Persistent Pulmonary Hypertension of the Newborn Pulmonary...Persistent pulmonary hypertension of the newborn (PPHN) is often secondary to pa renchymal lung disease (such as meconium

Persistent Pulmonary Hypertension of theNewbornSatyan Lakshminrusimha,

MD,* Martin Keszler, MD†

AUTHOR DISCLOSURE

Dr Lakshminrusimha

has disclosed that he

was previously

a member of the

speaker bureau for

Ikaria (until October

2014), manufacturer

of inhaled nitric oxide.

He also declares that

he has no competing

interest in published

data, and Ikaria had no

role in the preparation

of the manuscript. He

was supported by

grant HD072929 from

the Eunice Kennedy

Shriver National

Institute of Child

Health and Human

Development during

the preparation of the

manuscript. Dr Keszler

has disclosed no

financial relationships

relevant to this article.

This commentary does

contain a discussion of

an unapproved/

investigative use of

a commercial product/

device.

Educational Gap1. Complete understanding of the complex pathophysiology and optimal management of

persistent pulmonary hypertension remains elusive.

2. Persistent pulmonary hypertension among extremely preterm infants and infants with

congenital diaphragmatic hernia is associated with high morbidity and mortality.

AbstractPersistent pulmonary hypertension of the newborn (PPHN) is often secondary to pa-renchymal lung disease (such as meconium aspiration syndrome) or lung hypoplasia(with congenital diaphragmatic hernia) but can also be idiopathic. PPHN is character-ized by elevated pulmonary vascular resistance, resulting in right-to-left shunting ofblood and hypoxemia. The diagnosis of PPHN is based on clinical evidence of labilehypoxemia often associated with differential cyanosis and confirmed by echocardiogra-phy. Lung volume recruitment with optimal use of positive end-expiratory pressure ormean airway pressure and/or surfactant is very important in secondary PPHN due toparenchymal lung disease. Other management strategies include optimal oxygenation,avoiding respiratory and metabolic acidosis, blood pressure stabilization, sedation, andpulmonary vasodilator therapy. Failure of these measures leads to consideration of ex-tracorporeal membrane oxygenation, although this rescue therapy is needed less fre-quently with advances in medical management. Randomized clinical trials withlong-term follow-up are required to evaluate various therapeutic strategies in PPHN.

Objectives After completing this article, readers should be able to:

1. Understand the origin of persistent pulmonary hypertension of the newborn (PPHN)

and hypoxemic respiratory failure.

2. Optimize the use of oxygen during management of PPHN.

3. Outline the importance of lung recruitment using positive end-expiratory pressure or

mean airway pressure and/or surfactant in PPHN.

4. Rationalize the choice of inhaled, intravenous, and oral pulmonary vasodilators.

IntroductionSuccessful adaptation to extrauterine life requires a rapid increase in pulmonary blood flowat birth to establish the lungs as the site of gas exchange. Persistent pulmonary hypertensionof the newborn (PPHN) is secondary to failure of normal circulatory transition at birth. Itis a syndrome characterized by elevated pulmonary vascular resistance (PVR) that causeslabile hypoxemia due to decreased pulmonary blood flow and right-to-left shunting ofblood. Its incidence has been reported as 1.9 per 1,000 live births (0.4–6.8 per 1,000 livebirths) in the United States and 0.43 to 6 per 1,000 live births in the United Kingdom, withmortality rates ranging from 4% to 33%. (1)(2)

Fetal and Transitional CirculationPulmonary hypertension with reduced pulmonary blood flow is a normal physiologic statein the fetus because the placenta, not the lungs, serves as the organ of gas exchange. Most of

*Department of Pediatrics, University at Buffalo, Buffalo, NY.†Department of Pediatrics, Brown University, Providence, RI.

Article pulmonology

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the right ventricular output crosses the ductus arteriosusto the aorta, and only approximately 8% to 10% of com-bined ventricular output in an ovine fetus and 13% to 21%in human fetuses perfuse the fetal lungs due to high PVR.(3)(4) Mechanical factors such as fluid-filled lungs, hypoxicpulmonary vasoconstriction, and circulating vasoconstric-tors such as endothelin 1, and products of the prostaglan-din pathway (ie, leukotriene and thromboxane) all playa significant role in maintaining high fetal PVR. (5) Seroto-nin increases fetal PVR, and the use of selective serotoninreuptake inhibitors during the last half of pregnancy hasbeen associated with an increased incidence of PPHN, al-though recent studies have questioned this association.

A series of circulatory events take place at birth to en-sure a smooth transition from fetal to extrauterine life.Clamping of the umbilical cord removes the low-resistanceplacental circulation, increasing systemic arterial pressure.Various mechanisms operate simultaneously to rapidlyreduce pulmonary resistance and increase pulmonaryblood flow. The most important stimulus to promote pul-monary vasodilation appears to be ventilation of the lungsand an increase in oxygen tension. (5) An 8-fold increase inpulmonary blood flow occurs, which raises left atrialpressure, closing the foramen ovale. Because PVR decreaseslower than systemic vascular resistance, flow reverses acrossthe ductus arteriosus (from the aorta to the pulmonaryartery or left to right). The increase in arterial oxygensaturation leads to closure of the ductus arteriosus andductus venosus.

Endothelium-Derived Mediators andCirculatory Transition at BirthVascular endothelium releases several vasoactive productsthat play a primary role in cardiopulmonary transition atbirth. Pulmonary endothelial nitric oxide production in-creases markedly at the time of birth. The shear stress thatresults from increased pulmonary blood flow and in-creased oxygenation also induces endothelial nitric oxidesynthase (eNOS) expression, thus contributing to nitricoxide–mediated pulmonary vasodilation after birth. (5)Nitric oxide exerts its action through soluble guanylatecyclase and cyclic guanosine monophosphate (Fig 1).The arachidonic acid–prostacyclin pathway also playsan important role; prostaglandins activate adenylate cy-clase to increase cyclic adenosine monophosphate con-centrations in vascular smooth muscle cells (Fig 1).Inhibition of prostacyclin production by nonsteroidalanti-inflammatory drugs during late pregnancy has beenassociated with PPHN, (7) although this association hasalso been recently called into question. (8)

Etiology and Pathophysiology of PPHNPPHN can be secondary to lung parenchymal diseases,such as meconium aspiration syndrome (with or withoutasphyxia), respiratory distress syndrome (RDS), or pneu-monia or sepsis (maladaptation of pulmonary vasculature);remodeled pulmonary vasculature (maldevelopment) withnormal lung parenchyma (primary or idiopathic); or lunghypoplasia (underdevelopment) due to oligohydramniosor congenital diaphragmatic hernia (CDH) or intrinsic ob-struction (polycythemia with hyperviscosity). Disruptionof normal neonatal circulatory transition due to these fac-tors results in failure to resolve fetal pulmonary hyperten-sion and leads to the persistence of fetal pulmonaryhypertension or PPHN. High PVR decreases the bloodflow to the lungs because the blood takes the path of leastresistance, which is the systemic circulation. Ventilation-perfusion mismatch and extrapulmonary right-to-leftshunting of deoxygenated blood across the patent fora-men ovale (PFO) and patent ductus arteriosus (PDA) re-sult in cyanosis. Differential cyanosis (saturation in thelower limb is >5%–10% lower than right upper limb) oc-curs due to pulmonary artery to aorta shunt through thePDA. If the PDA is closed and the shunt exclusively is atthe PFO level, the degree of cyanosis is similar in boththe upper and lower limbs. Labile hypoxemia (markedchange in oxygen saturation with minimal or no changein ventilator settings or fraction of inspired oxygen[FIO2]) is characteristic of PPHN and is due to changein the volume of right-to-left shunt secondary to subtlechanges in the delicate balance between PVR and sys-temic vascular resistance. A few clinically important con-ditions associated with PPHN are outlined below.

Malignant TTNTransient tachypnea of newborn (TTN) has been associ-ated with PPHN. For example, after elective cesarean de-livery, newborns with TTN who have hypoxemia may begiven high concentrations of inspired oxygen (approxi-mately 100%) by hood or nasal cannula (without any pos-itive pressure). In these cases, absorption atelectasis candevelop, resulting in increasing oxygen requirementsand respiratory failure (Fig 2). Furthermore, the forma-tion of reactive oxygen species from the high alveolar ox-ygen can lead to increased pulmonary vascular reactivity,thereby contributing to PPHN. (9)(10) The termmalig-nant TTN has been used to describe severe respiratorymorbidity and subsequent mortality in newborns deliv-ered by elective cesarean delivery who developed PPHN.(11) One possible strategy when managing these new-borns (and to prevent malignant TTN) may be earlyuse of distending pressure (such as continuous positive

pulmonology persistant pulmonary hypertension

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airway pressure when FIO2 exceeds 0.5–0.6) to inflate andrecruit the lungs vs merely administering high amounts ofoxygen without positive pressure.

Pulmonary Hypertension in Premature InfantsAlthough PPHN is traditionally considered a disease of-term and late preterm infants, it is increasingly beingdiagnosed in extremely preterm infants. Some preterminfants with RDS present with PPHN in the firstfew days after birth, (12) whereas preterm infants withbronchopulmonary dysplasia (BPD) may be diagnosedas having pulmonary hypertension later in the hospitalcourse or after discharge from the NICU. Pulmonary ar-tery hypertension complicating BPD is a process some-what distinct from PPHN and tends to run a much

more protracted course. It appearsto be a consequence of the reducedpulmonary capillary bed secondaryto the simplified lung of new BPDand pulmonary vascular remodel-ing. Pulmonary vascular disease ischallenging to treat and significantlyincreases morbidity and mortality inBPD. (13)

Preterm infants with fetal growthrestriction and those who are bornafter prolonged rupture of mem-branes with varying degrees ofpulmonary hypoplas ia are athigher risk of developing pulmo-nary hypertension.

Congenital DiaphragmaticHernia

CDH is a developmental defect inthe diaphragm that separates thethorax and the abdomen and is themost important cause of pulmonaryhypoplasia resulting in PPHN. CDHhas a mortality rate of 20% to 30%,and the degree of associated pulmo-nary hypoplasia and the severityof pulmonary hypertension remainthe major determinants of survival.Despite marked improvement insurvival of PPHN resulting fromother causes, the mortality and needfor extracorporeal membrane oxy-genation (ECMO) remain high ininfants with CDH.

Alveolar Capillary DysplasiaAlveolar capillary dysplasia is generally associated withmalalignment of the pulmonary veins. It presents with re-spiratory failure and unremitting PPHN early in life andcarries a mortality rate that approaches 100%. (14) His-tologic examination of lung tissue remains the gold stan-dard for diagnosis. A lung biopsy to rule out alveolarcapillary dysplasia should be considered for neonateswho do not respond to conventional medical manage-ment or fail attempts at ECMO decannulation.

DiagnosisIn a hypoxemic neonate, differentiating cyanotic congenitalheart disease from PPHN is of paramount importance. The

Figure 1. Endothelium-derived mediators: the vasodilators prostacyclin (PGI2) and nitric oxide(NO) and the vasoconstrictor endothelin (ET-1). Cyclooxygenase (COX) and prostacyclinsynthase (PGIS) are involved in the production of prostacyclin. Prostacyclin acts on its receptor(IP) in the smooth muscle cell and stimulates adenylate cyclase (AC) to produce cyclic aden-osine monophosphate (cAMP). cAMP is broken down by phosphodiesterase 3A (PDE3A).Milrinone inhibits PDE3A and increases cAMP levels in arterial smooth muscle cells and car-diac myocytes. Endothelin acts on ET-A receptors causing vasoconstriction. A second endothelinreceptor (ET-B) on the endothelial cell stimulates NO release and vasodilation. Endothelial nitricoxide synthase (eNOS) produces NO, which stimulates soluble guanylate cyclase (sGC) enzyme toproduce cyclic guanosine monophosphate (cGMP). cGMP is broken down by PDE5 enzyme.Sildenafil inhibits PDE5 and increases cGMP levels in pulmonary arterial smooth muscle cells.cAMP and cGMP reduce cytosolic ionic calcium concentrations and induce smooth muscle cellrelaxation and pulmonary vasodilation. NO is a free radical and can avidly combine with su-peroxide anions to form the toxic vasoconstrictor peroxynitrite. Medications used in PPHN areshown in black boxes. Modified from Sharma et al. (6) Copyright Satyan Lakshminrusimha.





initial evaluation should include a thorough history andphysical examination, simultaneous measurement of pre-ductal and postductal oxygen saturation, chest radiography,

and arterial blood gas tests. Hypoxemia disproportionate tothe severity of parenchymal disease on chest radiographyshould suggest idiopathic PPHN (or cyanotic heart disease).Preductal and postductal oxygen saturation and PaO2 mea-surements are used to differentiate PPHN from structuralheart disease. Saturation differences of greater than 5% to10% or PaO2 differences of 10 to 20 mm Hg between rightupper limb and lower limbs are considered significant. Inneonates with PPHN and atrial-level right-to-left shuntingwithout a significant ductal shunt, both the right arm andthe right leg saturations will be low. Conversely, infants withPDA and coarctation of the aorta might have differential cy-anosis. In PPHN, hypoxemia is often labile unlike fixedhypoxemia seen in cyanotic congenital heart disease.Hyperoxia testing (obtaining an arterial gas measure-ment after 15 minutes of exposure to 100% oxygen)and hyperoxia-hyperventilation (hyperoxia and alkalosisto induce pulmonary vasodilation and improve PaO2)are no longer widely practiced because of the known ad-verse effects of hyperoxia and alkalosis. These tests can beavoided by confirming elevated pulmonary pressures byearly echocardiography, when available.

Echocardiography is the gold standard to confirm thediagnosis and to monitor the efficacy of specific therapeu-tic interventions in PPHN (Fig 3). Measurement of thedirection of the ductal and foramen ovale shunt (Fig 4),flattening or left deviation of the interventricular septum,and tricuspid regurgitation velocity on continuous waveDoppler with simultaneous systemic blood pressuremeasurement provides an indication of right-sided pres-sures and hemodynamic physiologic mechanisms. Evalu-ation of right and left ventricular function will guide thechoice of appropriate pulmonary vasodilator.

ManagementSupportive Therapy

The severity of PPHN can range from mild hypoxemiawith minimal respiratory distress to severe hypoxemia andcardiopulmonary instability that requires intensive caresupport. Infants with PPHN require supportive care, in-cluding optimal temperature and nutritional support,avoidance of stress, and handling with sedation and anal-gesia as needed. Paralysis should be avoided if possible be-cause it has been associated with increased mortality. (1)Additional therapy should target the underlying disease(such as antibiotics for pneumonia or sepsis) (Fig 5).

Mild cases of PPHN with minimal or no respiratorydistress may be detected in the newborn nursery eitherafter a desaturation episode or by low postductal oxygensaturation detected on critical congenital heart disease

Figure 2. Etiology and pathophysiology of persistent pulmonaryhypertension of the newborn (PPHN). Secondary PPHN can bedue to various lung diseases, such as retained lung fluid ortransient tachypnea of newborn (TTN), pneumonia, aspirationsyndromes, respiratory distress syndrome (RDS), and congenitaldiaphragmatic hernia with lung hypoplasia. Use of high con-centrations of inspired oxygen (approximately 100%) withoutpositive pressure (oxygen hood) can lead to absorption atelec-tasis and worsening of ventilation-perfusion mismatch. Lungdisease and V/Q mismatch result in hypoxemia. Increasedpulmonary vascular resistance results in reduced pulmonaryblood flow and right-to-left shunt through patent ductusarteriosus (PDA) and/or patent foramen ovale (PFO). Pulmonaryhypertension is often associated with systemic hypotension withdeviation of the interventricular septum to the left. The rightsubclavian artery (SCA) (and blood flowing to the right upperextremity) is always preductal. The left SCA may be preductal,juxtaductal, or postductal. Hence, preductal oxygen saturationsshould be obtained from the right upper extremity and comparedwith lower extremity to assess differential cyanosis.LA[left atrium; LV[left ventricle; PA[pulmonary artery; RA[right atrium

RV[right ventricle; TR[tricuspid regurgitation. Copyright Satyan Lakshminrusimha.





screening. (16) These infants can be managed with sup-portive care and oxygen supplementation. Close moni-toring is important because some of these infants mayrapidly deteriorate and require noninvasive ventilationor intubation and mechanical ventilation.

Hyperventilation and infusion of alkali were used inthe past but should be avoided because of adverse effectson cerebral perfusion and increased risk of sensorineuraldeafness. (17)(18) Alkali infusion was associated with in-creased use of ECMO and need for oxygen at 28 days.(1) Most centers avoid acidosis based on animal studiesthat found exaggerated hypoxic pulmonary vasoconstric-tion with pH less than 7.25. (19) We recommend main-taining pH greater than 7.25, preferably 7.30 to 7.40,during the acute phase of PPHN.

Mechanical VentilationOptimal lung recruitment (8- to 9-rib expansion on aninspiratory chest radiograph) with the use of positiveend-expiratory pressure (PEEP) or mean airway pressuredecreases PVR. Both underinflation and overinflation ofthe lung will lead to elevation of PVR. Gentle ventilationstrategies with optimal PEEP, relatively low peak infla-tion pressure or tidal volume, and a degree of permis-sive hypercapnia are recommended to ensure adequate

lung expansion while limitingbarotrauma and volutrauma. (20)In newborns with severe lung dis-ease, high-frequency ventilation isfrequently used to optimize lunginflation and minimize lung injury.(21) If a peak inflation pressure ofgreater than 25 to 28 cm H2O ortidal volumes greater than 6 mL/kgare required to maintain a PaCO2

less than 60 mm Hg on conven-tional ventilation, we recommendswitching to high-frequency (jet oroscillator) ventilation. In clinical stud-ies using inhaled nitric oxide (iNO),the combination of high-frequencyventilation and iNO resulted in thegreatest improvement in oxygenationin PPHN associated with diffuse pa-renchymal lung disease, such as RDSand pneumonia, but had no benefitin idiopathic PPHN or CDH. (22)

Oxygen is a specific and potentpulmonary vasodilator but may bedetrimental if used in excess. Me-chanical ventilation with high con-

centrations of oxygen used to be a mainstay of PPHNmanagement. More recently, it has been found that briefexposure to 100% oxygen in newborn lambs results in in-creased contractility of pulmonary arteries, (9) reducesresponse to iNO, (23) and increases the potential for ox-idative stress. We recommend maintaining preductal ox-ygen saturations in the low to mid-90s with PaO2 levelsbetween 55 and 80 mm Hg during management of in-fants with PPHN. If the serum lactate levels are normal(<3 mM/L) and urine output is adequate (‡1 mL/kgper hour), postductal oxygen saturations in the 70s and80s may be acceptable especially in infants with CDH.

SurfactantIn patients with PPHN secondary to parenchymal lungdisease, early administration of surfactant and lung re-cruitment is associated with better outcome with reducedrisk of ECMO or death. (24)(25) Surfactant inactivationand deficiency are observed in many neonatal respiratorydisorders, such as pneumonia, RDS, and meconium as-piration syndrome. We recommend that infants withPPHN secondary to parenchymal lung disease receivea dose of surfactant rich in surfactant protein B, suchas calfactant or poractant alfa. It is not clear whether sur-factant therapy is beneficial in infants with CDH. Animal

Figure 3. Echocardiographic features of persistent pulmonary hypertension of thenewborn (PPHN): high right ventricular pressure results in tricuspid regurgitation (TR) anddeviation of the interventricular septum to the left. Assessment of tricuspid regurgitationvelocity by continuous wave Doppler is used to calculate systolic pulmonary arterial pressure.The presence of right-to-left shunt at patent foramen ovale (PFO) and patent ductus arteriosus(PDA) is commonly observed in infants with severe PPHN. Impaired right and left ventricularfunction is associated with poor outcome in PPHN. Copyright Satyan Lakshminrusimha.





studies reveal benefit, but a review of the CDH registrydid not support the use of surfactant. (26) We recom-mend administration of surfactant only in the presenceof clinical, radiologic, or biochemical evidence of surfac-tant deficiency in CDH and administer only 50% of thedose because of pulmonary hypoplasia.

Pulmonary Vasodilator TherapyAfter achieving lung recruitment with and without surfac-tant therapy, further management should be based on ox-ygenation status, systemic blood pressure, and cardiac andventricular function on echocardiography (Fig 6). Varioustherapeutic strategies outlined in this figure are describedbelow.

iNO is a potent and selective pulmonary vasodilatorwithout a significant decrease in systemic blood pressure(selective effect of iNO). iNO is also preferentially distrib-uted to the ventilated segments of the lung, resulting inincreased perfusion of the ventilated segments, optimizingventilation-perfusion match (microselective effect of iNO).Studies have found that iNO therapy causes marked im-provement in oxygenation in term newborns with PPHN.(27) Multicenter randomized clinical studies subsequentlyconfirmed that iNO therapy reduces the need for ECMOin term neonates with hypoxemic respiratory failure. (28)(29)(30) iNO therapy is the only therapy approved by theUS Food and Drug Administration for clinical use in termor near-term newborn infants (>34 weeks’ gestation) with

Figure 4. Echocardiographic evaluation of neonatal hypoxemia based on ductal (black bar) and atrial (blue bar) shunts. Left-to-rightshunt at the ductal and atrial level is considered normal but can also be seen in the presence of parenchymal lung disease, resulting inhypoxemia in the absence of persistent pulmonary hypertension of the newborn (PPHN) (lower left quadrant). The presence of right-to-left shunt at the atrial and ductal levels is associated with PPHN (upper right quadrant). Right-to-left shunt at the ductal level but a left-to-right shunt at the atrial level is associated with left ventricular dysfunction, pulmonary venous hypertension, and ductal-dependentsystemic circulation (lower right quadrant) and is a contraindication for inhaled pulmonary vasodilators, such as inhaled nitric oxide. Inpatients with right-sided obstruction (such as critical pulmonary stenosis [PS]), right atrial blood flows to the left atrium through the PFO.Pulmonary circulation is dependent on a left-to-right shunt at the patent ductus arteriosus (PDA) (upper left quadrant).Ao[aorta; LA[left atrium; LV[left ventricle; PA[pulmonary artery; PGE1[prostaglandin E1; RA[right atrium; RV[right ventricle; Rx[treatment; TR[tricuspid

regurgitation.

Modified from Nair and Lakshminrusimha. (15) Copyright Satyan Lakshminrusimha.





PPHN. Konduri et al initially found that earlier initiationof iNO with an oxygenation index (OI) of 15 to 25 didnot reduce the need for ECMO but may have a tendencyto reduce the risk of progression to severe hypoxemic re-spiratory failure. (31) Post hoc analysis of the same studysuggested that the use of surfactant before randomizationand enrollment (and use of iNO) at an OI of 20 or less wasassociated with reduced incidence of ECMO or death.(25) A dose of 20 ppm results in improved oxygenationand the most optimal decrease in pulmonary to systemicarterial pressure ratio (32) and is the typical starting dose.Higher doses are not recommended because they are as-sociated with increased levels of nitrogen dioxide and met-hemoglobin. (27) To summarize, we recommend initiationof iNO if the OI is approximately 20 at a dose of 20 ppm.A complete response to iNO is defined as an increase in

Pao2/FIO2 ratio of 20 mm Hg ormore (20-20-20 rule for initiation ofiNO).Methemoglobin levels aremon-itored at 2 hours, 8 hours after initi-ation of iNO, and then once a dayfor the duration of iNO therapy.Some centers stop checking methe-moglobin levels after the first coupleof days if levels are low (<2%) andiNO dose remains less than 20 ppm.

Weaning iNO is a gradual pro-cess to minimize the risk of reboundvasoconstriction and resultant pul-monary hypertension associated withabrupt withdrawal. Weaning in stepsfrom 20 ppm gradually for a periodbefore its discontinuation preventsthe rebound effect. (33) If there isoxygenation response, inspired oxygenconcentration is first weaned below60%, and then iNO is weaned only ifPaO2 can be maintained at 60 mmHg or higher (or preductal oxygensaturation as measured by pulse oxi-metry ‡90%) for 60 minutes (60-60-60 rule of weaning iNO). Ourpractice is to wean iNO at a rate of5 ppm every 4 hours. Once iNO doseis 5 ppm, gradual weaning by 1 ppmevery 2 to 4 hours is performed. Con-tinuing iNO in infants unresponsiveto iNO or failure to wean iNO canpotentially lead to prolonged depen-dence on iNO due to suppression ofendogenous eNOS. (34)(35)

If iNO is not effective or not available and if hyp-oxemia persists, further management is based on sys-temic blood pressure and ventricular function onechocardiography:

1. If blood pressure is relatively stable but hypoxemiapersists, consider the use of phosphodiesterase (PDE)5 inhibitors, especially in the presence of a right-to-leftshunt at the PFO and/or PDA levels with good ven-tricular function (Fig 4). Sildenafil, administered byintravenous (preferred) or oral route, is usually the first-line agent. Sildenafil is metabolized by the liver, andsevere hepatic dysfunction may impair its metabolism.On the basis of pharmacokinetic data in neonates withPPHN, intravenous sildenafil is administered as a loadof 0.42 mg/kg for 3 hours (0.14 mg/kg per hour)

Figure 5. Management of acute persistent pulmonary hypertension of the newborn (PPHN)(suggested guidelines as recommended by the authors are shown in this figure): (1) minimalstimulation with the use of eye covers and ear muffs; (2) sedation and analgesia witha narcotic agent and a benzodiazepine (avoid muscle paralysis if possible); (3) maintainpreductal oxygen saturation in the low to mid-90s and postductal saturations above 70%as long as metabolic acidosis, lactic acidosis, and/or oliguria are not present; (4) lungrecruitment with adequate positive end-expiratory pressure (PEEP) or mean airway pressureand/or surfactant to maintain 8- to 9-rib expansion during inspiration; and (5) maintainadequate blood pressure and avoid supraphysiological systemic pressure. See text for details.HFOV[high frequency oscillatory ventilation; MAS[meconium aspiration syndrome; OI[oxygenation index;

PIP[peak inspiratory pressure.

Modified from Nair and Lakshminrusimha. (15) Copyright Satyan Lakshminrusimha.





followed by 1.6 mg/kg per day as a continuous mainte-nance infusion (0.07 mg/kg per hour). Careful monitor-ing of systemic blood pressure is necessary during sildenafiltherapy. Studies have found that oral sildenafil (dose range,1–2 mg/kg every 6 hours) improves oxygenation and re-duces mortality in centers limited by nonavailability of iNOand ECMO. (36)(37) Neonatal clinicians should beaware of the current US Food and Drug Administra-tion safety warning in the pediatric population basedon a dose escalation pediatric trial (all infants wereolder than 1 year) that demonstrated a higher mortal-ity in the high-dose group. (38)

Alternate agents (not approved by the US Food andDrug Administration) for iNO-resistant PPHN includeaerosolized prostaglandin E1 at 150 to 300 ng/kg per min-ute diluted in saline to provide 4 mL/h (39) and inhaledprostaglandin I2 at a dose of 50 ng/kg per minute. (40)The intravenous formulation epoprostenol sodium is dis-solved in 20 mL of manufacturer’s diluent (a glycine buffer,pH!10). Fresh solution is added to the nebulization cham-ber every 4 hours. (40) The effect of such alkaline pH onneonatal respiratory tract is not known. Iloprost is a synthetic

prostacyclin that can also be deliv-ered by aerosolization (1–2.5mg/kgevery 2–4 hours) (41) or by intrave-nous route (dose of 0.5 to 3 ng/kgper minute and titrated to 1–10 ng/kgper minute) (42) and improves oxy-genation in PPHN.

2. If blood pressure is normalbut there is evidence of ventriculardysfunction, an inodilator such asmilrinone might be the preferredtherapeutic agent in PPHN. (43)For example, if left ventricular dys-function is associated with high leftatrial pressures and a left-to-rightshunt at the level of the foramenovale in the presence of a right-to-left shunt at the ductus arterio-sus (Fig 4), iNO is contraindicatedbecause it may precipitate pulmo-nary edema and respiratory deteri-oration. Milrinone inhibits PDE3and increases concentration of cy-clic adenosine monophosphate inpulmonary and systemic arterialsmooth muscle and in cardiac mus-cle. (44) A loading dose (50 mg/kgfor 30–60 minutes) followed by

a maintenance dose (0.33 mg/kg per minute and esca-lated to 0.66 and then to 1 mg/kg per minute based onresponse) are commonly used. The loading dose is notrecommended in the presence of systemic hypotension.As with any systemic vasodilator, hypotension is a clinicalconcern, and blood pressure needs to be closely moni-tored. A fluid bolus (10mL/kg of lactated Ringer solutionor normal saline) before a loading dose may decrease therisk of hypotension.3. In the presence of systemic hypotension and goodcardiac function, 1 or 2 fluid boluses (10 mL/kg of lac-tated Ringer solution or saline) followed by dopamineare recommended. Some centers prefer the use of nor-epinephrine or vasopressin because these agents arethought to be more selective systemic vasoconstrictors.If high doses of vasopressors are needed, a cortisol levelis measured in these patients. If the levels are low rel-ative to the infant’s stress level and there is no evidenceof infection (viral, bacterial or fungal), the authors rec-ommend a stress dose of hydrocortisone.4. Hypotension is associated with cardiac dysfunction,and rapid deterioration with hemodynamic instability

Figure 6. Algorithm showing practical approach to persistent pulmonary hypertensionof the newborn (PPHN) based on oxygenation, systemic blood pressure, and cardiacfunction. See text for details.ECMO[extracorporeal membrane oxygenation; IV[intravenous; LR[lactated ringers solution; NO[nitric oxide;

OI=oxygenation index; Paw[mean airway pressure; PEEP[positive end-expiratory pressure; PGE1[prostaglandin E1;

PGI2[prostaglandin I2; PO-OG[per oral or orogastric.

Copyright Satyan Lakshminrusimha.





should precipitate cannulation for ECMO (or immediatetransfer to an ECMO center).

Chronic Pulmonary Hypertension in NeonatesNeonates with CDH and BPD can have pulmonary hy-pertension lasting for weeks or months. In the hospitalsetting, these patients are often managed with supplemen-tal oxygen, iNO (sometimes through a nasal cannula), andoral pulmonary vasodilators, such as sildenafil or bosentan.Because of its high cost, long-term therapy with iNO iscost prohibitive, and most patients can be successfully tran-sitioned to sildenafil after a few days.

Bosentan is an endothelin 1 receptor blocker (Fig 1)that may be beneficial in the management of PPHN. (45)However, the results of a multicenter, randomized, double-blind, placebo-controlled exploratory trial of bosentan(2 mg/kg per dose twice daily) did not have anyadditive effect on the top of iNO in term neonates withPPHN. (46)

ECMO is a modified cardiopulmonary bypass used fora prolonged period to support heart and lung function.The use of neonatal ECMO has decreased from a peakof more than 1,500 cases per year in the early 1990s toapproximately 750 cases per year. This decline is likelydue to improvements in both perinatal care and availabilityof advanced therapies for neonatal hypoxemic respiratoryfailure, including high-frequency ventilators, surfactant,and iNO. Generally accepted criteria to start ECMO arepersistent hypoxemia (with anOI of>40 or alveolar-arterialgradient >600 despite aggressive medical managementof PPHN with mechanical ventilation and iNO) andthe presence of hemodynamic instability (Fig 6).

Neurodevelopmental Outcome in NICUGraduates With Severe PPHNThe infants with PPHN who survive and are dischargedfrom the NICU have long-term consequences, such as neu-rodevelopmental, cognitive, and hearing abnormalities.(47)(48)(49) Thus, it is essential to provide long-termmultidisciplinary follow-up after discharge. In theirlong-term follow-up of infants randomized to earlyiNO in PPHN, Konduri et al noted neurodevelopmentalimpairment in approximately 25% of infants and hear-ing impairment in approximately 23%. (47) The UK col-laborative trial randomized critically ill neonates intotransfer to a regional center for ECMOor continued con-ventional care at the local NICU. At 7-year follow-up,mortality remained significantly lower in the ECMOgroup, with no increase in disability. (50) The presenceof neurodevelopmental and medical disabilities may

reflect the severity of the underlying illnesses experiencedby these infants rather than complications of iNO orECMO.

ConclusionThe management of PPHN has significantly improvedduring the last 2 decades. The emphasis has shifted fromhyperoxygenation-hyperventilation-alkalosis to improvedgentle ventilation strategies to optimize lung recruitmentand minimize oxygen toxic effects and permissive hyper-capnia paired with the therapeutic use of surfactant andiNO. These changes have led to a substantial decreasein the number of neonatal PPHN patients requiringECMO for respiratory disorders. Two remaining chal-lenges where large knowledge gaps persist include man-agement of pulmonary hypoplasia and pulmonaryhypertension in CDH and BPD-associated pulmonary hy-pertension in the premature infant. Newer pulmonary vas-odilators, such as antioxidants (superoxide dismutase),soluble guanylate cyclase activators, and rho-kinase inhib-itors, are currently under investigation. At the same time,many nurseries around the world cannot afford proven butexpensive therapies such as iNO and ECMO. Further re-search to develop appropriate cost-effective strategies toameliorate pulmonary vascular disease associated with con-ditions such as pneumonia and asphyxia andmeconium as-piration, common in developing countries, is warranted.

References1. Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonaryhypertension of the newborn in the era before nitric oxide: practicevariation and outcomes. Pediatrics. 2000;105(1, pt 1):14–202. Bendapudi P, Rao GG, Greenough A. Diagnosis and manage-ment of persistent pulmonary hypertension of the newborn.Paediatr Respir Rev. 2015;16(3):157–1613. Dawes GS. Pulmonary circulation in the foetus and new-born.Br Med Bull. 1966;22(1):61–65

American Board of Pediatrics Neonatal-PerinatalContent Specifications

• Know the pathogenesis, pathophysiology,pathologic features, and risk factors forpersistent pulmonary hypertension.

• Recognize the clinical features anddifferential diagnosis of persistentpulmonary hypertension.

• Recognize the laboratory, imaging, and other diagnosticfeatures of persistent pulmonary hypertension.

• Know the management of persistent pulmonary hypertensionincluding assisted ventilation, pharmacologic approaches,and ECMO.





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23. Lakshminrusimha S, Swartz DD, Gugino SF, et al. Oxygenconcentration and pulmonary hemodynamics in newborn lambs withpulmonary hypertension. Pediatr Res. 2009;66(5):539–54424. Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA,Gunkel JH; Survanta in Term Infants Study Group. Multicenterstudy of surfactant (Beractant) use in the treatment of term infantswith severe respiratory failure. J Pediatr. 1998;132(1):40–4725. Konduri GG, Sokol GM, Van Meurs KP, et al. Impact of earlysurfactant and inhaled nitric oxide therapies on outcomes in term/late preterm neonates with moderate hypoxic respiratory failure.J Perinatol. 2013;33(12):944–94926. Van Meurs K; Congenital Diaphragmatic Hernia Study Group.Is surfactant therapy beneficial in the treatment of the termnewborn infant with congenital diaphragmatic hernia? J Pediatr.2004;145(3):312–31627. Davidson D, Barefield ES, Kattwinkel J, et al; The I-NO/PPHN Study Group. Inhaled nitric oxide for the early treatment ofpersistent pulmonary hypertension of the term newborn: a random-ized, double-masked, placebo-controlled, dose-response, multicen-ter study. Pediatrics. 1998;101(3, pt 1):325–33428. Clark RH, Kueser TJ, Walker MW, et al; Clinical Inhaled NitricOxide Research Group. Low-dose nitric oxide therapy for persistentpulmonary hypertension of the newborn. N Engl J Med. 2000;342(7):469–47429. Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitricoxide in full-term and nearly full-term infants with hypoxicrespiratory failure [erratum appears in N Engl J Med. 1997;337(6):434]. N Engl J Med. 1997;336(9):597–60430. Roberts JD Jr, Fineman JR, Morin FC III, et al; The InhaledNitric Oxide Study Group. Inhaled nitric oxide and persistentpulmonary hypertension of the newborn. N Engl J Med. 1997;336(9):605–61031. Konduri GG, Kim UO. Advances in the diagnosis andmanagement of persistent pulmonary hypertension of the newborn.Pediatr Clin North Am. 2009;56(3):579–60032. Tworetzky W, Bristow J, Moore P, et al. Inhaled nitric oxide inneonates with persistent pulmonary hypertension. Lancet. 2001;357(9250):118–12033. Sokol GM, Fineberg NS, Wright LL, Ehrenkranz RA. Changesin arterial oxygen tension when weaning neonates from inhalednitric oxide. Pediatr Pulmonol. 2001;32(1):14–1934. Sheehy AM, Burson MA, Black SM. Nitric oxide exposureinhibits endothelial NOS activity but not gene expression: a role forsuperoxide. Am J Physiol. 1998;274(5 Pt 1):L833–L84135. Black SM, Heidersbach RS, McMullan DM, Bekker JM,Johengen MJ, Fineman JR. Inhaled nitric oxide inhibits NOSactivity in lambs: potential mechanism for rebound pulmonaryhypertension. Am J Physiol. 1999;277(5 Pt 2):H1849–H185636. Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oralsildenafil in infants with persistent pulmonary hypertension of thenewborn: a pilot randomized blinded study. Pediatrics. 2006;117(4):1077–108337. Vargas-Origel A, Gomez-Rodriguez G, Aldana-Valenzuela C,Vela-Huerta MM, Alarcon-Santos SB, Amador-Licona N. The useof sildenafil in persistent pulmonary hypertension of the newborn.Am J Perinatol. 2009;27(3):225–23038. Abman SH, Kinsella JP, Rosenzweig EB, et al; PediatricPulmonary Hypertension Network (PPHNet). Implications of theU.S. Food and Drug Administration warning against the use ofsildenafil for the treatment of pediatric pulmonary hypertension.Am J Respir Crit Care Med. 2013;187(6):572–575





39. Sood BG, Keszler M, Garg M, et al. Inhaled PGE1 in neonateswith hypoxemic respiratory failure: two pilot feasibility randomizedclinical trials. Trials. 2014;15(1):48640. Kelly LK, Porta NF, Goodman DM, Carroll CL, Steinhorn RH.Inhaled prostacyclin for term infants with persistent pulmonary hyperten-sion refractory to inhaled nitric oxide. J Pediatr. 2002;141(6):830–83241. Kahveci H, Yilmaz O, Avsar UZ, et al. Oral sildenafil andinhaled iloprost in the treatment of pulmonary hypertension of thenewborn. Pediatr Pulmonol. 2014;49(12):1205–121342. Janjindamai W, Thatrimontrichai A, Maneenil G, Chanvitan P,Dissaneevate S. Effectiveness and safety of intravenous iloprost forsevere persistent pulmonary hypertension of the newborn. IndianPediatr. 2013;50(10):934–93843. Lakshminrusimha S, Steinhorn RH. Inodilators in nitric oxideresistant persistent pulmonary hypertension of the newborn.Pediatr Crit Care Med. 2013;14(1):107–10944. McNamara PJ, Shivananda SP, Sahni M, Freeman D, TaddioA. Pharmacology of milrinone in neonates with persistent pulmo-nary hypertension of the newborn and suboptimal response toinhaled nitric oxide. Pediatr Crit Care Med. 2013;14(1):74–8445. Mohamed WA, Ismail M. A randomized, double-blind,placebo-controlled, prospective study of bosentan for the treatment

of persistent pulmonary hypertension of the newborn. J Perinatol.2012;32(8):608–61346. Steinhorn RH, Fineman J, Kusic-Pajic A, et al. Bosentan asadjunctive therapy for persistent pulmonary hypertension of the new-born: results of the FUTURE-4 study. Circulation. 2014;130:A1350347. Konduri GG, Vohr B, Robertson C, Sokol GM, Solimano A,Singer J, et al. Early inhaled nitric oxide therapy for term and near-term newborn infants with hypoxic respiratory failure: neurodevelop-mental follow-up. J Pediatr. 2007;150(3):235–240, 240 e23148. Robertson CM, Tyebkhan JM, Hagler ME, Cheung PY,Peliowski A, Etches PC. Late-onset, progressive sensorineuralhearing loss after severe neonatal respiratory failure. Otol Neurotol.2002;23(3):353–35649. Lipkin PH, Davidson D, Spivak L, Straube R, Rhines J, ChangCT. Neurodevelopmental and medical outcomes of persistentpulmonary hypertension in term newborns treated with nitricoxide. J Pediatr. 2002;140(3):306–31050. McNally H, Bennett CC, Elbourne D, Field DJ, GroupUKCET; UK Collaborative ECMO Trial Group. United Kingdomcollaborative randomized trial of neonatal extracorporeal mem-brane oxygenation: follow-up to age 7 years. Pediatrics. 2006;117(5):e845–e854





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1. A male infant cries soon after spontaneous vaginal delivery. He is vigorous and has good tone. He is initiallycyanotic, but gradually his skin turns pink. Which of the following statements regarding transitionalphysiology for the healthy term infant is correct?

A. Clamping of the umbilical cord causes a decrease in the infant’s systemic arterial pressure.B. Pulmonary blood flow doubles compared with fetal circulation.C. The flow across the ductus arteriosus switches from left to right to right to left.D. Approximately 25% to 35% of combined ventricular output in the fetus will perfuse the fetal lungs.E. Ventilation of the lungs and an increase in oxygen tension lead to pulmonary vasodilation.

2. A 1-hour-old term female infant is having respiratory distress. She was born in meconium-stained amnioticfluid. Her oxygen saturation is low, and the saturation in the lower limb is 10% lower than the saturationmeasured in the right wrist. You suspect possible persistent pulmonary hypertension of the newborn (PPHN).Which of the following statements correctly describes the pathophysiology of PPHN?

A. In PPHN, there is an excess induction of endothelial nitric oxide synthase, leading to an abundance of nitricoxide in the pulmonary vasculature.

B. In PPHN, high pulmonary vascular resistance decreases the blood flow to the lungs, and there is preferentialblood flow to the systemic circulation, which is the path of least resistance.

C. In PPHN, there will be excessive shunting of deoxygenated blood that flows from the aorta to thepulmonary arteries.

D. In PPHN, the oxygen saturation is likely to remain at a consistent, stable level with very little change.E. The foramen ovale must be closed for PPHN to have clinical manifestations in the newborn.

3. The same infant is in the neonatal intensive care unit (NICU) undergoing evaluation and treatment. Part of theinitial evaluation includes chest radiography and arterial blood gas analysis. Echocardiography is also ordered.Which of the following statements concerning diagnosis of PPHN and the consideration of congenital heartdisease is correct?

A. A fixed hypoxemia that is not labile would lead to a higher suspicion of PPHN rather than cyanoticcongenital heart disease.

B. Even when echocardiography is readily available, the best way to distinguish between PPHN and cyanoticheart disease is to induce a moderate hyperoxia combined with hyperventilation.

C. On echocardiography, flattening or left deviation of the interventricular septum is one sign that providesan indication of right-sided pressures.

D. Chest radiography in patients with PPHN typically reveals severe parenchymal disease, usually more thanone would expect considering the degree of hypoxemia.

E. Infants who have coarctation of the aorta will have a reverse pattern of differential cyanosis than infantswith PPHN, with the lower limbs having saturation approximately 10% higher than the right upper limb.

4. After diagnostic evaluation, the patient is diagnosed as having PPHN, and congenital heart disease has beenruled out. She is receiving mechanical ventilation and intravenous fluids. Which of the following treatmentswould be most appropriate for this patient?





A. Hyperventilation to induce moderate alkalosis with pH 7.45 or above is desirable.B. Although rapid boluses should be avoided, a slow infusion of sodium bicarbonate during the first 6 hours is

likely to shorten the duration of mechanical ventilation.C. The treatment of PPHN is optimized by using a positive end-expiratory pressure that is as low as possible to

maintain expansion of 6 to 7 ribs.D. High-frequency oscillatory ventilation is contraindicated in PPHN because it can cause increased

pulmonary vascular resistance.E. Although oxygen is a potent pulmonary vasodilator, excess use can be detrimental even in PPHN, and

therefore a strategy of using limited oxygen to achieve certain goals for oxygen saturation and Pao2 isrecommended.

5. The patient continues to have hypoxemia and appears to be worsening despite various adjustments inmechanical ventilation strategies. The respiratory therapist has brought out the inhaled nitric oxide (iNO)delivery system next to the ventilator. Which of the following statements regarding the use of iNO for PPHN iscorrect?

A. iNO is a potent and selective pulmonary vasodilator that does not cause a significant decrease in systemicblood pressure.

B. iNO is preferentially distributed to the parts of the lung that are not well ventilated.C. Although it is widely used in NICU practice as an off-label drug, the US Food and Drug Administration has

not approved iNO specifically for clinical use in term infants with PPHN or any kind of respiratory failure.D. iNO works better for term infants with PPHN when surfactant is not given.E. The current recommended practice is to begin iNO in this type of scenario at 1 ppm and titrate up to desired

effect.

Parent Resources from the AAP at HealthyChildren.org

• https://www.healthychildren.org/English/news/Pages/Pulmonary-Hypertension-in-Children-Accounts-for-Increasing-Share-of-Health-Care-Costs.aspx




http://HealthyChildren.org

https://www.healthychildren.org/English/news/Pages/Pulmonary-Hypertension-in-Children-Accounts-for-Increasing-Share-of-Health-Care-Costs.aspx

https://www.healthychildren.org/English/news/Pages/Pulmonary-Hypertension-in-Children-Accounts-for-Increasing-Share-of-Health-Care-Costs.aspx


DOI: 10.1542/neo.16-12-e6802015;16;e680NeoReviews

Satyan Lakshminrusimha and Martin KeszlerPersistent Pulmonary Hypertension of the Newborn

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Satyan Lakshminrusimha and Martin KeszlerPersistent Pulmonary Hypertension of the Newborn

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Persistent Pulmonary Hypertension of the Newborn Pulmonary...Persistent pulmonary hypertension of the newborn (PPHN) is often secondary to pa renchymal lung disease (such as meconium