Recent developments in the pathophysiology and treatment of persistent pulmonary hypertension of the newborn,☆☆,,★★

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FETAL AND TRANSITIONAL PULMONARY VASOREGULATION

The fetal circulation is characterized by high pulmonary vascular resistance; pulmonary blood flow accounts for less than 10% of combined ventricular output in the late-gestation ovine fetus.5 Mechanisms responsible for maintaining high fetal pulmonary vascular resistance and causing sustained pulmonary vasodilation at birth are incompletely understood; however, studies in fetal and transitional pulmonary vasoregulation have led to increased understanding of the normal physiologic control of

CLINICAL TRIALS OF INHALED NO IN INFANTS WITH PPHN

Recent studies have demonstrated that inhaled NO causes marked improvement in oxygenation in many newborn infants with PPHN. Roberts et al.33 reported that brief (30 minutes) inhalation of NO at 80 ppm improved oxygenation in patients with PPHN, but this response was sustained in only one patient after NO was discontinued. In another report, rapid improvement in oxygenation in neonates with severe PPHN was demonstrated with the use of doses of 20 ppm NO for 4 hours, after which the dose was

MANAGEMENT STRATEGIES IN PPHN

Increasing clinical experience with inhaled NO in PPHN has led to improved understanding of the potential role of this potent and selective pulmonary vasodilator. Although consensus on diagnostic criteria is lacking,38 for the purposes of this discussion PPHN is defined as severe neonatal hyoxemic respiratory failure associated with extrapulmonary right-to-left shunting of blood across the foramen ovale or patent ductus arteriosus or both. Patients with idiopathic PPHN have severe pulmonary

NITRIC OXIDE IN THE PREMATURE INFANT'S PULMONARY CIRCULATION

The fetus is characterized by both structural and functional pulmonary immaturity, including surfactant deficiency. Pulmonary immaturity and hyaline membrane disease lead to respiratory failure after premature delivery, and exogenous surfactant therapy can decrease the severity of the respiratory insufficiency.69 However, exogenous surfactant therapy results in suboptimal responses in up to 50% of human neonates thought to have HMD,70 which suggests that other problems of prematurity (e.g.,

TOXICITY

The clinical studies described above were designed to investigate the hemodynamic effects of inhaled NO within ”nontoxic“ concentrations, but concerns remain regarding potential toxic effects, including methemoglobinemia and lung injury caused by NO2, peroxynitrite, and hydroxyl radical formation.81, 82 Although little evidence exists for NO toxicity at low concentrations in adult animals,83, 84, 85 further studies in the neonatal lung are needed. Of particular concern are the potential effects

SUMMARY

Successful management of severe PPHN depends on the application of appropriate strategies to manage the cardiopulmonary interactions that characterize this syndrome. Manifestations of PPHN often involve dysfunctional pulmonary vasoregulation, with suprasystemic pulmonary vascular resistance causing extrapulmonary shunting, pulmonary parenchymal disease causing intrapulmonary shunting, and systemic hemodynamic deterioration. Inhaled NO can cause marked improvement in oxygenation when optimal

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References (98)

  • JP Kinsella et al.

    Cardiac performance in ECMO candidates: echocardiographic predictors for ECMO

    J Pediatr Surg

    (1992)
  • RL Geggel et al.

    The structural basis of PPHN

    Clin Perinatol

    (1984)
  • DA Clark et al.

    Surfactant displacement by meconium free fatty acids: an alternate explanation for atelectasis in meconium aspiration syndrome

    J PEDIATR

    (1987)
  • D Moses et al.

    Inhibition of pulmonary surfactant function by meconium

    Am J Ob Gynecol

    (1991)
  • A Lotze et al.

    Surfactant protein A concetrations in tracheal aspirate fluid from infants requiring extracorporeal membrane oxygenation

    J PEDIATR

    (1990)
  • A Lotze et al.

    Improved pulmonary outcome after exogenous surfactant therapy for respiratory failure in term infants requiring extracorporeal membrane oxygenation

    J PEDIATR

    (1993)
  • RH Clark et al.

    Prospective, randomized comparison of high-frequency oscillation and conventional ventilation in candidates for extracorporeal membrane oxygenation

    J PEDIATR

    (1994)
  • RH. Clark

    High-frequency ventilation

    J PEDIATR

    (1994)
  • JP Kinsella et al.

    Methaemoglobin during nitric oxide therapy with high frequency ventilation

    Lancet

    (1993)
  • AH. Jobe

    Surfactant in the perinatal period

    Early Hum Dev

    (1992)
  • M Lepoivre et al.

    Inactivation of ribonucleotide reductase by nitric oxide

    Blochem Biophys Res Commun

    (1991)
  • M Hogman et al.

    Bleeding time prolongation and NO inhalation

    Lancet

    (1993)
  • MW Radomski et al.

    Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium

    Lancet

    (1987)
  • B. Freeman

    Free radical chemistry of nitric oxide

    Chest

    (1994)
  • WM Gersony et al.

    “PFC“syndrome (persistence of the fetal circulation)

    Circulation

    (1969)
  • WH Drummond et al.

    The clinical profile of the newborn with persistent pulmonary hypertension

    Clin Pediatr

    (1977)
  • AM Rudolph et al.

    Circulation changes during growth in the fetal lamb

    Circ Res

    (1970)
  • M Yanagisawa et al.

    Endothelin, a novel endothelium derived peptide. Pharmacological activities, regulation and possible roles in cardiovascular control

    Biochem Pharmacol

    (1989)
  • BA Chatfield et al.

    Hemodynamic effects of endothelin-1 on ovine fetal pulmonary circulation

    Am J Physiol

    (1991)
  • S Cassin et al.

    Tone-dependent responses to endothelin in the isolated perfused fetal sheep pulmonary circulation in situ

    J Appl Physiol

    (1991)
  • DD Ivy et al.

    Physiologic characterization of endothelin A and B receptor activity in the ovine fetal pulmonary circulation

    J Clin Invest

    (1994)
  • HY Lin et al.

    Cloning and functional expression of a vascular smooth muscle endothelin-1 receptor

    Proc Natl Acad Sci USA

    (1991)
  • A Sakimoto et al.

    Cloning and functional expression of human cDNA for the ETa endothelin receptor

    Biochem Biophys Res Commun

    (1991)
  • ML Tod et al.

    Endothelin-1-induced pulmonary arterial dilation is reduced by AP-nitro-L-arginine in fetal lambs

    J Appl Physiol

    (1992)
  • OW Jones et al.

    Systemic and pulmonary hemodynamic effects of big endothelin-1 and phosphoramidon in the ovine fetus

    Am J Physiol

    (1994)
  • S Kourembanas et al.

    Hypoxia induces endothelin gene expression and secretion in cultured human endothelium

    J Clin Invest

    (1991)
  • DD Ivy et al.

    Role of endothelin in autoregulation of blood flow in the ovine fetal lung

    Pediatr Res

    (1994)
  • CA Gruetter et al.

    Relaxation of bovine coronary artery and activation of coronary arterial guanylate cyclase by nitric oxide, nitroprusside and a carcinogenic nitrosoamine

    J Cyclic Nucleotide Res

    (1979)
  • RMJ Palmer et al.

    Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor

    Nature

    (1987)
  • LJ Ignarro et al.

    Endothelium-derived relaxing factor produced and released from artery and vein in nitric oxide

    Proc Natl Acad Sci USA

    (1987)
  • SH Abman et al.

    Role of endothelium-derived relaxing factor activity during transition of pulmonary circulation at birth

    Am J Physiol (Heart Circ Physiol 28)

    (1990)
  • MH Tiktinsky et al.

    Increasing oxygen tension dilates fetal pulmonary circulation via endothelium-derived relaxing factor

    Am J Physiol

    (1993)
  • JA McQueston et al.

    Effects of oxygen and exogenous L-arginine on EDRF activity in fetal pulmonary circulation

    Am J Physiol (Heart Circ Physiol)

    (1993)
  • DN Cornfield et al.

    Effects of birth related stimuli on L-arginine-dependent vasodilation in the ovine fetus

    Am J Physiol (Heart Circ Physiol 31)

    (1992)
  • JA McQueston et al.

    Chronic intrauterine pulmonary hypertension impairs endothelium-dependent vasodilation in fetal lambs

    Am J Physiol

    (1995)
  • JP Kinsella et al.

    Hemodynamic effects of exogenous nitric oxide in ovine transitional pulmonary circulation

    Am J Physiol

    (1992)
  • Centers for Disease Control

    Recommendations for occupational safety and health standards

    MMWR Morb Mortal Wkly Rep

    (1988)
  • JD Roberts et al.

    Inhaled nitric oxide reverses pulmonary vasoconstriction in the hypoxic and acidotic newborn lamb

    Circ Res

    (1993)
  • JI Berger et al.

    Effect of inhaled nitric oxide during group B streptococcal sepsis in piglets

    Am Rev Respir Dis

    (1993)
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    From the Department of Pediatrics, Divisions of Neonatology and Pulmonary Medicine, Children's Hospital and the University of Colorado School of Medicine, Denver, Colorado

    ☆☆

    Reprint requests: John P. Kinsella, MD, Division of Neonatology, Box B-070, Children's Hospital, 1056 E. 19th Ave., Denver, CO 80218-1088.

    THE JOURNAL OF PEDIATRICS 1995;126:853-64

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    0022-3476/95/$3.00 + 0 9/18/64030

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