George T. El-Ferzli

A Potential Biomarker in the Cord Blood of Preterm Infants Who Develop Retinopathy of Prematurity

Preterm infants are at risk of developing sepsis, necrotizing enterocolitis (NEC), chronic lung disease (CLD), and retinopathy of prematurity (ROP). We used high-throughput mass spectrometry to investigate whether cord blood proteins can be used to predict development of these morbidities. Cord blood plasma from 44 infants with a birth weight of <1500 g was analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF). Six infants developed ROP ≥stage II, 10 CLD, three sepsis, and one NEC. We detected 814 protein signals representing 330 distinct protein species. Nineteen biomarkers were associated with development of ≥stage II ROP [false-discovery rate (FDR) <5%] and none with CLD. Several proteins with molecular weight (Mr) 15–16 kD and pI 4–5 were detected with increased abundance in infants with ROP, while similar Mr proteins with pI 7–9 were less abundant in these patients. Sodium dodecylsulfate–polyacrylamide gel electrophoresis (SDS-PAGE) and sequence analysis identified these proteins as α-, β-, and γ-globin chains. Partial deamidation of Asn139 in β-globin chains was observed only in the pI 4–5 proteins. We conclude that there are several promising biomarkers for the risk of ROP. Deamidation of globin chains is especially promising and may indicate underlying prenatal pathologic mechanisms in ROP. Validation studies will be undertaken to determine their clinical utility.

The Value of Paco2 in Relation to Outcome in Congenital Diaphragmatic Hernia

BACKGROUND Postnatal assessment of disease severity is critical for analysis of mortality rates and development of future interventions in congenital diaphragmatic hernia (CDH). OBJECTIVE The objective of this study was to stratify the risk of mortality based on arterial Paco 2. METHODS Retrospective analysis of infants (n = 133) with CDH admitted to a regional extracorporeal membrane oxygenation (ECMO) center in two different periods: period I (1987-1996; n = 46) and period II (2002-2010; n = 87). RESULTS The mortality rate (37%) was similar in both periods (p = 0.98). Paco 2 < 60 mm Hg in the first arterial blood gas (ABG) was an independent predictor of survival in both periods (p = 0.03). The predicted survival rate was 84% if initial Paco 2 was < 55 mm Hg. For infants with initial Paco 2 > 55 mm Hg treated with ECMO (n = 83), the predicted survival rate was 11% if the Paco 2 was > 88 mm Hg before the initiation of ECMO. CONCLUSION Paco 2, a surrogate of lung hypoplasia, may be useful for risk stratification in CDH. Paco 2 < 60 mm Hg in the first ABG may indicate milder pulmonary hypoplasia. A Paco 2 > 80 mm Hg in the first ABG and/or before ECMO may indicate severe pulmonary hypoplasia.

Nitric Oxide Administration Using an Oxygen Hood: A Pilot Trial

Background We have shown earlier that inhaled nitric oxide (iNO) administered by oxygen hood reduces pulmonary hypertension in an animal model (J Perinatol 2002; 22:50-6). Our objective in this study was to determine feasibility of iNO by oxygen hood in neonates with elevated alveolar-arterial oxygen gradients (A-aDO2). Methods/Principal Findings Masked randomized controlled pilot trial. Inclusion criteria were: gestation≥34 weeks, age<7 days, with post-ductal arterial line, and A-aDO2 400–600. Infants were randomized to study gas (iNO 20 ppm or equivalent O2 flow) for 1 hr which was then weaned over the next 4 hours. Primary outcome was PaO2 one hour post-randomization. Four infants each were randomized to iNO or O2 (controls). Two of the four infants given iNO had an increase in PaO2 of >100 torr, while oxygenation was unchanged in the controls. Methemoglobinemia and other adverse effects were not noted in any infant. Environmental levels of NO and NO2 were minimal (<1 ppm) at >0.3 m from the hood. Conclusions Administration of iNO by oxygen hood is feasible. Larger randomized controlled trials are required to measure the efficacy and determine an appropriate target population for this technique. Trial Registration ClinicalTrials.gov NCT00041548

ABO Blood Group Is Associated with Response to Inhaled Nitric Oxide in Neonates with Respiratory Failure

Background Inhaled nitric oxide (iNO) reduces death or need for extracorporeal membrane oxygenation (ECMO) in infants with persistent pulmonary hypertension of the newborn (PPHN). However, the response to iNO is variable and only 50–60% of infants demonstrate a response to iNO. It is not known why only some infants respond to iNO. Adults and children with blood groups B or AB do not respond as well to iNO as those with blood groups O/A. Methods/Principal Findings To determine if blood group was associated with iNO response in newborn infants, a retrospective medical record review was done of infants admitted to a regional NICU from 2002-9 with a diagnosis of PPHN. Data were collected during the first twelve hours post-initiation of treatment. Of 86 infants diagnosed with PPHN, 23 infants had blood group A [18 received iNO], 21 had group B [18 with iNO], 40 had group O [36 with iNO], and 2 had group AB [both received iNO]. Change in PaO2/FiO2 was less in infants with blood group A, of whom less than half were responders (ΔPaO2/FiO2>20%) at 12 h versus 90% of infants with either O or B. Race, sex, birth weight, gestational age, Apgar scores at 1 and 5 minutes, and baseline PaO2/FiO2 were similar among groups. Outcomes including need for ECMO, death, length of ventilatory support, length of iNO use, and hospital stay were statistically not different by blood groups. Conclusions/Significance Our results indicate that blood group influences iNO response in neonates. We hypothesize that either there is genetic linkage of the ABO gene locus with vasoregulatory genes, or that blood group antigens directly affect vascular reactivity.

Evaluation of a pumpless lung assist device in hypoxia-induced pulmonary hypertension in juvenile piglets.

Persistent pulmonary hypertension is an important cause of mortality and morbidity in term infants. The lung assist device (LAD) is a novel, pumpless, low-resistance extracorporeal oxygenator to supplement mechanical ventilation. The LAD may be associated with fewer complications compared with conventional extracorporeal membrane oxygenation. The objective was to test the feasibility and efficacy of the LAD in juvenile piglets with hypoxia-induced pulmonary hypertension. Pulmonary hypertension was acutely induced by hypoxia in six 3- to 4-wk-old acutely instrumented and intubated piglets. The LAD was attached between a carotid artery and jugular vein. Gas exchange and hemodynamic variables, including pulmonary arterial pressure (PAP) and cardiac output (CO), were measured. Successful LAD cannulation was achieved without complications in all animals. Extracorporeal shunt flow through the device averaged 18% of CO. The LAD achieved oxygen delivery of 20% of total oxygen consumption. PAP was reduced by 35% from 28 ± 5 to 18 ± 4 mm Hg (p < 0.05) and systemic Pao2 increased by 33% from 27 ± 2 to 36 ± 4 mm Hg (p < 0.05). Other hemodynamic variables remained stable. The novel LAD shows feasibility and efficacy in improving gas exchange and reducing PAPs in a juvenile animal model of hypoxia-induced pulmonary hypertension.

A Nitric Oxide-Releasing Self-Assembled Peptide Amphiphile Nanomatrix for Improving the Biocompatibility of Microporous Hollow Fibers.

Oxygenators are critical components of extracorporeal circuits used frequently in cardiopulmonary bypass and intensive care, but platelet activation and induction of a complex inflammatory response are usually observed with their use. To improve the biocompatibility of oxygenators, we developed a nitric oxide (NO)-releasing, self-assembled peptide amphiphile nanomatrix. The nanomatrix formed a homogenous coating over the microporous hollow fibers as demonstrated by scanning electron microscopy. We quantitated platelet adhesion to the artificial fibers by measuring absorbance/area of platelets (Abs/A; nm/m2) using acid phosphatase assay. There was a 17-fold decrease in platelet adhesion to the nanomatrix (Abs/A = 0.125) compared with collagen controls (Abs/A = 2.07; p < 0.05) and a 22-fold decrease compared with uncoated fibers (Abs/A = 2.75; p < 0.05). Importantly, the nanomatrix coating did not impede oxygen transfer in water through coated fiber modules (p > 0.05) in a benchtop test circuit at different flow rates as estimated by change in partial pressure of oxygen in relation to water velocity through fibers. These findings demonstrate the feasibility of coating microporous hollow fibers with a NO-releasing self-assembled amphiphile nanomatrix that may improve the biocompatibility of the hollow fibers without affecting their gas exchange capacity.

A Pumpless Lung Assist Device Reduces Mechanical Ventilation-Induced Lung Injury in Juvenile Piglets

Respiratory failure is a major contributor to mortality and morbidity in newborn infants. The lung assist device (LAD) is a novel gas exchange device that supplements mechanical ventilation. The objective is to test the effect of the LAD on pulmonary histopathology in juvenile piglets with acute lung injury caused by saline lung lavage (SLL) followed by intermittent mandatory ventilation (IMV). Three- to 4-wk-old piglets were randomized to no intervention (control group), SLL alone (SLL group), SLL + IMV (IMV group), or SLL + IMV + LAD (LAD group) (n = 6 per group). The carotid artery and jugular vein were cannulated and an arteriovenous circuit completed, and the LAD was inserted into this circuit. Gas exchange via the LAD was initiated by passage of 100% oxygen over the blood-carrying hollow fibers of the LAD. Hemodynamic variables were recorded. Mechanical ventilation was systematically weaned. Lung histology was scored by two observers masked to treatment group. There were no differences in hemodynamic variables between the study groups. There was a significant increase in the total lung injury score in the IMV group compared with the LAD group. The novel pumpless low-resistance LAD has shown feasibility and potential to decrease ventilator-induced lung injury in a juvenile animal model.

Development and Validation of the Proxy-Reported Pulmonary Outcomes Scale for Premature Infants

OBJECTIVE Test the feasibility of using a bedside nurse-reported tool (Proxy-Reported Pulmonary Outcome Scale, PRPOS) for evaluating the severity of bronchopulmonary dysplasia (BPD) by assessing functional, disease-related measures. STUDY DESIGN Bedside nurses tested the 26-item instrument by observing preterm infants (23-30 weeks at birth) at 36 to 37(4/7) weeks postmenstrual age before, during, and after a care time. We analyzed item reliability, validity, and model fit to determine the six items to include in the final measurement tool. RESULT We completed assessments on 188 preterm infants. The frequency of an abnormal PRPOS item score increased with increasing National Institute of Child Health and Development (NICHD) BPD category. The six-candidate items produced an internally consistent scale. Addition of the NICHD BPD classification increased reliability moderately; addition of feeding items decreased reliability. The PRPOS score correlated with postmenstrual age at discharge. Infants discharged on oxygen or diuretics had higher median PRPOS scores than did infants who were not prescribed those therapies. CONCLUSION The PRPOS is an internally consistent, proxy-reported measure of respiratory function in premature infants, based on observable, functional performance measures. Initial testing demonstrates known-groups validity and ongoing testing can assess predictive validity.

137 A NOVEL GAS EXCHANGE ASSIST DEVICE IN JUVENILE ACUTE LUNG INJURY.

Background Respiratory distress syndrome is an important cause of mortality and morbidity in newborn infants. The lung assist device (LAD) is a novel gas exchange device that supplements mechanical ventilation. The LAD (MC3 Inc., Ann Arbor, MI) is a pumpless, low-pressure extracorporeal oxygenator. The LAD has reproducibly improved mortality in adult animals. In an earlier study, we demonstrated the feasibility of the LAD in improving gas exchange in juvenile piglets. Objective To test the effect of the LAD on pulmonary histopathology and mechanics in juvenile piglets with acute lung injury caused by saline lung lavage (SLL) followed by mechanical ventilation (IMV). Design/Methods Three- to 4-week-old acutely instrumented and intubated piglets were randomized (n = 4 each) to no further intervention (normal), SLL (30 cc/kg 3 4), SLL + IMV 3 6 hrs or SLL + IMV + LAD 3 6 hrs. The LAD was attached between the carotid artery and jugular vein. Flow through the device, gas exchange, pulmonary arterial pressure, hemodynamic variables, and cardiac output were measured with and without flow through the device. Mechanical ventilation was systemically weaned in both study groups to keep PaCO2 = 35-45 mm and PaO2 = 50-60 mm Hg. Lung histology was scored by an observer masked to treatment group following a standardized system for lung injury scoring. Data were compared by ANOVA to detect differences between the groups. Results There was no difference in hemodynamic variables between the study groups. Mechanical ventilation could be successfully weaned in the SLL + IMV + LAD group. Adequate flow (25-40% of cardiac output) could be achieved through the LAD. There was a significant increase in the total lung injury score in the SLL + IMV group (p = .03) but the SLL + IMV + LAD group was comparable to both control groups. Prolonged mechanical ventilation significantly increased inflammation (p = .02) and airway injury (p < .01), while there were no differences in hemorrhage, septal thickening, and formation of hyaline membranes. Conclusions These results demonstrate the feasibility and potential of a novel pumpless low-pressure gas exchange assist device to decrease ventilator-induced lung injury in a neonatal animal model.

409 A NOVEL GAS EXCHANGE ASSIST DEVICE IN A MODEL OF NEONATAL PULMONARY HYPERTENSION

Introduction Respiratory failure and persistent pulmonary hypertension are important causes of mortality in term infants. Extracorporeal membrane oxygenation reduces mortality but is associated with morbidity. The lung assist device (LAD) is a novel gas exchange device that supplements mechanical ventilation. LAD (MC3 Inc., Ann Arbor, MI) is a pumpless, low pressure extracorporeal oxygenator. It has improved gas exchange in adult animals. Purpose To test the feasibility of the LAD in juvenile piglets with hypoxia-induced pulmonary hypertension. Methods The LAD was attached between the carotid artery and jugular vein of 4-week-old acutely instrumented piglets (n = 3). Pulmonary hypertension was acutely induced by hypoxia (FiO2 = 10%). Gas exchange, pulmonary pressure, hemodynamic variables, and cardiac output were measured with and without flow through the device. Results Successful LAD cannulation was achieved in all 3 animals with no complications. The LAD increased PaO2 from 26 mm Hg (pre-device) to 530 mm Hg (post-device) and decreased PaCO2 from 45 mm Hg (pre-device) to 5 mm Hg (post-device) (n = 2). In the three animals, systemic arterial pressure decreased by 1-9%, cardiac output remained stable, and hematocrit decreased by 1-10%. Acidosis developed in one animal. In one animal, pulmonary arterial pressures decreased by 62% (Figure) and systemic oxygenation improved marginally (PaO2 increased by 12%) with initiation of flow through LAD. Conclusion These preliminary results demonstrate the feasibility and potential of a novel pumpless low-pressure gas exchange assist device that is perfused by the cardiac output to maintain perfusion, improve gas exchange, and decrease pulmonary hypertension.