AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

During fetal life, pulmonary blood flow is low, with less than 10% of the combined cardiac output directed to the lungs. In fetal life, numerous factors, including hypoxia, maintain high pulmonary vascular resistance (PVR). After birth, PVR decreases, and pulmonary blood flow increases dramatically as the lungs assume the function of gas exchange. The combination of rhythmic ventilation of the lung and increased alveolar oxygen tension stimulate these changes. Each stimulus, by itself, decreases PVR and increases pulmonary blood flow, but effects are greatest when the 2 events occur simultaneously. In some newborns, the normal decrease in pulmonary vascular tone does not occur, and the result is persistent pulmonary hypertension of the newborn (PPHN). This syndrome causes substantial morbidity and mortality in otherwise healthy, term newborns.

Pathophysiology

PPHN is failure of the normal circulatory transition that occurs after birth. It is a syndrome characterized by marked pulmonary hypertension that causes hypoxemia and right-to-left extrapulmonary shunting of blood. With inadequate pulmonary perfusion, neonates develop refractory hypoxemia, respiratory distress, and acidosis.

Respiratory failure and hypoxemia in the term newborn results from a heterogeneous group of disorders, and the therapeutic approach and response often depend on the underlying disease. PPHN often results when structurally normal pulmonary vessels constrict in response to alveolar hypoxia due to hypoventilation or parenchymal disorders, such as hyaline membrane disease or meconium aspiration syndrome (MAS). However, PPHN can also occur idiopathically in the absence of underlying parenchymal disease. In these cases, the syndrome is believed to be the result of an abnormally remodeled vasculature that develops in utero in response to prolonged fetal stress, hypoxia, and/or pulmonary hypertension. Excessive and peripheral muscularization of pulmonary arterioles can be seen in these cases.

Finally, PPHN is commonly associated with lung hypoplasia, as seen in congenital diaphragmatic hernia. These underlying causes of PPHN are structurally different, and functional differences in response to vasodilators, such as inhaled nitric oxide (iNO), are commonly observed. Knowledge of biologic alterations seen with PPHN is instrumental in expanding available therapeutic options.

Frequency

United States

Neonatal respiratory failure affects nearly 80,000 newborns per year, and it is responsible for as many as one half of all neonatal deaths. Nearly one third of all infants with respiratory failure were born at term or near-term, and they are at risk for PPHN.

Recent data suggest that the PPHN syndrome may occur as often as 2-6 cases per 1000 live births. PPHN is a frequent complicating factor in the term or near-term newborn with parenchymal lung disease, such as MAS or pneumonia. An increased incidence of PPHN is reported for mothers who use selective serotonin reuptake inhibitors (SSRIs) during the last half of their pregnancies.

Mortality/Morbidity

• As recently as 15 years ago, the mortality rate reached 40%, and the prevalence of major neurologic disability was 15-60%.
• The introduction of extracorporeal membrane oxygenation (ECMO) and other new therapies has had a major effect on reducing the mortality rate associated with PPHN. In the United Kingdom, the effect of ECMO technology was studied in a randomized trial, the only one to use death as an endpoint (UK Collaborative ECMO Trail Group, 1996). The mortality rate decreased from approximately 60% in the group randomly assigned to receive conventional therapy to 30% for the group randomly assigned to receive ECMO.
• If all available therapies are used, the mortality rate appears to be less than 10%. However, the prevalence of major neurologic disabilities among surviving newborns remains approximately 15-20%.

Age

• By definition, PPHN a disorder of the newborn.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Newborns with PPHN typically present with cyanosis and tachypnea. Marked lability in oxygenation is frequently part of their history.

• The most common cause of PPHN is MAS, which affects 25,000-30,000 infants, with 1000 deaths occurring each year in the United States.
• • Approximately 13% of all live births are complicated by meconium-stained fluid, but only 5% of infants who had this complication subsequently develop MAS.
  • Although the traditional belief is that aspiration occurs with the first breath after birth, relatively recent data suggest that, in severely affected infants, aspiration most likely occurs in utero. Therefore, perinatal distress or meconium staining of the amniotic fluid may be part of the patient's antenatal history.

• Idiopathic PPHN, or black-lung PPHN, is the second most common etiology of PPHN and the most common in newborns born at term and near-term (>34 wks of gestation).
• • Evaluation of infants at autopsy shows clinically significant remodeling of their pulmonary vasculature, with vascular wall thickening and smooth muscle hyperplasia. Furthermore, the smooth muscle extends to the level of the intra-acinar arteries, which does not normally occur until late in the postnatal period.
  • One cause of idiopathic PPHN is constriction of the fetal ductus arteriosus in utero because of exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) during the third trimester. Therefore, a history of NSAID should be sought from the mother.
  • Another recently reported association with idiopathic PPHN is maternal use of SSRIs, particularly during the second trimester.

Physical

PPHN most typically affects infants who are phenotypically normal, though the syndrome may occur most frequently in newborns with Down syndrome. On initial examination, the primary finding is cyanosis, which is usually associated with tachypnea and respiratory distress. Cardiac examination may reveal a loud, single S2 or a harsh systolic murmur secondary to tricuspid regurgitation. The patient may have evidence of poor cardiac function and perfusion.

Causes

PPHN is most commonly associated with 1 of 3 underlying etiologies.

• The first and most commonly encountered scenario is acute pulmonary vasoconstriction due to acute perinatal events, such as the following:
• • Alveolar hypoxia secondary to parenchymal lung disease, such as respiratory distress syndrome (RDS) or pneumonia
  • Hypoventilation resulting from asphyxia or other neurologic conditions
  • Hypothermia
  • Hypoglycemia

• The second cause, idiopathic PPHN is associated with a normal chest radiograph and no parenchymal lung disease. Newborns with idiopathic PPHN present with pure vascular disease. Some clinicians refer to this syndrome as black-lung PPHN or clear-lung PPHN.
• • This syndrome typically results from an abnormally remodeled pulmonary arterial bed, which perhaps secondary to chronic stress in utero.
  • Other potential associations include maternal use of NSAIDs, such as ibuprofen or naproxen, or SSRIs in the last half of pregnancy

• Hypoplasia of the pulmonary vascular bed is a third cause of PPHN.
• • Congenital diaphragmatic hernia is an abnormality of diaphragmatic development that allows the abdominal viscera to enter the chest and compress the lung.
  • Patient may have an oligohydramnios sequence.
  • Another finding is congenital cystic adenomatoid malformation, though PPHN is rarely associated with this malformation, even if the defect is large.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Alveolar capillary dysplasia
Surfactant protein B deficiency

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Arterial blood gases
• • Check arterial blood gases (ABGs) initially and frequently. Assessing the pH, partial pressure of carbon dioxide in arterial gas (PaCO₂), and the alveolar-arterial (A-a) difference in the partial pressure of oxygen (PaO₂).
  • Be aware that the choice of sampling site can affect the ABG results. Newborns with PPHN frequently have extrapulmonary right-to-left shunting across the patent ductus arteriosus. Therefore, their PaO₂ values may be elevated when a preductal sampling site is used.
  • Oxygenation is often assessed by using the oxygenation index (OI), which accounts for the postductal PaO₂ and the ventilator settings. The OI is calculated as the mean airway pressure multiplied by the fraction of inspired oxygen (FiO₂) and the 100, and the product is divided by the postductal PaO₂. An OI of 40 typically prompts a consideration of ECMO support.

• Complete blood count
• • Evaluate the CBC for a high hematocrit level because polycythemia and hyperviscosity syndrome may produce or aggravate PPHN.
  • The WBC count and differential may help in determining whether an underlying sepsis syndrome or pneumonia is present.
  • The platelet count is frequently depressed, particularly in newborns with MAS or asphyxia.

• Serum electrolytes
• • Monitor serum electrolyte and glucose levels initially and frequently.
  • In particular, maintaining glucose and ionized calcium levels within the reference ranges is important because hypoglycemia and hypocalcemia tend to worsen PPHN.

Imaging Studies

• Chest radiography
• • Chest radiography is useful in determining whether underlying parenchymal lung disease (eg, MAS, pneumonia, surfactant deficiency) is present. Chest radiography also assists in excluding underlying disorders, such as congenital diaphragmatic hernia.
  • In newborns with idiopathic PPHN, the lung fields appear clear, with decreased vascular markings.
  • Heart size is typically normal or slightly enlarged.

• Cardiac ultrasonography (echocardiography)
• • Ultrasonography of the heart (echocardiography) is necessary to exclude cyanotic congenital heart disease. Defining the anatomy of the pulmonary veins can be extremely difficult if extrapulmonary right-to-left shunting of blood is present. Cardiac catheterization is occasionally required.
  • Cardiac sonograms can also be used to determine if right-to-left shunting of blood across the ductus arteriosus, foramen ovale, or both is present. A skilled sonographer can use the peak velocity of the regurgitant flow across the tricuspid valve to calculate right ventricular systolic pressures and, thus, estimate right-sided vascular pressures.
  • A cardiac sonogram is needed before therapy with iNO is begun. The image allows the clinician to rule out left-sided obstructive lesions, such as an interrupted aortic arch, a hypoplastic left ventricle, and critical aortic stenosis. These lesions require right-to-left shunting through the ductus to maintain systemic perfusion and, therefore, are contraindications to iNO treatment.

• Cranial ultrasonography
• • Perform cranial sonography if ECMO is being considered in a newborn. Take care to evaluate for intraventricular bleeding and for peripheral areas of hemorrhage or infarct.
  • Doppler flow studies can be a helpful adjunct for determining whether a nonhemorrhagic infarct is present.

Other Tests

• Pulse oximetry
• • Continuous pulse oximetry is extremely valuable in the ongoing treatment of the newborn with PPHN. The most important functions of this test are to assess the patient's oxygen saturation over time and to assist the caregiver in determining whether oxygen delivery at the tissue level is adequate.
  • Oximeter probes can be placed on preductal (right hand) and postductal (right or left foot) sites to assess for right-to-left shunt at the level of the ductus arteriosus. Remember that sites on the left hand should be avoided because it may be preductal or postductal.
  • Although it is a useful indicator of PPHN when present, a ductus-level shunt is frequently absent.

• Cardiac catheterization: In rare cases, cardiac sonographic findings are not definitive, and cardiac catheterization may be necessary to exclude congenital heart disease, particularly anomalous pulmonary venous return.

Procedures

• Mechanical ventilation
• • Endotracheal intubation and mechanical ventilation are almost always necessary for the newborn with PPHN. The goal of mechanical ventilation should to maintain normal functional residual capacity (FRC) by recruiting areas of atelectasis but also to avoid overexpansion.
  • Adjust ventilator settings to maintain normal expansion (ie, of approximately 9 ribs) on chest radiography. Monitoring of tidal volume and pulmonary mechanics monitoring is frequently helpful in preventing overexpansion, which can elevate PVR and aggravate right-to-left shunting.
  • In newborns with severe airspace disease who require high peak inspiratory pressures (ie, >30 cm H₂O) or mean airway pressures (>15 cm H₂O), consider high-frequency ventilation (HFV) to reduce barotrauma. When HFV is used, the goal should still be to optimize lung expansion and FRC and to avoid overdistension

• Central venous catheter placement
• • Place a venous catheter into the umbilical or femoral vein to allow for the administration of inotropic agents or hypertonic solutions (eg, calcium gluconate solution).
  • Avoid catheter placement into the jugular vessels; save these vessels for extracorporeal support, if needed.

• Arterial catheter placement: Place an indwelling catheter into the umbilical artery or a peripheral artery (eg, radial or posterior tibial artery) to allow for frequent monitoring of ABGs.
• Surfactant administration
• • Parenchymal lung disease of the term or near-term newborn is often associated with surfactant deficiency, inactivation, or both.
  • Data from small studies suggest that a benefit occurs after surfactant is administered to the newborn with MAS.
  • In a large multicenter study, the administration of surfactant reduced the need for extracorporeal support and appeared to be most effective early in the course of disease. The reduced need for ECMO was most apparent in newborns with primary diagnoses of MAS or sepsis.

• High-frequency ventilation
• • HFV is another important modality if a newborn has underlying parenchymal lung disease with low lung volumes. This modality is best used in a center with physicians experienced in achieving and maintaining optimal lung distension.
  • The response to HFV can be rapid, and care must be taken to prevent hypocarbia and lung overdistension.

• Extracorporeal membrane oxygenation
• • ECMO is used when optimal support fails to maintain acceptable oxygenation and perfusion. This therapy, which is an adaptation of cardiopulmonary bypass, is provided at fewer than 100 centers in the United States.
  • Recent developments allow ECMO support to be provided by using a double-lumen catheter in the internal jugular vein; thus, ligation of the right common carotid artery can be avoided.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• General considerations
• • The care of newborns with PPHN require meticulous attention to detail. Continuous monitoring of oxygenation, blood pressure, and perfusion is critical.
  
  
  • When one cares for newborns, use a minimal stimulation protocol to minimize the need to handle the patient and to perform invasive procedures, such as suctioning.
  
  
  • Management of fluid and electrolyte levels is important. An adequate circulating blood volume is necessary to maintain right ventricular filling and cardiac output; however, repeated bolus administration of crystalloid and colloid solutions does not provide additional benefit.
  
  
  • Inotropic support with dopamine, dobutamine, and/or milrinone alone or in combination, is frequently helpful in maintaining adequate cardiac output and systemic blood pressure while avoiding excessive volume administration. Although dopamine is frequently used as a first-line agent, other agents, such as dobutamine and milrinone, are helpful when myocardial contractility is poor.


• Mechanical ventilation
• • Mechanical ventilation is usually needed to maintain adequate oxygenation. Determine the exact strategy on the basis of the underlying lung disease. For instance, newborns with clinically significant airspace disease due to pneumonia or RDS likely require airway pressures higher than those needed for patients with idiopathic black-lung PPHN. Likewise, newborns with clinically significant airspace disease are most likely to respond to other lung recruitment strategies, such as surfactant administration and/or high-frequency oscillatory ventilation.
  
  
  • A frequent concern is determining the target arterial PaO₂ level. Levels of >50 mm Hg typically provide for adequate oxygen delivery. Aiming for high PaO₂ concentrations may lead to increased ventilator support and barotrauma. Because of their lability and ability to fight the ventilator, newborns with PPHN nearly always require sedation. The author's practice is to use fentanyl (often in combination with a benzodiazepine) because it tends to decrease the sympathetic response to pain and noxious stimuli.


• Acidosis and alkalosis
• • Metabolic acidosis and respiratory acidosis require correction. Sodium bicarbonate is typically used to correct metabolic acidosis. However, if carbon dioxide clearance is a problem, administering bicarbonate may produce a respiratory acidosis. In these situations, tromethamine (THAM) 1-2 mmol/kg may be a useful alternative. However, do not administer THAM to patients with anuria or uremia.
  
  
  • Forced alkalosis by using sodium bicarbonate and hyperventilation were popular therapies in the past because of their ability to produce acute pulmonary vasodilation and increase PaO₂. However, hypocarbia is associated with constriction of the cerebral vasculature, reduction of cerebral blood flow, and systemic hypotension. Extreme alkalosis and hypocarbia are strongly associated with late neurodevelopmental deficits, including a high rate of sensorineural hearing loss.
  
  
  • An alternate approach is maintaining an alkaline pH level of 7.45-7.5 by using sodium bicarbonate infusions. Serum sodium concentration should carefully be monitored if bicarbonate infusions are used, and ventilation must be adequate to allow for carbon dioxide clearance.
  
  
  • In 2000, Walsh-Sukys and colleagues reported that the use of alkaline infusions is associated with increased use of ECMO and oxygen when the newborn is aged 28 days. Therefore, use this approach with caution.
  
  
  • Many clinicians have good success without using alkalinization. In a series of 15 patients, Wung et al (1985) applied a strategy designed to maintain PaO₂ at 50-70 mm Hg and PaCO₂ <60 mm Hg (ie, gentle ventilation). This approach resulted in excellent outcomes and a low incidence of chronic lung disease.


• Induced paralysis
• • The use of paralytic agents is highly controversial and typically reserved for newborns who cannot be treated with sedatives alone. Be aware that paralysis, in particular with pancuronium, may promote atelectasis of dependent lung regions and promote ventilation-perfusion mismatch.
  
  
  • In their review of 385 newborns with PPHN by Walsh-Sukys and colleagues (2000) suggests that paralysis may be associated with an increased risk of death.
  
  
  • Another report indicates that prolonged administration of pancuronium during the neonatal period is associated with sensorineural hearing loss in childhood survivors of congenital diaphragmatic hernia.


• Treatment with iNO
• • Treatment with iNO is indicated for newborns with an OI >25. Nitric oxide (NO) is an endothelial-derived gas signaling molecule that relaxes vascular smooth muscle and that can be delivered to the lung by means of an inhalation device (INOVent; Datex-Ohmeda Inc, Madison, WI).
  
  
  • In 2 large randomized trials, NO reduced the need for ECMO support by approximately 40%.
  
  
  • Contraindications to iNO include congenital heart disease characterized by left ventricular outflow tract obstruction (eg, interrupted aortic arch, critical aortic stenosis, hypoplastic left heart syndrome) and severe left ventricular dysfunction.
  
  
  • The appropriate starting dose is 20 ppm. Doses higher than this have not been shown to be more effective and have been associated with adverse effects, including methemoglobinemia and increased levels of nitrogen dioxide (NO₂).
  
  
  • Appropriate lung recruitment and expansion are essential to achieve the best response. If a newborn has severe parenchymal lung disease and PPHN, strategies such as HFV may be required.
  
  
  • Most newborns require iNO for £5 days. In general, the dose can be weaned to 5 ppm after 6-24 hours of therapy. The dose is then weaned slowly and discontinued when the FiO₂ is <0.6 and the iNO dose is 1 ppm. Abrupt discontinuation should be avoided become it may cause abrupt rebound pulmonary hypertension.
  
  
  • In centers that do not have immediate availability of ECMO support, use of iNO must be approached with caution. Because iNO cannot be abruptly discontinued, transport with iNO is usually needed if a subsequent referral for ECMO is necessary. This capability should be determined in collaboration with the ECMO center before treatment is started. The use of iNO with HFV creates particular problems for transport, and this should be considered before these therapies are combined in a non-ECMO center.
  
  
  • The use of iNO has not been demonstrated to reduce need for ECMO in newborns with congenital diaphragmatic hernia. In these newborns, iNO should be used in non-ECMO centers to allow for acute stabilization, followed by immediate transfer to a center that can provide ECMO.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Sedation and analgesia with opioids is often necessary to achieve adequate mechanical ventilation. Muscle paralysis may be used for the same purpose; however, this method is controversial because adverse circulatory effects and alveolar collapse in dependent regions of the lung may develop. The administration of a surfactant may be helpful if parenchymal disease is present.

Cardiac output is maintained with the use of inotropic agents and with judicious volume replacement.

Maintaining a normal or alkaline pH level with infusions of sodium bicarbonate may decrease pulmonary-artery pressure and improve oxygenation. The administration of intravenous vasodilators, such as tolazoline, an alpha-receptor antagonist, is extremely controversial. iNO appears to produce a selective pulmonary vasodilation and reduce the need for invasive therapies (eg, ECMO).

Drug Category: Opioid analgesics

These drugs are used for deep sedation and analgesia to enable adequate mechanical ventilation. Use of agents such as fentanyl may also decrease sympathetic tone during stressful interventions and maintain a relaxed pulmonary vascular bed.

Drug Category: Neuromuscular-blocking agents

Paralysis is sometimes required in newborns whose condition remains unstable despite adequate sedation.

Drug Category: Vasopressors

Judicious use of vasoactive agents may increase cardiac output without affecting systemic or PVR.

Dopamine is unique compared to other catecholamines. Unlike norepinephrine, epinephrine, and isoproterenol, low doses of dopamine increase renal blood flow without increasing heart rate or systemic arterial pressure. It is an effective vasopressor for treating shock and hypotension in cases unresponsive to plasma volume expansion (eg, with crystalloids or colloids). Dopamine also dilates the mesenteric and renal blood vessels to improve renal blood flow and increase the glomerular filtration rate, sodium excretion, and urine output. However, dosages >20 mcg/kg/min may decrease renal blood flow secondary to reversal of the dopaminergic vasodilation.

Dobutamine produces selective positive inotropic effects and therefore produces a mild chronotropic effect. Its structure is similar to those of isoproterenol and epinephrine. Dobutamine is characterized as a selective beta1-agonist as a result of its primary effect of increasing myocardial contractility by means of beta1 stimulation.

Drug Category: Surfactants

Exogenous surfactant can help in the treatment of airspace disease (eg, RDS). If administered under carefully controlled conditions, surfactant may also be helpful in other conditions, such as MAS, though it is not yet approved for such use. After inhaled administration, surface tension is reduced and alveoli are stabilized to decrease the work of breathing and increase lung compliance.

Drug Category: Alkalinizing agents

These drugs are used to correct metabolic acidosis. In addition, maintaining a normal or slightly alkaline pH with sodium bicarbonate may decrease PVR.

Drug Category: Pulmonary vasodilating agents

NO is the most specific therapeutic modality for newborns with PPHN, and it is an important mediator of vascular tone. NO is delivered to the lung as inhaled gas. Three multicenter studies demonstrated that NO decreases the need for extracorporeal support by >35%. NO is a compound that many cells of the body produce. It relaxes vascular smooth muscle by binding to heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate (cGMP), which leads to vasodilation. When inhaled, NO produces pulmonary vasodilation.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Neurologic evaluation
• • After recovery, evaluate each newborn for CNS injury by performing brain CT or MRI.
  • Advise complete examination by a neurologist or a developmental pediatrician.
  • Because the prevalence of hearing loss is high, order an automated hearing test before discharging the patient.

• Feeding
• • Newborns recovering from PPHN often feed poorly for several days or weeks.
  • Nasogastric (NG) feeding is frequently required to support the newborn until oral feeding is established.
  • Speech therapists may be helpful in reestablishing normal patterns of feeding.

Further Outpatient Care

• Because of the risk of CNS insult and sensorineural hearing loss, infants should be monitored closely for the first 2 years of life, preferably in a specialty follow-up clinic, for developmental follow-up care.
• Recommend complete screening before pediatric patients enter school to determine if they have any subtle deficits that may predispose them to learning disabilities.
• Reassess the infant's hearing when he or she is aged 6 months and again as the results indicate. Late sensorineural hearing loss has been reported in a high percentage of patients.

Transfer

• Guidelines for transfer to an ECMO center for consultation are published on the Extracorporeal Life Support Organization (ELSO) Web site. Individual centers may have modified guidelines. Therefore, developing an ongoing relationship the closest ECMO center is frequently helpful.


• Baseline criteria for a consideration for ECMO include an evaluation for risk factors because of the invasive nature of the therapy and a need for heparinization.


• Baseline criteria for newborns on ECMO are as follows:
• • Gestation >34 weeks
  
  
  • Weight >2000 g
  
  
  • No major intracranial hemorrhage on cranial sonograms (ie, larger than a grade II hemorrhage)
  
  
  • Reversible lung disease, or mechanical ventilation for £10-14 days
  
  
  • No evidence of lethal congenital anomalies or inoperable cardiac disease


• The timing of a referral to an ECMO center is often difficult. However, referral and transfer should occur before refractory hypoxemia develops. Early consultation and discussion with clinicians at the ECMO center is strongly recommended.

Prognosis

• Pulmonary recovery
• • Overall, the survival rate for newborns with PPHN is greater than 85% when all resources, including ECMO, are provided.
  • Pulmonary recovery is typically complete, and survivors do not have residual pulmonary disease.

• Neurologic sequelae
• • Most surviving newborns with PPHN have normal neurodevelopmental outcomes.
  • Prolonged hyperventilation is associated with an increased prevalence of neurodevelopmental sequelae, including sensorineural hearing loss.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The main pitfall in the treatment of PPHN is in recognizing its existence and severity. ECMO remains the criterion standard for the treatment of PPHN, and timely transfer to an ECMO center is life saving for newborns with severe PPHN.
• Identifying and maintaining communication with clinicians at an ECMO center is especially important given the widespread availability of iNO therapy. Continuous delivery of NO is required during transport. The referring center is responsible for determining what transport capabilities are available before they start a therapeutic iNO program.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Abman SH. New developments in the pathogenesis and treatment of neonatal pulmonary hypertension. Pediatr Pulmonol Suppl. 1999;18:201-4. [Medline].
• Abman SH. Neonatal pulmonary hypertension: a physiologic approach to treatment. Pediatr Pulmonol Suppl. 2004;26:127-8. [Medline].
• Alano MA, Ngougmna E, Ostrea EM Jr, et al. Analysis of nonsteroidal antiinflammatory drugs in meconium and its relation to persistent pulmonary hypertension of the newborn. Pediatrics. Mar 2001;107(3):519-23. [Medline].
• Auten RL, Notter RH, Kendig JW, et al. Surfactant treatment of full-term newborns with respiratory failure. Pediatrics. Jan 1991;87(1):101-7. [Medline].
• Bahrami KR, Van Meurs KP. ECMO for neonatal respiratory failure. Semin Perinatol. Feb 2005;29(1):15-23. [Medline].
• Chambers CD, Hernandez-Diaz S, Van Marter LJ. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. Feb 9 2006;354(6):579-87. [Medline].
• Cheung PY, Tyebkhan JM, Peliowski A, et al. Prolonged use of pancuronium bromide and sensorineural hearing loss in childhood survivors of congenital diaphragmatic hernia. J Pediatr. Aug 1999;135(2 Pt 1):233-9. [Medline].
• Clark RH, Gerstmann DR. Controversies in high-frequency ventilation. Clin Perinatol. Mar 1998;25(1):113-22. [Medline].
• Clark RH, Kueser TJ, Walker MW, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Engl J Med. Feb 17 2000;342(7):469-74. [Medline].
• Davidson D, Barefield ES, Kattwinkel J, et al. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo- controlled, dose-response, multicenter study. The I-NO/PPHN Study Group. Pediatrics. Mar 1998;101(3 Pt 1):325-34. [Medline].
• Farrow KN, Fliman P, Steinhorn RH. The diseases treated with ECMO: focus on PPHN. Semin Perinatol. Feb 2005;29(1):8-14. [Medline].
• Findlay RD, Taeusch HW, Walther FJ. Surfactant replacement therapy for meconium aspiration syndrome. Pediatrics. Jan 1996;97(1):48-52. [Medline].
• Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev. 2001;CD000399. [Medline].
• Hintz SR, Suttner DM, Sheehan AM, et al. Decreased use of neonatal extracorporeal membrane oxygenation (ECMO): how new treatment modalities have affected ECMO utilization. Pediatrics. Dec 2000;106(6):1339-43. [Medline].
• Kanto WP Jr, Bunyapen C. Extracorporeal membrane oxygenation. Controversies in selection of patients and management. Clin Perinatol. Mar 1998;25(1):123-35. [Medline].
• Kelly LK, Porta NF, Goodman DM, et al. Inhaled prostacyclin for term infants with persistent pulmonary hypertension refractory to inhaled nitric oxide. J Pediatr. Dec 2002;141(6):830-2. [Medline].
• Kinsella JP, Abman SH. Inhaled nitric oxide: current and future uses in neonates. Semin Perinatol. Dec 2000;24(6):387-95. [Medline].
• Kinsella JP, Griebel J, Schmidt JM, et al. Use of inhaled nitric oxide during interhospital transport of newborns with hypoxemic respiratory failure. Pediatrics. Jan 2002;109(1):158-61. [Medline].
• Kinsella JP, Abman SH. Clinical approach to inhaled nitric oxide therapy in the newborn with hypoxemia. J Pediatr. Jun 2000;136(6):717-26. [Medline].
• Kinsella JP, Ivy DD, Abman SH. Pulmonary vasodilator therapy in congenital diaphragmatic hernia: acute, late, and chronic pulmonary hypertension. Semin Perinatol. Apr 2005;29(2):123-8. [Medline].
• Lotze A, Mitchell BR, Bulas DI, et al. Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. Survanta in Term Infants Study Group. J Pediatr. Jan 1998;132(1):40-7. [Medline].
• Morin FC 3rd, Stenmark KR. Persistent pulmonary hypertension of the newborn. Am J Respir Crit Care Med. Jun 1995;151(6):2010-32. [Medline].
• Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med. Feb 27 1997;336(9):597-604. [Medline].
• Paranka MS, Clark RH, Yoder BA, Null DM Jr. Predictors of failure of high-frequency oscillatory ventilation in term infants with severe respiratory failure. Pediatrics. Mar 1995;95(3):400-4. [Medline].
• Roberts JD Jr, Fineman JR, Morin FC 3rd, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N Engl J Med. Feb 27 1997;336(9):605-10. [Medline].
• Steinhorn RH, Millard SL, Morin FC 3rd. Persistent pulmonary hypertension of the newborn. Role of nitric oxide and endothelin in pathophysiology and treatment. Clin Perinatol. Jun 1995;22(2):405-28. [Medline].
• Tworetzky W, Bristow J, Moore P, et al. Inhaled nitric oxide in neonates with persistent pulmonary hypertension. Lancet. Jan 13 2001;357(9250):118-20. [Medline].
• UK Collaborative ECMO Trial Group. UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. Lancet. Jul 13 1996;348(9020):75-82. [Medline].
• Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics. Jan 2000;105(1 Pt 1):14-20. [Medline].
• Wung JT, James LS, Kilchevsky E, James E. Management of infants with severe respiratory failure and persistence of the fetal circulation, without hyperventilation. Pediatrics. Oct 1985;76(4):488-94. [Medline].
• Ziegler JW, Ivy DD, Kinsella JP, Abman SH. The role of nitric oxide, endothelin, and prostaglandins in the transition of the pulmonary circulation. Clin Perinatol. Jun 1995;22(2):387-403. [Medline].

Article Last Updated: Apr 19, 2007