Correlations between oxygen and positive pressure exposure in the neonatal intensive care unit and wheezing in preterm infants without bronchopulmonary dysplasia.

BACKGROUND: Oxygen exposure has been associated with increased wheezing and respiratory morbidity after discharge in extremely preterm infants and those with bronchopulmonary dysplasia. More mature preterm infants with less severe disease are also at risk for pulmonary complications, including rehospitalization for respiratory illnesses and wheezing disorders. Our aim was to evaluate associations between respiratory support and morbidity in preterm infants without bronchopulmonary dysplasia. METHODS: A secondary analysis was performed on 300 infants born at 28-34 weeks gestation without bronchopulmonary dysplasia. Exposure included oxygen or positive pressure, (continuous positive airway pressure or mechanical ventilation). The primary outcome was recurrent wheezing. Secondary outcomes were respiratory medications, emergency room visits, and hospitalizations. RESULTS: 50% of infants who received oxygen experienced recurrent wheezing compared to 42.4% of infants who did not (OR 1.15 CI 0.72-1.85 adjusted OR 1.15 CI 0.67-1.98). 51.1% of infants who received positive pressure experienced recurrent wheezing compared to 38.1% who did not (OR 1.57 CI 0.97-2.53 adjusted OR 1.58 CI 0.90-2.77). There were no significant associations between oxygen and positive pressure exposure and any primary or secondary outcomes in the adjusted analyses. CONCLUSIONS: After adjustment for known risk factors the analyses showed no significant associations between oxygen and positive pressure with respiratory morbidity in this population. Further study of infants with mild disease is needed.

Bronchopulmonary dysplasia appropriateness as a surrogate marker for long-term pulmonary outcomes: A Systematic review.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is used to clinically describe the severity of lung disease and to serve as a common surrogate endpoint for long-term pulmonary morbidity in clinical trials, but its performance as a surrogate end-point warrants evaluation. Our objective was to assess real-world performance of BPD as a surrogate marker for long-term pulmonary outcomes. METHODS: We performed a systematic review of large, multi-centered, blinded, randomized control trials to evaluate the use of BPD as a surrogate marker for long-term pulmonary outcomes. Long-term pulmonary outcomes occurred within two years and included measures of hospital utilization, respiratory illness, respiratory medication, and mortality. Direction and magnitude of effect were evaluated using number needed to treat analysis. RESULTS: Five studies were included in our review. Studies varied in definition of BPD and in long-term outcomes measured. Only one study found a significant, consistent risk reduction in both BPD and any long-term pulmonary outcome. Two studies found significant reductions in long-term pulmonary outcomes with a non-significant reduction in BPD. CONCLUSIONS: BPD is an imperfect surrogate marker for long-term pulmonary outcomes. It did not consistently predict the magnitude or direction of the effect of an intervention on longer-term pulmonary outcomes. Furthermore, there was significant variation in the definitions of BPD and in the long-term pulmonary outcomes used. There is a need for future work to identify more predictive surrogate markers and a need for better standardization of assessments of long-term pulmonary outcomes.

Race differences in the association between multivitamin exposure and wheezing in preterm infants.

OBJECTIVE: We aimed to determine whether vitamin D exposure, as estimated by use of multivitamins, is positively or negatively associated with recurrent wheezing in infants born preterm. STUDY DESIGN: This prospective cohort study enrolled 300 infants, born at 28(0/7) to 34(6/7) weeks gestational age, and conducted follow-up at 3-, 6-, 9- and 12-month adjusted age. RESULT: Black (55.9%) and non-black (36.6%) infants experienced recurrent wheezing. Adjusted odds ratios (ORs) for the association between multivitamin exposure at 3 months and recurrent wheezing were 2.15 (95% confidence interval (CI): 0.97, 4.75) for black and 0.43 (95% CI: 0.19, 0.96) for non-black infants with an interaction by race (P=0.003). In lag-effect models, ORs were 2.69 (95% CI: 1.41, 5.14) for black and 0.50 (95% CI: 0.27, 0.92) for non-black infants. CONCLUSION: Differences by race were seen in association between multivitamins and wheezing; population heterogeneity should be considered when evaluating vitamin supplementation.

Multiples and parents of multiples prefer same arm randomization of siblings in neonatal trials.

OBJECTIVE: Although common among Neonatal Intensive Care Units, multiples births are randomized inconsistently within trials, which can impact enrollment, analytical approach and trial outcomes. It is not known what randomization approach (same arm, different arm and independent randomization) is preferred by multiples and their families. STUDY DESIGN: Surveys distributed to parents of multiples and adult multiples addressed the preferences on randomization by eliciting the most desired method and likelihood of enrolling twins for each randomization approach. RESULT: Populations included 209 parents and 321 adult multiples. Seventy-eight percent of parents and 59% of multiples prefer same arm placement of multiples over other methods (both P<0.001), which also had highest likelihood of enrollment among both the groups. CONCLUSION: Parents of multiples and adult multiples prefer placement of multiples into same treatment arm in randomized trials, making such methodology a potential way to optimize consent rates while ethically approaching human subject research.

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 (FiO(2) × 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.

Characterization of cardiorespiratory events following gastroesophageal reflux in preterm infants.

OBJECTIVE: The aim of this study was to characterize cardiorespiratory events in preterm infants after both acid and nonacid gastroesophageal reflux (GER) as detected by pH and multiple intraluminal impedance (MII). STUDY DESIGN: Twelve hour overnight studies were performed in 71 preterm infants (gestational age 29.4±3.0 weeks, birth weight 1319±496 g). Apnea ≥10 s in duration, bradycardia ≤80 b.p.m. and oxygen desaturation ≤85% that occurred within 30 s after the initiation of GER were classified as associated with GER. RESULT: A total of 12,957 cardiorespiratory events and 4164 GER episodes were documented. Less than 3% of all cardiorespiratory events were preceded by GER constituting 3.4% of apnea, 2.8% of oxygen desaturation and 2.9% of bradycardia events. GER did not prolong cardiorespiratory event duration or increase severity. In contrast, GER was associated with a shorter duration of oxygen desaturation events (7.8±4.6 vs 6.3±5.6 s, P<0.05). CONCLUSION: GER is rarely associated with cardiorespiratory events, and has no detrimental effect on cardiorespiratory event duration or severity.

Apnea, bradycardia and desaturation in preterm infants before and after feeding.

OBJECTIVE: A common clinical impression is that both gastroesophageal reflux (GER) and cardiorespiratory events increase after feeding in preterm infants. We aimed to measure objectively the effects of feeding on GER, apnea, bradycardia and desaturations. STUDY DESIGN: We conducted a retrospective review of premature infants with a gestational age of 23 to 37 weeks at birth and a post-conceptional age of 34 to 48 weeks, who were referred for multichannel intraluminal impedance (MII), pH probe and 12-h apnea evaluation. Cardiorespiratory and GER event rates during pre- and post-feeding intervals were compared. RESULT: Thirty-six infants met the inclusion criteria. More GER events occurred after a feed than before (P=0.012). After feeds, reflux was less acidic and higher in the esophagus (P<0.05). In contrast, the rates of apnea, bradycardia and desaturations were not altered by infant feeding. Apnea of >5 s occurred at a median frequency of 0 (range 0 to 3) events per hour before a feed and 0 (0 to 2) events per hour after a feed (P=0.61). CONCLUSION: The frequency, height and pH of GER are significantly altered by feedings in preterm infants. However, the common clinical impression that apnea, bradycardia and desaturations are more prevalent after feeding is not supported.

The effect of inhaled nitric oxide on pulmonary function in preterm infants.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) in preterm infants is associated with impaired alveolar growth, inflammation and airway hyperreactivity. In animal models of BPD, inhaled nitric oxide (NO) improves alveolar growth and inhibits airway smooth muscle proliferation. This study was designed to assess the effect of inhaled NO on resistance and compliance in ventilated preterm infants with evolving BPD. STUDY DESIGN: Expiratory resistance and compliance of the respiratory system were measured in 71 ventilated preterm infants, < or = 32 weeks gestation, randomized to NO (n=34) versus placebo (n=37) for > or = 24 days at 7 to 21 days of life. RESULT: At baseline expiratory resistance (231+/-71 versus 215+/-76 cm H(2)O l(-1) s(-1)) and compliance (0.49+/-0.14 versus 0.53+/-0.13 ml cm H(2)O(-1) kg(-1)) were comparable between placebo and NO groups, respectively. There was no effect of NO on expiratory resistance or compliance at 1 h, 1 week or 2 weeks of study gas administration. CONCLUSION: NO had no short- or medium-term effect on expiratory resistance or compliance in ventilated preterm infants.

Ulcerative colitis in a renal transplant patient with previous Goodpasture disease.

A renal transplant was performed in a 6-year-old boy who developed end stage renal disease (ESRD) after presenting with antiglomerular basement membrane (anti-GBM) disease. At 10 years of age he developed ulcerative colitis while being immunosuppressed with cyclosporin, prednisone, and azothioprine. He had a pancolectomy, and at 14 years has no symptoms of ulcerative colitis or anti-GBM disease. HLA typing revealed that he was homozygous for HLA DR2. The co-occurrence of anti-GBM disease and ulcerative colitis has not previously been described. Although there is no known common etiology for these two autoimmune diseases, we propose that the patient's homozygosity at HLA DR2 may have predisposed him to both.

The murine Niemann-Pick type C lesion affects testosterone production.

We have determined the effects of the Niemann-Pick type C (NPC) lesion, which impairs transport of cholesterol from lysosomes, on the androgenic status of male NPC mice. The mice have low serum testosterone levels resulting from decreased testosterone secretion. Testosterone secretion is reduced in NPC mouse testes incubated with 8-bromo-cAMP, 20 alpha-hydroxycholesterol, and pregnenolone compared to testosterone release by normal mouse testes under identical conditions. Ultrastructural examination of testes revealed a paucity of lipid droplets, extensive accumulation of inclusion bodies, and distorted endoplasmic reticulum in Leydig cells of adult NPC mice. The hypoandrogenemia caused systemic deficiencies in NPC mice. Seminal vesicles, a testosterone-responsive tissue, were underdeveloped in NPC male mice. The testosterone-responsive kidney beta-glucuronidase activity was also underexpressed. Seminal vesicle mass and beta-glucuronidase activity were increased by testosterone treatment of NPC mice. Many hepatic proteins, identified by microsequencing, were also deficient in NPC male mice. Levels of alpha 2-mu-globulin, glutathione S-transferase-pi, carbonic anhydrase-III, and selenium-binding protein increased in normal male mice during puberty, but did not increase in the NPC male mice. Based on the increases in protein expression during puberty, differential expression in males and females, and the reported involvement of androgens in regulating expression of some of these proteins, deficient expression of most of these proteins in male NPC mice appears to result from low testosterone levels. We conclude that a defect in testicular testosterone production in NPC male mice causes a pleiotropic deficiency in androgen-sensitive expression of proteins in various organs.