Gary Stahl

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.

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.

Fluconazole prophylaxis in extremely low birth weight infants: association with cholestasis.

Background:Extremely low birth weight (ELBW) infants are at increased risk for invasive candidiasis and associated morbidity and mortality. The use of fluconazole prophylaxis in this population has raised a benefit versus risk concern among clinicians.Objectives:To evaluate the effectiveness and safety of fluconazole prophylaxis in ELBW infants.Study design:ELBW infants (BW⩽1000 g) born during the pre-prophylaxis era (PPE, January 1998–February 2002) were compared with prophylaxis era (PE, March 2002–September 2005). Infants born during PE received fluconazole prophylaxis for 6 weeks, as long as they had intravenous access. Demographic and clinical data were collected. The two groups were compared for baseline demographics, risk factors for candidiasis, the incidence of invasive candidiasis, liver enzymes, alkaline phosphatase, and bilirubin (total and direct).Results:Nine out of 137 infants (6.6%) developed invasive candidiasis during PPE compared to none of 140 (0%) during PE (P=0.006). During PE, 60/140 (42.9%) infants developed conjugated hyperbilirubinemia compared to 12/137 (8.8%) during PPE (P<0.001).Conclusion:Although a fluconazole prophylaxis regimen for ELBW infants was effective in preventing invasive candidiasis, an increase in the incidence of conjugated hyperbilirubinemia was observed. Further studies are needed to evaluate the safety of fluconazole prophylaxis in this population.

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.

Impact of histological chorioamnionitis on tracheal aspirate cytokines in premature infants.

BACKGROUND Histological chorioamnionitis (CHORIO) may increase inflammatory mediators in the lungs of preterm infants. OBJECTIVE To study the impact of CHORIO on tracheal aspirate (TA) cytokines in ventilated infants. DESIGN/METHODS TA samples collected within 48 hours after birth from 40 ventilated neonates (gestational age [GA] <30 weeks, body weight [BW] <1250 g) were analyzed. Levels of 12 cytokines (interleukin [IL]-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, epidermal growth factor [EGF], interferon-γ [IFN-γ], monocyte chemotactic protein-1 [MCP-1], tumor necrosis factor-α [TNF-α], vascular endothelial growth factor [VEGF]) were measured using a biochip multianalyte immunoassay (Randox Laboratories, Antrim, UK). Total protein was measured by the Bradford assay. CHORIO assessment was done by a blinded pathologist. RESULTS Twenty-six infants (GA 26.6 ± 1.4 weeks, BW 852 ± 162 g) had no CHORIO and 14 (GA 25.1 ± 1.0 weeks, BW 776 ± 164 g) had CHORIO. IL-1α, IL-1β, IL-8, and VEGF were significantly higher in TA of infants with CHORIO. After correction for dilution, IL-1α, IL-1β, and IL-8 were significantly elevated. Increased TA total cell count correlated with CHORIO, VEGF, EGF, MCP-1, IL-8, and IL-6 TA levels (all p ≤ 0.02). Ventilator, oxygen supplementation, and hospital days correlated with TA IFN-γ levels (all p ≤ 0.01). CONCLUSION CHORIO is associated with increased specific proinflammatory mediators in TA samples of preterm infants.

High-mobility group box-1 protein in tracheal aspirates from premature infants: relationship with bronchopulmonary dysplasia and steroid therapy

Objective:High-mobility group box-1 (HMGB1) is a potent inflammatory mediator and contributes to acute lung injury in adults. The role of HMGB1 in neonatal lung injury and the development of bronchopulmonary dysplasia (BPD) is unknown. We studied the association between HMGB1 levels in tracheal aspirates (TAs) and adverse outcomes (BPD/death) in ventilated premature infants (VPIs) and modulation of HMGB1 levels with dexamethasone (Dex) use.Study Design:Infants born before 32 weeks gestation and requiring mechanical ventilation were enrolled. Serial TA samples were collected on days 1, 3, 5 and 7 and HMGB1 levels were measured. HMGB1 levels in TA samples were compared between infants with no BPD and infants who developed BPD or died. HMGB1 TA levels were also compared before and after using Dex.Result:In all, 24 infants (gestational age 26.4±1.9 weeks, birth weight 859±200 g) had no BPD, 60 infants (gestational age 25.4±1.8 weeks, birth weight 749±156 g) developed BPD or died before 36 weeks postmenstrual age. Mean HMGB1 level in first week of life was significantly lower in infants with no BPD (27.3±16.5 ng mg–1) compared with those who developed BPD or died (45.1±30.9 ng mg–1, P=0.004). In total, 29 VPIs received Dex. There was no significant change in HMGB1 levels with steroid therapy (before 47.0±43.9, after 60.1.5±58.8, P=0.3).Conclusion:Our data suggest that higher HMGB1 levels in TA are associated with the development of BPD or death in VPI. Dex use had no effect on HMGB1 levels.

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.

Utility of performing routine head ultrasounds in preterm infants with gestational age 30-34 weeks

Background. The American Academy of Neurology and Child Neurology Society recommend performing routine screening head ultrasounds (HUS) on preterm infants of less than 30 weeks gestation. Objective. To study the incidence of intraventricular hemorrhage (IVH) and evaluate the need for screening HUS in preterm infants with gestational age (GA) of 30–34 weeks. Design/Methods. Preterm infants (GA; 30–34 weeks) admitted to the neonatal intensive care unit (NICU) between January 1997 and September 2007 were included in this study. Grades of IVH were defined as per the Papile classification. Results. Screening HUS were performed on 463 infants with GA of 30–34 weeks. Twenty-seven (5.8%) infants had abnormal cranial ultrasound (US) (IVH or periventricular leucomalacia [PVL]). The incidence of IVH ranged from 3.3% to 6.3% at various GA. Seven (1.5%) infants had severe abnormalities on HUS (grades III/IV or PVL). Conclusions. A significant number of infants born between 30 and 34 weeks of gestation have abnormalities on screening cranial US. Since not all infants born at 30–34 weeks of gestation received a HUS, the incidence of HUS abnormalities might have been overestimated due to a possible ‘selection bias’. Additional studies are needed to examine the adverse neurodevelopmental outcomes in this group of preterm infants with mild abnormalities (IVH grades I or II) on cranial US before recommending routine screenings for IVH.

Unbound Free Fatty Acids from Preterm Infants Treated with Intralipid Decouples Unbound from Total Bilirubin Potentially Making Phototherapy Ineffective

Extremely low birth weight (ELBW; <1,000 g) infants have poor outcomes, often compromised by bilirubin neurotoxicity. We measured unbound bilirubin (B_f) and unbound free fatty acid (FFA_u) levels in 5 ELBW infants in a trial examining the effects of pharmacologic ductal closure on infants treated with Intralipid infusion (3 g/kg/day). The levels for all infants (mean ± SD) were: total serum bilirubin (TSB) 4.6 ± 1.7 mg/dl, FFA_u 376 ± 496 n<smlcap>M</smlcap>, and B_f 42 ± 30 n<smlcap>M</smlcap>. Of the 3 infants who died, 2 had TSB <5.9 mg/dl but FFA_u >580 n<smlcap>M</smlcap> and B_f >75 n<smlcap>M</smlcap>. Multiple regression revealed a major effect on B_f levels due to FFA_u, indicating that Intralipid elevated levels of FFA_u and B_f. Indomethacin or ibuprofen reduced B_f levels, most likely by reducing FFA_u levels through lipase inhibition. Because displacement of B_f by FFA_u decouples B_f from TSB, phototherapy may not reduce the risk of bilirubin or FFA_u toxicity in Intralipid-treated ELBW infants.

Detection of pepsin in mouth swab: correlation with clinical gastroesophageal reflux in preterm infants.

Abstract Objective: To study the relationship between pepsinogen/pepsin in a mouth swab and clinical gastroesophageal reflux (GER) in preterm infants. Methods: Preterm infants (birth weight ≤ 2000 g) on full enteral feeds were enrolled. Mouth swabs from cheek and below the tongue were collected one, two and three hours after feeding. An enzymatic assay with substrate fluorescein isothiocyanate-casein was used to detect pepsin A and C activities with further confirmation by western blot. Blinded investigators reviewed the infant’s medical record to clinically diagnose GER. Results: A total of 101 premature infants were enrolled. Pepsinogen/pepsin was detected in 45/101 (44.5%) infants in at least one sample. A clinical diagnosis of GER was made in 36/101 (35.6%) infants. Mouth swabs were positive in 26/36 (72%) infants with clinical GER and only 19/65 (29%) infants without GER (p < 0.001). Similarly, the levels of pepsinogen/pepsin A and C were higher in the mouth swabs of infants with clinical GER. Conclusion: The detection of pepsinogen/pepsin in a mouth swab correlates with clinical GER in premature infants.