Hendrik Fischer

Avoiding Endotracheal Ventilation to Prevent Bronchopulmonary Dysplasia: A Meta-analysis

BACKGROUND AND OBJECTIVE: Mechanical ventilation via an endotracheal tube is a risk factor for bronchopulmonary dysplasia (BPD), one of the most common morbidities of very preterm infants. Our objective was to investigate the effect that strategies to avoid endotracheal mechanical ventilation (eMV) have on the incidence of BPD in preterm infants <30 weeks’ gestational age (GA). METHODS: In February 2013, we searched the databases Medline, Embase, and the Cochrane Central Register of Controlled Trials. Study selection criteria included randomized controlled trials published in peer-reviewed journals since the year 2000 that compared preterm infants <30 weeks’ GA treated by using a strategy aimed at avoiding eMV with a control group in which mechanical ventilation via an endotracheal tube was performed at an earlier stage. Data were extracted and analyzed by using the standard methods of the Cochrane Neonatal Review Group. The authors independently assessed study eligibility and risk of bias, extracted data and calculated odds ratios and 95% confidence intervals, employing RevMan version 5.1.6. RESULTS: We identified 7 trials that included a total of 3289 infants. The combined odds ratio (95% confidence interval) of death or BPD was 0.83 (0.71–0.96). The number needed to treat was 35. The study results were remarkably homogeneous. Avoiding eMV had no influence on the incidence of severe intraventricular hemorrhage. CONCLUSIONS: Strategies aimed at avoiding eMV in infants <30 weeks’ GA have a small but significant beneficial impact on preventing BPD.

Manual ventilation devices in neonatal resuscitation: Tidal volume and positive pressure-provision

BACKGROUND Excessive peak inspiratory pressures (PIP) and high tidal volumes (Vt) during manual ventilation can be detrimental to the neonatal lung. We compared the influence of different manual ventilation devices and individual professional experience on the extent of applied Vt and PIP in simulated neonatal resuscitation. MATERIAL AND METHODS One hundred and twenty medical professionals were studied. An intubated mannequin (equivalent to 1.0 kg neonate) was ventilated using two different devices: a self-inflating bag and a T-piece resuscitator. Target value was a PIP of 20 cm H(2)O. Applied PIP and the resulting Vt were recorded continuously using a respiratory function monitor (CO(2)SMO(+), Novametrix, USA). RESULTS Vt and PIP provision was significantly higher in SI-bags, compared to T-piece devices: median (interquartile range) PIP 25.6 (18.2) cm H(2)O vs 19.7 (3.2) cm H(2)O (p<0.0005), and Vt 5.1(3.2) ml vs Vt 3.6 (0.8) ml (p<0.0005) respectively. The intersubject variability of Vt and PIP provision was distinctly higher in SI-bags, compared to T-piece devices. Professional experience had no significant impact on the level and the variability of Vt or PIP provided. CONCLUSION Use of T-piece devices guarantees reliable and constant Vt and PIP provision, irrespective of individual, operator dependent variables. Methods to measure and to avoid excessive tidal volumes in neonatal resuscitation need to be developed.

Comparison of different techniques to measure air leaks during CPAP treatment in neonates

UNLABELLED Continuous positive airway pressure (CPAP) is routinely used for respiratory support in neonates. Air leaks are not uncommon and can hinder treatment. This study compared leak flow data obtained using different leak definitions through modeling and in vitro measurements. METHODS Using a computer simulation of an ideal CPAP system, the relationship between leak flow and three leak definitions was investigated. The leak flow was based on the measured inspiratory, expiratory and averaged breathing flow as commonly used in neonates. The theoretical results were compared with in vitro measurements using a commercial CPAP device for neonates (Leoni, Heinen & Löwenstein, Germany). Spontaneous breathing was simulated using a mechanical lung model, and defined air leaks were simulated using open silicone tubes of different lengths. RESULTS Computer simulations showed that leak calculations were affected by leak flow and breathing pattern, and that the relationships were mostly non-linear. There were large differences in the results between the three leak definitions. The in vitro measurements correlated strongly with the theoretical modeling results. The derived numerical volume correction reduced the leak-dependent volume error in the mean (S.D.) to -1.6 (4.6)%. CONCLUSION It is difficult to compare different measuring conditions and different CPAP devices due to the variation in results depending on the leak definition and the breathing pattern. Leak flow displays would provide superior air leak monitoring.

Essential Structural Features of TNF-α Lectin-like Domain Derived Peptides for Activation of Amiloride-Sensitive Sodium Current in A549 Cells

The amiloride-sensitive epithelial sodium channel (ENaC) plays a prominent role in sodium uptake from alveolar fluid and is the major component in alveolar fluid clearance in normal and diseased lungs. The lectin-like domain of TNF-α has been shown to activate amiloride-sensitive sodium uptake in type II alveolar epithelial cells. Therefore, several synthetic peptides that mimic the lectin-like domain of TNF-α (TIP) were synthesized and their ability to enhance sodium current through ENaC was studied in A549 cells with the patch clamp technique. Our data suggest that a free positively charged N-terminal amino group on residue 1 and/or a free negatively charged carboxyl group on residue 17 of the TIP peptide is essential for the ENaC-activating effect. Ventilation strategies apart, no standard treatment exists for pulmonary permeability edema. Therefore, novel therapies activating sodium uptake from the alveolar fluid via ENaC could improve clinical outcome.

Assessment of volume and leak measurements during CPAP using a neonatal lung model.

Although several commercial devices are available which allow tidal volume and air leak monitoring during continuous positive airway pressure (CPAP) in neonates, little is known about their measurement accuracy and about the influence of air leaks on volume measurement. The aim of this in vitro study was the validation of volume and leak measurement under CPAP using a commercial ventilatory device, taking into consideration the clinical conditions in neonatology. The measurement accuracy of the Leoni ventilator (Heinen & Löwenstein, Germany) was investigated both in a leak-free system and with leaks simulated using calibration syringes (2-10 ml, 20-100 ml) and a mechanical lung model. Open tubes of variable lengths were connected for leak simulation. Leak flow was measured with the flow-through technique. In a leak-free system the mean relative volume error +/-SD was 3.5 +/- 2.6% (2-10 ml) and 5.9 +/- 0.7% (20-60 ml), respectively. The influence of CPAP level, driving flow, respiratory rate and humidification of the breathing gas on the volume error was negligible. However, an increasing F(i)O(2) caused the measured tidal volume to increase by up to 25% (F(i)O(2) = 1.0). The relative error +/- SD of the leak measurements was -0.2 +/- 11.9%. For leaks > 19%, measured tidal volume was underestimated by more than 10%. In conclusion, the present in vitro study showed that the Leoni allowed accurate volume monitoring under CPAP conditions similar to neonates. Air leaks of up to 90% of patient flow were reliably detected. For an F(i)O(2) > 0.4 and for leaks > 19%, a numerical correction of the displayed volume should be performed.

The lung clearance index in young infants: impact of tidal volume and dead space.

Lung clearance index (LCI), measured by multiple breath washout (MBW), is one of the most frequently used measures of ventilation inhomogeneity. This study was designed to investigate the effect of lung volumes on LCI in young infants. The dependence of LCI on dead space volume (VD), tidal volume (VT) and functional residual capacity (FRC) was investigated by mathematical modeling and by MBW measurements using sulfur hexafluoride (SF6) as a tracer gas. MBW was performed in 150 infants, of median postmenstrual age 46.7 weeks, followed up after neonatal intensive care. Wheezing was assessed in 90 of these infants by computerized respiratory sound analysis during quiet sleep. The strongest correlation was observed between LCI and the volume ratios VT/FRC (Spearman rank order correlation coefficient Rs = 0.688, p < 0.001), VD/VT (Rs = 0.733, p < 0.001) and VD/FRC (Rs = 0.854, p < 0.001). LCI calculated from VD, VT, and FRC was linearly related to measured LCI with a coefficient of determination of 75%. There were no significant differences between wheezers and non-wheezers in postmenstrual age and body weight, but FRC was significantly increased (p < 0.001) and median (interquartile range) LCI significantly decreased (5.83 (5.45-6.51) versus (6.54 (6.03-7.22), p < 0.001) in wheezing compared to non-wheezing infants. Model calculations also showed that LCI was significantly reduced in wheezing infants (5.09 (4.79-5.62) versus 5.43 (5.08-5.82), p < 0.018), indicating that the reduction can be explained by differences in the lung volumes, not by improved ventilation homogeneity. In conclusion, the strong dependence of LCI on lung volumes in young infants can lead to misinterpretations regarding the homogeneity of alveolar ventilation.

Mechanism of action of novel lung edema therapeutic AP301 by activation of the epithelial sodium channel.

AP301 [Cyclo(CGQRETPEGAEAKPWYC)], a cyclic peptide comprising the human tumor necrosis factor lectin-like domain (TIP domain) sequence, is currently being developed as a treatment for lung edema and has been shown to reduce extravascular lung water and improve lung function in mouse, rat, and pig models. The current paradigm for liquid homeostasis in the adult mammalian lung is that passive apical uptake of sodium via the amiloride-sensitive epithelial Na+ channel (ENaC) and nonselective cyclic-nucleotide–gated cation channels creates the major driving force for reabsorption of water through the alveolar epithelium in addition to other ion channels such as potassium and chloride channels. AP301 can increase amiloride-sensitive current in A549 cells as well as in freshly isolated type II alveolar epithelial cells from different species. ENaC is expressed endogenously in all of these cell types. Consequently, this study was undertaken to determine whether ENaC is the specific target of AP301. The effect of AP301 in A549 cells as well as in human embryonic kidney cells and Chinese hamster ovary cells heterologously expressing human ENaC subunits (α, β, γ, and δ) was measured in patch clamp experiments. The congener TIP peptide AP318 [Cyclo(4-aminobutanoic acid-GQRETPEGAEAKPWYD)] activated ENaC by increasing single-channel open probability. AP301 increased current in proteolytically activated (cleaved) but not near-silent (uncleaved) ENaC in a reversible manner. αβγ- or δβγ-ENaC coexpression was required for maximal activity. No increase in current was observed after deglycosylation of extracellular domains of ENaC. Thus, our data suggest that the specific interaction of AP301 with both endogenously and heterologously expressed ENaC requires precedent binding to glycosylated extracellular loop(s).

A FIM study to assess safety and exposure of inhaled single doses of AP301-A specific ENaC channel activator for the treatment of acute lung injury.

AP301 is an activator of ENaC‐mediated Na+ uptake for the treatment of pulmonary permeability edema in acute respiratory distress syndrome (ARDS). The purpose of this “first‐in‐man” study was to examine local and systemic safety and systemic exposure of ascending single doses of AP301, when inhaled by healthy male subjects. In a double‐blind, placebo‐controlled study, 48 healthy male subjects were randomized to 6 ascending dose groups (single doses up to 120 mg) of 8 subjects each (3:1 randomization of AP301: placebo). Serial assessments included spirometry, exhaled nitric oxide (eNO), vital signs, ECG, safety laboratory, adverse events (AE), and blood samples for the quantification of AP301 in plasma. Descriptive statistics was applied. All 48 subjects received treatment, and completed the study as per protocol. No serious, local (e.g., hoarseness, cough, bronchospasm), or dose‐limiting AEs were noted. None of the assessments indicated notable dose or time‐related alterations of safety outcomes. Observed AP301 systemic exposure levels were very low, with mean Cmax values of <2.5 ng/mL in the highest dose groups. Inhaled AP301 single doses up to 120 mg were safe and well tolerated by healthy male subjects. Distribution of inhaled AP301 was largely confined to the lung, as indicated by very low AP301 systemic exposure levels.

Prophylactic Early Erythropoietin for Neuroprotection in Preterm Infants: A Meta-analysis

This meta-analysis of RCTs investigates whether prophylactic recombinant erythropoietin in preterm infants improves neurodevelopmental outcomes at 18 to 24 months’ corrected age. CONTEXT: Recombinant human erythropoietin (rhEPO) is a promising pharmacological agent for neuroprotection in neonates. OBJECTIVE: To investigate whether prophylactic rhEPO administration in very preterm infants improves neurodevelopmental outcomes in a meta-analysis of randomized controlled trials (RCTs). DATA SOURCES: Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched in December 2016 and complemented by other sources. STUDY SELECTION: RCTs investigating the use of rhEPO in preterm infants versus a control group were selected if they were published in a peer-reviewed journal and reported neurodevelopmental outcomes at 18 to 24 months’ corrected age. DATA EXTRACTION: Data extraction and analysis followed the standard methods of the Cochrane Neonatal Review Group. The primary outcome was the number of infants with a Mental Developmental Index (MDI) <70 on the Bayley Scales of Infant Development. Secondary outcomes included a Psychomotor Development Index <70, cerebral palsy, visual impairment, and hearing impairment. RESULTS: Four RCTs, comprising 1133 infants, were included in the meta-analysis. Prophylactic rhEPO administration reduced the incidence of children with an MDI <70, with an odds ratio (95% confidence interval) of 0.51 (0.31–0.81), P < .005. The number needed to treat was 14. There was no statistically significant effect on any secondary outcome. CONCLUSIONS: Prophylactic rhEPO improved the cognitive development of very preterm infants, as assessed by the MDI at a corrected age of 18 to 24 months, without affecting other neurodevelopmental outcomes. Current and future RCTs should investigate optimal dosing and timing of prophylactic rhEPO and plan for long-term neurodevelopmental follow-up.

Influence of nose and mouth leaks on peripheral oxygen saturation during continuous positive airway pressure in neonates.

BackgroundNose and mouth leaks impair effective pressure transmission during neonatal continuous positive airway pressure (CPAP), but little is known about how these leaks affect physiological parameters. This study investigated the influence of nose leaks and spontaneous mouth opening on peripheral oxygen saturation (SpO2) and respiratory rate (RR) using nasopharyngeal CPAP.MethodsIn 32 neonates with a gestational age of 30 (24–38) weeks and a birth weight of 1435 (710–2730) g, SpO2 and RR measurements were taken with and without occlusion of the contralateral nostril in a randomized cross-over trial in 1-minute intervals over a 10-minute period during each condition. Mouth opening and newborn activity were documented.ResultsSpO2 with open nostril was comparable to that with occluded nostril [93 (78.5–99.5)% vs. 94 (80–100)%, P=0.20]. RR decreased from 51 (26–82)/min to 48 (32–85)/min (P=0.027). In infants with an SpO2≤93% during open nostril (n=17), SpO2 increased after nostril occlusion [91 (80–96)% vs. 89.5 (78.5–93)%, P=0.036]. The mouth was open in 78.5% of measurements with open nostril, and in 87.4% of measurements after nostril occlusion (P=0.005). No significant influence of mouth opening or closure on SpO2 or RR was detected.ConclusionsIn neonates on unilateral nasopharyngeal CPAP with an SpO2 ≤93%, occlusion of the contralateral nostril significantly increased SpO2 and reduced RR. The beneficial physiological effects further support using binasal prongs to minimize nose leaks in this population. Future studies should investigate the beneficial effects of reducing mouth leaks when applying CPAP to these infants.