Henry J. Rozycki

Prophylaxis of Early Adrenal Insufficiency to Prevent Bronchopulmonary Dysplasia: A Multicenter Trial

Background. Infants developing bronchopulmonary dysplasia (BPD) show decreased cortisol response to adrenocorticotropic hormone. A pilot study of low-dose hydrocortisone therapy for prophylaxis of early adrenal insufficiency showed improved survival without BPD at 36 weeks’ postmenstrual age, particularly in infants exposed to histologic chorioamnionitis. Methods. Mechanically ventilated infants with birth weights of 500 to 999 g were enrolled into this multicenter, randomized, masked trial between 12 and 48 hours of life. Patients received placebo or hydrocortisone, 1 mg/kg per day for 12 days, then 0.5 mg/kg per day for 3 days. BPD at 36 weeks’ postmenstrual age was defined clinically (receiving supplemental oxygen) and physiologically (supplemental oxygen required for O2 saturation ≥90%). Results. Patient enrollment was stopped at 360 patients because of an increase in spontaneous gastrointestinal perforation in the hydrocortisone-treated group. Survival without BPD was similar, defined clinically or physiologically, as were mortality, head circumference, and weight at 36 weeks. For patients exposed to histologic chorioamnionitis (n = 149), hydrocortisone treatment significantly decreased mortality and increased survival without BPD, defined clinically or physiologically. After treatment, cortisol values and response to adrenocorticotropic hormone were similar between groups. Hydrocortisone-treated infants receiving indomethacin had more gastrointestinal perforations than placebo-treated infants receiving indomethacin, suggesting an interactive effect. Conclusions. Prophylaxis of early adrenal insufficiency did not improve survival without BPD in the overall study population; however, treatment of chorioamnionitis-exposed infants significantly decreased mortality and improved survival without BPD. Low-dose hydrocortisone therapy did not suppress adrenal function or compromise short-term growth. The combination of indomethacin and hydrocortisone should be avoided.

Circulating pro- and counterinflammatory cytokine levels and severity in necrotizing enterocolitis.

Objectives. To evaluate the relationship between the severity of necrotizing enterocolitis (NEC) and circulating concentrations of proinflammatory cytokines interleukin (IL)-1β and IL-8 and counterinflammatory cytokines IL-1 receptor antagonist (IL-1ra) and IL-10. These cytokines have been associated with bowel injury or inflammation and may be released more slowly or later than previously examined cytokines. Also, to determine if any one of these cytokines will predict the eventual severity of NEC when measured at symptom onset. Method. Serial blood samples at onset, 8, 24, 48, and 72 hours were obtained from newborn infants with predefined signs and symptoms of NEC. Normal levels were defined from weight-, gestation-, and age-matched controls. Concentrations of the four cytokines were determined by enzyme-linked immunosorbent assay and compared throughout the time period by stage of NEC, using sepsis as a co-factor. Mean concentrations of each cytokine at onset were compared with the controls. Threshold values were obtained with the best combination of high sensitivity and high specificity for defining stage 1 NEC or for diagnosing stage 3 NEC at onset. Results. There were 12 cases of stage 1, 18 cases of stage 2, and 6 cases of stage 3 NEC included in the study, as well as 20 control infants. Concentrations of IL-8 and IL-10 were significantly higher in infants with stage 3 NEC from onset through 24 hours compared with infants with less severe NEC. At onset, concentrations of all four cytokines were significantly higher in stage 3 NEC. To identify, at onset, the infants with a final diagnosis of stage 3 NEC, an IL-1ra concentration of >130 000 pg/mL had a sensitivity of 100% and a specificity of 92%. At 8 hours, an IL-10 concentration of >250 pg/mL had a sensitivity of 100% and a specificity of 90% in identifying stage 3 NEC in infants with symptoms suggestive of NEC at onset. Conclusions. The severity of NEC and its systemic signs and symptoms are not due to a deficiency of counterregulatory cytokines. In fact, mean concentrations of IL-1ra in NEC are higher than what has been reported in other populations. The cytokines IL-8, IL-1ra, and IL-10 are released later or more slowly after a stimulus and may be more useful in identifying, within hours of symptom onset, which infant will develop significant NEC.

NF-κB in tracheal lavage fluid from intubated premature infants: Association with inflammation, oxygen and outcome

Objectives: To determine if tracheal lavage concentrations of the transcription factor NF-κB, which is activated by risk factors associated with bronchopulmonary dysplasia (BPD) and induces expression of cytokines associated with BPD, is related to BPD in premature infants. Design: Serial tracheal lavage samples from intubated premature infants were analysed for cell count and concentrations of interleukin (IL)8 and NF-κB, corrected for dilution by secretory component concentrations. Setting: Level III university hospital neonatal intensive care unit. Patients: Thirty three intubated infants (mean (SD) birth weight 903 (258) g, median gestation 27 weeks (range 24–31)) in the first 14 days of life. Main outcome measures: Tracheal effluent NF-κB, IL8, and cell counts, corrected for dilution by secretory component measurement. Results: Square root transformed NF-κB concentrations were significantly related to signs of inflammation (cell count, p  =  0.002; IL8, p  =  0.019) and to simultaneous fraction of inspired oxygen in samples from the first 3 days of life (r  =  0.512, p<0.003). Of the 32 subjects with samples in the first 3 days of life, the half who either died or had BPD had higher NF-κB concentrations than those without BPD (square root concentration 0.097 (0.043) v 0.062 (0.036) μg/μg protein/μg secretory component, p  =  0.018). Conclusions: Tracheobronchial lavage NF-κB concentrations are related to lung inflammation, oxygen exposure, and pulmonary outcome in intubated preterm infants. NF-κB activation may be an early critical step leading to BPD.

Postnatal SNAP-II scores in neonatal intensive care unit patients: relationship to sepsis, necrotizing enterocolitis, and death.

Objective. To determine if daily SNAP-II scores (Score for Neonatal Acute Physiology) after the first day are useful in identifying neonatal intensive care unit (NICU) patients who die or develop sepsis or necrotizing enterocolitis. Study design. Prospective data were collected on all 141 admissions to a university level III NICU over 4 months. SNAPPE-II scores were calculated from the day of admission and SNAP-II scores from subsequent hospital days. The scores were compared between those who developed events and those who did not. Results. At least 64% of the daily SNAP-II scores on the day of and the preceding 4 days from the event were 0. Admission SNAPPE-II scores correlated with length of stay (r = 0.44, p < 0.01) but patient average SNAP-II did not (r = 0.02, p > 0.5). Conclusions. SNAP-II scores from after the first day of life did not accurately assess or predict neonatal morbidity and mortality.

Dexamethasone dosing, mechanical ventilation and the risk of cerebral palsy

Objective. Risk factors for cerebral palsy (CP) in premature infants include duration of mechanical ventilation and exposure to postnatal dexamethasone (DEX). Since DEX can reduce the duration of mechanical ventilation, limited DEX exposure could be beneficial. Methods. This was a retrospective, cohort study of infants of less than 1500 g birth weight surviving to discharge between 1 January 1996 and 30 June 2001 who received postnatal dexamethasone. DEX administration was based only on the need for O2 and/or mechanical ventilation. CP was diagnosed at over 10 months post-conceptional age. Univariate and multivariate analyses were used to determine significant risk factors and the relative contribution of these factors to overall risk of CP. Results. Of 218 eligible infants 162 were followed-up (74%). The CP rate was 27.3%. Significant risk factors for CP included gestational age, ventilator duration, DEX dose, presence of periventricular leukomalacia (PVL), seizures, diagnosis of retinopathy of prematurity (ROP) and use of vasopressors. By multiple logistic regression, ventilator duration, PVL, grade III/IV intraventricular hemorrhage (IVH) and DEX dose were significantly related to CP. By stepwise multiple regression, grade III/IV IVH and ventilator duration were the strongest risk factors, but DEX dose continued to be a significant risk factor. Conclusions. The risk of CP was significantly related to the total cumulative dose of DEX. This could be due to a smaller exposure to DEX or to a reduced need for mechanical ventilation.

Guaifenesin Has No Effect on Sputum Volume or Sputum Properties in Adolescents and Adults With Acute Respiratory Tract Infections

BACKGROUND: Guaifenesin (glyceryl guaiacolate ether [GGE]) has been studied as a cough suppressant and as an expectorant; however, published studies to date have failed to find a consistent benefit. METHODS: An 8-day multi-center clinical trial was conducted to study the effect of two 600-mg extended-release GGE tablets twice daily for 1 week on cold symptoms, sputum volume, and properties in adolescents and adults with productive cough from an acute respiratory tract infection (RTI). The study enrolled 378 subjects (GGE, n = 188; and placebo, n = 190) who were otherwise healthy and had an RTI for up to 5 days before enrollment. Subjects suffered from at least 2 of 3 symptoms of cough, thickened mucus, and chest congestion. A total of 151 GGE and 144 control subjects completed the full protocol. Single-sputum samples were collected from each subject on days 1, 3, 4, and 8 of the study. The rheology and interfacial tension of sputum were measured, and 24-h collected samples from days 1 and 4 were analyzed for total volume and hydration. RESULTS: Symptoms in both the GGE and placebo groups improved to a similar degree over time. There were no significant differences between the GGE and placebo groups for sputum volume (P = .41), percent solids (P = .69), interfacial tension (P = .88), elasticity (P = .71), viscosity (P = .45), or mechanical impedance (P = .75). CONCLUSIONS: The recommended dose of GGE had no measurable effect on sputum volume or properties and is unlikely to be an expectorant or mucolytic when used to treat acute RTI. (ClinicalTrials.gov registration NCT01046136.)

Cardiac asthma: new insights into an old disease

Cardiac asthma has been defined as wheezing, coughing and orthopnea due to congestive heart failure. The clinical distinction between bronchial asthma and cardiac asthma can be straight forward, except in patients with chronic lung disease coexisting with left heart disease. Pulmonary edema and pulmonary vascular congestion have been thought to be the primary causes of cardiac asthma but most patients have a poor response to diuretics. There appears to be limited effectiveness of classical asthma medications like bronchodilators or corticosteroids in treating cardiac asthma. Evidence suggests that circulating inflammatory factors and tissue growth factors also lead to airway obstruction suggesting the possibility of developing novel therapies.

The Impact of Hyperoxia on the Neonatal and Adult Developing Dendritic Cell

Oxygen is essential therapy for neonates with acute respiratory failure, including those with infections. However, high oxygen levels may be counterproductive for overcoming infections because hyperoxia may kill cells, including dendritic cells that are essential to the emergence of the pulmonary immune system and pivotal in mounting immune responses to infections. We studied the impact of hyperoxia on developing dendritic cells from neonatal cord blood and adult blood monocytes, comparing viability, development of maturation, and endocytic function. Our data suggest that cord blood–derived dendritic cells may be more resistant to hyperoxic-induced cell death than adult blood–derived cells. Moreover, the surviving cells in either group are those that maintain an immature phenotype. This may impair their ability to perform optimal immune function.

Potential contribution of type I alveolar epithelial cells to chronic neonatal lung disease.

The alveolar surface is covered by large flat Type I cells (alveolar epithelial cells 1, AEC1). The normal physiological function of AEC1s involves gas exchange, based on their location in approximation to the capillary endothelium and their thinness, and in ion and water flux, as shown by the presence of solute active transport proteins, water channels, and impermeable tight junctions between cells. With the recent ability to produce relatively pure cultures of AEC1 cells, new functions have been described. These may be relevant to lung injury, repair, and the abnormal development that characterizes bronchopulmonary dysplasia (BPD). To hypothesize a potential role for AEC1 in the development of lung injury and abnormal repair/development in premature lungs, evidence is presented for their presence in the developing lung, how their source may not be the Type II cell (AEC2) as has been assumed for 40 years, and how the cell can be damaged by same type of stressors as those which lead to BPD. Recent work shows that the cells are part of the innate immune response, capable of producing pro-inflammatory mediators, which could contribute to the increase in inflammation seen in early BPD. One of the receptors found exclusively on AEC1 cells in the lung, called RAGE, may also have a role in increased inflammation and alveolar simplification. While the current evidence for AEC1 involvement in BPD is circumstantial and limited at present, the accumulating data supports several hypotheses and questions regarding potential differences in the behavior of AEC1 cells from newborn and premature lung compared with the adult lung.

Lack of prognostic significance of early elevated serum uric acid levels in low birthweight infants

This study examined the utility of serum uric acid concentrations in the first day of life to identify infants with severe brain injury (grade III or IV intraventricular hemorrhage and/or periventricular leukomalacia). The serum uric acid concentrations in infants with severe brain injury were compared to those without. Severe brain injury was assessed in 151 infants with birthweight ≤1,251 g admitted before 24 h of life. The risk of severe brain injury was related to 5-min Apgar scores (odds ratio 0.79, CI 0.63–0.98, p < 0.05) and seizures in the first day of life (odds ratio 4.44, CI 1.004–19.66, p < 0.05), but the mean uric acid levels did not differ between those with and without severe brain injury [5.11 ± 1.88 mg/dl (303.9 ± 111.8 µmol/l) vs. 5.77 ± 2.13 mg/dl (343.2 ± 126.7 µmol/l), p = 0.200]. Uric acid levels were related to serum creatinine (p < 0.001), time of uric acid sample (p < 0.001), maternal hypertension (p < 0.001), and base deficit (p = 0.032). Of the 80 infants seen in neurodevelopmental follow-up at a median 11 months postconceptional age, uric acid concentrations did not differ between the abnormal (n = 20) and normal subjects [5.38 ± 1.72 mg/dl (320.0 ± 102.3 µmol/l) vs. 6.02 ± 2.55 mg/dl (358.1 ± 151.8 µmol/l), p = 0.197]. Uric acid may not be a useful early marker for premature infants with severe brain injury.