**4. Update on the clinical application of iNO in pediatric patients**

After NO was identified as an endothelial cell-derived relaxation factor and following preclinical studies, iNO therapy has been studied extensively in multicenter randomized trials as well as in early pilot studies of infants with severe hypoxemia associated with PH or infants with congenital diaphragmatic hernia (CDH) [60]. These studies have demonstrated improved oxygenation and reduction in the need for extracorporeal membrane oxygenation (ECMO) therapy, leading to the approval of iNO therapy by the Food and Drug Administration for use in patients at >34-week gestation with hypoxemic respiratory failure and persistent PH of the newborn (PPHN). Over the last two decades, the discussion of its application has been extended to premature infants and acute pulmonary vascular response testing to assess indications for specific pulmonary vasodilator therapy for patients with PAH or operability for children with congenital heart disease.

### **4.1 Role of inhaled NO in the prevention of bronchopulmonary dysplasia in premature newborns**

Bronchopulmonary dysplasia (BPD), which is characterized by impaired pulmonary development resulting from insults affecting the immature lung, including inflammation, hyperoxia, and mechanical ventilation, is associated with high mortality and adverse long-term neurological and respiratory outcomes in infants born very preterm. Although the effectiveness of iNO for the treatment of PPHN is largely due to its function as a selective pulmonary vasodilator, laboratory observations also suggest other important biological effects of NO, such as roles in decreasing lung inflammation (e.g., lung vascular protein leak; pulmonary neutrophil accumulation) [61], reducing oxidant stress [62], decreasing pulmonary vascular cell proliferation [63], and enhancing alveolarization and lung growth [64–66]. These observations have led to investigations into the use of iNO to prevent the development of BPD in premature newborns. In an initial randomized,

placebo-controlled study in a single center, 7 days of iNO prevented chronic lung disease in premature infants [67]. Despite promising findings in some subsequent studies showing a reduction in BPD in premature newborns [68, 69], later trials did not confirm the beneficial effects [70]. Meta-analyses of these studies have not found evidence for a net improvement in either chronic lung disease or developmental sequelae [71], leading to the conclusion by the National Institutes of Health Consensus Development Conference [72] and the American Academy of Pediatrics Committee on the Fetus and Newborn [73] that the use of iNO to prevent BPD is not supported by available evidence [74].

#### **4.2 iNO for the treatment of severe pulmonary hypertension in preterm infants**

In addition to the use of iNO for BPD prevention, its use in preterm infants for acute management of severe hypoxemic respiratory failure has been discussed. Several case series have described responses to iNO in premature newborns with PPHN associated with prolonged oligohydramnios and pulmonary hypoplasia. Chock et al. evaluated a subset of 12 premature newborns enrolled in the Preemie Inhaled Nitric Oxide Trial with pulmonary hypoplasia after preterm premature rupture of membranes (PPROM) [75]. Six infants were treated with iNO with a mortality rate of 33% compared with 67% mortality for six infants in the placebo control group. Shah and Kluckow described outcomes for infants with PPROM and reported that survival improved from 62 to 90% after the introduction of iNO and high-frequency oscillatory ventilation [76]. Semberova et al. reported a series of 22 premature infants with a history of PPROM, pulmonary hypoplasia, and PPHN who were treated with iNO, with a survival rate of 86% [77]. Thus, iNO therapy may have important benefits in subgroups of preterm infants with severe PH, especially in patients with oligohydramnios and lung hypoplasia. Further studies of the precise effects of iNO in premature neonates are needed.

#### **4.3 Role of iNO in newborns with congenital diaphragmatic hernia**

iNO in neonates with CDH has been evaluated in three randomized trials [78–80]. Finer and Barrington performed a Cochrane Review [81] of the use of iNO for respiratory failure in infants born at or near term. They concluded that while iNO might transiently improve oxygenation, its use is not recommended for infants with CDH because the risks of a composite of either death or ECMO are similar to or worse than those of controls [82].

Based on this evidence, iNO cannot be recommended for the routine treatment of PH in patients with CDH. However, iNO continues to be regularly used for CDH. Indeed, iNO was used at some point during preoperative stabilization in 36% (191/526) of infants with CDH from the population-based CAPSNet database. The ability of iNO to improve oxygenation and reduce the need for ECMO in non-CDH patients with PH explains its continued use in patients with CDH. The lack of a response to pulmonary vasodilators in CDH is speculated to be likely due to left atrial/pulmonary vein hypertension rather than to functional changes in the pulmonary arterial vasculature [83]. A recent study suggests that the response to pulmonary vasodilators in neonates with CDH may be limited by the severity of left ventricular (LV) dysfunction and/or hypoplasia, which impairs LV filling. Careful echocardiographic assessment, therefore, may guide treatment by identifying patients who may benefit from pulmonary vasodilators, including iNO [83].

**79**

**Figure 10.**

*to 60/14/32 mmHg, 3.14 Wood units m<sup>2</sup>*

*nitric oxide; AO, aorta; PA, pulmonary artery.*

*Endogenous and Inhaled Nitric Oxide for the Treatment of Pulmonary Hypertension*

*4.3.2 Acute vasoreactivity testing to assess operability of PAH associated with* 

AVT (**Figure 10**) is also used to assess operability in children with PAH associated with a systemic-to-pulmonary shunt [87, 88]. Although pulmonary vasodilators other than iNO, such as inhaled iloprost or other orally or intravenously administered compounds (e.g., sildenafil and treprostinil), can be used for AVT, iNO ± oxygen is recommended [87]. The hemodynamic change that defines a positive response to AVT

*Acute vasoreactivity testingto assess operability. AVT is also used to assess operability in children with PAH associated with a systemic-to-pulmonary shunt [87, 88]. (Figure 10, unpublished). A 5-month-old infant with Down syndrome and an atrial septal defect was evaluated for operability by acute vasoreactivity testing using inhaled nitric oxide. Pulmonary hemodynamic parameters at baseline, including pulmonary arterial* 

*to systemic vascular resistance (0.45), and the ratio of pulmonary to systemic blood flow (1.74), are changed* 

*underwent surgical closure of the shunt, and no postoperative pulmonary hypertension was observed. NO,* 

*, 0.20, and 2.2 after nitric oxide inhalation, respectively. The patient* 

*), the ratio of pulmonary* 

*pressure (76/29/49 mmHg), pulmonary vascular resistance index (6.7 Wood units m<sup>2</sup>*

*4.3.1 Acute vasoreactivity testing to assess prognosis and indications for specific PH* 

The prognosis of children with PAH has improved in the past decade owing to new therapeutic agents and aggressive treatment strategies [84]. In idiopathic or heritable PAH (I/H-PAH), acute vasodilator testing (AVT) is recommended to identify patients who have a good long-term prognosis when treated with a long-term calcium channel blocker (CCB), accounting for 7–37% of children with PAH. For example, a >20% decrease in PAP or pulmonary vascular resistance (PVR) to inhaled NO accurately predicts a subsequent response to oral vasodilators, such as nifedipine. To identify such patients, the Sitbon criteria for positive AVT, as defined by a decrease in mean PAP by ≥10 mmHg to a value of <40 mmHg with an increased or unchanged cardiac output, is commonly used in adult I/H-PAH [85]. The Sitbon criteria can also be used to identify children who are expected to show a sustained response to CCB therapy [86]. Based on these data, the use of the Sitbon criteria is advised for AVT in children. Because only half of adult responders have a long-term hemodynamic and clinical improvement in response to CCB therapy,

*DOI: http://dx.doi.org/10.5772/intechopen.89381*

close long-term follow-up is required [87].

*congenital heart disease*

*therapy*

*Endogenous and Inhaled Nitric Oxide for the Treatment of Pulmonary Hypertension DOI: http://dx.doi.org/10.5772/intechopen.89381*

### *4.3.1 Acute vasoreactivity testing to assess prognosis and indications for specific PH therapy*

The prognosis of children with PAH has improved in the past decade owing to new therapeutic agents and aggressive treatment strategies [84]. In idiopathic or heritable PAH (I/H-PAH), acute vasodilator testing (AVT) is recommended to identify patients who have a good long-term prognosis when treated with a long-term calcium channel blocker (CCB), accounting for 7–37% of children with PAH. For example, a >20% decrease in PAP or pulmonary vascular resistance (PVR) to inhaled NO accurately predicts a subsequent response to oral vasodilators, such as nifedipine. To identify such patients, the Sitbon criteria for positive AVT, as defined by a decrease in mean PAP by ≥10 mmHg to a value of <40 mmHg with an increased or unchanged cardiac output, is commonly used in adult I/H-PAH [85]. The Sitbon criteria can also be used to identify children who are expected to show a sustained response to CCB therapy [86]. Based on these data, the use of the Sitbon criteria is advised for AVT in children. Because only half of adult responders have a long-term hemodynamic and clinical improvement in response to CCB therapy, close long-term follow-up is required [87].

## *4.3.2 Acute vasoreactivity testing to assess operability of PAH associated with congenital heart disease*

AVT (**Figure 10**) is also used to assess operability in children with PAH associated with a systemic-to-pulmonary shunt [87, 88]. Although pulmonary vasodilators other than iNO, such as inhaled iloprost or other orally or intravenously administered compounds (e.g., sildenafil and treprostinil), can be used for AVT, iNO ± oxygen is recommended [87]. The hemodynamic change that defines a positive response to AVT

#### **Figure 10.**

*Acute vasoreactivity testingto assess operability. AVT is also used to assess operability in children with PAH associated with a systemic-to-pulmonary shunt [87, 88]. (Figure 10, unpublished). A 5-month-old infant with Down syndrome and an atrial septal defect was evaluated for operability by acute vasoreactivity testing using inhaled nitric oxide. Pulmonary hemodynamic parameters at baseline, including pulmonary arterial pressure (76/29/49 mmHg), pulmonary vascular resistance index (6.7 Wood units m<sup>2</sup> ), the ratio of pulmonary to systemic vascular resistance (0.45), and the ratio of pulmonary to systemic blood flow (1.74), are changed to 60/14/32 mmHg, 3.14 Wood units m<sup>2</sup> , 0.20, and 2.2 after nitric oxide inhalation, respectively. The patient underwent surgical closure of the shunt, and no postoperative pulmonary hypertension was observed. NO, nitric oxide; AO, aorta; PA, pulmonary artery.*

in PAH associated with a shunt (a ratio of pulmonary to systemic blood flow >1.5) for children should be a >20% decrease in PVR index and a ratio of pulmonary to systemic vascular resistance with respective final values of <6 Wood units m2 and <0.3. However, specific criteria for defining a positive AVT response that predicts the reversal of PAH and good long-term prognosis have not been described. The pediatric task force of the Sixth World Symposium on Pulmonary Hypertension agreed on a general guidance for assessing operability in CHD-PAH but emphasized that the long-term impact of defect closure in the presence of PAH with increased PVR is unknown [84].
