Zubair H. Aghai

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 <2.0u2009kg on HFNC or NCPAP support were studied in a random order. A ventilator was used to deliver 6u2009cm H2O of NCPAP with nasal prongs. High-flow nasal cannula delivered with Vapotherm (VAPO) at 3, 4 and 5u2009l/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 5u2009l/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 <1500u2009g who required NCPAP for mild respiratory distress. Each infant was studied on bubble and VF-NCPAP at 8, 6, 4, and 0u2009cmH2O. 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 8u2009cmH2O.RESULTS:Provision of NCPAP with either device decreased inspiratory work of breathing, tidal volume, and minute ventilation relative to NCPAP of 0u2009cmH2O. Bubble NCPAP did not decrease resistive work of breathing relative to 0u2009cmH2O. 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.

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⩽1000u2009g) 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.

A Role for Matrix Metalloproteinase 9 in IFNγ-Mediated Injury in Developing Lungs: Relevance to Bronchopulmonary Dysplasia

We noted a marked increase in IFNγ mRNA in newborn (NB) murine lungs after exposure to hyperoxia. We sought to evaluate the role of IFNγ in lung injury in newborns. Using a unique triple-transgenic (TTG), IFNγ-overexpressing, lung-targeted, externally regulatable NB murine model, we describe a lung phenotype of impaired alveolarization, resembling human bronchopulmonary dysplasia (BPD). IFNγ-mediated abnormal lung architecture was associated with increased cell death and the upregulation of cell death pathway mediators caspases 3, 6, 8, and 9, and angiopoietin 2. Moreover, an increase was evident in cathepsins B, H, K, L, and S, and in matrix metalloproteinases (MMPs) 2, 9, 12, and 14. The IFNγ-mediated abnormal lung architecture was found to be MMP9-dependent, as indicated by the rescue of the IFNγ-induced pulmonary phenotype and survival during hyperoxia with a concomitant partial deficiency of MMP9. This result was concomitant with a decrease in caspases 3, 6, 8, and 9 and angiopoietin 2, but an increase in the expression of angiopoietin 1. In addition, NB IFNγ TTG mice exhibited significantly decreased survival during hyperoxia, compared with littermate controls. Furthermore, as evidence of clinical relevance, we show increased concentrations of the downstream targets of IFNγ chemokine (C-X-C motif) ligands (CXCL10 and CXCL11) in baboon and human lungs with BPD. IFNγ and its downstream targets may contribute significantly to the final common pathway of hyperoxia-induced injury in the developing lung and in human BPD.

A Role for Macrophage Migration Inhibitory Factor in the Neonatal Respiratory Distress Syndrome

Using a mouse model of neonatal respiratory distress syndrome (RDS), we demonstrate a central role for macrophage migration inhibitory factor (MIF) in lung maturation at the developmental stage when human neonates are most susceptible to RDS. We prematurely delivered mouse pups at embryonic day 18, during the early saccular stage of pulmonary development. Only 8% of the prematurely delivered pups genetically deficient in MIF survived 8 h vs 75% of wild-type controls (p < 0.001). This phenotype was corrected when pups of all genotypes were bred from dams heterozygote for MIF deficiency. Local production of MIF in the lung increased at embryonic day 18, continued until full-term at embryonic day 19.5, and decreased in adulthood, thus coinciding with this developmental window. The lungs of pups genetically deficient in MIF were less mature upon histological evaluation, and demonstrated lower levels of vascular endothelial growth factor and corticosterone – two factors that promote fetal lung maturation. In vitro studies support a role for MIF in surfactant production by pulmonary epithelial cells. In a cohort of human neonates with RDS, higher intrapulmonary MIF levels were associated with a lower likelihood of developing bronchopulmonary dysplasia, a sequelae of RDS (p < 0.03). This study demonstrates for the first time a role for MIF in lung maturation, and supports a protective role for MIF in newborn lung disease.

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 72u2009h 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±230u2009g) had no BPD, 32 infants (GA 25.8±1.4 weeks, BW 768±157u2009g) developed BPD and 16 infants (GA 24.5±1.1 weeks, BW 710±143u2009g) died before 36 weeks PMA. Ang2 concentrations were significantly lower in infants with no BPD (median, 25th and 75th percentile) (157, 16 and 218u2009pgu2009mg−1) compared with those who developed BPD (234, 138 and 338u2009pgu2009mg−1, P=0.03) or BPD and/or death (234, 157 and 347u2009pgu2009mg−1, P=0.017), in the first week of life. Twenty-six VPIs (BW 719±136u2009g, GA 25.1±1.3 weeks) received 27 courses of Dex. Ang2 concentrations before starting Dex were 202, 137 and 278u2009pgu2009mg−1 and significantly decreased to 144, 0 and 224u2009pgu2009mg−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.

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±200u2009g) had no BPD, 60 infants (gestational age 25.4±1.8 weeks, birth weight 749±156u2009g) 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±16.5u2009ngu2009mg–1) compared with those who developed BPD or died (45.1±30.9u2009ngu2009mg–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.

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

Background.u2003The 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.u2003To 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.u2003Preterm 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.u2003Screening 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.u2003A 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.

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 weightu2009≤u20092000u2009g) 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 (pu2009<u20090.001). 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.

Twice-weekly fluconazole prophylaxis in premature infants: association with cholestasis.

Background:u2002 Fluconazole prophylaxis is effective in preventing invasive candidiasis in extremely low‐birthweight (ELBW) infants. The authors previously reported an increased incidence of cholestasis with fluconazole prophylaxis in ELBW infants, which led to fluconazole prophylaxis being changed to a less frequent dosing (LFD) schedule of twice a week at their institution. The purpose of the present study was therefore to evaluate the effectiveness and safety of LFD fluconazole prophylaxis in preventing invasive candidiasis in ELBW infants.