Tarek Nakhla

Work of breathing using high-flow nasal cannula in preterm infants

Objective:To compare the work of breathing (WOB) in premature neonates supported with high-flow nasal cannula (HFNC) and nasal continuous positive airway pressure (NCPAP).Study Design:Eighteen preterm neonates <2.0 kg on HFNC or NCPAP support were studied in a random order. A ventilator was used to deliver 6 cm H2O of NCPAP with nasal prongs. High-flow nasal cannula delivered with Vapotherm (VAPO) at 3, 4 and 5 l/min was used. Tidal ventilation was obtained using respiratory inductance plethysmography calibrated with face-mask pneumotachography. An esophageal balloon estimated pleural pressure from which changes in end distending pressure were calculated. Inspiratory, elastic and resistive WOB and respiratory parameters were calculated.Results:No differences were found in the WOB for all settings. Changes in end distending pressure did not vary significantly over all device settings except VAPO at 5 l/min.Conclusion:In these preterm infants with mild respiratory illness, HFNC provided support comparable to NCPAP.

Work of breathing during nasal continuous positive airway pressure in preterm infants : A comparison of bubble vs variable-flow devices

OBJECTIVE:To compare work of breathing and breathing asynchrony during bubble nasal continuous positive airway pressure (NCPAP) vs variable-flow (VF)-NCPAP in premature infants.STUDY DESIGN:We studied 18 premature infants of birth weight <1500 g who required NCPAP for mild respiratory distress. Each infant was studied on bubble and VF-NCPAP at 8, 6, 4, and 0 cmH2O. Tidal volumes were obtained by calibrated respiratory inductance plethysmography. Esophageal pressure estimated intrapleural pressure. Inspiratory and resistive work of breathing were calculated from pressure–volume data. Breathing asynchrony was assessed with phase angle. The results at all NCPAP levels were referenced to VF-NCPAP values at 8 cmH2O.RESULTS:Provision of NCPAP with either device decreased inspiratory work of breathing, tidal volume, and minute ventilation relative to NCPAP of 0 cmH2O. Bubble NCPAP did not decrease resistive work of breathing relative to 0 cmH2O. Resistive work of breathing (p=0.01), respiratory rate (p<0.03), and phase angle (p=0.002) were all greater with bubble compared to VF-NCPAP.CONCLUSION:The more labored and asynchronous breathing seen with bubble NCPAP may lead to higher failure rates over the long term than with VF-NCPAP.

Azithromycin Suppresses Activation of Nuclear Factor-kappa B and Synthesis of Pro-inflammatory Cytokines in Tracheal Aspirate Cells From Premature Infants

Nuclear factor-kappaB (NF-κB) plays a central role in regulating key proinflammatory mediators. The activation of NF-κB is increased in tracheal aspirate (TA) cells from premature infants developing bronchopulmonary dysplasia (BPD). We studied the effect of azithromycin (AZM) on the suppression of NF-κB activation and the synthesis of pro-inflammatory cytokines IL-6 and IL-8 by TA cells obtained from premature infants. Tracheal aspirate cells were stimulated with tumor necrosis factor-alpha (TNF-α) and incubated with AZM. The nuclear NF-κB-DNA binding activity, the levels of inhibitory kappaB-alpha (IκB-α) in the cytoplasmic fraction and IL-6 and IL-8 release in the cell culture media were measured. Stimulation of TA cells by TNF-α increased the activation of NF-κB, which was suppressed by the addition of AZM. Increased activation of NF-κB was also associated with increased levels of pro-inflammatory cytokines (IL-6 and IL-8). AZM significantly reduced the IL-6 and IL-8 production to the levels similar to control. TNF-α stimulation also increased the degradation of IκB-α, which was restored with the addition of AZM. Our data suggest that AZM therapy may be an effective alternative to steroids in reducing lung inflammation and prevention of BPD in ventilated premature infants.

Pepsin, a Marker of Gastric Contents, Is Increased in Tracheal Aspirates From Preterm Infants Who Develop Bronchopulmonary Dysplasia

OBJECTIVE. The objective of this study was to study the association between pepsin in tracheal aspirate samples and the development of bronchopulmonary dysplasia in preterm infants. METHODS. Serial tracheal aspirate samples were collected during the first 28 days from mechanically ventilated preterm neonates. Bronchopulmonary dysplasia was defined as the need for supplemental oxygen at 36 weeks’ postmenstrual age. An enzymatic assay with a fluorescent substrate was used to detect pepsin. Total protein was measured by the Bradford assay to correct for the dilution during lavage. Immunohistochemistry using antibody against human pepsinogen was performed in 10 lung tissue samples from preterm infants. RESULTS. A total of 256 tracheal aspirate samples were collected from 59 preterm neonates. Pepsin was detected in 234 (91.4%) of 256 of the tracheal aspirate samples. Twelve infants had no bronchopulmonary dysplasia, 31 infants developed bronchopulmonary dysplasia, and 16 infants died before 36 weeks’ postmenstrual age. The mean pepsin concentration was significantly lower in infants with no bronchopulmonary dysplasia compared with those who developed bronchopulmonary dysplasia or developed bronchopulmonary dysplasia/died before 36 weeks’ postmenstrual age. Moreover, the mean pepsin level was significantly higher in infants with severe bronchopulmonary dysplasia compared with moderate bronchopulmonary dysplasia. The mean pepsin level in tracheal aspirate samples from the first 7 days was also lower in infants with no bronchopulmonary dysplasia compared with those who developed bronchopulmonary dysplasia or developed bronchopulmonary dysplasia/died before 36 weeks’ postmenstrual age. Pepsinogen was not localized in the lung tissues by immunohistochemistry. CONCLUSION. The concentration of pepsin was increased in the tracheal aspirate of preterm infants who developed bronchopulmonary dysplasia or died before 36 weeks’ postmenstrual age. Recovery of pepsin in tracheal aspirate samples is secondary to gastric aspiration, not by hematogenous spread or local synthesis in the lungs. Chronic aspiration of gastric contents may contribute in the pathogenesis of bronchopulmonary dysplasia.

Pepsin, a reliable marker of gastric aspiration, is frequently detected in tracheal aspirates from premature ventilated neonates: relationship with feeding and methylxanthine therapy.

Objectives: To determine the frequency of pepsin detection in tracheal aspirate (TA) samples of mechanically ventilated premature neonates and its association with feedings and methylxanthine therapy. Patients and Methods: Serial TA samples (days 1, 3, 5, 7, 14, 21, 28 and >28vdays) were collected from premature neonates receiving ventilatory support. An enzymatic assay with a fluorescent substrate was used to detect pepsin. Pepsin was also measured in 10 serum samples collected in conjunction with the TA samples from 8 neonates. Results: A total of 239 TA samples was collected from 45 premature neonates (mean birth weight, 762 ± 166 g; mean gestational age, 25.5 ± 1.5 wk). Pepsin was detectable in 222 of 239 TA samples (92.8%) and in none of the serum samples. Pepsin was significantly lower on day 1 (mean, 170 ± 216 ng/mL) when compared with all other time points (P < 0.05). Mean concentration of pepsin was significantly lower when infants were unfed (265 ± 209 ng/mL) compared with levels during feeding (390 ± 260 ng/mL, P = 0.02). The mean level of pepsin was significantly higher in infants during xanthine therapy (419 ± 370 ng/mL) compared with no xanthine therapy (295 ± 231 ng/mL, P = 0.037). Conclusion: Pepsin, a marker of gastric contents, was detected in more than 92% of TA samples from premature infants on mechanical ventilation. The level of pepsin was higher in fed infants when compared with unfed infants. Xanthine therapy was also associated with increased pepsin in TA samples. Chronic aspiration of gastric contents may worsen lung disease in premature infants.

Angiopoietin 2 concentrations in infants developing bronchopulmonary dysplasia: attenuation by dexamethasone

Objectives:To study the association between angiopoietin 2 (Ang2) concentrations in tracheal aspirates (TAs) and adverse outcome (bronchopulmonary dysplasia (BPD)/death) in ventilated premature infants (VPIs) and modulation of Ang2 concentrations with dexamethasone (Dex) use.Study Design:Serial TA samples were collected on days 1, 3, 5 and 7, and Ang2 concentrations were measured. Ang2 TA concentrations were compared prior to and after 48 to 72 h of using Dex.Result:A total of 151 TA samples were collected from 60 VPIs. BPD was defined as the oxygen requirement at 36 weeks postmenstrual age (PMA). Twelve infants (mean±s.d.) (gestational age (GA) 26.5±2.1 weeks, birth weight (BW) 913±230 g) had no BPD, 32 infants (GA 25.8±1.4 weeks, BW 768±157 g) developed BPD and 16 infants (GA 24.5±1.1 weeks, BW 710±143 g) died before 36 weeks PMA. Ang2 concentrations were significantly lower in infants with no BPD (median, 25th and 75th percentile) (157, 16 and 218 pg mg−1) compared with those who developed BPD (234, 138 and 338 pg mg−1, P=0.03) or BPD and/or death (234, 157 and 347 pg mg−1, P=0.017), in the first week of life. Twenty-six VPIs (BW 719±136 g, GA 25.1±1.3 weeks) received 27 courses of Dex. Ang2 concentrations before starting Dex were 202, 137 and 278 pg mg−1 and significantly decreased to 144, 0 and 224 pg mg−1 after therapy (P=0.007).Conclusions:Higher Ang2 concentrations in TAs are associated with the development of BPD or death in VPIs. Dex use suppressed Ang2 concentrations.

Dexamethasone Suppresses Expression of Nuclear Factor-kappaB in the Cells of Tracheobronchial Lavage Fluid in Premature Neonates with Respiratory Distress

Nuclear Factor-kappaB (NF-κB) plays a central role in regulating the key mediators of inflammation involved in acute lung injury. The anti-inflammatory effect of steroids by suppressing pro-inflammatory cytokines may be mediated by inhibition of transcription factor NF-κB. The objective of this study was to determine the effect of glucocorticoid therapy on the expression of NF-κB in the cells of tracheobronchial lavage fluid (TBLF) in premature neonates with respiratory distress. Nineteen premature neonates requiring mechanical ventilation and receiving glucocorticoids were enrolled. Their gestational age (mean ± SD) was 25.0 ± 1.2 wk, birth weight 714 ± 105 g and age of starting dexamethasone was 33 ± 15 d. Tracheobronchial lavage fluid was collected before and 48–72 h after starting dexamethasone. NF-κB expression was measured by immunocytochemistry using mouse MAb against the p65 subunit of NF-κB on cytospin slides. The percent of cells stained and the intensity staining index were significantly higher before starting dexamethasone compared with after steroid therapy. Localization of NF-κB was significantly decreased in the cytoplasm and nuclei of mononuclear cells after initiation of dexamethasone therapy. The concentration of IL-8 was also significantly lower after starting dexamethasone. In conclusion, dexamethasone suppressed the expression of NF-κB in the cytoplasm and nuclei of mononuclear cells and decreased levels of IL-8 in TBLF from premature neonates with respiratory distress. The anti-inflammatory effects of corticosteroids may be mediated through NF-κB.

DOES PRETERM HUMAN MILK (PM) CONTAIN MORE PROTECTIVE OLIGOSACCHARIDES THAN TERM MILK (TM)? ♦ 1329

Human milk oligosaccharides (OS) play a role in protection against certain infectious diseases. Because manufacture of human OS is now possible on a large scale, some OS may be added to infant formulas. Previous reports on human milk OS indicate a wide individual variation but lack information on PM.Objectives: To evaluate levels of 9 neutral OS (N-OS) in PM and compare them to levels in TM. Methods: So far, we have analyzed 19 samples of PM collected between days 0-33 of lactation from 11 mothers delivering at a mean GA of 30±3.0 wks. After removal of fat and proteins, N-OS were separated by ion exchange chromatography, followed by gel filtration. N-OS in each fraction were analyzed and quantified by Dionex HPLC-PAD. Of 5 mothers tested for secretor status, all were H/Lewis secretors.Results: PM ranges of 9 N-OS and their median perecentage of the total, as well as previously reported levels for TM, are shown below. Conclusion: N-OS levels in PM do not differ substantially from those reported in TM. Table