Jeffrey D. Merrill

Dysfunction of pulmonary surfactant in chronically ventilated premature infants

Infants of <30 wk gestation often require respiratory support for several weeks and may develop bronchopulmonary dysplasia (BPD), which is associated with long-term pulmonary disability or death in severe cases. To examine the status of surfactant in infants at high risk for BPD, this prospective study analyzed 247 tracheal aspirate samples from 68 infants of 23–30 wk gestation who remained intubated for 7–84 d. Seventy-five percent of the infants had one or more surfactant samples with abnormal function (minimum surface tension 5.1–21.7 mN/m by pulsating bubble surfactometer), which were temporally associated with episodes of infection (p = 0.01) and respiratory deterioration (p = 0.005). Comparing normal and abnormal surfactant samples, there were no differences in amount of surfactant phospholipid, normalized to total protein that was recovered from tracheal aspirate, or in relative content of phosphatidylcholine and phosphatidylglycerol. Contents of surfactant proteins (SP) A, B, and C, measured in the surfactant pellet by immunoassay, were reduced by 50%, 80%, and 72%, respectively, in samples with abnormal surface tension (p ≤ 0.001). On multivariable analysis of all samples, SP-B content (r = −0.58, p < 0.0001) and SP-C content (r = −0.32, p < 0.001) were correlated with surfactant function. We conclude that most premature infants requiring continued respiratory support after 7 d of age experience transient episodes of dysfunctional surfactant that are associated with a deficiency of SP-B and SP-C.

Morphine enhances HIV infection of neonatal macrophages.

Perinatal transmission of HIV accounts for almost all new HIV infections in children. There is an increased risk of perinatal transmission of HIV with maternal illicit substance abuse. Little is known about neonatal immune system alteration and subsequent susceptibility to HIV infection after morphine exposure. We investigated the effects of morphine on HIV infection of neonatal monocyte-derived macrophages (MDM). Morphine significantly enhanced HIV infection of neonatal MDM. Morphine-induced HIV replication in neonatal MDM was completely suppressed by naltrexone, the opioid receptor antagonist. Morphine significantly up-regulated CCR5 receptor expression and inhibited the endogenous production of macrophage inflammatory protein-1β in neonatal MDM. Thus, morphine, most likely through alteration of β-chemokines and CCR5 receptor expression, enhances the susceptibility of neonatal MDM to HIV infection, and may have a cofactor role in perinatal HIV transmission and infection.

Risk factors for extended-spectrum beta-lactamase-producing Enterobacteriaceae in a neonatal intensive care unit.

Risk factors for colonization or infection with extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae during an outbreak in a neonatal intensive care unit (NICU) included low gestational age and exposure to third-generation cephalosporins. We also reviewed the existing medical literature regarding the clinical epidemiology of ESBLs in NICUs .

Plasma Biomarkers of Oxidative Stress: Relationship to Lung Disease and Inhaled Nitric Oxide Therapy in Premature Infants

OBJECTIVES. Inhaled nitric oxide treatment for ventilated premature infants improves survival without bronchopulmonary dysplasia. However, there has been no information regarding possible effects of this therapy on oxidative stress. We hypothesized that inhaled nitric oxide therapy would not influence concentrations of plasma biomarkers of oxidative stress. PATIENTS AND METHODS. As part of the Nitric Oxide Chronic Lung Disease Trial, we collected blood samples at specified intervals from a subpopulation of 100 infants of <1250 g birth weight who received inhaled nitric oxide (20 ppm, weaned to 2 ppm) or placebo gas for 24 days. Plasma was assayed for total protein and for 3-nitrotyrosine and carbonylation by using immunoassays. RESULTS. The demographic characteristics and primary outcome for the infants were representative of the entire group of infants who were in the Nitric Oxide Chronic Lung Disease Trial. For all infants at baseline, before receiving study gas, the concentration of total protein was inversely correlated with the respiratory severity score, and plasma carbonyl was positively correlated with severity score, supporting an association between oxidative stress and severity of lung disease. Infants who survived without bronchopulmonary dysplasia had 30% lower protein carbonylation concentrations at study entry than those who had an adverse outcome. At each of 3 time points (1–10 days) during exposure to study gas, there were no significant differences between control and treated infants for concentrations of plasma protein, 3-nitrotyrosine, and carbonylation. CONCLUSIONS. Inhaled nitric oxide treatment for premature infants who are at risk for bronchopulmonary dysplasia does not alter plasma biomarkers of oxidative stress, which supports the safety of this therapy.

Surfactant Function and Composition in Premature Infants Treated With Inhaled Nitric Oxide

OBJECTIVES. We hypothesized that inhaled nitric oxide treatment of premature infants at risk for bronchopulmonary dysplasia would not adversely affect endogenous surfactant function or composition. METHODS. As part of the Nitric Oxide Chronic Lung Disease Trial of inhaled nitric oxide, we examined surfactant in a subpopulation of enrolled infants. Tracheal aspirate fluid was collected at specified intervals from 99 infants with birth weights <1250 g who received inhaled nitric oxide (20 ppm, weaned to 2 ppm) or placebo gas for 24 days. Large-aggregate surfactant was analyzed for surface activity with a pulsating bubble surfactometer and for surfactant protein contents with an immunoassay. RESULTS. At baseline, before administration of study gas, surfactant function and composition were comparable in the 2 groups, and there was a positive correlation between minimum surface tension and severity of lung disease for all infants. Over the first 4 days of treatment, minimum surface tension increased in placebo-treated infants and decreased in inhaled nitric oxide–treated infants. There were no significant differences between groups in recovery of large-aggregate surfactant or contents of surfactant protein A, surfactant protein B, surfactant protein C, or total protein, normalized to phospholipid. CONCLUSIONS. We conclude that inhaled nitric oxide treatment for premature infants at risk of bronchopulmonary dysplasia does not alter surfactant recovery or protein composition and may improve surfactant function transiently.

Prior Treatment History and Its Impact on Criminal Recidivism

This study examines the hypothesis that treatment is a cumulative process; that is, treatment success is best viewed in terms of the patients entire treatment history, rather than the index treatment episode. Three-hundred and eight patients with a primary heroin addiction were studied for 2 years posttreatment. Using posttreatment arrests as the dependent variable, the effects of prior treatment were assessed. Those with six or more prior treatment episodes and who had been in treatment for 12 or more months during the most recent episode averaged only 0.2 arrests in the 2 years posttreatment, while those with no prior treatment, but 12 or more months in the recent treatment averaged 0.88 arrests. Logistic analysis found that each prior treatment reduced the probability of a posttreatment arrest by 25%. Based on a linear regression, patients with six or more treatments prior treatments averaged half the number of posttreatment arrests as someone with no treatments before the index episode.

Characterization of natural killer and antibody-dependent cellular cytotoxicity of preterm infants against human immunodeficiency virus-infected cells.

The odds risk of vertical transmission of human immunodeficiency virus(HIV) to preterm infants is almost four times that of term infants and may relate to maternal and neonatal factors. We characterized the competence of early nonspecific cellular immunity, namely natural killer cytotoxicity (NKC) and antibody-dependent cellular cytotoxicity (ADCC), of peripheral blood mononuclear cells (PBMC) from preterm (n = 20) and term neonates(n = 28) versus adult controls against a T cell line infected with the human T cell lymphotrophic virus-IIIB using a chromium-51 release assay. PBMC from term neonates exhibited levels of NKC activity equal to adults against HIV-infected targets, yet the NKC capacity of preterm neonatal PBMC was significantly diminished. The ADCC activity of both term and preterm neonatal PBMC against HIV-infected targets was significantly less than that of adult PBMC. Overnight stimulation of a subset of samples with IL-12 augmented the NKC activity of both infant groups and adults, whereas the ADCC activity remained unchanged. These findings demonstrate that term neonates are deficient in ADCC against HIV-infected targets, whereas preterm infants are deficient in both NKC and ADCC, which may relate, in part, to the increased risk of transmission of HIV with preterm delivery. In addition, IL-12 has the potential to augment both term and preterm neonatal antiviral defense.

Inflammatory markers and mediators in tracheal fluid of premature infants treated with inhaled nitric oxide.

OBJECTIVE. We compared serial measurements of inflammatory mediators and markers in infants treated with inhaled nitric oxide or placebo to assess the effects of inhaled nitric oxide therapy on lung inflammation during bronchopulmonary dysplasia. We investigated relationships between respiratory severity scores and airway concentrations of inflammatory markers/mediators. METHODS. As part of the Nitric Oxide (to Prevent) Chronic Lung Disease trial, a subset of 99 infants (52 placebo-treated infants and 47 inhaled nitric oxide-treated infants; well matched at baseline) had tracheal aspirate fluid collected at baseline, at 2 to 4 days, and then weekly while still intubated during study gas treatment (minimum of 24 days). Fluid was assessed for interleukin-1β, interleukin-8, transforming growth factor-β, N-acetylglucosaminidase, 8-epi-prostaglandin F2α, and hyaluronan. Results were normalized to total protein and secretory component of immunoglobulin A. RESULTS. At baseline, there was substantial variability of each measured substance and no correlation between tracheal aspirate fluid levels of any substance and respiratory severity scores. Inhaled nitric oxide administration did not result in any time-matched significant change for any of the analytes, compared with the placebo-treated group. There was no correlation between any of the measured markers/mediators and respiratory severity scores throughout the 24 days of study gas administration. In the posthoc analysis of data for inhaled nitric oxide-treated infants, there was a difference at baseline in 8-epi-prostaglandin F2α levels for infants who did (n = 21) and did not (n = 26) develop bronchopulmonary dysplasia at postmenstrual age of 36 weeks. CONCLUSIONS. Inhaled nitric oxide, as administered in this study, seemed to be safe. Its use was not associated with any increase in airway inflammatory substances.

Urinary Metabolites of Oxidative Stress and Nitric Oxide in Preterm and Term Infants

Background: Many neonatal diseases have been associated with oxidative stress and altered nitric oxide status. Objective: To determine the effects of clinical interventions on the levels of urinary peroxides, a marker of oxidative stress, and urinary nitrate/nitrites, indices of nitric oxide production and metabolism, in the first 72 h of life in premature infants. Methods: A single, spot urine sample was collected from 82 premature and 20 healthy term infants within the first 72 h of life. The peroxide levels were quantified using a fluorometric method, and nitrate/nitrite levels were quantified by chemiluminescence. Results: Premature infants had a median peroxide level of 10.0 µmol/mmol creatinine (Cr) (interquartile range 4.8–20.0 µmol/mmol Cr). These values were significantly higher than term infants (median 5.0 µmol/mmol Cr, interquartile range 2.7–10.0 µmol/mmol Cr). Urinary nitrate/nitrite levels were not significantly different between preterm (220.5 µmol/mmol Cr, interquartile range 161–287 µmol/mmol Cr) and healthy term infants (244 µmol/mmol Cr, interquartile range 194–316 µmol/mmol Cr). For urinary peroxides, infants on TPN had significantly higher urinary peroxide levels than infants who were not on TPN at the time of urine collection (p = 0.006). Administration of indomethacin was associated with lower levels of urinary nitrate/nitrites (p = 0.0003). Both effects remained significant after controlling for gestational age, degree of respiratory distress and day of urine collection. Conclusion: Monitoring the level of both peroxides and nitrate/nitrite may offer added information about the degree of oxidative stress experienced by a newborn but needs to account for clinical and therapeutic interventions.

Pilot trial of late booster doses of surfactant for ventilated premature infants.

Objective:Many premature infants at risk for bronchopulmonary dysplasia experience episodes of surfactant dysfunction with reduced surfactant protein B (SP-B). In this study, we investigated the safety and responses to booster doses of surfactant.Study Design:A total of 87 infants, 500 to 1250 g birth weight, who were ventilated at 7 to 10 days received 2 or 3 doses of Infasurf (Calfactant, Forest Pharmaceuticals, St Louis, MO, USA) within a 1-week period.Result:For 184 doses, occurrence rates of transient bradycardia (13) and plugged endotracheal tube (5) were low, and no other adverse effects were noted. Treatment transiently improved the respiratory severity score (FiO2 × mean airway pressure), SP-B content (+75%) and surface properties of isolated surfactant. Levels of eight proinflammatory cytokines in tracheal aspirate were interrelated and unchanged from baseline after surfactant treatment.Conclusion:Booster doses of surfactant for premature infants with lung disease are safe and transiently improve respiratory status as well as composition and function of endogenous surfactant.