Persistent Pulmonary Hypertension of the Newborn

Sandra J. Suchomski, M.D.

The opening of the pulmonary vascular bed at birth and the establishment of low pulmonary vascular resistance are crucial events in the transition from fetal to postnatal life. The process includes both vasodilation and structural vascular remodeling. Disturbance of this process can lead to the clinical syndrome of persistent pulmonary hypertension of the newborn (PPHN).

Fetal circulation

The fetal pulmonary circulation is characterized by high arterial pressure and vascular resistance that cause the blood ejected by the right ventricle to bypass the lungs. This ensures adequate blood flow to the placenta, which is a low-resistance circulatory bed that functions as the organ of gas exchange in utero. Because the lungs are not required for gas exchange during fetal life, pulmonary blood flow is low.

Transition at birth

At birth, the fetal pulmonary circulation undergoes a striking transition. Pulmonary vascular resistance decreases more than tenfold which leads to an eight- to tenfold increase in pulmonary blood flow. Systemic vascular resistance increases at birth, in part because of the removal of the low resistance bed of the placenta. As pulmonary vascular resistance becomes less than systemic, flow through the ductus arteriosus reverses. Within the first 5 minutes after birth, oxygen-induced vasodilation and lung expansion decrease pulmonary vascular resistance to approximately half of systemic resistance. Over the first few hours after birth, the ductus arteriosus closes, largely in responses to the increase in oxygen tension. At this point, the normal postnatal circulatory pattern is established. This crucial transition at birth from fetal to postnatal circulation is influenced by an array of stimuli and vasoactive products. The stimuli that seem to be most important in decreasing pulmonary vascular resistance and increasing pulmonary blood flow are ventilation of the lungs with a gas and an increase in oxygen tensions. Each of these stimuli by itself will decrease pulmonary vascular resistance and increase pulmonary blood flow.1,2 The largest effects are seen when they occur simultaneously.3

Central to the smooth transition from the high-resistance bed in utero to the low-resistance circuit after birth is the endothelial cell.4 The endothelium releases vasoactive products which mediate the transition that occurs in the pulmonary vasculature at birth. These products include nitric oxide and arachidonic acid metabolites.

There is strong evidence that NO is an important mediator of the decrease in pulmonary vascular resistance at birth. NO is a potent dilator of the fetal pulmonary circulation.5 The fetal pulmonary circulation can be dilated by endogenously produced NO.6 Nitric oxide activates soluble guanylate cyclase to produce cyclic guanosine monophosphate (cGMP). cGMP induces relaxation of smooth muscle in the perinatal pulmonary circulation via the activation of a cGMP-dependent protein kinase.7 Oxygen is an important stimulus for endothelial production during this transition although the mechanism is unclear.8

Arachidonic acid is degraded by different enzymes to produce a variety of inflammatory mediators, including thromboxane, leukotrienes and prostaglandins. Thromboxane and leukotrienes are potent vasoconstrictors.9 Many different prostaglandins are formed including those that are vasodilators (prostacyclin) and those that are vasoconstrictors (PGFa 2). Prostacyclin is a potent pulmonary vasodilator that relaxes smooth muscles via the production of cAMP. 10 Prostacyclin production in the whole lung increases dramatically during late gestation and early postnatal life.11 Prostaglandin synthesis can be inhibited by indomethacin which results in a blunted increase in pulmonary blood flow following ventilation of the fetal lung with a gas.12

In some newborn infants, the normal decrease in pulmonary vascular resistance and increase in pulmonary blood flow seen at birth do not occur, resulting in persistent pulmonary hypertension of the newborn (PPHN). A recent multicenter epidemiologic evaluation of the natural history of PPHN in a large cohort of neonates found the prevalence of PPHN to be 1.9 per 1000 live births.13 In this same study13, the mean gestational age at which PPHN was diagnosed was 39 ± 2 weeks with a mean birthweight of 3.3 ± 0.6 kg. Fifty-eight percent of the neonates with PPHN were male; 49% of the cases occurred in Caucasians, and 33% in blacks. In 64% of their cases, the mothers had Medicaid or were self-pay.

PPHN is characterized by marked pulmonary arterial hypertension that causes right-to-left extrapulmonary shunting of blood and hypoxemia. Extrapulmonary shunting of blood can occur at the level of the patent foramen ovale and/or the patent ductus arteriosus. PPHN is often a complication of several neonatal respiratory diseases or asphyxia but can occur without coexisting lung parenchymal disease.

Etiologies of PPHN

Several parenchymal lung diseases are commonly associated with persistent pulmonary hypertension of the newborn. These include meconium aspiration syndrome and severe respiratory distress syndrome, both which cause right-to-left shunting of blood that may be extrapulmonary. Pneumonia, particularly that from Group B Streptococci, can also cause PPHN. These diseases can cause acidosis, hypoxia, hypercarbia, or lung inflammation _ all important factors for the inducement of PPHN.

The exact mechanisms which cause these respiratory diseases to progress to PPHN remain unclear. Because of the airway plugging and/or atelectasis that is often prominent in these respiratory disease, there may be a lack of an increase in alveolar ventilation and oxygenation after birth.14 There also is the potential of release of vasoconstrictors by the accompanying inflammatory process. These inflammatory substances, such as leukotriene C4 and D4, thromboxane and platelet-activating factor, are metabolites of arachidonic acid and have each been found to be elevated in infants with PPHN.15 They are known to increase pulmonary arterial pressure and pulmonary vascular resistance in newborn animals.16

PPHN also can occur in infants without parenchymal lung disease. An abnormal pulmonary vascular bed can be a contributing factor to the development of PPHN. Lambs who have had prenatal closure of the ductus arteriosus have the physiologic characteristics of PPHN at birth.17 Constriction of the ductus arteriosus can occur with the use of prostaglandin synthesis inhibitors such as acetylsalicylic acid or indomethacin. PPHN has been reported in newborns of mothers who received indomethacin, aspirin or other prostaglandin synthesis inhibitors.18.19

In neonates with hypoplastic lungs as seen in congenital diaphragmatic hernias and alveolar capillary dysplasia, the total cross-sectional area of the vascular bed is markedly decreased. There is also abnormal muscularization of pulmonary vessels, with hypertrophy of the muscular arteries and neomuscularization of precapillary vessels, normally void of muscle.20 These abnormalities increase the degree of pulmonary vascular resistance and contribute to the development of PPHN.

Diagnosis of PPHN

PPHN must be included in the differential diagnosis whenever a term or postdates neonate presents with hypoxia. Prenatal and perinatal history may provide clues as to the etiology of the PPHN. Indicators of intrauterine or perinatal stress that may have caused hypoxemia are important findings. These include the presence of meconium, acidosis, and lethargy at delivery. The maternal history may disclose the use of over-the-counter medications containing prostaglandin-synthesis inhibitors. Maternal history of risk factors for infection such as prolonged rupture of membranes, increased maternal white blood cell count, maternal fever, or positive group B streptococcus carrier status is also important.

The neonate with PPHN is often extremely labile, with frequent desaturation episodes. Blood pressure may rapidly fluctuate from hypotension to hypertension. Chest x-ray findings vary, depending on etiology. In cases with underlying parenchymal disease, the chest x-ray will be compatible with the underlying disease (e.g., meconium aspiration, RDS, neonatal pneumonia, diaphragmatic hernia). In idiopathic PPHN, the lung fields are often hyperlucent, indicative of decreased pulmonary blood flow.

PPHN is diagnosed when there is pulmonary hypertension, decreased pulmonary blood flow, and increased right-to-left extrapulmonary shunting of blood causing hypoxemia. Clinically, labile hypoxemia indicates right-to-left extrapulmonary shunting. Right-to-left shunting, either at the ductus arteriosus or at the foramen ovale, can be confirmed in several ways. If the shunt is primarily across the ductus arteriosus, oxygen content of the blood will be lower below the ductus arteriosus than above it. Differences in the pO2 in arterial blood gas samples taken simultaneously from the right upper extremity and the umbilical artery can be measured. Monitoring of preductal and postductal hemoglobin saturation can be performed noninvasively. If the shunt is largely across the foramen ovale, preductal to postductal differences may be obscured or absent. Two-dimensional echocardiography with contrast or color doppler may be helpful in documenting right-to-left shunting at the ductus arteriosus or foramen ovale. Tricuspid regurgitation is a common finding in PPHN. Right ventricle systolic pressure (an indicator of pulmonary arterial pressure) equal to or greater than systemic systolic pressure is also seen in PPHN.

Management of PPHN

Lability

A neonate already compromised by a perinatal event, such as meconium aspiration, may progress to PPHN if allowed to remain hypoxic with labored breathing. In PPHN, even a mild stress may cause pO2 to plummet within minutes. Vigorous and persistent resuscitative measures are often necessary to regain lost vasorelaxation. Understanding the dynamic pathophysiology underlying right-to-left shunting is important to successful management of PPHN. Accordingly, neonates with PPHN are often very sensitive to activity and agitation. Sedation and minimal stimulation are often used. Use of narcotics such as fentanyl or morphine or sedative such as phenobarbital or lorazepam is often employed. Phenobarbital, with a long half-life, provides extended sedation without frequent dosing. Use of paralysis in PPHN is less common as it may result in massive tissue edema. It may also be less necessary with newer patient-triggered ventilators.

Systemic circulatory support

Systemic blood pressures should be maintained at the upper limits of normal. This provides for an increased systemic resistance that may decrease the degree of right-to-left shunting at the ductus arteriosus or foramen ovale. If hypotension is due to hypovolemia, as may be the case in a neonate with sepsis and endotoxin-induced capillary leak, then replacement of the intravascular volume is indicated. This can be achieved through the use of colloid-based volume expanders such as blood, plasmanate, or salt-poor albumin. Ionized calcium levels should be monitored and treated. If hypotension persists despite normal vascular volume and calcium status, then pressor agents, such as dopamine, dobutamine, and epinephrine, may be required.

Lung recruitment strategies

Surfactant

If the cause of PPHN is respiratory distress syndrome secondary to inadequate endogenous surfactant in the near-term infant, exogenous surfactant may be administered to reverse atelectasis and alveolar hypoxia. Surfactant may also be inactivated in severe parenchymal disease such as meconium aspiration or pneumonia. Surfactant administration may increase pulmonary blood flow as well as decrease pulmonary vascular resistance.

High frequency oscillatory ventilation

Infants with PPHN from a variety of causes have been successfully treated with high frequency oscillatory ventilation (HFOV).21 HFOV decreases pCO2 and increases oxygenation in infants with PPHN. HFOV appears to improve oxygenation through the safer use of higher mean airway pressures to maintain lung volume and prevent atelectasis.

Vasodilation

If treatment of the underlying disease is ineffective or if there is no such underlying disease and the hypertension appears to be caused by abnormal pulmonary vasoconstriction, then direct attempts to dilate the pulmonary circulation should be made. When used in the treatment of PPHN, vasodilators are described as either nonselective or selective. Nonselective vasodilators are nonspecific and can cause both pulmonary and systemic vasodilation. Selective vasodilators are those agents that act specifically on the pulmonary vasculature and in general, do not cause systemic vasodilation.

Nonselective vasodilators

With the discovery of inhaled nitric oxide (see selective dilators) nonselective dilators are not used as often as before for the management of PPHN. Tolazoline was the most extensively used nonselective vasodilators. It has been shown to increase oxygen tension.22 However, tolazoline has never undergone a controlled clinical trial of any significant size and will soon cease to be manufactured. Many other vasodilators, including nitroprusside, PGI2, fentanyl, isoproterenol and chlorpromazine, have also been given in both intravenous and intratracheal forms to neonates with persistent pulmonary hypertension. Unfortunately, none of these agents is a selective pulmonary vasodilator. They all decrease both pulmonary and systemic vascular resistance, and thus, their use is often associated with significant systemic hypotension.

Selective vasodilators

Respiratory alkalosis is a selective pulmonary vasodilator in the newborn lamb. When neonates with PPHN are intentionally hyperventilated, pulmonary arterial pressure decreases and oxygenation increases. The effects of hyperventilation are due to the increasing pH rather than the decreased pCO2. However, infusion of a buffer to enhance alkalization is not equivalent to treatment with hyperventilation.13

Nitric oxide (NO) binds to hemoglobin much more actively than does carbon monoxide. Thus inhaled NO is unavailable to the systemic circulation.23 Inhaled NO has been shown to selectively dilate the pulmonary circulation of newborn lambs with pulmonary hypertension of the newborn caused by prenatal closure of the ductus arteriosus.24 Inhaled NO increases oxygenation in PPHN and appears to be effective in many of the diseases associated with PPHN. However, inhaled NO is not effective in increasing oxygenation in all patients with PPHN, and an increase in oxygenation to inhaled NO does not always predict recovery in PPHN. Inhaled NO may be less effective in treating neonates with PPHN associated with severe parenchymal lung disease, perhaps because it is not adequately delivered to the terminal lung site where the pulmonary vasoconstriction is occurring. High frequency oscillatory ventilation (HFOV) can be used to maintain adequate lung volumes and airway patency to which inhaled NO can be added.25 The use of surfactant with inhaled NO has improved the efficacy of NO when used in the lamb model of congenital diaphragmatic hernia.26 Partial liquid ventilation is another method of recruiting lung volume, and partial lung ventilation allows inhaled NO to be effective in lambs with congenital diaphragmatic hernia.27

In 1997, the results of two multicenter trials that compared the use of inhaled NO were published. The Neonatal Inhaled Nitric Oxide Study Group28 conducted a prospective, multicenter, randomized, controlled, double-blind trial to evaluate whether inhaled NO would reduce mortality or the need for extracorporeal membrane oxygenation (ECMO - see next section) in neonates born at or near term who had hypoxic respiratory failure that was unresponsive to aggressive conventional therapy, including high frequency oscillatory ventilation and/or surfactant. The etiologies of hypoxic respiratory failure included persistent pulmonary hypertension of the newborn, meconium aspiration, pneumonia, sepsis, respiratory distress syndrome or suspected pulmonary hypoplasia associated with oligohydramnios and premature rupture of the membranes.

Neonates were eligible for this study if their gestational age was = 34 weeks, if postnatal age was less than 14 days, if they had no evidence of congenital heart disease and their oxygenation index was greater than 25 on two measurements. Neonates were randomized to receive either inhaled nitric oxide at 20 parts per million (ppm) or 1.0 FiO2 (the control group).

One hundred twenty-one neonates were assigned to the control group and 114 neonates received inhaled nitric oxide. Inhaled NO reduced the use of ECMO as 54% in the control group required the use of ECMO compared to 39% of those neonates who received inhaled NO (p = 0.014). The use of inhaled NO had no apparent effect on mortality as 17% of the control group died compared to 14% of the neonates who received inhaled NO (p=0.6). There were no toxic effects noted with the inhaled NO use. There were no differences between the groups in the overall incidence or severity of intracranial hemorrhage, brain infarction, seizures requiring anticonvulsive therapy and either pulmonary or gastrointestinal hemorrhage.

Roberts29 et al examined the effects of inhaled NO at 80 ppm on systemic oxygenation in term infants with severe hypoxemia and pulmonary hypertension through a prospective, randomized, blinded multicenter study. Inclusion criteria included a gestational age = 37 weeks, birthweight = 2500 g, postductal pO2 of = 55 mmHg on two consecutive arterial blood gases 30 minutes apart while on mechanical ventilation, completion of echocardiogram and placement of a postductal arterial line. Infants who had received HFOV or jet ventilation were ineligible. The use of surfactant was allowed in this study. Infants were randomized to receive either nitrogen (control group) or 80 ppm inhaled NO.

Fifty-eight neonates participated in this clinical study with 30 randomized to receive inhaled NO. Sixteen of the 30 neonates who received inhaled NO had increased systemic oxygenation with an average increase in pO2 from 41 ± 9 mmHg to 89 ± 70 mmHg while only two of the 28 neonates in the control group had an increase in systemic oxygenation. In those infants who had initial improvements in systemic oxygenation with inhaled NO, 75% (12/16) of these neonates has sustained improvement in systemic oxygenation. Forty percent of the neonates who received inhaled NO required ECMO compared to 71% of the control group. Inhaled NO did not cause systemic hypotension, and the number of deaths was similar in each group.

In 2000, the results of a multicenter randomized blinded clinical trial by Clark et al30 to determine whether low-dose inhaled NO reduced the use of ECMO in neonates with pulmonary hypertension were published. This trial enrolled neonates who were > 34 weeks gestational age, = 4 days of age, required assisted ventilation and had an oxygenation index = 25. The neonates also had clinical or echocardiographic evidence of pulmonary hypertension without structural cardiac disease. Pre-enrollment use of HFOV and/or surfactant was encouraged. To balance the distribution of pulmonary disease diagnoses in the two treatment groups, each neonate was assigned to one of five diagnostic categories: meconium aspiration syndrome, pneumonia, respiratory distress syndrome, lung hypoplasia syndromes and idiopathic persistent pulmonary hypertension. The neonates were then randomized to receive either inhaled NO at 20 ppm or nitrogen (control group). Inhaled NO was administered at 20 ppm for a maximum of 20 hours followed by 5 ppm for no more than 96 hours.

A total of 248 infants were enrolled with 126 randomized to receive inhaled NO. The use of ECMO was less in the inhaled NO group, 38%, compared to 64 % for the control group. There was also a greater increase in the ratio of arterial-to-alveolar oxygen in the inhaled NO group than in the control group. Thirty day mortality rates were similar in the two groups. There was also no difference in the incidence of intraventricular hemorrhage or infarct.

While all three of these clinical trials demonstrated that inhaled NO does reduce the need for ECMO, not all neonates with pulmonary hypertension responded to inhaled NO. However, no major adverse effects of inhaled NO were documented. The initial clinical trials of inhaled NO focused on those neonates with pulmonary hypertension who were also eligible for ECMO based on gestational age (>34 weeks ) and birthweight (>2500 g).

For the neonate population < 34 weeks, severe respiratory disease can also be complicated by pulmonary hypertension. The use of inhaled NO in these neonates has been examined in several smaller clinical trials with promising results regarding improvement in oxygenation, reduction in the days on mechanical ventilation, and a lower incidence of chronic lung disease. These trials have not identified that inhaled NO changes the incidence or severity of intracranial hemorrhage. Because preterm infants are at risk for intraventricular hemorrhage (IVH) and NO is thought to affect platelet aggregation and adhesion,31 an important aspect of any clinical trial that involves that use of inhaled NO in preterm infants will be close monitoring for an increase in the incidence or severity of IVH. Currently, the NICUs at WCH and Shands-Jacksonville are participating in a multicenter randomized clinical trial to evaluate inhaled NO as a potential therapy for the premature infant with respiratory failure as defined by an oxygenation index = 10.

Extracorporeal membrane oxygenation (ECMO)

ECMO can be defined as the use of a modified heart-lung machine combined with a membrane oxygenator to provide long-term cardiopulmonary support for patients with reversible pulmonary and/or cardiac insufficiency. ECMO is not a specific treatment for any disease but rather a method of supportive care in which the patient is kept alive while the lungs and their vasculature recover on their own. PPHN without associated parenchymal lung disease accounts for approximately 14% of neonates requiring ECMO therapy, and the majority of other infants who require ECMO have PPHN physiology as a co-morbidity.32 Infants treated with ECMO have excellent survival rates, including an 80% survival in neonates with idiopathic PPHN. 32,33

Complications of PPHN

Because PPHN is a disease in which hypoxemia occurs, it can be difficult to ascertain whether complications seen during and after recovery are due to the disease process itself or some of the therapies used to treat the disease. Therapies such as hyperventilation have not been subject to controlled clinical trials. Hyperventilation may contribute to lung injury.34 There is also an association between the requirement for prolonged hyperventilation and sensorineural hearing loss (SNHL) and worse developmental outcome.35 HFOV and ECMO have also been associated with bilateral progressive SNHL in survivors, many of whom had passed their newborn auditory brainstem evoked screen.36 Hypoxemia, the induction of alkalosis, and the use of ototoxic medications are believed to be important causal factors but the specific insult that leads to progressive SNHL in this setting remains unclear. Children with a history of PPHN may need to receive audiological evaluations every 6 months until the age of 3 years.37

Many questions remain about the use of inhaled NO. The optimal inhaled concentration is not known. There are concerns about the toxicity of NO as an oxidant free radical. NO combines with oxygen to form NO2, an even more toxic gas. ECMO, while improving survival rates in infants with PPHN, can also have significant morbidity. The requirement for systemic heparinization to keep the ECMO circuits patent may lead to new bleeding or extension of bleeding in already injured areas of the brain. The incidence of major intracranial hemorrhage is 4.6% with an overall survival rate of 50% and is associated with a poor outcome in survivors.32 Outcome data for survivors of ECMO are encouraging, with one 5 year followup study reporting a mean full scale, verbal and performance IQ of ECMO treated children were within normal range, although as a group, they were significantly lower than that of the control patients.38

Summary

PPHN remains a common disease process in neonatal intensive care units. Management of PPHN in the future depends on the understanding of the mechanisms controlling pulmonary vascular resistance and how these mechanisms are disrupted to cause pulmonary hypertension.

References

  1. Reid DL, Thornburg KL: Pulmonary pressure-flow relationships in the fetal lamb during in utero ventilation. J Appl Physiol 1990;69:1630-36.
  2. Teitel DF, Iwamoto HS, Rudolph AM: Changes in the pulmonary circulation during birth related events. Pediatr Res 1990;27:372-78.
  3. Morin FC III, Stenmark KR: Persistent pulmonary hypertension of the newborn. Am J Respir Crit Care Med 1995;151:2010-2032.
  4. Lakshminrusimha S, Steinhorn RH: Pulmonary vascular biology during neonatal transition. Clinics Perinatol 1999;26(3):601-619.
  5. Kinsella JP, McQueston JA, Rosenberg AA, et al: Inhaled nitric oxide causes selective and sustained vasodilatation of the ovine transitional pulmonary circulation. Pediatr Res 1992;31:313A.
  6. Tiktinsky M, Cummings J, Morin FC: Acetylcholine increased pulmonary blood flow in intact fetuses via endothelium-dependent vasodilation. Am J Physiol 1992;262:H406.
  7. Archer S, Huang J, Hampl V: Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K+ channel by cGMP-dependent protein kinase. Proc Natl Acad Sci USA 1994;91:7583.
  8. Shaul PW, Farrar MA, Zellers TM: Oxygen modulates endothelium derived relaxing factor production in fetal pulmonary arteries. Am J Physiol 1992;262:H355-H364.
  9. Soifer SJ, Schreiber MD, Heymann MA: Leukotriene antagonists attenuate thromboxane-inducible pulmonary hypertension. Pediatr Res 1989;26:83-87.
  10. Tod M, Cassin S: Effects of 6-keto-prostaglandin E1 on perinatal pulmonary vascular resistance. Proc Soc Exp Biol Med 191;166:148-152.
  11. Abman SH, Stenmark KR: Changes in lung eicosanoid content during normal and abnormal transition in perinatal lambs. Am J Physiol 1992;262:L214-L222.
  12. Tod ML, Yoshimnrak, Rubin LJ: Indomethicin prevents ventilation-induced decreases in pulmonary vascular resistance of the middle region in fetal lambs. Pediatr Res 1991;29:449-454.
  13. Walsh-Sukys ML, Tyson JE, Wright LL, et al: Persistent pulmonary hypertension in the newborn in the era before nitric oxide: Practice variation and outcomes. Pediatr 2000;105:12-20.
  14. Suchomski SJ, Morin III FC: Diseases of pulmonary circulation. In Fuhrman B, Zimmerman J, editors: Pediatric Critical Care, St. Louis, 1997, Mosby.
  15. Dobyns E, Westcott J, Kennaugh J, et al: Eicosanoids decrease in newborns with persistent pulmonary hypertension successfully treated with extracorporeal membrane oxygenation. Am J Respir Crit Care Med 1994;149:873.
  16. Schreiber M, Heymann M, Soifer S: Leukotriene inhibition prevents and reverses hypoxic pulmonary vasoconstriction in newborn lambs. Pediatr Res 1985;19:437-441.
  17. Morin III FC: Ligating the ductus arteriosus before birth causes persistent pulmonary hypertension in the newborn lamb. Pediatr Res 1989;25(3):245.
  18. Manchester D, Margolis H, Sheldon R: Possible association between maternal indomethacin therapy and primary pulmonary hypertension of the newborn. Am J Obstet Gynecol 1976;467-469.
  19. Wilkin A, Aynsley-Green A, Mitchell M: Persistent pulmonary hypertension and abnormal prostaglandin E levels in preterm infants after maternal treatment with naproxen. Arch Dis Child 1979;54:942-945.
  20. Haworth SG: Pulmonary vascular remodeling in neonatal pulmonary hypertension. Chest 1988;93:133S-138S.
  21. Kinsella JP, Abman SH: Clinical approach to the use of high frequency oscillatory ventilation in neonatal respiratory failure. J Perinatal 1996;16:S52-55.
  22. Goetzman B, Sunshine P, Johnson J, et al: Neonatal hypoxia and pulmonary vasospasm: response to tolazoline. J Pediatr 1976;89:617-621.
  23. Rimar S,Gillis N: Pulmonary vasodilatation by inhaled nitric oxide after endothelial injury. J Appl Physio 1992;73(5):2179.
  24. Zayek M, Cleveland D, Morin III FC: Treatment of persistent pulmonary hypertension of the newborn lamb by inhaled nitric oxide. J Pediatr 1993;122:743.
  25. Kinsella J, Neish S, Ivy D, et al: Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide. J Pediatr 1993;123:103.
  26. Karamanoukaian HL, Glick PL, Wilcox DT, et al: Pathophysiology of congenital diaphragmatic hernia. VIII. Inhaled nitric oxide requires exogenous surfactant therapy in the lamb model of congenital diaphragmatic hernia. J Pediatr Surg 1995;30:1-4.
  27. Wilcox DT, Glick PL, Karamanoukaian HL, et al: Perfluorocarbon-associated gas exchange improves pulmonary mechanics, oxygenation, ventilation and allows nitric oxide delivery in the hypoplastic lung congenital diaphragmatic hernia lamb model. Crit Care Med 1995;23:1858-1863.
  28. The Neonatal Inhaled Nitric Oxide Study Group: Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Eng J Med 1997;336:597-604.
  29. Roberts Jr. JD, Fineman JR, Morin III FC, et al: Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Eng J Med 1997;336:605-10.
  30. Clark RH, Kueser TJ, Walker MW, et al: Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Eng J Med 2000;342:469-75.
  31. Hogman M, Forstell C, Arnberg H, et al: Bleeding time prolongation and NO inhalation. Lancet 1993;341:1664-65.
  32. Rais-Bahrami K, Short BL: The current status of neonatal extracorporeal membrane oxygenation. Sem Perinatal 2000;24(6):406-417.
  33. UK Collaborative ECMO Trial Group: UK collaborative randomized trial of neonatal extracorporeal membrane oxygenation. Lancet 1996;348:75-82.
  34. Davis J, Whitin J: Prophylactic effects of dexamethasone in lung injury caused by hyperoxia and hyperventilation. J Appl Physiol 1992;72:1320.
  35. Walton J, Hendricks-Munoz K: Profile and stability of sensorineural hearing loss in persistent pulmonary hypertension of the newborn. J Speech Hearing Res 1991;34:1362.
  36. Lasky RE, Wiorek L, Becker TR: Hearing loss in survivors of neonatal extracorporeal membrane oxygenation and high-frequency oscillatory therapy. J Am Acad Audiol 1998;9:47-58.
  37. Hutchin ME, Gilmor C, Yarbrough WG: Delayed-onset sensorineural hearing loss in a 3 year-old survivor of persistent pulmonary hypertension of the newborn. Arch Otolaryngol Head Neck Surg 2000;126:1014-1017.
  38. Glass P, Wagner AE, Papero PH, et al: Neurodevelopmental status at age 5 years of neonates treated with extracorporeal membrane oxygenation. J Pediatr 1995;127:447-457
December, 2001/ Jacksonville Medicine

What's New · Northeast Florida Medicine Journal · Know Your Physician · Legal & Legislative
· DCMS Alliance · Academy of Medicine · Member Websites · Community Health
About the DCMS · Meetings Calendar · Member Benefits · Employment Connection · Home

Duval County Medical Society   ·   555 Bishopgate Lane  ·   Jacksonville, FL  32204
Phone: (904) 355-6561   ·     FAX:  (904) 353-5848   
General Email: dcms@dcmsonline.org    ·   Webmaster's Email: mdoran@dcmsonline.org
Privacy Policy and Disclaimers