Inhaled nitric oxide enhances oxygenation but not survival in infants with alveolar capillary dysplasia

doi:10.1016/S0022-3476(97)70203-8

The Journal of Pediatrics

Volume 130, Issue 3, March 1997, Pages 417-422

Presented in part at the 1994 American Pediatric Society–Society for Pediatric Research Annual Meeting, Seattle, Washington, May 2-5, 1994.

https://doi.org/10.1016/S0022-3476(97)70203-8 Get rights and content

Abstract

A complex vascular abnormality in the lungs, termed alveolar capillary dysplasia (ACD) and misalignment of the lung vessels, has been recently recognized in some infants with persistent pulmonary hypertension. These infants die despite maximal medical support including extracorporeal membrane oxygenation (ECMO). Inhaled nitric oxide has been reported to improve oxygenation in neonates with persistent pulmonary hypertension of the newborn, and may allow some infants to avoid the need for ECMO. We identified five infants who had received inhaled nitric oxide to treat refractory hypoxemia caused by persistent pulmonary hypertension of the newborn, and who subsequently died and had autopsy confirmation of ACD. Each infant received care at a different medical center. In each patient, inhaled NO increased the arterial partial pressure of oxygen dramatically. Despite initial clinical improvement, the response to NO was not sustained in any patient. As responsiveness was lost, each infant with ACD required inhaled NO concentrations of 80 ppm or higher to sustain oxygenation. Each infant died, four after extensive periods of ECMO support. This experience demonstrates that a short-term improvement after inhalation of nitric oxide does not lead to long-term survival in ACD. Further, in three infants the diagnosis of ACD was established by lung biopsy before death. Increasing awareness of this clinical entity may allow for the avoidance of costly, invasive procedures such as ECMO until more specific therapies become available. (J Pediatr 1997;130:417-22)

Section snippets

METHODS

Each infant was born at term after a normal pregnancy and delivery and received care at a different medical center. The mean birth weight was 2780 ± 228 (SD) gm. Four infants were boys. Four infants had other congenital anomalies, including phocomelia (n = l), absent gallbladder (n = l), imperforate anus (n = l), Hirschsprung disease (n = l), and intestinal malrotation (n = 2). All infants died (mean age = 19.2 ± 3.7 days); four died after prolonged courses of extracorporeal life support.

RESULTS

Clinical responses to inhaled NO are detailed for each infant in the Table. After initiation of inhaled NO, the arterial partial pressure of oxygen increased by 207 ± 62 mm Hg for the five infants. The Pa o ₂ subsequently decreased despite continued inhaled NO in each infant. In each infant, the concentration of inhaled NO was increased in response to the falling Pao₂, and all patients were receiving at least 80 ppm nitric oxide before initiation or resumption of extracorporeal membrane

DISCUSSION

We have described five infants, each with histologic features of ACD confirmed by examination of a lung specimen obtained during a postmortem examination. Each infant had an immediate, dramatic improvement in Pao₂ after inhalation of NO. This improvement was not sustained in any infant, and each infant died.

This experience may provide important information about the pathophysiology of ACD, as well as long-term inhalation of NO. Because a prominent pathologic feature of ACD is paucity of

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We hypothesize that “atypical” patients meet a critical threshold for areas of normal lung parenchyma and/or overall mildness of ACD features allowing for early survival and may be affected by growth of “normal” lung tissue relative to the growth of the diseased areas. The combined pre- and postcapillary obstruction in ACD creates a management paradox, as pulmonary vasodilators to treat elevated pulmonary vascular resistance can lead to poorly tolerated pulmonary edema.19 We speculate that areas with thin alveolar walls and normal capillary pattern may be more responsive to pulmonary vasodilators, leading to preferential recruitment in acute management and proliferative expansion of these areas if treatment can be maintained without development of substantial pulmonary edema.
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No significant complications of the procedure were reported. In the literature most reports deal with the issue of a solid pathology diagnosis to determine whether treatment should be continued or considered futile [5,7]. As the majority of the biopsies was performed in neonates with therapy-resistant atypical PH, the subsequent requests to the pathologist involved primarily ACD/MPV.
Open lung biopsy can help differentiate between reversible and irreversible lung disease and may guide therapy. To assess the risk–benefit ratio of this procedure in pediatric extracorporeal membrane oxygenation (ECMO) patients, we reviewed data of all patients who underwent an open lung biopsy during ECMO in one of the two pediatric ECMO centers in a nationwide study in the Netherlands.
In nineteen neonatal and six pediatric patients (0–15.5 years), twenty-five open lung biopsies were performed during the study period. In 13 patients (52%), a classifying diagnosis of underlying lung disease could be made. In another nine patients (36%), specific pathological abnormalities were described. In three patients (12%), only nonspecific abnormalities were described. The histological results led to withdrawal of ECMO treatment in 6 neonates with alveolar capillary dysplasia/misalignment of pulmonary veins (24%) and in another 6 patients, corticosteroids were started (24%). All patients survived the biopsy procedure. Hemorrhagic complications were rare.
An open lung biopsy during an ECMO run in neonates and children is a safe procedure with a minimum risk for blood loss and biopsy-related death. It can be very useful in diagnosing the underlying pathology and can guide cessation of ECMO treatment and thereby avoid continuation of futile treatment, especially in neonatal patients.
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Misalignment of lung vessels and alveolar capillary dysplasia: A case report with autopsy
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The frequencies of these accompanying anomalies were 40%, 32%, and 16%, respectively.11 Other rare associations have also been reported, such as anterior segment dysgenesis of the eyes, hemivertebrae, and phocomelia.5,22,24 Chest radiography is usually nonspecific, although in some reported cases it has revealed pneumothorax.2,5,6,14,17,21,25,28
Misalignment of lung vessels (MLV) with or without alveolar capillary dysplasia (ACD) is a rare cause of idiopathic persistent pulmonary hypertension of the neonate. This report describes a full-term infant with severe and intractable pulmonary hypertension. The patient’s condition progressively deteriorated despite high-frequency oscillatory ventilation, infusion of magnesium sulfate, dopamine, and dobutamine to control blood pressure, and nitric oxide inhalation therapy. The infant died at 5 days of age. The diagnosis of MLV with ACD was established by autopsy. Histopathologic analysis revealed a failure of formation and an ingrowth of alveolar capillaries, thickening of the alveolar walls, poor contact of capillaries with alveolar epithelium, small intra-acinar muscularized arterioles, and anomalous pulmonary veins within bronchovascular bundles. The low rate of diagnosis of MLV with or without ACD may be because of the early high mortality rate or patchy involvement in some cases. Increasing awareness of this clinical entity may prevent the use of costly, invasive, and probably ineffective procedures. Short-term improvement after inhalation of nitric oxide does not lead to long-term survival but merely provides time for potential lung transplantation.
Genomic and Genic Deletions of the FOX Gene Cluster on 16q24.1 and Inactivating Mutations of FOXF1 Cause Alveolar Capillary Dysplasia and Other Malformations
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Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, neonatally lethal developmental disorder of the lung with defining histologic abnormalities typically associated with multiple congenital anomalies (MCA). Using array CGH analysis, we have identified six overlapping microdeletions encompassing the FOX transcription factor gene cluster in chromosome 16q24.1q24.2 in patients with ACD/MPV and MCA. Subsequently, we have identified four different heterozygous mutations (frameshift, nonsense, and no-stop) in the candidate FOXF1 gene in unrelated patients with sporadic ACD/MPV and MCA. Custom-designed, high-resolution microarray analysis of additional ACD/MPV samples revealed one microdeletion harboring FOXF1 and two distinct microdeletions upstream of FOXF1, implicating a position effect. DNA sequence analysis revealed that in six of nine deletions, both breakpoints occurred in the portions of Alu elements showing eight to 43 base pairs of perfect microhomology, suggesting replication error Microhomology-Mediated Break-Induced Replication (MMBIR)/Fork Stalling and Template Switching (FoSTeS) as a mechanism of their formation. In contrast to the association of point mutations in FOXF1 with bowel malrotation, microdeletions of FOXF1 were associated with hypoplastic left heart syndrome and gastrointestinal atresias, probably due to haploinsufficiency for the neighboring FOXC2 and FOXL1 genes. These differences reveal the phenotypic consequences of gene alterations in cis.
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Common causes of neonatal respiratory distress include meconium aspiration, pneumonia, persistent pulmonary hypertension of the newborn, pneumothorax and cystic adenomatoid malformation. Genomics and proteomics have enabled the recent recognition of several additional disorders that lead to neonatal death from respiratory disease. These are broadly classified as disorders of lung homeostasis and have pathological features of proteinosis, interstitial pneumonitis or lipidosis. These pathological changes result from inherited disorders of surfactant proteins or granulocyte-macrophage colony stimulating factor.
Abnormal lung vascular development is the basis for another cause of fatal neonatal respiratory distress, alveolar capillary dysplasia with or without associated misalignment of veins. Diagnosis of these genetically transmitted disorders is important because of the serious implications for future siblings. There is also a critical need for establishing an archival tissue bank to permit future molecular biological studies.

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^☆: From the Departments of Pediatrics and Physiology, Children's Hospital and State University of New York at Buffalo, Buffalo, New York; the Departments of Pediatrics and Pathology, Hospital for Sick Children, Toronto, Ontario, Canada; the Department of Pediatrics, University of California, San Francisco, California; the Department of Pediatrics, Royal Alexandra Hospital, Edmonton, Alberta, Canada; and the Department of Pediatrics, Children's Hospital and Ohio State University, Columbus, Ohio.

^☆☆: Reprint requests: Robin H. Steinhorn, MD, Neonatology, Children's Hospital of Buffalo, 219 Bryant St., Buffalo, NY 14222.

^★: 0022-3476/97/$5.00 + 0 9/21/78222

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Inhaled nitric oxide enhances oxygenation but not survival in infants with alveolar capillary dysplasia☆,☆☆,★

Abstract

Section snippets

METHODS

RESULTS

DISCUSSION

J Pediatr

J Pediatr

Lancet

J Pediatr

Lancet

J Am Coll Cardiol

J Pediatr

J Pediatr

J Pediatr

J Pediatr

Congenital alveolar capillary dysplasia—an unusual cause of respiratory distress in the newborn

Am J Clin Pathol

Primary alveolar capillary dysplasia

Pediatr Radiol

Misalignment of pulmonary veins and alveolar capillary dysplasia

Pediatr Pathol