief report, ENO briefly improved post-ductal arterial saturation for 4 hours in 7 neonates. However, only a few patients improved oxygenation and the response was small, was associated with a rapid rise in methemoglobinemia, and may have had systemic effects. Another potential approach to augment pulmonary vasodilation may be to combine treatment with PGI2. Whereas intravenous PGI2 can decrease systemic arterial pressure, inhaled improved oxygenation in 4 infants with PPHN who did not respond or sustain their response to iNO without worsening systemic hemodynamics (35). Whether these strategies will be more effective or will improve responsiveness in neonates who fail to respond to iNO therapy is unknown.

Finally, although newer therapies, including HFOV and inhaled NO, have led to a dramatic reduction in the need for ECMO therapy (30, 36), ECMO remains an effective rescue agent for severe PPHN. Current patterns of ECMO use demonstrate persistent use in neonates with congenital diaphragmatic hernia and patients with severe hemodynamic instability, with less need for ECMO in meconium aspiration, RDS, idiopathic PPHN and other disorders.

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  • Tiia
    How does alkalosis improve pphn in infant?
    8 years ago

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