nicu-new.gif University of Washington Academic Medical Center | Copyright © 2000 | Disclaimer
Children's Hospital and Regional Medical Center | Copyright © 2002 | Disclaimer
go to home page go to search page go to about page go to contact us page

Persistent Pulmonary Hypertension Of The Newborn
Authors References Created
07/20/96		 Reviewed
04/10/00		 Revised
04/10/00
Table of Contents
  1. Nomenclature
  2. Definition
  3. Changes in Pulmonary Circulation at Birth
  4. Pathophysiology
  5. Diagnosis
  6. Treatment - Discussion
  7. Treatment - Local Practice
  8. Outcome
Nomenclature

Persistent pulmonary hypertension of the newborn is a cardiopulmonary disorder characterized by systemic arterial hypoxemia secondary to elevated pulmonary vascular resistance with resultant shunting of pulmonary blood flow to the systemic circulation. This pathophysiologic syndrome has been variously described as:

  • Persistent pulmonary vascular obstruction
  • Persistent fetal circulation
  • Pulmonary vasospasm
  • Neonatal pulmonary ischemia
  • Persistent transitional circulation
Definition

Persistent pulmonary hypertension of the newborn (PPHN) is the result of elevated pulmonary vascular resistance to the point that venous blood is diverted to some degree through fetal channels (i. e. the ductus arteriosus and foramen ovale) into the systemic circulation and bypassing the lungs, resulting in systemic arterial hypoxemia.

This disorder can be classified into three forms dependent on the likely etiology of the pulmonary hypertension:

  1. PPHN associated with pulmonary parenchymal disease, such as hyaline membrane disease, meconium aspiration, or transient tachypnea of the newborn as the cause of alveolar hypoxia
    • known as secondary PPHN or appropriate PPHN
    • alveolar oxygen tension appears to be the major determinant of pulmonary artery vasoconstriction.
  2. PPHN with radiographically normal lungs and no evidence of parenchymal disease
    • frequently called Persistent Fetal Circulation (PFC), or primary or inappropriate PPHN
  3. PPHN associated with hypoplasia of the lungs
    • most often in the form of diaphragmatic hernia
    • associated with an anatomic reduction in capillary number in addition to the pathophysiology listed below
Changes in the Pulmonary Circulation at Birth

Fetal Development and Characteristics

Very little blood flows into the fetal lungs prior to birth because pulmonary vascular resistance is very high compared to systemic vascular resistance. The placenta, the fetal gas exchange organ, is a very low resistance outlet for fetal systemic blood flow. With the loss of the placenta at the time of birth, systemic vascular resistance increases.

Several factors are thought to play a role in maintaining high fetal pulmonary vascular resistance.

  1. Hypoxia is a potent vasoconstrictor - especially below 40-45 torr. Fetal PaO2 averages 20-25 torr, so that persistent hypoxemia exists producing persistent active pulmonary vasoconstriction.
  2. Because the lungs are not fully expanded in utero, an element of mechanical compression of the vessels exists. During lung expansion, the arteries straighten out and become less resistant to blood flow.
  3. Carbon dioxide appears to play a minor role in maintaining vasoconstriction. However, hypocapnia (PaCO2's less than 30 torr) is known to blunt hypoxic vasoconstriction.

Because of the high pulmonary vascular resistance, blood is diverted away from the lungs through the foramen ovale and the patent ductus arteriosus into the low resistance systemic and placental circuit. The ductus arteriosus is also oxygen sensitive and remains patent when hypoxia persists. It remains anatomically patent for several weeks to months after birth, but because the neonate is so much better oxygenated than the fetus, the ductus becomes functionally closed in the full-term infant by 24-36 hours after birth.

Transition at Birth

With birth the following sequence occurs:

  1. The placental circulation is removed and systemic vascular resistance increases. This in turn, increases pressures in the left ventricle and left atrium.
    • The foramen will tend to close when pulmonary blood flow increases as increased pulmonary flow will increase the blood volume entering the left atrium and in so doing, increase left atrial pressure
    • Increased left atrial pressure (more than right atrial pressure) results in functional closure of the foramen ovale
  2. With the onset of ventilation, the oxygen tension in the alveolus and in arterial blood increases.
    • as alveolar PaO2 increases, pulmonary vasoconstriction relaxes and pulmonary vascular resistance becomes less than systemic vascular resistance
    • increased oxygenation also results in constriction of the ductus arteriosus
  3. The onset of ventilation also represents the onset of lung expansion resulting in the straightening out of mechanically compressed vessels
  4. The end result of these changes is a closure of the fetal conduits that carried blood by the lungs, but not into them
  5. In addition, even with the conduits open, the balance of vascular resistances shifts so that increased systemic vascular resistance directs blood flow into the low-resistance pulmonary bed
  6. With the redirection of blood into the lungs and the complete transition of the lung into an air-filled structure, neonatal cardiopulmonary adaptation is complete
Pathophysiology

Persistent pulmonary hypertension of the newborn in a pathophysiologic syndrome that results when the pulmonary vascular resistance fails to decrease after birth, despite improved alveolar oxygenation and lung expansion. Although systemic vascular resistance has increased (with the loss of the placenta), pulmonary vascular resistance remains equal to or greater than systemic vascular resistance. This results in blood continuing to flow through the foramen ovale and ductus arteriosus. Subsequently, with the loss of placental gas exchange and the inability to increase pulmonary blood flow, arterial oxygen tension falls to very low levels. If this situation is not reversed, the infant may die of severe hypoxemia.

Since both the pulmonary and systemic resistances are high, a large mechanical load is placed on the heart (especially the right heart) to continue to pump blood to either vascular bed. With high vascular resistance and the subsequent hypoxemia, myocardial performance may become extremely compromised resulting in right heart dilation, tricuspid insufficiency, and right heart failure.

The specific abnormality which produces persistent pulmonary hypertension is not known. Possible pathogenetic mechanisms include:

  1. Repeated intrauterine closure of the ductus with redirection of blood flow into the high-resistance fetal pulmonary vasculature. This may occur in mothers who take high dose aspirin near term {Perkin, 1980}. In studies in fetal lambs, other prostaglandin inhibitors have been found to close the ductus in utero resulting most often in stillbirths. The survivors often have a clinical picture of PPHN. Similar findings have been reported in human infants {Levin, 1978b}
  2. Abnormal responsiveness of the pulmonary vasculature to hypoxia with an inability to relax after the stimulus for vasoconstriction is removed, i.e. birth asphyxia.
  3. Repeated intrauterine hypoxia, which stimulates the hypertrophy of medial smooth muscle which surrounds pulmonary arterioles, enabling vessels to constrict to an extreme degree for long periods of time. There is pathologic evidence that babies with PPHN have greater thickness of medial muscle in pulmonary arteries that in normal full-term infants {Haworth, 1976},{Levin, 1978a},{Murphy, 1981},{Geggel, 1984} .
  4. Regional alveolar hypoxia due to poor ventilation which is not apparent radiographically, even though other parts of the lung are ventilating normally.
  5. Undergrowth of the pulmonary vascular tree. This is frequently the cause in infants with congenital diaphragmatic hernia or other causes of pulmonary hypoplasia.
  6. Alterations in vasoactive mediator levels. It is clear that a variety of vasoactive mediators participate in the changes in pulmonary vasomotor activity during transition from fetal to neonatal circulation. Nitric oxide, eicosanoids, and endothelin {Steinhorn, 1995},{Ziegler, 1995}, all play a role in transitional circulation. Other mediators such as leukotrienes {Stenmark, 1983}, tumor necrosis factor {Truog, 1990}, and platelet activating factor {Caplan, 1990} may participate in active pulmonary vasoconstriction with its resultant hypoxemia
  7. Microthrombus formation in the pulmonary vascular bed. Thrombocytopenia and pathological evidence of platelet-fibrin microthromboembolism has been reported in infants succumbing to Persistent Pulmonary Hypertension of the Newborn {Morrow, 1982},{Levin, 1983}. These microthrombi and accompanying released mediators may induce pulmonary hypertension.

This condition is most often associated with perinatal asphyxia in 50-70% of reported cases. Other conditions associated with this syndrome include hypoglycemia, hypocalcemia, hyperviscosity syndrome and sepsis.

Diagnosis

This syndrome is usually noted in term or post-term infants. The baby presents clinically with cyanosis and respiratory distress, with tachypnea, but with minimal retractions during the first day of life. The infants chest radiograph may be normal (as noted in infants with primary PPHN, i.e. PFC) or demonstrate various abnormalities compatible with aspiration, pneumonia, diaphragmatic hernia, or hyaline membrane disease. Supplemental oxygen is needed in an attempt to correct arterial hypoxemia. With a large right-to-left shunt through a patent ductus arteriosus, an oxygen tension gradient may be noted between the preductal arterial circulation (i.e. right upper extremity) and the postductal arterial circulation (i.e. lower extremities). However, this gradient may not be present if substantial shunting is present at the level of the foramen ovale. Systemic hypotension is a late finding usually resulting from both heart failure and persistent hypoxemia.

The diagnosis is confirmed echocardiographically.

Treatment -- Discussion

The most appropriate treatment of Persistent Pulmonary Hypertension of the Newborn remains unclear {Walsh-Sukys, 1994}, {Sahni, 1994}, {Weigel, 1990},. Substantial variation in clinical practice exists between institutions. However, basic treatment goals do exist {Fox, 1983}, {Perkin, 1984}. In order of increasing aggressiveness and invasiveness:

  1. Improve alveolar oxygenation
  2. Minimize pulmonary vasoconstriction
  3. Maintain systemic blood pressure and perfusion
  4. Consider induction of an alkalotic state
  5. Consider a trial of vasodilatation
  6. Consider extracorporeal membrane oxygenation support
  1. Improving alveolar oxygenation with supplemental oxygen (FiO2).
    • This is especially important when pulmonary parenchymal disease exists, as improvement in alveolar oxygenation will often result in a normal relaxation of the pulmonary arteries and improved pulmonary blood flow.
  2. Minimize "inappropriate" pulmonary vasoconstriction
    • By overventilating an infant and producing hypocapnia, hypoxic vasoconstriction can be blunted allowing pulmonary blood flow to increase. This may result in improvement in oxygenation. However, use of mechanical ventilatory support to achieve hypocapnic alkalosis can result in pulmonary trauma and may be related to long term hearing deficits noted in follow-up. Since vaosconstriction appears related to intracellular pH rather than pCO2 levels {Schreiber, 1986}, use of alkalinizing agents such as sodium bicarbonate has become commonplace. Controlled trials of alkalosis do suggest a positive benefit in some infants, but not all.
    • Maintenance of systemic arterial blood pressure and, by inference, pulmonary perfusion, appears to have some benefit. Theoretically, increasing system arterial pressure may result in decreased right-to-left shunt flow across a patent ductus arteriosus, increased pulmonary blood flow, and hopefully, improved oxygenation. Dopamine and dobutamine are frequently utilized to improve cardiac output and systemic blood pressure.
    • Vasodilators have been reported to be effective in a certain proportion of infants. However, these agents are nonspecific and frequently result in vasodilatation of both the pulmonary and systemic vascular beds. Most commonly used is tolazoline (Priscoline) {Stevenson, 1979}. The complete mechanism of action of tolazoline is not clear although it appears to be an alpha-sympathetic blocker. Such substances as norepinephrine which are a-sympathetic agents are known vasoconstrictors. By blocking this effect, tolazoline might produce vasodilation. Other work suggests that tolazoline's effect is mediated by histamine. When histamine receptors in the lung are blocked chemically (experimentally), tolazoline becomes a vasoconstrictor {Goetzman, 1979}. Endotracheally administered tolazoline has been reported to be helpful {Welch, 1995}
    • Nitric Oxide Inhaled nitric oxide has been studied intensively as therapy for Persistent Pulmonary Hypertension of the Newborn. This gaseous free-radical compound was previously known as endothelial-derived-relaxation-factor. Inhaled nitric oxide directly activates soluble guanylate cyclase resulting in increased levels of cyclic-GMP in vascular smooth muscle cells. This results in vascular relaxation by prohibiting myosin protein cross-bridge formation in smooth muscle. Multiple controlled trials have demonstrated that inhaled nitric oxide improves oxygenation in many infants with PPHN. {Kinsella, 1997},{Roberts, 1997},{Wessel, 1997}, {NINOS, 1997A},{Davidson, 1998} A controlled trial of inhaled nitric oxide in infants with congenital diaphragmatic hernia demonstrated no efficacy. {NINOS, 1997B} Nitric oxide was FDA approved 12/23/99 for use in term and near-term infants with hypoxic respiratory failure requiring ventilatory support who have clinical and/or echocardiographic evidence of pulmonary hypertension.
    • Prostaglandin I2 (prostacyclin) This is a complex molecule made from arachadonic acid and is one of the major endogenous vasodilators in the lung. It is normally produced by the lung when lung vessels are in a constricted state, thereby relaxing them. Whether PPHN is the result of faulty PGI2 production is not known. Administration of pharmacologic doses of PGI2 to babies with persistent pulmonary hypertension has proven successful even when tolazoline failed. {Kaapa, 1985}
  3. Other therapies proposed as beneficial in Persistent Pulmonary Hypertension of the Newborn include magnesium sulphate {Tolsa, 1995},{Wu, 1995}, and arginine infusion {Vosatka, 1994},{McCaffrey, 1995}, and the use of perflourocarbon liquid ventilation. At this point, these therapies are experimental and cannot be recommended.
    • When circulatory collapse has occurred, the use of an inotropic agent such as dopamine can increase systemic resistance and improved perfusion. Use of both dopamine and tolazoline together have been tried in desperation with occasional beneficial results {Drummond, 1981}.
  4. When other therapies have failed to result in patient improvement, Extracorporeal Membrane Oxygenation (ECMO) support has been used with good success.

    ELSO Homepage Extracorporeal Life Support Organization, Ann Arbor, Michigan

    Children's Hospital and Medical Center ECLS program information

Treatment -- Local Practice

These treatment guidelines for Persistent Hypertension of the Newborn are derived from review of the relevant medical literature and from clinical consensus. Variation may be necessary dependent on the clinical situation.

Diagnosis
When Persistent Pulmonary Hypertension of the Newborn is suspected, echocardiographic examination is requested to rule-out cardiac anatomic defects and confirm the presence of pulmonary hypertension. This examination also provides helpful detail regarding volume status and cardiac contractile function.

Ventilatory Support and Alkalosis
These infants usually have been placed on mechanical ventilatory support. The aim of this support technology is to achieve adequate ventilation and oxygenation. Mild hypocapnic alkalosis is recommended (pH 7.45 - 7.55 and PaCO2 25 - 35 torr) in an attempt to attenuate hypoxic pulmonary vasoconstriction. The use of high frequency oscillatory ventilation (HFOV) may be considered if conventional ventilatory support fails to achieve desired blood gas values at acceptable rates and peak inspiratory pressures {Varnholt, 1992},{Clark, 1994}. Treatment of Persistent Pulmonary Hypertension of the Newborn without hyperventilation (gentle ventilation) has been recommended by some {Wung, 1985},{Dworetz, 1989}

Alkalosis can also be achieved with parenteral infusion of agents such as sodium bicarbonate. Initial bolus dosing can be tried (2-3 mEq/kg/dose). If unable to maintain the alkalotic state in this manner, continuous infusion at 1-2 mEq/kg/hour can be tried. Frequent monitoring of serum sodium levels is indicated.

Sedation and Paralysis
These infants are frequently quite agitated and often breathe out-of-phase with ventilatory support. The use of sedation and paralysis in such infants is routine. For both physiologic and humane reasons, sedation is provided concurrently with paralysis. Sedation is provided by morphine sulphate by continuous infusion starting at 10 micrograms/kg/hour. Bolus or continuous infusion dosing of lorazepam can be added for further sedation. Paralysis is usually achieved with pancuronium bromide administered every 1-3 hours intravenously at 0.1-0.2 mg/kg/dose.
{see Drug List}

Vasodilators
The use of vasodilatory agents can not be recommended at this time because of lack of specificity and efficacy {Gouyon, 1992}.

Therapeutic Goals

  1. Arterial blood gas values
    • pH 7.45 - 7.55
    • PaO2 50-100 torr
    • PaCO2 25-40 torr
  2. Systemic blood pressure
  3. Adequate paralysis and sedation
  4. Ensure adequate oxygen carrying capacity. Maintain hematocrit greater than 40%

Use of Extracorporeal Life Support
Consider the use of extracorporeal membrane oxygenation support if unable to maintain systemic arterial pressure due to cardiac contractile dysfunction, inability to maintain adequate oxygenation, need for maintenance of extreme alkalosis to oxygenate infant, or failure to wean from high levels of support on HFOV.

Children's Hospital and Medical Center ECLS program information

Outcome

If this syndrome is severe, it can result in death. Prior to the introduction of extracorporeal membrane oxygenation support, mortality rates were reported from 12 to 50% {Fox, 1977},{Dworetz, 1989}. Although extracorporeal membrane oxygenation support has increased survival to about 85% in infants with severe Persistent Pulmonary Hypertension of the Newborn, it may be associated with significant morbidity in 10-45% of patients {Andrews, 1984},{Donn, 1988},{Schumacher, 1988},{Taylor, 1989}. "Spontaneous" resolution of this condition may occur 36 hours to several weeks after birth.

Follow-up of survivors (without congenital diaphragmatic hernia) several months after birth has revealed few abnormalities of pulmonary or circulatory systems. However, other significant problems have been reported. In those infants treated with hyperventilation, sensorineural hearing loss has been found in up to 53% of survivors {Walton,1991},{Hendricks-Munoz, 1988}. Others reports did not substantiate such a high incidence of hearing loss {Ferrara, 1984}. Advocates of "gentle ventilation" reported no hearing loss {Marron, 1992}. The length of hyperventilation needed was predictive of neurodevelopmental outcome {Bifano, 1988} in the pre-ECMO era. In general, most reports demonstrated excellent neurodevelopmental outcomes in survivors of Persistent Pulmonary Hypertension of the Newborn {Brett, 1981},{Bernbaum, 1984},{Ferrara, 1984}.

References
  1. Andrews AF, Roloff DN, Bartlett RH: 1984 Use of extracorporeal membrane oxygenation in persistent pulmonary hypertension of the newborn. Clin Perinatol 11:729-735.
  2. Bernbaum JC, Russell P, Sheridan PH, Gewitz MH, Fox WW, Peckham GJ: 1984 Long-term follow-up of newborns with persistent pulmonary hypertension. Crit Care Med 12:579-583.
  3. Bifano EM, Pfannenstiel A: 1988 Duration of hyperventilation and outcome in infants with persistent pulmonary hypertension. Pediatr 81:657-661.
  4. Brett C, Dekle M, Leonard CH, Clark C, Sniderman S, Roth R, Ballard R, Clyman R: 1981 Developmental follow-up of hyperventilated neonates: preliminary observations. Pediatr 68:588-591.
  5. Caplan MS, Hsueh W, Sun X-M, Gidding SS, Hegeman JR: 1990 Circulating plasma platelet activating factor in persistent pulmonary hypertension of the newborn. Am Rev Respir Dis 142:1258-1262.
  6. Clark RH, Yoder BA, Sell MS: 1994 Prospective, randomized comparison of high-frequency oscillation and conventional ventilation in candidates for extracorporeal membrane oxygenation. J Pediatr 123:447-454.
  7. Davidson D, Barefield ES, Kattwinkel J, Dudell G, Damask M, Straube R, Rhines J, Chang C-T, I-NO/PPHN Study Group: 1998 Inhaled nitric oxide for the early treatment persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose-response, multicenter study. Pediatr 101:325-334.
  8. Donn SM: 1988 Neonatal extracorporeal membrane oxygenation. Pediatr 82:276-277.
  9. Drummond WH, Gregory GA, Heymann MA, Phibbs RA: 1981 The independent effects of hyperventilation, tolazoline, and dopamine on infants with persistent pulmonary hypertension. J Pediatr 98:603-611.
  10. Dworetz AR, Moya FR, Sabo B, Gladstone I, Gross I: 1989 Survival of infants with persistent pulmonary hypertension without extracorporeal membrane oxygenation. Pediatr 84:1-6.
  11. Ferrara B, Johnson DE, Chang P-N, Thompson TR: 1984 Efficacy and neurologic outcome of profound hypocapneic alkalosis for the treatment of persistent pulmonary hypertension in infancy. J Pediatr 105:457-461.
  12. Fox WW, Gewitz MH, Dinwiddie R, Drummond WH, Peckham GJ: 1977 Pulmonary hypertension in the perinatal aspiration syndromes. Pediatr 59:205-211.
  13. Fox WW, Duara S: 1983 Persistent pulmonary hypertension in the neonate: diagnosis and management. J Pediatr 103:505-514.
  14. Geggel RL, Reid L: 1984 The structural basis of PPHN. Clin Perinatol 11:525-549.
  15. Goetzman BW, Milstein JM: 1979 Pulmonary vasodilator action of tolazoline. Pediatr Res 13:942-944.
  16. Gouyon JB, Francoise M: 1992 Vasodilators in persistent pulmonary hypertension of the newborn: a need for optimal appraisal of efficacy. Dev Pharmacol Ther 19:62-68.
  17. Haworth SG, Reid L: 1976 Persistent fetal circulation: newly recognized structural features. J Pediatr 88:614-620.
  18. Hendricks-Munoz KD, Walton JP: 1988 Hearing loss in infants with persistent fetal circulation. Pediatr 81:650-656.
  19. Kaapa P, Koivisto M, Ylikorkala O, Kouvalainen K: 1985 Prostacyclin in the treatment of neonatal pulmonary hypertension. J Pediatr 107:951-953.
  20. Kinsella JP, Truog WE, Walsh WF, Goldberg RN, Bancalari E, Mayock DE, Redding GJ, deLemos RA, Sardesai S, McCurnin DC, Moreland SG, Cutter GR, Abman SH: 1997 Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. J Pediatr 131:55-62.
  21. Levin DL, Hyman AI, Heymann MA, Rudolph AM: 1978a Fetal hypertension and the development of increased pulmonary vascular smooth muscle: a possible mechanism for persistent pulmonary hypertension of the newborn infant. J Pediatr 92:265-269.
  22. Levin DL, Fixler DE, Morriss FC, Tyson J: 1978b Morphologic analysis of the pulmonary vascular bed in infants exposed in utero to prostaglandin synthetase inhibitors. J Pediatr 92:478-483.
  23. Levin DL, Weinberg AG, Perkin RM: 1983 Pulmonary microthrombi syndrome in newborn infants with unresponsive persistent pulmonary hypertension. J Pediatr 299:299-303.
  24. Marron M-J, Crisafti MA, Driscoll JM, Wung J-T, Driscoll YT, Fay TH, James LS: 1992 Hearing and neurodevelopmental outcome in survivors of persistent pulmonary hypertension of the newborn. Pediatr 90:392-396.
  25. McCaffrey MJ, Bose CL, Reiter PD, Stiles AD: 1995 Effect of L-arginine infusion on infants with persistent pulmonary hypertension of the newborn. Biol Neonate 67:240-243.
  26. Morrow WR, Haas JE, Benjamin DR: 1982 Nonbacterial endocardial thrombosis in neonates: relationship to persistent fetal circulation. J Pediatr 100:117-122.
  27. Murphy JD, Rabinovitch M, Goldstein JD, Reid LM: 1981 The structural basis of persistent pulmonary hypertension of the newborn infant. J Pediatr 98:962-967.
  28. The Neonatal Inhaled Nitric Oxide Study Group: 1997A Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Eng J Med 336:597-604.
  29. The Neonatal Inhaled Nitric Oxide Study Group (NINOS): 1997B Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatr 99:838-45.
  30. Perkin RM, Levin DL, Clark R: 1980 Serum salicylate levels and right-to-left ductus shunts in newborn infants with persistent pulmonary hypertension. J Pediatr 96:721-726.
  31. Perkin RM, Anas NG: 1984 Pulmonary hypertension in pediatric patients. J Pediatr 105:511-522.
  32. Roberts JD, Fineman JR, Morin FC, Shaul PW, Rimar S, Schreiber MD, Polin RA, Zwass MS, Zayek MM, Gross I, Heymann MA, Zapol WM, for the Inhaled Nitric Oxide Study Group: 1997 Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Eng J Med 336:605-610.
  33. Sahni R, Wung JT, James LS: 1994 Controversies in management of persistent pulmonary hypertension of the newborn. Pediatr 94:307-309.
  34. Schreiber MD, Heymann MA, Soifer SJ: 1986 Increased arterial pH, not decreased PaCO2, attenuates hypoxia-induced pulmonary vasoconstriction in newborn lambs. Pediatr Res 20:113-117.
  35. Schumacher RE, Barks JDE, Johnston MV, Donn SM, Scher MS, Roloff DW, Bartlett RH: 1988 Right-sided brain lesions in infants following extracorporeal membrane oxygenation. Pediatr 82:155-161.
  36. Steinhorn RH, Millard SL, Morin FC: 1995 Persistent pulmonary hypertension of the newborn. Role of nitric oxide and endothelin in pathophysiology and treatment. Clin Perinatol 22:405-428.
  37. Stenmark KR, James SL, Voelkel NF, Toews WH, Reeves JT, Murphy RC: 1983 Leukotriene C4 and D4 in neonates with hypoxemia and pulmonary hypertension. N Engl J Med 309:77-80.
  38. Stevenson DK, Kasting DS, Darnell RA, Ariagno RL, Johnson JD, Malachowski N, Beets CL, Sunshine P: 1979 Refractory hypoxemia associated with neonatal pulmonary disease: the use and limitations of tolazoline. J Pediatr 95;595-599.
  39. Taylor GA, Short BL, Fitz CR: 1989 Imaging of cerebrovascular injury in infants treated with extracorporeal membrane oxygenation. J Pediatr 114:635-639.
  40. Tolsa JF, Cotting J, Sekarski N, Payot M, Micheli JL, Calame A: 1995 Magnesium sulphate as an alternative and safe treatment for severe persistent pulmonary hypertension of the newborn. Archiv Dis Child Fetal Neonat 72:F184-187.
  41. Truog WE, Gibson RL, Henderson WR, Redding GJ: 1990 Tumor necrosis factor-induced neonatal pulmonary hypertension: effects of dazmegrel pretreatment. Pediatr Res 27:466-471.
  42. Varnholt V, Lasch P, Suske G, Kachel W, Brands W: 1992 High frequency oscillatory ventilation and extracorporeal membrane oxygenation in severe persistent pulmonary hypertension of the newborn. Eur J Pediatr 151:769-774>
  43. Vosatka RJ, Kashyap S, Trifiletti RR: 1994 Arginine deficiency accompanies persistent pulmonary hypertension of the newborn. Biol Neonate 66:65-70.
  44. Walsh-Sukys MC, Cornell DJ, Houston LN, Keszler M, Kanto WP: 1994 Treatment of persistent hypertension of the newborn without hyperventilation: an assessment of diffusion of innovation. Pediatr 94:307-309.
  45. Walton JP, Hendricks-Munoz K: 1991 Profile and stability of sensorineural hearing loss in persistent pulmonary hypertension of the newborn. J Speech Hear Res 34:1362-1370.
  46. Weigel TJ, Hageman JR: 1990 National survey of diagnosis and management of persistent pulmonary hypertension of the newborn. J Perinatol 10:369-375.
  47. Welch JC, Bridson JM, Gibbs JL: 1995 Endotracheal tolazoline for severe persistent pulmonary hypertension of the newborn. Br Heart J 73:99-100.
  48. Wessel DL, Adatia I, Van Marter LJ, Thompson JE, Kane JW, Stark AR, Kourembanas S: 1997 Improved oxygenation in a randomized trial of inhaled nitric oxide for persistent pulmonary hypertension of the newborn. Pediatr 100; URL:http://www.pediatrics.org/cgi/content/full/100/5/e7.
  49. Wu TJ, Teng RJ, Tsou KI: 1995 Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates. Pediatr 96:472-474.
  50. Wung JT, James LS, Kilchevsky E, James E: 1985 Management of infants with severe respiratory failure and persistence of fetal circulation, without hyperventilation. Pediatr 76:488-494.
  51. Ziegler JW, Ivy DD, Kinsella JP, Abman SH: 1995 The role of nitric oxide, endothelin, and prostaglandins in the transition of the pulmonary circulation. Clin Perinatol 22:387-403.
Author

Dennis E. Mayock, M.D.
Associate Professor of Pediatrics
EMAIL feedback to Web site author