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Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome

Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome
Literature review current through: May 2024.
This topic last updated: Mar 08, 2023.

INTRODUCTION — Persistent pulmonary hypertension of the newborn (PPHN) occurs when pulmonary vascular resistance (PVR) remains abnormally elevated after birth, resulting in right-to-left shunting of blood through fetal circulatory pathways. This in turn leads to severe hypoxemia that may not respond to conventional respiratory support.

The management and prognosis of PPHN are discussed here. The pathophysiology, clinical features, and diagnosis are discussed separately. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

Related neonatal conditions are discussed in separate topic reviews:

Meconium aspiration syndrome (see "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis")

Neonatal sepsis (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates")

Pneumonia (see "Neonatal pneumonia")

Respiratory distress syndrome (see "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis")

Congenital diaphragmatic hernia (see "Congenital diaphragmatic hernia (CDH) in the neonate: Management and outcome")

Pulmonary hypertension in infants with bronchopulmonary dysplasia (see "Pulmonary hypertension associated with bronchopulmonary dysplasia")

GENERAL PRINCIPLES

Setting of care — Patients should be cared for in a neonatal intensive care unit (NICU) with staff experienced in the care of patients with PPHN. Patients with severe/refractory hypoxemia should be managed in centers where multiple modes of respiratory support, rescue therapies, and use of inhaled nitric oxide (iNO) are available; extracorporeal membrane oxygenation (ECMO) should be available at the center or there should be an established arrangement for timely transfer to an ECMO center [1].

General supportive care — Newborns depressed at birth should be resuscitated promptly and monitored closely. (See "Neonatal resuscitation in the delivery room".)

General supportive care measures for all neonates with PPHN aim to reverse or prevent further increases in pulmonary vascular resistance (PVR). This generally includes the following:

Supplemental oxygen, which improves oxygen delivery and acts as a pulmonary vasodilator (see 'Supplemental oxygen' below)

Mechanical ventilation, if necessary, to recruit atelectatic lung segments and ensure adequate oxygenation and ventilation (see 'Respiratory support' below)

Hemodynamic support, including intravenous fluids, vasopressors, and/or inotropic agents, if necessary (see 'Hemodynamic support' below)

All ill-appearing neonates should be cared for in a neutral thermal environment to minimize oxygen consumption. (See "Neonatal resuscitation in the delivery room", section on 'Temperature control'.)

Identify and treat underlying conditions — It is important to identify and treat any underlying conditions that may be causing or contributing to PPHN, including:

Sepsis/pneumonia – Blood cultures should be obtained and empiric antibiotics provided pending culture results since sepsis and pneumonia are common causes of PPHN. (See "Management and outcome of sepsis in term and late preterm neonates" and "Neonatal pneumonia".)

Meconium aspiration syndrome (MAS) – Infants with severe MAS are typically treated with surfactant therapy, as discussed separately. (See "Meconium aspiration syndrome: Management and outcome", section on 'Surfactant'.)

Respiratory distress syndrome (RDS) – Surfactant therapy is appropriate for any infant in whom RDS is the presumed cause of PPHN. (See "Respiratory distress syndrome (RDS) in preterm infants: Management", section on 'Surfactant therapy'.)

Congenital diaphragmatic hernia (CDH) – Management of CDH is discussed separately. (See "Congenital diaphragmatic hernia (CDH) in the neonate: Management and outcome", section on 'Postnatal management'.)

Identify and correct metabolic abnormalities — Metabolic abnormalities (eg, acid/base disturbances, hypoglycemia, electrolyte derangements) are common in infants with PPHN and may have adverse hemodynamic consequences. These should be identified and treated accordingly:

Correction of metabolic acidosis – Metabolic acidosis should be avoided in patients with PPHN because it increases PVR. Acetate may be added to infused intravenous fluids at a dose of 2 to 3 mEq/kg per day. However, rapid infusion of sodium bicarbonate should be avoided since it may worsen intracellular acidosis in the face of impaired ventilation [2,3]. (See "Approach to the child with metabolic acidosis", section on 'Intravenous bicarbonate therapy'.)

Hypoglycemia – Management of neonatal hypoglycemia is discussed separately. (See "Management and outcome of neonatal hypoglycemia".)

Hypocalcemia – Management of neonatal hypocalcemia is discussed separately. (See "Neonatal hypocalcemia".)

SEVERITY ASSESSMENT

Severity of hypoxemia — The oxygenation index (OI) is used to assess the severity of hypoxemia, which reflects the degree of the right-to-left shunting. The OI guides the timing of interventions, such as inhaled nitric oxide (iNO) or extracorporeal membrane oxygenation (ECMO) support. (See 'Management approach' below.)

The OI is calculated based upon the fraction of inspired oxygen (FiO2), the mean airway pressure (MAP), and the arterial partial pressure of oxygen (PaO2) as follows (calculator 1):

OI = [MAP x FiO2 ÷ PaO2] x 100

The OI is used to categorize the severity of hypoxemia as follows:

Mild hypoxemia: OI <15

Moderate hypoxemia: OI ≥15 and <25

Severe hypoxemia: OI ≥25 and <40

Very severe hypoxemia: OI ≥40

Serial measurements are more informative than a single assessment.

Severity of pulmonary hypertension (PH) — In addition to the OI, the severity of PPHN can be assessed according to echocardiographic findings (eg, estimated right ventricular pressure [RVp], evidence of ventricular dysfunction), as discussed in detail separately. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis", section on 'Severity of PH'.)

PH severity is categorized based upon the estimated RVp relative to the systemic blood pressure (BP) as follows:

Mild to moderate PPHN – Estimated RVp between one-half to three-quarters systemic BP

Moderate to severe PPHN – Estimated RVp greater than three-quarters systemic BP but less than systemic BP

Severe PPHN – Estimated RVp greater than systemic BP

MANAGEMENT APPROACH — The following sections detail our suggested approach to managing neonates with PPHN. Initial measures include general supportive cardiorespiratory care for all neonates with PPHN. For neonates who fail to respond to supportive measures, pulmonary vasodilator therapy (typically with inhaled nitric oxide [iNO]) is used to reduce pulmonary vascular resistance (PVR). Patients with severe hypoxemia and/or ventricular dysfunction that is refractory to medical management may require extracorporeal membrane oxygenation (ECMO) to maintain adequate tissue oxygenation until PVR falls. Additional details regarding these interventions are provided below. (See 'Interventions' below.)

PPHN can be caused by a variety of different primary disorders (eg, meconium aspiration syndrome [MAS], respiratory distress syndrome [RDS], congenital diaphragmatic hernia [CDH], sepsis/pneumonia) or it may be idiopathic and may develop in a newborn with little to no parenchymal lung disease. The course and response to therapy vary substantially from one patient to another. Thus, individualized management and frequent reassessment are critical.

PPHN with severe lung disease — For neonates with PPHN and underlying parenchymal lung disease (eg, MAS, RDS, pneumonia,) our general approach to management is as follows (table 1):

Most neonates with PPHN in the setting of severe lung disease require intubation and mechanical ventilation. We begin with conventional mechanical ventilation (CMV) using a patient-triggered volume-targeted mode. We start with tidal volumes (Tv) of 4 to 6 mL/kg and positive end-expiratory pressure (PEEP) of 5 to 7 cm H2O, depending on the appearance of the chest radiograph (eg, if lung volumes are low on chest radiograph, we would start at the higher end of this range). In general, we use a high PEEP strategy to recruit atelectatic segments, maintain resting lung volume, and ensure adequate oxygenation. If gas exchange targets are not met with low Tv ventilation, the Tv setting can be liberalized. However, if the neonate requires Tv >7 to 8 mL/kg to maintain gas exchange targets, we suggest transitioning to high frequency ventilation (HFV). (See 'Conventional mechanical ventilation' below and 'Gas exchange targets' below.)

A key to optimizing CMV in neonates with PPHN is providing adequate sedation and, if needed, neuromuscular blockade. This is because agitation and dyssynchrony with the ventilator can increase PVR and worsen hypoxemia. Opioid analgesia with or without a benzodiazepine provides sufficient sedation in most cases; neuromuscular blockade is occasionally necessary. (See 'Sedation and neuromuscular blockade' below.)

In conjunction with providing respiratory support, most neonates with PPHN require hemodynamic support, which may include vasopressors and/or inotropic support. Dopamine is the agent most commonly used when vasopressor therapy is required. However, for neonates with significant ventricular dysfunction, epinephrine and/or milrinone may be preferred. (See 'Hemodynamic support' below and "Neonatal shock: Management", section on 'Vasoactive agents'.)

Neonates with PPHN are monitored closely and respiratory and hemodynamic interventions are adjusted as needed to achieve gas exchange and hemodynamic targets, as summarized below. (See 'Monitoring' below and 'Goals of therapy' below.)

For patients requiring FiO2 >0.6 to achieve the target oxygenation saturation, other interventions should be implemented. These may include optimizing respiratory support (eg, increasing PEEP or transitioning to HFV) and optimizing hemodynamic support. In addition, factors contributing to hypoxemia and right-to-left shunting (eg, metabolic acidosis, inadequate sedation, pneumothorax) should be identified and addressed. (See 'Hemodynamic support' below and 'Sedation and neuromuscular blockade' below and 'Identify and correct metabolic abnormalities' above and "Pulmonary air leak in the newborn", section on 'Management'.)

If, despite optimizing CMV and sedation, the neonate continues to have OI ≥25, we recommend iNO. (See 'Inhaled nitric oxide (iNO)' below.)

For neonates requiring high pressures on CMV (eg, peak pressures of 28 to 30 cm H2O) to achieve gas exchange targets, we transition to HFV. It is reasonable to transition to HFV sooner if the neonate has signs of ventilator-induced lung injury (eg, pneumothorax). Ideally, the transition to HFV should take place before the neonate becomes clinically unstable. (See 'High frequency ventilation (HFV)' below.)

Other interventions for neonates with ongoing hypoxemia and/or hemodynamic instability due to PPHN may include:

Surfactant – Surfactant is administered early in the course for neonates with MAS or RDS. In our practice, we also administer surfactant in most neonates with severe PPHN associated with significant parenchymal lung disease, even if the etiology is not clearly MAS or RDS. In these cases, surfactant is given within the first few hours after birth if there is no improvement with standard therapies. (See 'Surfactant' below.)

Transfusion – For neonates with severe hypoxemia (OI ≥25), the threshold we use to trigger red blood cell (RBC) transfusion is hemoglobin level <15 g/dL (hematocrit <40 percent). (See "Red blood cell (RBC) transfusions in the neonate".)

Neonates with severe hypoxemia and/or ventricular dysfunction that are refractory to medical management generally require ECMO. (See 'Extracorporeal membrane oxygenation (ECMO)' below.)

PPHN without severe lung disease — In neonates with PPHN without underlying parenchymal lung disease, hypoxemia is predominantly caused by severe right-to-left shunting. Our management approach for these neonates is as follows:

We initially manage neonates in this category with 100 percent oxygen administered noninvasively (eg, low flow nasal cannula, high flow nasal canula [HFNC], or continuous positive airway pressure [CPAP]). This may be sufficient for some neonates. (See 'Supplemental oxygen' below.)

For neonates who have persistent shunting and hypoxemia but who are ventilating adequately, iNO can be administered noninvasively (typically via HFNC or CPAP). (See 'Inhaled nitric oxide (iNO)' below.)

Neonates who fail noninvasive iNO require intubation and mechanical ventilation. In these neonates, we start with modest levels of PEEP (5 cm H2O) and minimize mean airway pressure (MAP) by using low inspiratory pressures and short inspiratory times or volume targeted ventilation. This is because high PEEP levels are often ineffective in improving oxygenation in this setting and may in fact worsen the patient's clinical status by impeding cardiac output. (See 'Conventional mechanical ventilation' below.)

Sedation and neuromuscular blocking agents may be required in this setting to decrease dyssynchronous breathing and facilitate ventilation. (See 'Sedation and neuromuscular blockade' below.)

These interventions are generally sufficient to improve shunting for these neonates.

Monitoring — Appropriate monitoring for infants with PPHN includes:

Pre- and post-ductal oxygen saturation (eg, with pulse oximetry probes placed on the right thumb and either great toe) are monitored continuously. The preductal saturation is the value used for titrating respiratory support since it assesses oxygen delivery to the brain and heart. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Pulse oximetry'.)

Serial clinical assessments, including assessment of perfusion.

Blood pressure (BP) – Systemic BP is monitored continuously with an indwelling arterial line (typically a radial or umbilical arterial catheter [UAC]).

Serial blood gases – Arterial blood gases (ABGs) are obtained to measure the PaO2 and calculate the OI at least every four to six hours initially; they are subsequently spaced out once the neonate's clinical status stabilizes. Most neonates with PPHN undergo arterial line placement, either with a UAC or radial artery catheter. This facilitates both ABG sampling and continuous BP monitoring. ABGs drawn from a right radial catheter provide measurements of preductal oxygenation, whereas ABGs drawn from left radial catheters and UACs measure postductal oxygenation. If a post-ductal arterial line is used, preductal oxygenation is monitored with pulse oximetry. (See 'Severity assessment' above and "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Arterial blood gas measurement'.)

Blood lactate levels – Lactate levels are monitored serially (we typically obtain them with blood gases as part of point-of-care testing). An elevated lactate level is an indicator of inadequate oxygen delivery to tissues, which may be due to poor perfusion and/or hypoxemia.

Ventilator data – For neonates managed with CMV, it is important to monitor the peak inspiratory pressures and exhaled tidal volumes. (See "Approach to mechanical ventilation in very preterm neonates", section on 'Monitoring'.)

Methemoglobin levels – Practice varies regarding routine monitoring of methemoglobin levels in neonates receiving iNO. We do not routinely measure methemoglobin, as the risk of toxicity is low when using a maximum iNO concentration of 20 ppm. However, other centers may routinely monitor these levels.

Echocardiography – All neonates with suspected PPHN have an initial echocardiogram. Follow-up echocardiography is warranted if the initial study showed depressed ventricular function or if the neonate is not improving. However, not all patients require repeat echocardiography. The timing of repeat echocardiography varies depending on the clinical status of the neonate. Serial echocardiograms should assess ventricular function, estimate right ventricular pressure, and assess the degree of right-to-left shunting. In some centers, serial bedside functional echocardiograms may be performed by the neonatologist to monitor cardiac function.

Transcutaneous carbon dioxide monitoring (TCOM) – Our centers do not routinely use TCOM to assess ventilation since we rely mostly on ABGs for this purpose. However, other centers may routinely use TCOM.

Chest radiographs – Routine daily chest radiographs are generally not necessary. A chest radiograph may be warranted to assess lung volumes (eg, after initiating HFV) or if there is an acute change in the neonate's clinical status.

Goals of therapy

Gas exchange targets

Oxygenation – We target a preductal SpO2 in the range of 90 to 95 percent. A high FiO2 (ie, 90 to 100 percent) may be required initially to control pulmonary hypertension and improve shunting. However, hyperoxemia should be avoided because the administration of high oxygen concentrations, even for a relatively short period, may cause lung injury and there is no advantage to maintaining SpO2 >95 percent.

Ventilation (carbon dioxide [CO2] clearance) – We initially attempt to achieve and maintain normal ventilation (arterial partial pressure of carbon dioxide [PaCO2] 40 to 45 mmHg). This is because hypercarbia and acidosis increase PVR. As the infant's oxygenation and ventilatory status become more stable, we maintain PaCO2 in the range of 40 to 50 mmHg to minimize lung injury associated with more aggressive ventilation.

Pre- and post-ductal SpO2 difference – A difference of >10 percent between the pre- and post-ductal saturation indicates significant right-to-left shunting. The goal of management is to minimize right-to-left shunting (ie, a difference between pre- and post-ductal saturation that is no more than 3 to 5 percent).

Hemodynamic targets

Blood pressure – We set systemic BP targets at the upper limits of normal (eg, for term neonates, mean BP 45 to 55 mmHg; systolic BP 50 to 70 mmHg). This is because pulmonary arterial pressure in patients with PPHN may be at or near normal systemic levels and right-to-left shunting increases as systemic BP decreases. Thus, maintaining systemic BP is important to reduce the right-to-left shunting and to maintain adequate tissue oxygenation.

Lactate – Lactate levels should be in the normal range. An elevated lactate level generally indicates that tissue perfusion is compromised and treatment should be escalated.

Echocardiography – If serial echocardiograms are performed, findings that indicate improvement include reduction in the estimated right ventricular pressure, a reduction or resolution in the degree of right-to-left shunting, and improvement in ventricular function (if it was depressed initially).

Refractory PPHN

Extracorporeal membrane oxygenation (ECMO) — Infants with severe PPHN who remain persistently severely hypoxemic (OI ≥40) on maximal ventilatory support despite administration of iNO are candidates for ECMO. If the infant is not being managed at an ECMO center, transfer to an ECMO center should ideally occur before the time that the patient requires this level of support.

Criteria for ECMO vary among institutions with ECMO capability. Generally accepted requirements include the following:

OI consistently ≥40 (some centers use OI ≥60 if the infant is on HFV since MAPs are higher on HFV than CMV).

Birth weight >1800 g.

Gestational age >34 weeks.

Reversible lung disease.

No evidence of cyanotic congenital heart disease (CHD) on echocardiogram.

No other conditions that would be considered contraindications to ECMO (including multiple organ system failure; contraindications to full anticoagulation [eg, coagulopathy, grade 2 or greater intracranial hemorrhage]; massive cerebral edema; irreversible pulmonary or cardiac disease; or multiple congenital anomalies).

The goal of ECMO is to support the patient and maintain adequate oxygen delivery without causing ongoing lung injury from mechanical ventilation while the underlying disease process and associated pulmonary hypertension resolve. Most patients with PPHN are weaned from ECMO within 7 to 10 days [4,5]. However, in severe cases, two or more weeks occasionally may be necessary for adequate remodeling of the pulmonary vasculature.

In a report from the Extracorporeal Life Support Organization registry that included data on >5000 ECMO runs in neonates with PPHN from 1989 through 2016, 77 percent of infants survived to discharge [5]. The average duration of ECMO support was 6.5 days.

Consideration of alternative diagnoses — In patients with ongoing severe hypoxemia who are unable to be weaned off of ECMO, the possibility of an underlying irreversible lung condition, such as alveolar capillary dysplasia (ACD), genetic disorders of surfactant dysfunction, or severe pulmonary hypoplasia should be considered [6]. If ACD is suspected, further evaluation including catheterization and lung biopsy are needed to confirm the diagnosis. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis", section on 'Differential diagnosis' and "Classification of diffuse lung disease (interstitial lung disease) in infants and children", section on 'Disorders more prevalent in infancy'.)

INTERVENTIONS — The following sections summarize the different interventions used in the management of PPHN. A stepwise approach to the application of these therapies is provided above. (See 'Management approach' above.)

Most neonates with PPHN do not require all of these interventions. In studies reporting on neonates with PPHN managed in the contemporary era, these interventions were used with the following frequencies [7-9]:

Mechanical ventilation – 89 to 100 percent

Sedation – 85 to 100 percent

Vasopressors and inotropes – 67 to 81 percent

Inhaled nitric oxide – 64 to 100 percent

High frequency ventilation – 47 to 59 percent

Surfactant – 44 to 59 percent

Extracorporeal membrane oxygenation (ECMO) – 5 to 27 percent

Respiratory support

Supplemental oxygen — Oxygen is a pulmonary vasodilator and it should be initially administered at a concentration of 100 percent to infants with PPHN in an attempt to reverse pulmonary vasoconstriction. However, there is no advantage to maintaining an elevated PaO2. Moreover, the administration of high oxygen concentrations, even for a short time period, may cause lung injury. Thus, the oxygen concentration should be adjusted to maintain the target oxygen saturation (ie, preductal oxygen saturation 90 to 95 percent) (see 'Gas exchange targets' above). Although uncommon in PPHN, persistent hyperoxemia should be avoided.

The initial mode of oxygen administration (low flow nasal cannula, high flow nasal canula [HFNC], or continuous positive airway pressure [CPAP]) depends on the infant's underlying pulmonary condition and degree of respiratory distress. Most infants with moderate to severe PPHN require intubation and mechanical ventilation.

Additional details regarding oxygen delivery, and noninvasive respiratory support (eg, HFNC, CPAP) in neonates are provided separately. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn".)

Conventional mechanical ventilation — The strategy of ventilator support depends upon the presence or absence of parenchymal lung disease, and the infant's response to treatment.

When PPHN is associated with lung disease, atelectasis and the resulting maldistribution of ventilation may exacerbate high pulmonary vascular resistance (PVR). Mechanical ventilation uses an open lung strategy, providing positive end-expiratory pressure (PEEP) to recruit atelectatic segments, maintain adequate resting lung volume, and ensure appropriate oxygenation and ventilation. We typically use a patient-triggered volume-targeted mode. Additional details regarding different modes of mechanical ventilation in neonates are provided in a separate topic review. (See "Overview of mechanical ventilation in neonates", section on 'Ventilator modes'.)

In infants without associated lung disease, hypoxemia is caused by right-to-left shunting rather than ventilation-perfusion imbalance. As a result, hypoxemia may not respond to conventional ventilator maneuvers. In this circumstance, strategies that elevate mean airway pressure (MAP) may actually impede cardiac output and increase PVR. Thus, we minimize MAP by using low inspiratory pressures and short inspiratory times or volume targeted ventilation. However, it is essential to maintain adequate lung recruitment with modest levels of PEEP.

High frequency ventilation (HFV) — Patients with PPHN often require high ventilator settings. We typically transition to HFV when peak pressures on conventional mechanical ventilation (CMV) reach 28 to 30 cm H2O, or if the neonate develops significant air leak. It is reasonable to transition to HFV sooner, particularly if the neonate is persistently requiring high FiO2. Ideally, the transition to HFV should take place before the neonate becomes clinically unstable. The theoretical rationale for HFV in this setting is that it may be "lung-protective" relative to CMV, particularly when high CMV settings are required to achieve adequate gas exchange (ie, HFV may limit lung-injury from the tissue stretch that can occur with cyclic peak inflations in CMV).

The use of HFV in this setting is supported by a clinical trial involving 205 infants with severe PPHN, of whom 60 percent were refractory to initial therapy with either iNO with CMV or HFV alone (without iNO) [10]. One-third of these refractory patients responded to treatment with HFV plus iNO.

Details regarding initiating and titrating HFV and additional discussion of data supporting use of HFV in other neonatal populations (eg, preterm neonates with RDS) are provided in a separate topic review. (See "Approach to mechanical ventilation in very preterm neonates", section on 'Refractory respiratory failure'.)

Sedation and neuromuscular blockade

Sedation – Sedation is appropriate for infants with PPHN who have significant agitation and/or ventilator dyssynchrony despite efforts to optimize ventilator settings (eg, using a patient-triggered mode). This is because pain and agitation cause catecholamine release, resulting in increased PVR and increased right-to-left shunting. In addition, agitation may result in ventilator asynchrony which can worsen hypoxemia.

For neonates requiring sedation, we typically use opioid analgesia (morphine or fentanyl) alone or in combination with a benzodiazepine (midazolam). Initial dosing for these agents is as follows:

Intravenous (IV) morphine sulfate – Loading dose of 100 to 150 mcg/kg over one hour followed by a continuous infusion of 10 to 20 mcg/kg per hour)

IV fentanyl – 1 to 5 mcg/kg per hour

IV midazolam – 15 to 60 mcg/kg per hour

Use of opioids and benzodiazepines for management of sedation in intubated neonates is discussed in greater detail separately. (See "Management and prevention of pain in neonates", section on 'Opioids' and "Management and prevention of pain in neonates", section on 'Midazolam'.)

Neuromuscular blockade – We reserve use of neuromuscular blocking agents (NMBAs; eg, vecuronium, pancuronium) for neonates with dyssynchronous breathing associated with persistent severe hypoxemia without another identified cause (eg, airway obstruction or air leak). We generally avoid more routine use of NMBAs because of potential adverse effects, which can include hypotension, prolonged blockade, and post-extubation muscle weakness [11].

Pulmonary vasodilator therapy — Infants with OI >25 and/or severe right ventricular dysfunction due to PPHN are candidates for pulmonary vasodilator therapy to decrease PVR. iNO is the preferred pulmonary vasodilator agent for neonates with PPHN, as discussed below. (See 'Inhaled nitric oxide (iNO)' below.)

Sildenafil, which is a phosphodiesterase type 5 inhibitor, plays a limited role in the management of acute PPHN, as discussed below. (See 'Sildenafil' below.)

Other pulmonary vasodilators (eg, prostacyclin analogues [epoprostenol, iloprost, treprostinil] and endothelin receptor antagonists [ERAs; eg, bosentan]) do not play a role in the management of acute PPHN. Use of these agents in young infants is limited to patients with pulmonary hypertension secondary to bronchopulmonary dysplasia (BPD) or congenital heart disease (CHD), as discussed separately. (See "Pulmonary hypertension associated with bronchopulmonary dysplasia", section on 'Targeted pulmonary hypertension pharmacotherapy' and "Pulmonary hypertension in children: Management and prognosis", section on 'Specific agents for targeted PH therapy'.)

Inhaled nitric oxide (iNO) — iNO is a potent pulmonary vasodilator that decreases pulmonary artery pressure and pulmonary-to-systemic arterial pressure ratio [12]. Oxygenation improves as vessels are dilated in well-ventilated parts of the lung, thereby redistributing blood flow from regions with decreased ventilation and reducing intrapulmonary shunting. In the circulation, NO combines with hemoglobin and is rapidly converted to methemoglobin and nitrate. As a result, there is little effect on systemic vascular resistance (SVR) and systemic blood pressure.

Our approach to using iNO outlined in the sections below is generally consistent with the recommendations of the American Academy of Pediatrics (AAP) for the use of iNO in infants with severe hypoxemic respiratory failure [1]. (See 'Society guideline links' below.)

Pretreatment evaluation — The evaluation prior to starting iNO includes:

An arterial blood gas to assess the severity of hypoxemia, as measured by the OI. (See 'Severity of hypoxemia' above.)

Echocardiography to confirm the diagnosis of PPHN and exclude congenital heart disease. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis", section on 'Echocardiography'.)

Dosing and administration

Initial dose – We start iNO at an initial dose of 20 ppm [13-15]. In infants who respond, an improvement PaO2 or SpO2 levels (typically a relative increase of approximately 20 percent) occurs within 15 to 20 minutes. It becomes crucial to initially recruit the lung prior to administering iNO so that the gas can reach its sites of action.

We do not use doses >20 ppm because higher doses do not appear to improve the response and are associated with increased risk of toxicity (eg, methemoglobinemia). (See 'Side effects' below.)

Weaning – We begin weaning iNO once the infant’s FiO2 is ≤0.6. The iNO concentration is decreased slowly as oxygenation improves [16]. Neonates with PPHN can decompensate if iNO is turned off too quickly so weaning should be performed gradually. Our usual approach is as follows:

We initially wean by 5 ppm every two to four hours as tolerated until reaching a dose of 5 ppm.

If the neonate tolerates this, we then wean further by 1 ppm every two to four hours until reaching a dose of 1 ppm. The final steps of the wean may need to be slowed down if the patient becomes more hypoxemic during weaning.

If the neonate is stable on 1 ppm, we discontinue iNO and monitor for rebound hypoxemia.

If the neonate has worsening of hypoxia and/or hemodynamic instability after stopping iNO, we restart iNO at 5 ppm until the patient stabilizes, and subsequently wean more slowly.  

Patients who respond to iNO typically require treatment for three to four days, although some require longer courses.

Side effects — iNO is generally safe when administered in the established therapeutic dosing range for PPHN [17,18]. Potential toxicity of iNO includes:

Methemoglobinemia caused by excess iNO levels or impaired metabolism. Practice varies regarding routine monitoring of methemoglobin levels. We do not routinely measure methemoglobin, as the risk of toxicity is low when using a maximum iNO concentration of 20 ppm. However, other centers may routinely monitor these levels. (See 'Monitoring' above.)

Airway irritation from exposure to nitrogen dioxide, which is formed when iNO mixes with oxygen [19].

Contamination of ambient air; however, this will not occur if standard monitoring and air handling practices are in place.

Prolonged bleeding times due to inhibition of platelet function by iNO; however, clinically significant bleeding has not been observed in term or late preterm infants [20].

Efficacy — The efficacy of iNO in this setting is supported by randomized trials and meta-analyses demonstrating that iNO improves oxygenation and reduces the need for ECMO in term and late preterm infants with severe PPHN (OI ≥25) [10,13,14,18,21-23]. In a meta-analysis of seven trials involving 815 term and near term neonates with severe hypoxic respiratory failure, iNO reduced the need for ECMO compared with control (31 versus 51 percent; risk ratio [RR] 0.6, 95% CI 0.5-0.71) [18]. Mortality was similar in both groups (11 versus 12 percent, respectively). In the two trials (n=301) that reported outcomes at 18 to 24 months of age, both treatment groups had similar rates of neurodevelopmental disability (26 and 27 percent, respectively).

Use in special populations

Preterm neonates – iNO does not play a role in the routine management of hypoxic respiratory failure in preterm neonates <34 weeks gestation (ie, respiratory distress syndrome) [24,25], as discussed separately. (See "Respiratory distress syndrome (RDS) in preterm infants: Management", section on 'Inhaled nitric oxide'.)

However, pulmonary hypertension can rarely occur in a small subset of very low birth weight infants (BW <1500 g), and these neonates may benefit from iNO therapy if they are refractory to surfactant and conventional respiratory care [23,26]. The benefit of iNO in this setting remains unproven as there are few published studies. A retrospective case control study evaluated outcomes in mechanically ventilated preterm infants (gestational age 22 to 29 weeks) who did and did not receive iNO [25]. The study used propensity score analysis in an attempt to control for selection bias and found that mortality was similar in both groups.

Congenital diaphragmatic hernia – iNO is commonly used in neonates with congenital diaphragmatic hernia, though the available evidence from clinical trials and observational studies has not consistently demonstrated benefit in this population. These data are discussed separately. (See "Congenital diaphragmatic hernia (CDH) in the neonate: Management and outcome", section on 'Management of pulmonary hypertension'.)

Sildenafil — The advantages of sildenafil are that it is less costly and more widely available than iNO. However, there are limited data on the efficacy and safety of sildenafil in neonates with PPHN.

Clinical useSildenafil's use in managing PPHN is generally limited to resource-limited settings where iNO is not available [27].

In resource-abundant settings, iNO is the preferred agent for PPHN, as discussed above (see 'Inhaled nitric oxide (iNO)' above). However, sildenafil is occasionally used as an adjunct to iNO (eg, if there is difficulty weaning from iNO). There are limited data to support this indication, as described below.

While sildenafil plays a limited role in managing neonates with acute PPHN, it is more commonly used in the management of infants with pulmonary hypertension secondary to BPD or CHD. This is discussed separately. (See "Pulmonary hypertension associated with bronchopulmonary dysplasia", section on 'Targeted pulmonary hypertension pharmacotherapy' and "Pulmonary hypertension in children: Management and prognosis", section on 'Phosphodiesterase type 5 inhibitors'.)

DosingSildenafil is available in both enteral and intravenous (IV) dosage forms. Most studies evaluating sildenafil in infants with PPHN used the enteral form. Dosing is as follows:

Enteral dosing – 0.5 to 2 mg/kg per dose every 6 to 12 hours [28-31].

IV dosing – 0.4 mg/kg loading dose administered over 3 hours followed by continuous infusion of 1.6 mg/kg/day for up to seven days [32].

Efficacy – Successful use of enteral sildenafil in neonates with PPHN has been described [28,29,33-37]. In a meta-analysis of four trials involving 112 infants with PPHN managed in resource-limited settings (ie, without access to iNO), enteral sildenafil improved oxygenation and reduced mortality (relative risk 0.27, 95% CI 0.12-0.61) [36]. However, the trials included in the meta-analysis had important limitations, including small sample size and limited follow-up. In addition, the trials were performed in resource-limited settings, which limits the generalizability of these findings.

Data on use of IV sildenafil in infants with PPHN are limited [32,38]. In a randomized trial involving 29 neonates with PPHN who were receiving iNO, the addition of IV sildenafil did not result in faster weaning from iNO compared with placebo [38]. Hypotension was the most commonly reported adverse event. In an earlier dose-escalation study involving 36 neonates with PPHN, IV sildenafil was well tolerated and was associated with improved oxygenation [32].

Surfactant — Surfactant should be administered early in the disease course if the neonate has an associated condition for which surfactant has established efficacy (eg, respiratory distress syndrome [RDS], meconium aspiration syndrome [MAS]). (See "Respiratory distress syndrome (RDS) in preterm infants: Management", section on 'Surfactant therapy' and "Meconium aspiration syndrome: Management and outcome", section on 'Surfactant'.)

For neonates with severe PPHN without RDS or MAS, it is unclear whether surfactant is beneficial. Our practice is to administer surfactant in patients with severe PPHN associated with significant parenchymal lung disease, even if the etiology is not clearly RDS or MAS. For patients with idiopathic primary PPHN without associated lung disease, surfactant therapy does not appear to be beneficial [39].

The evidence regarding surfactant use in infants with PPHN is inconclusive. In a placebo-controlled trial of 328 neonates with severe hypoxic respiratory failure (OI>20), surfactant reduced the need for ECMO (29 versus 40 percent; absolute risk reduction [ARR] 11 percent) [39]. The absolute benefit was greatest among patients with MAS (n=168) or sepsis (n=99) as the underlying diagnosis (ARR 15 and 10 percent, respectively); whereas patients with isolated primary PPHN (n=61) had only modest benefit (ARR 2 percent). Similar findings were noted in a subsequent placebo-controlled trial involving 100 neonates with OI ≥20, in which surfactant reduced the composite outcome of death or need for ECMO (16 versus 36 percent; ARR 20 percent) [40]. As in the earlier trial, approximately half of patients in this trial had MAS as the underlying diagnosis. Thus, it is difficult to draw firm conclusions from these trials as to whether surfactant is beneficial for infants without MAS. Other important limitations of these trial data include small sample size and limited follow-up. In addition, one trial was performed in a resource-limited setting, so the findings may not be generalizable to other settings [40].

Hemodynamic support — Neonates with PPHN often require hemodynamic support, which may include intravenous (IV) fluids, vasopressors, and/or inotropic agents.

In patients with PPHN, right-to-left shunting increases as cardiac output and systemic blood pressure (BP) decrease. Thus, maintaining optimal cardiac output and systemic BP is important to reduce the right-to-left shunting and to maintain adequate tissue oxygenation. BP targets are provided above. (See 'Hemodynamic targets' above.)

Hemodynamic support is accomplished by:

Maintaining adequate intravascular volume by providing IV fluids and, if needed, transfusion. (See "Fluid and electrolyte therapy in newborns" and 'Transfusion' below.)

Vasoactive infusions – Most neonates with PPHN require vasopressor and/or inotropic support [41]. Commonly used agents are briefly summarized here and are discussed in greater detail separately. (See "Neonatal shock: Management", section on 'Vasoactive agents'.)

Dopamine is the most commonly used agent in neonates requiring hemodynamic support. Dopamine is often chosen because there is extensive experience with this agent in neonates and most neonatal providers are familiar with its use. Some experts have raised concerns that dopamine may not be an optimal vasoactive agent for PPHN since it nonselectively increases afterload (ie, it increases PVR just as much as it increases SVR) and this may counteract any beneficial inotropic effect [41,42]. However, there is little clinical evidence comparing the effects of dopamine with other alternative vasoactive agents in PPHN and these arguments are purely theoretical.

Epinephrine may be preferred over dopamine in neonates with significant ventricular dysfunction since it both improves ventricular contractility and increases systemic BP (ie, increases SVR). However, it may increase PVR to a lesser extent, which may exacerbate right ventricle (RV) dysfunction.

Milrinone may also be useful in neonates with significant ventricular dysfunction. It has inotropic and vasodilatory effects and can be used alone or in combination with epinephrine to improve ventricular function [27]. Milrinone should be avoided or used with extreme caution in patients who are hypotensive since hypotension is the main side effect of this agent. There are limited data on the use of milrinone in patients with PPHN [43-45].

Dobutamine is an inotropic agent that can improve cardiac function if ventricular dysfunction is present. However, it does not reliably increase BP in neonates and it is not commonly used for management of PPHN.

Transfusion — For neonates with severe hypoxemia (OI ≥25), the threshold we use to trigger red blood cell (RBC) transfusion is hemoglobin (Hgb) level <15 g/dL (hematocrit <40 percent). This target is higher than the target used in other neonatal populations (eg, preterm neonates). The rationale for maintaining a higher Hgb level in neonates with PPHN is based upon the following:

Neonates with severe PPHN are at high risk of developing tissue hypoxemia due to the compound effects of right-to-left shunting and impaired cardiac function. Transfusion increases oxygen carrying capacity and helps meet the oxygen demands of tissues.

Neonates with severe PPHN undergo frequent phlebotomy and thus have considerable iatrogenic blood loss. RBC transfusion is often necessary to replace these losses.

Other details of RBC transfusions in neonates, including selection of RBC products, risks associated with transfusion, and details of administration are discussed separately. (See "Red blood cell (RBC) transfusions in the neonate".)

OUTCOME — The estimated mortality rate associated with PPHN in developed countries is between 7 and 10 percent [46-48].

In a report based on a state-wide dataset of records from 2005 to 2012, the discharge mortality during birth hospitalization was 6.5 percent and one-year postdischarge mortality was 0.7 percent [48]. There was a 28.6 percent readmission rate to the hospital within the first year of life for survivors with PPHN compared with 9.8 percent of infants without PPHN. Approximately one-third of readmissions were due to respiratory disease. Adjusted analysis (gestational age, sex, birth weight, and ethnicity) showed survivors compared with controls without PPHN were more likely to have died postdischarge or be readmitted to the hospital within the first year of life (adjusted relative risk [aRR] 3.5, 95% 3.3-3.7). In a subgroup analysis, infants with mild PPHN (no evidence of positive pressure ventilation) were also more likely than those without PPHN to have died or be readmitted within the first year of life (aRR 2.2, 95% CI 2.0-2.5). Of note, infants with congenital pulmonary anomalies (eg, diaphragmatic hernia) who have a higher risk of mortality and morbidity were included in this analysis. As a result, the risk of mortality and readmission may be lower in term infants without congenital pulmonary anomalies. Nevertheless, these data underscore the need for close follow-up for all survivors, even those with mild disease, and ongoing research efforts to identify measures that will prevent PPHN.

Survivors of severe PPHN and/or extracorporeal membrane oxygenation (ECMO) treatment are at increased risk of developmental delay, motor disability, hearing deficits, and chronic health problems compared with individuals without PPHN [49-55]. Inhaled nitric oxide (iNO) does not appear to increase the risk of adverse outcomes, including risk of neurodevelopmental impairment or pulmonary function [49,56,57].

These data draw attention to the need for ongoing follow-up, especially in the first year of life, due to the increased risk of mortality and morbidity even in patients with mild disease.

FOLLOW-UP — As noted above, all survivors of PPHN are at risk for postdischarge mortality and morbidity. As a result, both primary care providers and parents need to be aware of the increased vulnerability of this group of patients. These patients may require more frequent primary care visits than are routinely scheduled.

All infants with severe PPHN who have been treated with inhaled nitric oxide (iNO) and/or extracorporeal membrane oxygenation (ECMO) should have neurodevelopmental follow-up [1]. Assessment should be performed through infancy at 6- to 12-month intervals, and longer if abnormalities are present. Hearing should be tested prior to hospital discharge and at 18 to 24 months corrected age.

Additional details of follow-up after discharge from the neonatal intensive care unit are provided in a separate topic. (See "Care of the neonatal intensive care unit graduate".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Persistent pulmonary hypertension of the newborn (The Basics)")

SUMMARY AND RECOMMENDATIONS

Definition and severity – Persistent pulmonary hypertension of the newborn (PPHN) occurs when pulmonary vascular resistance (PVR) remains abnormally elevated after birth, resulting in right-to-left shunting of blood through fetal circulatory pathways. This in turn leads to severe hypoxemia that may not respond to conventional respiratory support. (See 'Introduction' above and "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

The severity of hypoxemia in PPHN is determined by calculating the oxygenation index (OI) (calculator 1). Severity of pulmonary hypertension (PH) is assessed by echocardiography. (See 'Severity of hypoxemia' above and 'Severity of pulmonary hypertension (PH)' above.)

Management approach – Patients with PPHN should be cared for in a neonatal intensive care unit (NICU) with experienced staff and where multiple modes of respiratory support, rescue therapies, and inhaled nitric oxide (iNO) are available. Extracorporeal membrane oxygenation (ECMO) should be available at the center or there should be an established transfer arrangement to an ECMO center. (See 'Setting of care' above.)

The course and response to therapy vary substantially from one patient to another. Thus, individualized management and frequent reassessment are critical. Our general approach is as follows (table 1) (see 'Management approach' above):

Identify and treat underlying conditions – A key principle of management is to identify and treat the underlying condition, if present (eg, sepsis/pneumonia, meconium aspiration syndrome [MAS], respiratory distress syndrome [RDS], congenital diaphragmatic hernia [CDH]). (See "Management and outcome of sepsis in term and late preterm neonates" and "Neonatal pneumonia" and "Meconium aspiration syndrome: Management and outcome", section on 'Surfactant' and "Respiratory distress syndrome (RDS) in preterm infants: Management", section on 'Surfactant therapy' and "Congenital diaphragmatic hernia (CDH) in the neonate: Management and outcome", section on 'Postnatal management'.)

PPHN with severe lung disease – For neonates with PPHN due to underlying parenchymal lung disease (eg, MAS, RDS, pneumonia), management generally includes the following (see 'PPHN with severe lung disease' above):

-Mechanical ventilation – Most neonates with severe lung disease require intubation and mechanical ventilation. We begin with conventional mechanical ventilation (CMV) using a patient-triggered volume-targeted mode. Ventilator settings are adjusted to maintain preductal oxygen saturation of 90 to 95 percent and normal ventilation initially. Once the neonate’s respiratory status is more stable, we allow mild hypercapnia. (See 'Conventional mechanical ventilation' above and 'Gas exchange targets' above.)

For patients who require peak pressures on CMV that are ≥28 to 30 cm H2O and those who develop significant air leak on CMV, we suggest transitioning to high frequency ventilation (HFV) (Grade 2C). (See 'High frequency ventilation (HFV)' above.)

-Sedation – Sedation with or without neuromuscular blockade may be required for neonates with ventilatory dyssynchrony or agitation. (See 'Sedation and neuromuscular blockade' above and "Management and prevention of pain in neonates".)

-Hemodynamic support – Neonates with depressed ventricular function and/or shock secondary to PPHN require hemodynamic support with vasopressors and/or inotropes. Dopamine is the agent used most commonly. (See 'Hemodynamic support' above and "Neonatal shock: Management", section on 'Vasoactive agents'.)

-Inhaled nitric oxide – For neonates with persistent severe hypoxemia (OI ≥25) despite optimizing mechanical ventilation and sedation, we recommend iNO (Grade 1B). It is given at a dose of 20 ppm via the ventilator. In infants who respond, an improvement oxygen saturation typically occurs within 15 to 20 minutes. (See 'Inhaled nitric oxide (iNO)' above.)

In resource-limited settings where iNO is not available, enteral sildenafil is a reasonable alternative option. (See 'Sildenafil' above.)

PPHN without severe lung disease – In neonates with idiopathic PPHN (ie, without underlying parenchymal lung disease), hypoxemia is predominantly caused by severe right-to-left shunting. Our suggested approach for such patients is as follows (see 'PPHN without severe lung disease' above):

-Management begins with 100 percent oxygen administered noninvasively (eg, low flow nasal cannula, high flow nasal canula [HFNC], or continuous positive airway pressure [CPAP]). This may be sufficient for some neonates. (See 'Supplemental oxygen' above and "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn".)

-For patients with persistent shunting and hypoxemia despite supplemental oxygen, we suggest iNO (Grade 2C), which can be administered noninvasively (typically via HFNC). (See 'Inhaled nitric oxide (iNO)' above.)

-Neonates who fail iNO via HFNC generally require intubation and mechanical ventilation. (See 'Conventional mechanical ventilation' above.)

Monitoring – Neonates with PPHN are monitored closely and respiratory and hemodynamic interventions are adjusted as needed to achieve gas exchange and hemodynamic targets. (See 'Monitoring' above and 'Goals of therapy' above.)

Refractory PPHN – Infants with severe PPHN who remain severely hypoxemic (OI ≥40) on maximal ventilatory support despite administration of iNO are candidates for extracorporeal membrane oxygenation (ECMO). (See 'Extracorporeal membrane oxygenation (ECMO)' above.)

Outcome – The estimated mortality rate associated with PPHN in developed countries is between 7 and 10 percent. Survivors of severe PPHN are at increased risk of neurodevelopmental disabilities and chronic health problems. (See 'Outcome' above.)

Follow-up – Survivors of PPHN require frequent follow-up post-discharge. Patients treated with iNO or ECMO should have neurodevelopmental assessments performed at 6- to 12-month intervals through infancy and longer if abnormalities are present. Hearing should be tested prior to hospital discharge and at 18 to 24 months corrected age. (See 'Follow-up' above and "Care of the neonatal intensive care unit graduate".)

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