Table 3.
An overview of therapeutic approaches for PPHN whose use has been studied in human infants.
| Treatment options | Mechanism of action | Type of evidence | Efficacy | Dosage schedule and clinically relevant observations | |
|---|---|---|---|---|---|
| iNO | Exogenous NO | Meta-analysis (including 17 RCTs) (32) | •Decreased need for ECMO: RR = 0.60 (0.50–0.71) •Improved OI: MD = −8.45 (−11.42 to −5.48) •Improved PaO2: MD = 32.62 mmHg (23.56–41.67) |
•Dose: 10–80 ppm (inhaled) •iNO initiated if OI ≥ 25 or PaO2 <100 mmHg with 100% O2 •Quality of evidence: high |
|
| Sildenafil | PDE5 inhibitor | Meta-analysis (including 5 RCTs) (33) | •Mortality reduction: RR = 0.20 (0.07–0.56) | •Dose: 0.5–3.0 mg/kg every 6 h + variable loading doses (IV, oral or inhaled) •Quality of evidence: low |
|
| PGI2 analogues | Iloprost | Exogenous PGI2 | Case series (33 infants) (34) | •Improved OI, PaO2, and SpO2 (p <0.05) •Improved AaDO2: MD = −24 mmHg (p = 0.02) |
•Dose: 110 ng/kg/min, for a median duration of 97 h (11–480 h) (IV) •Decreased systemic blood pressure |
| Observational: iloprost vs. sildenafil (20 infants received iloprost) (35) | •Decreased duration of MV: MD = −3.8 days (p < 0.001) •Improved PAP (p < 0.05) and AaDO2 (p < 0.001) •Shorter time to an adequate response (p < 0.03) |
•Dose: 1–2.5 mg/kg every 2–4 h, for a mean duration of 5.41 ± 2.79 days (inhaled) •No systemic hypotension |
|||
| Epoprostenol | Case series (8 infants) (36) | •Decreased PAP: MD = −19.4 mmHg (p < 0.0005) | •Dose: 20 ng/kg/min, increased to a mean dose of 60 ng/kg/min, for a median duration of 3.6 days (IV) •No systemic hypotension |
||
| Case series (4 preterm infants) (37) | •Improved OI: MD = −32 (39 ± 13.3 to 7 ± 2.5) •Improved PaO2/FiO2: MD = 171 (47 ± 13.0 to 218 ± 66.6) |
•Dose: 50 ng/kg (endotracheal single bolus) •No systemic hypotension |
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| Treprostinil | Case reports (2 preterm infants) (38) | •Substantial clinical improvement in the first hours after treatment | •Dose: 5 ng/kg/min, titrated to a max. of 20 ng/kg/min, for 5 or 7 days (IV) •No apparent systemic adverse effects, including intraventricular hemorrhage |
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| Beraprost | Case series (7 infants) (39) | •Improved OI: MD = −18.2 (p = 0.018) | •Dose: 1 mcg/kg every 6 h, for a median duration of 101 h (40–205 h) (oral) •Decreased systemic blood pressure |
||
| Alprostadil | Exogenous PGE1 | Case series (9 infants) (40) | •Shortened length of stay: MD = 11 days (p = 0.004) | •Dose: 20 (5–100) ng/kg/min (IV) •No need for higher rates of ventilation or inotrope use |
|
| Milrinone | PDE3 inhibitor | Case series(9 infants) (41),(11 infants) (42) | •Improved OI: MD = −8.00 (−14.6 to −1.4) (p < 0.05) | •Dose: 0.33–0.99 mcg/kg/min, for a median duration of 70 h (23–136 h) (IV) •No systemic hypotension |
|
| •Improved PaO2: MD = 31 mmHg (p = 0.002) •Improved OI: MR = 65% (6–87%) (p < 0.001) •Improved echocardiographic indices: lower PAP, improved RV + LV output and reduced shunting (p < 0.05) |
•Dose: 50 mcg/kg (loading dose) + 0.33 mcg/kg/min, titrated to a max. of 1.4mg/kg/day, for a median duration of 24 h (24-42 h) (IV) •No systemic hypotension or intraventricular hemorrhage |
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| Bosentan | ET-receptors non-selective antagonist | Case series (40 infants) (43) | •Improved OI (p = 0.002) and AaDO2 (p = 0.01) •Improved SpO2: MD = 5% (p < 0.001) |
•Dose: 1 mg/kg b.i.d, for a mean duration of 6.2 ± 3.1 days (oral) •No hepatotoxicity or systemic hypotension |
|
| RCTs(24 infants) (44)(13 infants) (45) | •Improved OI: MD = −10 (p < 0.05) •Decreased duration of MV: MD = −7.2 days (p < 0.001) |
•Dose: 1 mg/kg b.i.d, for a mean duration of 4.8 ± 1.1 days (oral) | |||
| •No improvement in oxygenation or other outcomes | •Dose: 2 mg/kg b.i.d, for a mean duration of 5.0 ± 2.6 days (oral) •No hepatotoxicity or systemic hypotension •Delayed absorption of bosentan in critically ill neonates |
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| Glucocorticoids | Anti-inflammatory | Case series (15 infants) (46) | •Increased systolic blood pressure and decreased need for inotropic support (p < 0.001) •Improved OI (p < 0.001) and PaO2/FiO2 (p < 0.001) |
•Hydrocortisone; Dose: 4 mg/kg, followed by 1 mg/kg every 6 hours for 48 h (IV) | |
Only statistically significant results are presented. AaDO2, alveolar–arterial oxygen difference; ET, endothelin; FiO2, fraction of inspired oxygen; iNO, inhaled nitric oxide; IV, intravenous; LV, left ventricle; MD, mean decrease; MR, mean reduction; MV, mechanical ventilation; NO, nitric oxide; OI, oxygenation index; PaO2, arterial partial pressure of oxygen; PAP, pulmonary artery pressure; PDE3, phosphodiesterase 3; PDE5, phosphodiesterase 5; PGE1, prostaglandin E1; PGI2, prostacyclin; RCTs, randomized controlled trials; RR, relative risk; RV, right ventricle; SpO2, oxygen saturation.