First 24-h SNAP-II score and highest PaCO2 predict the need for ECMO in congenital diaphragmatic hernia.

BACKGROUND/PURPOSE: Early clinical predictors for the use of ECMO in patients with congenital diaphragmatic hernia (CDH) are lacking. We sought to evaluate the first 24-h SNAP-II score and highest PaCO2 as predictors of ECMO support and in-hospital mortality in neonates with CDH. METHODS: Retrospective review of 47 consecutive neonates with CDH admitted to our institution from January 2007 to December 2010 was performed. Covariates of ECMO use including SNAP-II score and highest PaCO2 within the first 24 h of NICU admission were evaluated. RESULTS: Of the 47 infants in this study, 24 patients were supported with ECMO. The ECMO group had a higher incidence of pulmonary hypertension, higher PaCO2, and higher 24-h SNAP-II scores. Only the SNAP-II score and not highest PaCO2 predicted mortality following multivariate adjustment. CONCLUSIONS: The first 24-h SNAP-II score and highest PaCO2 may provide some prognostic value in identifying neonates who undergo ECMO support; however neither measure was independently associated with the use of therapy. Only the SNAP-II score was associated with in-hospital mortality following multivariate adjustment. Additional study is needed to validate these results in a larger data set.

Stability prior to surgery in Congenital Diaphragmatic Hernia: is it necessary?

BACKGROUND: Delaying surgery for infants with CDH until they achieve clinical stability is common practice. Stability, however, is inconsistently defined, and many infants fail to reach pre-established criteria. We sought to determine if infants undergoing surgery without meeting pre-established criteria could achieve meaningful survival. METHODS: All infants in the CAPSNet database were analyzed (2005-2010). Patients undergoing operative repair were divided into two groups based on whether they met strict (FiO2<0.40, conventional ventilation, preductal saturation >92%, no inotropes or vasodilators), or lenient (FiO2 <0.60, conventional ventilation, preductal saturation >88%, no vasodilators) criteria. Univariate analyses were performed comparing characteristics of those who survived after surgery (N=273) with those who did not (N=21). RESULTS: 294 patients (85%) survived to surgery. Predictors of post-operative survival included prenatal liver position (p=0.003), preoperative oxygen requirements (p=0.008), preoperative inotropes (p<0.0001), and non-conventional ventilation (p=0.004). Infants meeting strict criteria had increased survival (99%; p<0.0001). Infants meeting lenient criteria constituted 70% of survivors. Nearly one-third of survivors met neither strict nor lenient criteria. CONCLUSIONS: Infants with CDH can achieve good survival even when criteria for pre-operative stability are not met. We suggest that all infants should be repaired even if lenient criteria for ventilatory, inotrope, or vasodilator requirements are not achieved.

Cord blood endothelial colony-forming cells from newborns with congenital diaphragmatic hernia.

Endothelial colony-forming cells (ECFCs) are decreased in the cord blood of preterm infants with moderate-to-severe bronchopulmonary dysplasia. We quantified ECFCs from infants with congenital diaphragmatic hernia, a neonatal disorder with severe lung hypoplasia. Unlike newborns who develop bronchopulmonary dysplasia, those with congenital diaphragmatic hernia had increased and highly-proliferative cord blood ECFCs.

A family-based paradigm to identify candidate chromosomal regions for isolated congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn mortality. Isolated or non-syndromic CDH is considered a multifactorial disease, with strong evidence implicating genetic factors. As low heritability has been reported in isolated CDH, family-based genetic methods have yet to identify the genetic factors associated with the defect. Using the Utah Population Database, we identified distantly related patients from several extended families with a high incidence of isolated CDH. Using high-density genotyping, seven patients were analyzed by homozygosity exclusion rare allele mapping (HERAM) and phased haplotype sharing (HapShare), two methods we developed to map shared chromosome regions. Our patient cohort shared three regions not previously associated with CDH, that is, 2q11.2-q12.1, 4p13 and 7q11.2, and two regions previously involved in CDH, that is, 8p23.1 and 15q26.2. The latter regions contain GATA4 and NR2F2, two genes implicated in diaphragm formation in mice. Interestingly, three patients shared the 8p23.1 locus and one of them also harbored the 15q26.2 segment. No coding variants were identified in GATA4 or NR2F2, but a rare shared variant was found in intron 1 of GATA4. This work shows the role of heritability in isolated CDH. Our family-based strategy uncovers new chromosomal regions possibly associated with disease, and suggests that non-coding variants of GATA4 and NR2F2 may contribute to the development of isolated CDH. This approach could speed up the discovery of the genes and regulatory elements causing multifactorial diseases, such as isolated CDH.

Congenital diaphragmatic hernia interval on chromosome 8p23.1 characterized by genetics and protein interaction networks.

Chromosome 8p23.1 is a common hotspot associated with major congenital malformations, including congenital diaphragmatic hernia (CDH) and cardiac defects. We present findings from high-resolution arrays in patients who carry a loss (n = 18) or a gain (n = 1) of sub-band 8p23.1. We confirm a region involved in both diaphragmatic and heart malformations. Results from a novel CNVConnect algorithm, prioritizing protein-protein interactions between products of genes in the 8p23.1 hotspot and products of previously known CDH causing genes, implicated GATA4, NEIL2, and SOX7 in diaphragmatic defects. Sequence analysis of these genes in 226 chromosomally normal CDH patients, as well as in a small number of deletion 8p23.1 patients, showed rare unreported variants in the coding region; these may be contributing to the diaphragmatic phenotype. We also demonstrated that two of these three genes were expressed in the E11.5-12.5 primordial mouse diaphragm, the developmental stage at which CDH is thought to occur. This combination of bioinformatics and expression studies can be applied to other chromosomal hotspots, as well as private microdeletions or microduplications, to identify causative genes and their interaction networks.

Use of a continuous glucose sensor in an extracorporeal life support circuit.

BACKGROUND: Standard care for infants on extracorporeal life support (ECLS) relies on intermittent measurement of blood glucose (BG); however, this can lead to significant changes in BG that go unrecognized for several hours. The present study was designed to assess performance and clinical applicability of a subcutaneous glucose sensor technology modified for use as a blood-contacting sensor within the ECLS circuit. METHODS: Twelve children, aged 3 years or less, requiring ECLS support were studied. Three continuous glucose sensors (Medtronic MiniMed) were inserted into hubs placed in line with the ECLS circuit. Blood glucose was assessed with a laboratory analyzer (BG(LAB); Bayer Rapidlab 860) approximately every 5 h (mean 4.9 ± 3.3 h) with more frequent samples obtained with a bedside monitor (HemoCue) as needed. Sensor current (I(SIG)) was transmitted to a laptop computer and retrospectively calibrated using BGLAB. Sensor performance was assessed by mean absolute relative difference (MARD), linear regression slope and intercept, and correlation, all with BGLAB as reference. RESULTS: The BGLAB averaged 107.6 ± 36.4 mg/dl (mean ± standard deviation) ranging from 58 to 366 mg/dl. The MARD was 11.4%, with linear regression slope (0.86 ± 0.030) and intercept (9.0 ± 3.2 mg/dl) different from 1 and 0, respectively (p < .05), and correlation (r² = 0.76; p < .001). The system was not associated with any adverse events, and placement and removal into the hubs was easily accomplished. Instances in which more frequent BG values were obtained using a bedside HemoCue (BGHEMO) monitor showed the sensor to respond rapidly to changes. CONCLUSIONS: We conclude that continuous sensors can be adapted for use in an ECLS circuit with accuracy similar to or better than that achieved with the subcutaneous site. Continuous glucose monitoring in this population can rapidly detect changes in BG that would not otherwise be observed. Further studies will be needed to assess the benefit of continuous glucose monitoring in this population.

Plasma B-type natriuretic peptides in children with cardiovascular diseases.

Natriuretic peptides (NP) are released from the heart in response to pressure and volume overload. The biologic properties of NPs include counterregulation of the rennin-angiotensin-aldosterone pathway and a decrease in sympathetic tone resulting in diuresis, natriuresis, and vasodilation. Natriuretic peptides help to maintain fluid balance and blood pressure in a healthy physiologic range. The B-type natriuretic peptide (BNP) and its N-terminal precursor (NTpBNP) have become important diagnostic biomarkers of cardiovascular diseases (CVDs) in adults. Although many studies suggest that BNP also is a reliable test for diagnosing significant CVDs in children, data are lacking on whether additional use of BNP increases diagnostic accuracy and predicts prognosis. This comprehensive review describes the utility of BNP and NTpBNP for various CVDs of the neonatal and pediatric age groups. Because BNP is not a stand-alone test, it should not replace history, physical examination, or clinical judgment, but it has a clear value in adding details to the whole story for children, thus enabling the front-line physicians to make a diagnosis, especially in the acute care setting.

Retinol status of newborn infants is associated with congenital diaphragmatic hernia.

OBJECTIVE: Genetic analyses in humans suggest a role for retinoid-related genes in the pathogenesis of congenital diaphragmatic hernia (CDH). The goal of this study was to investigate the vitamin A status of mothers and their newborns in association with CDH. METHODS: We conducted a hospital-based, case-control study with 22 case and 34 control mothers and their newborns. In maternal and cord blood samples, retinol and retinol-binding protein (RBP) levels were measured with high-performance liquid chromatography and an enzyme-linked immunosorbent assay, respectively. Univariate and multivariate logistic regression analyses were performed to determine crude and adjusted risk estimates. RESULTS: Case newborns had significantly lower levels of retinol (0.60 vs 0.76 µmol/L; P=.003) and RBP (5.42 vs 7.11 mg/L; P=.02) than did control newborns. The multivariate logistic regression analysis showed lower levels of retinol and RBP in association with CDH risk; the odds ratio for retinol levels of <15th percentile (<0.61 µmol/L) was 11.11 (95% confidence interval: 2.54-48.66; P=.001), and that for RBP levels of <15th percentile (<4.54 mg/L) was 4.00 (95% confidence interval: 1.00-15.99; P=.05). Retinol and RBP levels were not different between case and control mothers. CONCLUSIONS: CDH is strongly associated with low retinol and RBP levels in newborns, independent of maternal retinol status. This is an important finding supporting the idea that human CDH is linked with abnormal retinoid homeostasis.

Impact of target blood gases on outcome in congenital diaphragmatic hernia (CDH).

INTRODUCTION: Neonatal intensive care unit (NICU) stabilization strategies which normalize physiology according to predetermined blood gas targets may contribute to observed improved survival rates of patients with CDH. The purpose of our study was to compare risk-adjusted outcomes of CDH patients managed with or without blood gas targets established at NICU admission. METHODS: Cases were collected from a national CDH network between May 2005 and November 2007. On NICU admission, the responsible neonatologist was asked to establish target ranges for pH, pCO (2), pO (2), and pre/post-ductal O (2) saturation. The outcomes analyzed were mortality, need for ECMO, days of mechanical ventilation/supplemental oxygen, and length of stay. RESULTS: Of 147 CDH infants, 63 had admission blood gas targets. Severity of illness and gestational age in both groups were comparable (SNAP-II score). Infants with blood gas targets had a significantly lower mortality than those without (Hazard ratio 0.27, p=0.006). CONCLUSIONS: Blood gas targets for the management of infants with CDH are associated with improved survival. Although the willingness to create and use stabilization targets to guide early NICU care may be a surrogate for other factors (experience, staffing, lack of interest), it is clearly associated with improved survival in CDH.

Congenital diaphragmatic hernia: endothelin-1, pulmonary hypertension, and disease severity.

RATIONALE: Endothelin-1 (ET1) is dysregulated in pulmonary hypertension (PH). It may be important in the pathobiology of congenital diaphragmatic hernia (CDH). OBJECTIVES: We hypothesized that ET1 levels in the first month would be higher in infants with CDH who subsequently expired or were discharged on oxygen (poor outcome). We further hypothesized that ET1 levels would be associated with concurrent severity of PH. METHODS: We sampled plasma at 24 to 48 hours, and 1, 2, and 4 weeks of age in 40 prospectively enrolled newborns with CDH. We performed echocardiograms to estimate pulmonary artery pressure at less than 48 hours of age and weekly to 4 weeks. PH was classified in relationship to systemic blood pressure (SBP): less than 2/3 SBP, 2/3 SBP-systemic is related to pressure, or systemic-to-suprasystemic pressure. MEASUREMENTS AND MAIN RESULTS: ET1 levels at 1 and 2 weeks were higher in infants with poor outcome compared with infants discharged on room air (median and interquartile range: 27.2 [22.6, 33.7] vs. 19.1 [16.1, 29.5] pg/ml, P = 0.03; and 24.9 [17.6, 39.5] vs. 17.4 [13.7, 21.8] pg/ml, P = 0.01 at 1 and 2 weeks, respectively). Severity of PH was significantly associated with increasing ET1 levels at 2 weeks (16.1 [13.7, 21.8], 21.0 [17.4, 31.1], and 23.6 [21.9, 39.5] pg/ml for increasing PH class, P = 0.03). Increasing severity of PH was also associated with poor outcome at that time (P = 0.001). CONCLUSIONS: Infants with CDH and poor outcome have higher plasma ET1 levels and severity of PH than infants discharged on room air. Severity of PH is associated with ET1 levels.

Thoracoscopic repair of congenital diaphragmatic hernia: intraoperative ventilation and recurrence.

INTRODUCTION: Thoracoscopic repair of congenital diaphragmatic hernia (CDH) has been described, but its efficacy and safety have not been validated. The aim was to compare our experience of thoracoscopy with laparotomy repair. METHODS: After ethics approval, we reviewed the notes of neonates with CDH operated in our institution between 2003 and 2008. Two historical groups were compared: infants who underwent laparotomy (2003-2008) or thoracoscopy (2007-2008). Data were compared by t test or Mann-Whitney tests. RESULTS: Thirty-five children had open repair of CDH, and 13 had thoracoscopic repair. Groups were homogeneous for age and weight. Five (38%) neonates who had thoracoscopy were converted to open for surgical difficulties (n = 4) and O(2) desaturation (n = 1). Patch repair was used in 12 (34%) open and 6 (46%) thoracoscopic repairs. End-tidal CO(2) was significantly elevated during thoracoscopy, but this was not reflected in arterial CO(2) or pH. There were 3 (8%) recurrences after open repair and 2 (25%) after thoracoscopy (P = .19). CONCLUSION: Thoracoscopic repair of CDH is feasible. Arterial blood gases should be closely monitored. Despite higher EtCO(2), conversion to open was mainly because of difficult repair. A randomized trial is necessary to assess the effect of thoracoscopy on ventilation and recurrences.

Membranas de látex natural na herniorrafia diafragmática experimental em cães / Natural latex membranes in experimental diaphragmatic hernioplasty in dogs

Utilizaram-se membranas de látex para o reparo de defeitos diafragmáticos em 12 cães, distribuídos em três grupos: no G1 utilizou-se membrana comercial e no G2, membrana experimental. O G3 foi usado como controle. Foi feito um defeito retangular no músculo diafragma, com 4cm de comprimento por 3cm de largura, que nos grupos G1 e G2 foi substituído pelo implante da membrana de látex correspondente. Os animais foram avaliados por estudo radiográfico, hemograma, videocirurgia e análise histológica. Os resultados mostraram que a membrana de látex do grupo 2 foi eficiente na correção de defeito no diafragma, promovendo a reparação e neovascularização tecidual local, sem causar rejeição durante o período de avaliação.

Latex membranes were experimentally used to repair diaphragmatic defects in 12 dogs, distributed in 3 groups. In group 1, a commercial membrane was used, and in group 2, an experimental membrane. Group 3, animals were used as control. A rectangular defect (4cm in length and 3cm in width) was surgically performed in the diaphragm muscle, which was substituted, in group 1 and 2, by the implantation of corresponding latex membrane. The animals were evaluated by radiography, blood count, video-surgery, and histologic study. Results showed that the latex membrane of group 2, were efficient in the correction of the defect in the diaphragm, promoting the repairing and local neovascularization, without causing rejection during the evaluated period.

N-terminal-pro-B type natriuretic peptide as a useful tool to evaluate pulmonary hypertension and cardiac function in CDH infants.

OBJECTIVE: In congenital diaphragmatic hernia (CDH) the severity of pulmonary hypertension (PH) is considered, by several authors, determinant of clinical outcome. Plasmatic N-terminal-pro-B type natriuretic peptide (NT-proBNP) might be useful in diagnosis and management of PH in newborns, although its interest in CDH infants remains to be defined. Early NT-proBNP levels were assessed in CDH infants and correlated with cardiovascular echocardiographic parameters. PATIENTS AND METHODS: 28 newborns, CDH and age-matched controls were enrolled in a prospective study. Clinical condition, NT-proBNP plasmatic levels, echo parameters of PH and biventricular function were assessed at 24 h after delivery as well as survival outcome. RESULTS: Estimated mean pulmonary pressure and NT-proBNP were significantly higher in CDH than control infants. NT-proBNP significantly correlated with estimated pulmonary artery pressure, right ventricular Tei index, and tricuspid E/A ratio. Additionally, we found that CDH infants with NT-proBNP >11,500 pg/ml experienced a worse prognosis. CONCLUSIONS: We demonstrated that PH is associated with NT-proBNP elevation and diastolic impairment in CDH infants. Early elevations in NT-proBNP levels seem to alert for a subset of CDH infants with worse prognosis.

Serum monocyte chemotactic protein-1 levels in congenital diaphragmatic hernia.

To measure serum monocyte chemotactic protein-1 (MCP-1) in patients with congenital diaphragmatic hernia (CDH) and investigate its relationship to the development of persistent pulmonary hypertension (PPH). Serum MCP-1 was measured in 13 neonates with high risk for CDH at the time of diagnosis and postoperatively, and in five age-matched controls using an ELISA system. The 13 CDH subjects were divided into four groups according to the presence of PPH and outcome. Group I (severe-pre group): subjects with severe PPH who died prior to surgery (n = 5); Group II (mild-pre group): subjects with mild PPH controlled by medications (n = 8); Group IIa (severe-post group): subjects who subsequently developed severe PPH postoperatively and died (n = 3); and Group IIb (mild-post group): subjects who continued to have mild PPH controlled by medications. We also examined nitrofen-induced hypoplastic lungs from five rat fetuses with CDH and five control lung specimens for MCP-1 using immunohistochemistry. Mean serum MCP-1 in Group I was (1038.0 +/- 95.8 pg/ml), which was significantly higher than Group II (444.9 +/- 39.7 pg/ml) (P < 0.0001) and controls (147.3 +/- 11.3 pg/ml) (P < 0.0001). Postoperatively, Group IIa was significantly higher than Group IIb from 24 to 120 h postoperatively (P < 0.001). In Group IIb serum MCP-1 did not rise at all between 24 and 120 h postoperatively. Hypoplastic fetal rat CDH lungs had strong expression of MCP-1 compared with control lungs. Up-regulated expression and high circulating levels of MCP-1 in CDH patients with PPH suggest that MCP-1 may play a role in the development of PPH in CDH.

Administration of prenatal betamethasone suppresses the adrenal-hypophyseal axis in newborns with congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a condition that is characterized by pulmonary hypoplasia and pulmonary hypertension. Prenatal betamethasone often is administered to fetuses with CDH to improve pulmonary function. In this study, the authors investigate the possible role of the adrenal-hypophyseal axis in CDH in an animal model and subsequently in human infants with CDH. METHODS: Twin fetal sheep underwent creation of DH or a sham thoracotomy, and levels of plasma and lung ACTH and plasma cortisol were compared. For the human studies, plasma levels of ACTH, cortisol, and DHEA were measured in cord blood samples collected from 9 CDH (5 that received prenatal betamethasone) and compared with those of 14 normal newborns. In both studies, ACTH and cortisol levels were determined by radioimmunoassay (RIA). Human (DHEA) levels were determined by ELISA. RESULTS: Plasma ACTH and cortisol levels were elevated in fetal DH sheep compared with sham-operated controls; however, levels of ACTH in lung tissues were not different. Human newborns with CDH who have been exposed to prenatal steroids have significantly lower plasma ACTH, cortisol, and DHEA levels than normal newborns and CDH newborns not exposed to prenatal betamethasone. CONCLUSIONS: In an ovine model of CDH, the adrenal-hypophyseal axis appears up-regulated in DH fetuses compared with sham-operated animals. Conversely, the adrenal-hypophyseal axis in human CDH newborns appears normal but is suppressed by the administration of prenatal betamethasone.

Factors influencing survival in newborns with congenital diaphragmatic hernia: the relative role of timing of surgery.

PURPOSE: Controversy persists regarding the factors influencing survival in patients with congenital diaphragmatic hernia (CDH), in particular, the role of timing of surgery. The authors therefore sought to determine such factors and to assess the relative role of timing of surgery on outcome. METHODS: All CDH newborns 1991 through 2002 (n = 111) were divided into those undergoing repair before ("early" n = 35), or after ("late" n = 76) 48 hours. A multivariate analysis was performed to determine the relative impact of various factors on survival rate. RESULTS: Overall survival rate was 64%. There was no effect on survival of heart rate, temperature, systolic blood pressure, age, extracorporeal membrane oxygenation use, mesh use, infections, or intracranial hemorrhage, and there was no difference between early (68%) or late (62%) repair (P =.2). Initial pCO2 greater than 50, pO2 less than 40, cardiac defects, or renal failure significantly decreased survival rate. CONCLUSIONS: Significant factors influencing survival rate in patients with CDH include cardiac defects, renal failure, and the initial blood gases and not the timing of surgery. CDH repair should be based on the optimization of clinical parameters as opposed to a specific time period to improve outcome.

Impact of a current treatment protocol on outcome of high-risk congenital diaphragmatic hernia.

BACKGROUND: There is considerable debate regarding the optimal management of congenital diaphragmatic hernia (CDH) in high-risk infants (those cases presenting with respiratory distress within 2 hours of birth or those diagnosed prenatally). The aim of this study was to analyze patient outcomes using a new treatment protocol for CDH in a tertiary care non-extracorporeal membrane oxygenation (ECMO) neonatal unit. METHODS: The records of 78 consecutive neonates with CDH presenting to Bambino Gesù Children's Hospital from 1996 to 2001 were analyzed retrospectively. Of these infants, 70 high-risk patients were identified (prenatal diagnosis or respiratory distress requiring intubation and assisted ventilation within 2 hours after birth), regardless of associated anomalies, medical condition on presentation, or degree of pulmonary hypoplasia. A prenatal diagnosis was made in 46 of 70 (66%) patients. Associated lethal malformations were present in 6 of the children (8.5%). The patients were placed in 3 historical groups: group 1, 19 patients from 1996 to 1997, group 2, 22 patients from 1998 to 1999, and group 3, 29 patients from 2000 to 2001. In the first 2 groups, a new protocol was introduced using inhaled nitric oxide (iNO) and high-frequency oxygen ventilation (HFOV). In the third group, gentle ventilation and permissive hypercarbia were also used routinely. Mortality and severe morbidity--defined as O2 requirement at discharge, need for a tracheostomy, neurologic impairment, or bilateral hearing loss-were evaluated when the patients were at 6 months old. Univariate analysis was performed. RESULTS: The 3 groups were comparable with respect to predictive risk factors such as side of hernia, prenatal diagnosis, polyhydramnios, stomach and liver in the thorax, associated lethal malformations, and patch. Overall survival rate significantly increased from 47% (9 of 19) in group 1 and 50% (11 of 22) in group 2 to 90% (26 of 29) in group 3 (P =.02). None of the 19 patients in group 1 had severe morbidity compared with 2 of 22 (9%) patients in group 2 and 2 of 29 (7%) patients in group 3. Hearing loss was observed in 4 patients. Mortality rate and preoperative pneumothorax significantly decreased in group 3 compared with groups 1 and 2 (P =.03 and P =.00, respectively). CONCLUSIONS: (1) The application of new treatment protocol for CDH, using gentle ventilation and permissive hypercarbia, produced a significant increase in survival with concomitant decrease in morbidity. (2) The rate of pneumothorax was significantly decreased by the introduction of permissive hypercarbia and gentle ventilation. (3) As more infants survive CDH without the use of ECMO, severe long-term sequelae of CDH can be recognized in these children.

Is adrenomedullin involved in the pathophysiology of persistent pulmonary hypertension of the newborn?

Although adrenomedullin (ADM) is a potent vasodilating peptide reported to play a possible role in the mechanisms of fetal lung differentiation and maturation, the ADM blood level in fetuses and in neonates with persistent pulmonary hypertension (PPHN) and pulmonary hypoplasia is not known. Therefore, we examined 15 patients with PPHN: 10 with congenital diaphragmatic hernia, four with congenital cystic adenomatoid malformation of the lung, and one with misalignment of pulmonary vessels with alveolar capillary dysplasia. Eight surgical patients with neonatal conditions such as intestinal atresia served as controls. Blood samples were drawn from the umbilical artery and vein at birth, and arterial blood was drawn from patients with PPHN on the 3rd and 6th days after birth. Plasma levels of ADM were measured by radiometric assay. Plasma levels of ADM in the umbilical artery and vein were elevated in patients with PPHN compared with controls, and in all groups the levels in the umbilical vein were higher than those in the umbilical artery. The arterial levels in patients with poor prognoses were elevated on the 3rd and 6th days after birth compared with those in survivors. These results indicate that ADM may be involved in the pathophysiology of PPHN and in the mechanisms of lung differentiation and/or maturation.

Increased levels of circulating adhesion molecules in neonates with congenital diaphragmatic hernia complicated by persistent pulmonary hypertension.

The aim of this study was to determine circulating levels of adhesion molecules in serum from patients with congenital diaphragmatic hernia (CDH) to investigate the relationship between soluble ICAM-1, ELAM-1, and VCAM-1 liberated by activated vascular endothelium and the development of persistent pulmonary hypertension (PPH) in patients with CDH. We measured serum levels of ICAM-1, ELAM-1, and VCAM-1 in 20 high-risk neonates with CDH at the time of diagnosis (11 with PPH and 9 without PPH) and 7 age-matched controls using ELISA system. We further examined the lungs of 5 patients with CDH complicated by PPH who died during resuscitation and stabilization, and three control lung specimens for the expression of adhesion molecules using immunohistochemistry. The mean serum ICAM-1 levels in CDH patients with PPH (227.0+/-98.9 ng/ml) were increased compared with levels in CDH patients without PPH (140.29+/-37.4 ng/ml; p<0.05) and controls (130.0+/-23.8 ng/ml; p<0.05). Mean serum ELAM-1 levels in CDH patients with PPH (116.5+/-19.2 ng/ml) were significantly increased compared with levels in CDH patients without PPH (79.3+/-27.9 ng/ml; p<0.01) and controls (58.4+/-14.5 ng/ml; p<0.001). Mean serum VCAM-1 levels in CDH patients with PPH (1596.9+/-460.4 ng/ml) were significantly higher compared with levels in CDH patients without PPH (1069.3+/-444.6 ng/ml; p<0.01) and controls (838.0+/-171.2 ng/ml; p<0.001). But serum adhesion molecule levels in CDH patients without PPH were no different from controls statistically. Pulmonary vascular endothelial cells from CDH lung with PPH had strong expression of adhesion molecules compared with controls. Up-regulated expression of adhesion molecules on the endothelium of pulmonary vessels and high circulating levels of adhesion molecules in CDH patients with PPH suggest that adhesion molecules may play a role in the development of PPH in CDH.