eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Cardiology
Pulmonary Hypertension, Persistent-Newborn: Treatment & Medication
Updated: Sep 22, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
- General considerations
- The care of newborns with persistent pulmonary hypertension of the newborn (PPHN) requires meticulous attention to detail. Continuous monitoring of oxygenation, blood pressure, and perfusion is critical.
- When one cares for newborns, use a minimal stimulation protocol to minimize the need to handle the patient and to perform invasive procedures, such as suctioning.
- Management of fluid and electrolyte levels, particularly calcium, is important. An adequate circulating blood volume is necessary to maintain right ventricular filling and cardiac output; however, repeated bolus administration of crystalloid and colloid solutions does not provide additional benefit.
- Inotropic support with dopamine, dobutamine, and/or milrinone alone or in combination, is frequently helpful in maintaining adequate cardiac output and systemic blood pressure while avoiding excessive volume administration. Although dopamine is frequently used as a first-line agent, other agents, such as dobutamine and milrinone, are helpful when myocardial contractility is poor.
- Mechanical ventilation
- Mechanical ventilation is usually needed to maintain adequate oxygenation. Determine the exact strategy on the basis of the underlying lung disease. For instance, newborns with clinically significant airspace disease due to pneumonia or respiratory distress syndrome likely require airway pressures higher than those needed for patients with idiopathic "black lung" persistent pulmonary hypertension of the newborn. Likewise, newborns with clinically significant airspace disease are most likely to respond to other lung recruitment strategies, such as surfactant administration and/or high-frequency oscillatory ventilation.
- A frequent concern is determining the target arterial PaO2 level. Although hyperoxic ventilation continues to be a mainstay in the treatment of persistent pulmonary hypertension of the newborn, surprisingly little is known about what oxygen concentrations maximize benefits and minimize risks.Levels of 50 mm Hg or more typically provide for adequate oxygen delivery. Aiming for high PaO2 concentrations may lead to increased ventilator support and barotrauma. Further, the use of extreme hyperoxia in persistent pulmonary hypertension of the newborn management may be toxic to the developing lung by the formation of reactive oxygen species.
- Because of their lability and ability to fight the ventilator, newborns with persistent pulmonary hypertension of the newborn nearly always require sedation. The author's practice is to use fentanyl (often in combination with a benzodiazepine) because it tends to decrease the sympathetic response to pain and noxious stimuli.
- Acidosis and alkalosis
- Metabolic acidosis and respiratory acidosis require correction. Sodium bicarbonate is typically used to correct metabolic acidosis. However, if carbon dioxide clearance is a problem, administering bicarbonate may produce a respiratory acidosis. In these situations, tromethamine (THAM) 1-2 mmol/kg may be a useful alternative, although THAM should never be administered to patients with anuria or uremia.
- Forced alkalosis by using sodium bicarbonate and hyperventilation were popular therapies in the past because of their ability to produce acute pulmonary vasodilation and increase PaO2. These therapies have little evidence base. Further, hypocarbia is associated with constriction of the cerebral vasculature, reduction of cerebral blood flow, and systemic hypotension. Extreme alkalosis and hypocarbia are strongly associated with late neurodevelopmental deficits, including a high rate of sensorineural hearing loss.
- Some advocate using sodium bicarbonate infusions to maintain an alkaline pH. Serum sodium concentration should carefully be monitored if bicarbonate infusions are used, and ventilation must be adequate to allow for carbon dioxide clearance. Walsh-Sukys and colleagues reported that the use of alkaline infusions is associated with increased use of extracorporeal membrane oxygenation (ECMO) and oxygen when the newborn is aged 28 days.2 Therefore, use this approach with caution.
- Many clinicians have good success without using alkalinization. In a series of 15 patients, Wung et al applied a strategy designed to maintain PaO2 at 50-70 mm Hg and PaCO2 at less than 60 mm Hg (ie, gentle ventilation).3 This approach resulted in excellent outcomes and a low incidence of chronic lung disease.
- Induced paralysis
- The use of paralytic agents is highly controversial and typically reserved for newborns who cannot be treated with sedatives alone. Be aware that paralysis, in particular with pancuronium, may promote atelectasis of dependent lung regions and promote ventilation-perfusion mismatch.
- A review of 385 newborns with persistent pulmonary hypertension of the newborn by Walsh-Sukys and colleagues suggests that paralysis may be associated with an increased risk of death.2
- Another report indicates that prolonged administration of pancuronium during the neonatal period is associated with sensorineural hearing loss in childhood survivors of congenital diaphragmatic hernia.
- Treatment with inhaled nitric oxide (iNO)
- Treatment with iNO is indicated for newborns with an oxygen index (OI) of less than 25. Nitric oxide (NO) is an endothelial-derived gas signaling molecule that relaxes vascular smooth muscle and that can be delivered to the lung by means of an inhalation device (INOVent; Ikaria, Clinton NJ).
- In 2 large randomized trials, NO reduced the need for ECMO support by approximately 40%. Although these trials led to the US Food and Drug Administration (FDA) approving iNO as a therapy for persistent pulmonary hypertension of the newborn, iNO did not reduce mortality, length of hospitalization, or reduce the risk of neurodevelopmental impairment.
- A randomized study has confirmed that beginning iNO at a milder or earlier point in the disease course (for an oxygenation index of 15-25) did not decrease the incidence of ECMO and/or death or improve other patient outcomes, including the incidence of neurodevelopmental impairment.
- Contraindications to iNO include congenital heart disease characterized by left ventricular outflow tract obstruction (eg, interrupted aortic arch, critical aortic stenosis, hypoplastic left heart syndrome) and severe left ventricular dysfunction.
- The appropriate starting dose is 20 ppm. Doses higher than this have not been shown to be more effective and have been associated with adverse effects, including methemoglobinemia and increased levels of nitrogen dioxide (NO2).
- Appropriate lung recruitment and expansion are essential to achieve the best response. If a newborn has severe parenchymal lung disease and PPHN, strategies such as HFV may be required.
- Most newborns require iNO for less than 5 days. In general, the dose can be weaned to 5 ppm after 6-24 hours of therapy. The dose is then slowly weaned and discontinued when the FiO2 is less than 0.4-0.6 and the iNO dose is 1 ppm. Abrupt discontinuation at higher doses should be avoided become it may cause abrupt rebound pulmonary hypertension.
- In centers that do not have immediate availability of ECMO support, use of iNO must be approached with caution. Because iNO cannot be abruptly discontinued, transport with iNO is usually needed if a subsequent referral for ECMO is necessary. This capability should be determined in collaboration with the ECMO center before treatment is started. The use of iNO with high-frequency ventilation (HFV) creates particular problems for transport, and this should be considered before these therapies are combined in a non-ECMO center.
- The use of iNO has not been demonstrated to reduce need for ECMO in newborns with congenital diaphragmatic hernia. In these newborns, iNO should be used in non-ECMO centers to allow for acute stabilization, followed by immediate transfer to a center that can provide ECMO.
Medication
Sedation and analgesia with opioids is often necessary to achieve adequate mechanical ventilation in patients with persistent pulmonary hypertension of the newborn (PPHN). Muscle paralysis may be used for the same purpose; however, this method is controversial because adverse circulatory effects and alveolar collapse in dependent regions of the lung may develop. The administration of a surfactant may be helpful if parenchymal disease is present.
Cardiac output is maintained with the use of inotropic agents and with judicious volume replacement.
Maintaining a normal or alkaline pH level with infusions of sodium bicarbonate may decrease pulmonary-artery pressure and improve oxygenation. Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator that reduces the need for invasive therapies (eg, extracorporeal membrane oxygenation [ECMO]).Opioid analgesics
These drugs are used for deep sedation and analgesia to enable adequate mechanical ventilation. Use of agents such as fentanyl may also decrease sympathetic tone during stressful interventions and maintain a relaxed pulmonary vascular bed.
Fentanyl (Sublimaze)
Synthetic opioid 75-200 times more potent than morphine. Highly lipophilic and protein bound. Prolonged exposure leads to accumulation in fat and delays weaning. By itself, causes little cardiovascular compromise, though addition of benzodiazepines or other sedatives may decrease cardiac output and blood pressure.
Adult
Pediatric
Intermittent: 1-5 mcg/kg slow IV bolus q2h
Continuous infusion: 1-2 mcg/kg IV initially, followed by 0.5-1 mcg/kg/h; may slowly uptitrate
Phenothiazines may antagonize analgesic effects of opiate agonists; tricyclic antidepressants (TCAs) may potentiate adverse effects of fentanyl when used concurrently
Documented hypersensitivity; hypotension or potentially compromised airway when establishing rapid airway control may be difficult
Pregnancy
Precautions
Acute muscle rigidity or chest-wall syndrome may occur after rapid infusion; tolerance develops rapidly; notable withdrawal symptoms may develop if infusions used for >5 d; prescribing clinicians must be skilled in airway management
Neuromuscular-blocking agents
Paralysis is sometimes required in newborns whose condition remains unstable despite adequate sedation.
Pancuronium (Pavulon)
Relatively long-acting nondepolarizing muscle relaxant. Onset of action 1-2 min. Duration of action typically 45-90 min; may be prolonged in renal or hepatic failure. Excretion 80% renal and 20% hepatic.
Adult
Pediatric
0.05-0.15 mg/kg/dose IV bolus q1-2h prn movement; alternatively, 0.01-0.1 mg/kg/h IV continuous infusion
Increased toxicity with magnesium sulfate and furosemide (dose dependently); can increase or decrease neuromuscular blockade
Documented hypersensitivity
Pregnancy
Precautions
Blocks cardiac muscarinic receptors and commonly produces tachycardia; hypotension frequent; infants often require expansion of intravascular blood volume to maintain blood pressure; assess (and may need to frequently adjust) ventilation and gas exchange after administration because of spontaneous ventilation loss; consider airway protection
Vecuronium (Norcuron)
Intermediate-acting nondepolarizing muscle relaxant. Onset of action 1-2 min; duration of action typically 45-90 min. Primary route of excretion is hepatic.
Adult
Pediatric
0.05-0.15 mg/kg/dose IV q1-2h prn; alternatively, may be administered as continuous infusion
Enhances neuromuscular blockage when used concurrently with inhalational anesthetics; renal or hepatic failure and concomitant administration of steroids may prolong blockade despite withdrawal
Documented hypersensitivity; myasthenia gravis or related syndromes
Pregnancy
Precautions
Few or no adverse hemodynamic adverse effects; may be preferred to pancuronium as muscle relaxant in infants with PPHN; 4 times more expensive than pancuronium; as with pancuronium, assess (and may need to frequently adjust) ventilation and gas exchange after administration because of spontaneous ventilation loss
Vasopressors
Targeted use of vasoactive agents may increase cardiac output without affecting systemic or pulmonary vascular resistance (PVR).
Dopamine is unique compared to other catecholamines. Unlike norepinephrine, epinephrine, and isoproterenol, low doses of dopamine increase renal blood flow without increasing heart rate or systemic arterial pressure. It is an effective vasopressor for treating shock and hypotension in cases unresponsive to plasma volume expansion (eg, with crystalloids or colloids). Dopamine also dilates the mesenteric and renal blood vessels to improve renal blood flow and increase the glomerular filtration rate, sodium excretion, and urine output. However, dosages of more than 20 mcg/kg/min may decrease renal blood flow secondary to reversal of the dopaminergic vasodilation.
Dobutamine produces selective positive inotropic effects and therefore produces a mild chronotropic effect. Its structure is similar to those of isoproterenol and epinephrine. Dobutamine is characterized as a selective beta1-agonist as a result of its primary effect of increasing myocardial contractility by means of beta1 stimulation. Milrinone is a cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase inhibitor that also produces positive inotropic and lusitropic effects. Recent evidence suggests it may enhance the pulmonary vasodilatory effects of iNO.
Dopamine (Intropin)
Believed to increase blood pressure primarily by stimulating alpha-adrenergic receptors. Mechanism of action in newborn infants remains controversial. Because of developmental differences in endogenous norepinephrine stores and expression and function of alpha-adrenergic receptors. Therefore, individualize dose for each patient.
Adult
Pediatric
Continuous infusion: 2-20 mcg/kg/min IV
Incompatible when IV mixed with acyclovir, amphotericin B, indomethacin, insulin, or sodium bicarbonate; phenytoin, alpha- and beta-adrenergic blockers, general anesthesia, and monoamine oxidase inhibitors (MAOIs) increase and prolong effects.
Outflow tract obstructions (eg, subaortic stenosis)
Pregnancy
Precautions
Dosages >10 mcg/kg/min may cause pulmonary vasoconstriction; severe local tissue ischemia and sloughing may occur with IV infiltration (therefore best administered by means of central access); if administration by using peripheral IV unavoidable, promptly treat extravasation with phentolamine (Regitine) SC
Dobutamine (Dobutrex)
Increases blood pressure primarily by stimulating beta1-adrenergic receptors. Appears to have more prominent effect on cardiac output than on blood pressure.
Adult
Pediatric
Continuous infusion: 2-25 mcg/kg/min IV
Beta-adrenergic blockers antagonize effects; general anesthetics may increase toxicity
Outflow-tract obstruction (eg, subaortic stenosis)
Pregnancy
Precautions
Extreme caution after myocardial infarction; correct hypovolemic state before use
Milrinone (Primacor)
Bipyridine inotropic/vasodilator agent with phosphodiesterase inhibitor activity. Increases blood pressure primarily by increasing cardiac cAMP. Appears to have more prominent effect on cardiac output than on blood pressure.
Adult
Pediatric
Continuous infusion: 0.2-0.5 mcg/kg/min IV
Incompatible with furosemide when administered within same IV (forms precipitates)
Documented hypersensitivity
Pregnancy
Precautions
Monitor fluids, electrolyte changes and renal function during therapy (decrease dose with insufficient renal function); excessive diuresis may increase potassium loss and predispose digitalized patients to arrhythmias; important to correct hypokalemia with potassium supplementation prior to treatment; patients showing excessive decreases in blood pressure should have infusion rates slowed or stopped; previous vigorous diuretic therapy has caused significant decreases in cardiac filling pressure, cautiously administer milrinone and monitor blood pressure, heart rate, and clinical symptomatology
Surfactants
Exogenous surfactant can help in the treatment of airspace disease (eg, RDS). Surfactant may also be helpful in other conditions, such as MAS, though it is not yet approved for such use. After inhaled administration, surface tension is reduced and alveoli are stabilized to decrease the work of breathing and increase lung compliance.
Beractant (Survanta)
Semisynthetic bovine-lung extract containing phospholipids, fatty acids, and surfactant-associated proteins B (7 mcg/mL) and C (203 mcg/mL).
Adult
Pediatric
Intratracheal: 100 mg (ie, 4 mL)/kg divided in 4 aliquots administered at least 6 h apart
None reported
None known
Pregnancy
Precautions
Must be warmed to room temperature; administer only under carefully supervised conditions because of risk of acute airway obstruction
Calfactant (Infasurf)
Natural calf-lung extract containing phospholipids, fatty acids, and surfactant-associated proteins B (260 mcg/mL) and C (390 mcg/mL).
Adult
Pediatric
Intratracheal: 3 mL/kg; may repeat q6-12h, not to exceed 3-4 doses
None reported
None known
Pregnancy
Precautions
Administer only under carefully supervised conditions because of risk of acute airway obstruction
Alkalinizing agents
These drugs are used to correct metabolic acidosis. In addition, maintaining a normal or slightly alkaline pH with sodium bicarbonate may decrease PVR.
Sodium bicarbonate
Buffer that breaks down to water and carbon dioxide after picking up free hydrogen ions. Acts as buffer against acidosis by raising blood pH.
Adult
Pediatric
Slow bolus infusion: 2-3 mEq/kg IV
Precipitates if administered with calcium or phosphate; inactivates catecholamines, calcium salts, and atropine when mixed; urinary alkalinization induced by increased concentrations may decrease levels of lithium, tetracyclines, chlorpropamide, methotrexate, and salicylates; increases levels of amphetamines, pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and quinine
Alkalosis; hypernatremia; hypocalcemia; severe pulmonary edema; unknown abdominal pain
Pregnancy
Precautions
Use neonatal dilution of 4.2% or 0.5 mEq/mL because of hypertonicity of concentrated solutions; administer only when ventilation is adequate (otherwise PCO2 rises); avoid extravasation
Pulmonary vasodilating agents
NO is the most specific therapeutic modality for newborns with persistent pulmonary hypertension of the newborn, and it is an important mediator of vascular tone. NO is delivered to the lung as inhaled gas. Three multicenter studies demonstrated that NO decreases the need for extracorporeal support by more than 35%. NO is produces by a wide range of cell types under normal physiologic conditions. It relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate (cGMP), which leads to vasodilation. When inhaled, NO produces pulmonary vasodilation.
The efficacy of sildenafil has been clearly demonstrated in adults with pulmonary hypertension, leading the FDA to approve it in 2005 for use in pulmonary arterial hypertension in adults under a different brand name (Revatio). Baquero et al conducted a small randomized and blinded study testing the effect of enteral sildenafil in persistent pulmonary hypertension of the newborn, treating 13 patients with severe persistent pulmonary hypertension of the newborn with either sildenafil or placebo in a NICU in Colombia, a country with no access to iNO or ECMO. They reported improved oxygenation and lower mortality with oral sildenafil.4
Steinhorn et al recently reported the results of an open-label pharmacokinetic trial of intravenous sildenafil in 36 infants with persistent pulmonary hypertension of the newborn.5 Sildenafil was effective in improving oxygenation in patients with persistent pulmonary hypertension of the newborn with and without prior exposure to iNO. Systemic hypotension was the most common adverse effect. These data suggest a beneficial effect for oral as well as intravenous sildenafil in persistent pulmonary hypertension of the newborn, although sildenafil is not yet FDA approved for use in pediatric patients.
Nitric oxide, inhaled (INOmax)
Exogenous or inhaled NO is used to decrease PVR and improve lung blood flow. Administer only under controlled conditions in which NO and NO2 can be monitored accurately. Monitor methemoglobin levels at start of therapy because some infants may have relative deficiency of methemoglobin reductase. Wean gradually because abrupt discontinuation may be associated with severe rebound pulmonary hypertension. Relaxes vascular smooth muscle by binding heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cGMP, leading to vasodilation.
Adult
Pediatric
20 ppm inhaled via respirator initially; ongoing dose ranges between 5-20 ppm by means of inhalation-controlled device; taper dose to 1 ppm before discontinuing
Administered by system that measures NO concentrations in breathing gas with a constant concentration throughout respiratory cycle and that does not cause generation of excessive inhaled nitrogen dioxide (NO2)
None known; theoretically, other NO-donor compounds (eg, nitroprusside, nitroglycerin) may add to risk of methemoglobinemia
Left ventricular outflow tract obstruction and/or known dependency on right-to-left shunting of blood; congenital or acquired methemoglobin reductase deficiency
Pregnancy
Precautions
Monitor for excess PaO2, methemoglobin, and NO2; abrupt discontinuation may lead to worsening oxygenation and increasing pulmonary arterial pressure (PAP); caution in thrombocytopenia, anemia, leukopenia, or bleeding disorders
Sildenafil citrate (Revatio)
Promotes selective smooth muscle relaxation in lung vasculature possibly by inhibiting phosphodiesterase type 5 (PDE5). This results in subsequent reduction of blood pressure in pulmonary arteries and increase in cardiac output.
Adult
Pediatric
Not established; limited data suggest 1 mg/kg q6h
Potentiates vasodilatory effect of NO or other organic nitrates, resulting in potentially sudden drop in blood pressure; coadministration with ketoconazole, erythromycin, or cimetidine increases plasma sildenafil concentrations; coadministration with rifampin decreases plasma levels of sildenafil; coadministration with bosentan increases bosentan levels by 50% and reduces sildenafil levels by 63%
Documented hypersensitivity
Pregnancy
Precautions
Currently only available for enteral use; may cause headache, flushing, upset stomach, and nasal congestion
More on Pulmonary Hypertension, Persistent-Newborn |
| Overview: Pulmonary Hypertension, Persistent-Newborn |
| Differential Diagnoses & Workup: Pulmonary Hypertension, Persistent-Newborn |
 Treatment & Medication: Pulmonary Hypertension, Persistent-Newborn |
| Follow-up: Pulmonary Hypertension, Persistent-Newborn |
| Multimedia: Pulmonary Hypertension, Persistent-Newborn |
| References |
| « Previous Page | Next Page » |
References
UK Collaborative ECMO Trial Group. UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. UK Collaborative ECMO Trail Group. Lancet. Jul 13 1996;348(9020):75-82. [Medline].
Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics. Jan 2000;105(1 Pt 1):14-20. [Medline].
Wung JT, James LS, Kilchevsky E, James E. Management of infants with severe respiratory failure and persistence of the fetal circulation, without hyperventilation. Pediatrics. Oct 1985;76(4):488-94. [Medline].
Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics. Apr 2006;117(4):1077-83. [Medline].
Steinhorn RH, Kinsella JP, Pierce C, Butrous G, Dilleen M, Oakes M, et al. Intravenous Sildenafil in the Treatment of Neonates With Persistent Pulmonary Hypertension of the Newborn (PPHN). J Pediatr. 2009; in press.
Abman SH. Neonatal pulmonary hypertension: a physiologic approach to treatment. Pediatr Pulmonol Suppl. 2004;26:127-8. [Medline].
Abman SH. New developments in the pathogenesis and treatment of neonatal pulmonary hypertension. Pediatr Pulmonol Suppl. 1999;18:201-4. [Medline].
Alano MA, Ngougmna E, Ostrea EM Jr, Konduri GG. Analysis of nonsteroidal antiinflammatory drugs in meconium and its relation to persistent pulmonary hypertension of the newborn. Pediatrics. Mar 2001;107(3):519-23. [Medline].
Auten RL, Notter RH, Kendig JW, Davis JM, Shapiro DL. Surfactant treatment of full-term newborns with respiratory failure. Pediatrics. Jan 1991;87(1):101-7. [Medline].
Bahrami KR, Van Meurs KP. ECMO for neonatal respiratory failure. Semin Perinatol. Feb 2005;29(1):15-23. [Medline].
Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. Feb 9 2006;354(6):579-87. [Medline].
Cheung PY, Tyebkhan JM, Peliowski A, Ainsworth W, Robertson CM. Prolonged use of pancuronium bromide and sensorineural hearing loss in childhood survivors of congenital diaphragmatic hernia. J Pediatr. Aug 1999;135(2 Pt 1):233-9. [Medline].
Clark RH, Gerstmann DR. Controversies in high-frequency ventilation. Clin Perinatol. Mar 1998;25(1):113-22. [Medline].
Clark RH, Kueser TJ, Walker MW, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Engl J Med. Feb 17 2000;342(7):469-74. [Medline].
Davidson D, Barefield ES, Kattwinkel J, et al. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose-response, multicenter study. The I-NO/PPHN Study Group. Pediatrics. Mar 1998;101(3 Pt 1):325-34. [Medline].
Farrow KN, Fliman P, Steinhorn RH. The diseases treated with ECMO: focus on PPHN. Semin Perinatol. Feb 2005;29(1):8-14. [Medline].
Findlay RD, Taeusch HW, Walther FJ. Surfactant replacement therapy for meconium aspiration syndrome. Pediatrics. Jan 1996;97(1):48-52. [Medline].
Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev. 2001;CD000399. [Medline].
Hintz SR, Suttner DM, Sheehan AM, Rhine WD, Van Meurs KP. Decreased use of neonatal extracorporeal membrane oxygenation (ECMO): how new treatment modalities have affected ECMO utilization. Pediatrics. Dec 2000;106(6):1339-43. [Medline].
Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. The Neonatal Inhaled Nitric Oxide Study Group. N Engl J Med. Feb 27 1997;336(9):597-604. [Medline].
Kanto WP Jr, Bunyapen C. Extracorporeal membrane oxygenation. Controversies in selection of patients and management. Clin Perinatol. Mar 1998;25(1):123-35. [Medline].
Kelly LK, Porta NF, Goodman DM, Carroll CL, Steinhorn RH. Inhaled prostacyclin for term infants with persistent pulmonary hypertension refractory to inhaled nitric oxide. J Pediatr. Dec 2002;141(6):830-2. [Medline].
Kinsella JP, Abman SH. Clinical approach to inhaled nitric oxide therapy in the newborn with hypoxemia. J Pediatr. Jun 2000;136(6):717-26. [Medline].
Kinsella JP, Griebel J, Schmidt JM, Abman SH. Use of inhaled nitric oxide during interhospital transport of newborns with hypoxemic respiratory failure. Pediatrics. Jan 2002;109(1):158-61. [Medline].
Kinsella JP, Ivy DD, Abman SH. Pulmonary vasodilator therapy in congenital diaphragmatic hernia: acute, late, and chronic pulmonary hypertension. Semin Perinatol. Apr 2005;29(2):123-8. [Medline].
Konduri GG, Solimano A, Sokol GM, et al. A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure. Pediatrics. Mar 2004;113(3 Pt 1):559-64. [Medline].
Lakshminrusimha S, Russell JA, Steinhorn RH, et al. Pulmonary hemodynamics in neonatal lambs resuscitated with 21%, 50%, and 100% oxygen. Pediatr Res. Sep 2007;62(3):313-8. [Medline].
Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH. Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. Survanta in Term Infants Study Group. J Pediatr. Jan 1998;132(1):40-7. [Medline].
Paranka MS, Clark RH, Yoder BA, Null DM Jr. Predictors of failure of high-frequency oscillatory ventilation in term infants with severe respiratory failure. Pediatrics. Mar 1995;95(3):400-4. [Medline].
Pawlik TD, Porta NF, Steinhorn RH, Ogata E, deRegnier RA. Medical and financial impact of a neonatal extracorporeal membrane oxygenation referral center in the nitric oxide era. Pediatrics. Jan 2009;123(1):e17-24. [Medline].
Steinhorn RH. Nitric oxide and beyond: new insights and therapies for pulmonary hypertension. J Perinatol. Dec 2008;28 Suppl 3:S67-71. [Medline].
Tworetzky W, Bristow J, Moore P, et al. Inhaled nitric oxide in neonates with persistent pulmonary hypertension. Lancet. Jan 13 2001;357(9250):118-20. [Medline].
Ziegler JW, Ivy DD, Kinsella JP, Abman SH. The role of nitric oxide, endothelin, and prostaglandins in the transition of the pulmonary circulation. Clin Perinatol. Jun 1995;22(2):387-403. [Medline].
Further Reading
Keywords
persistent fetal circulation, PFC, persistent pulmonary hypertension in the newborn, persistent pulmonary hypertension of the newborn, PPHN, pulmonary vascular resistance, PVR, pulmonary perfusion, black lung PPHN, clear lung PPHN, pulmonary vasodilation, persistent newborn pulmonary hypertension, patent foramen ovale, patent ductus arteriosus, meconium aspiration syndrome, respiratory distress syndrome, pneumonia, congenital diaphragmatic hernia, bronchopulmonary dysplasia, hypothermia, hypoglycemia, cystic adenomatoid malformations, treatment, diagnosis
