Ulrich Thome

Randomized comparison of high-frequency ventilation with high-rate intermittent positive pressure ventilation in preterm infants with respiratory failure

OBJECTIVE In a randomized, controlled, multicenter trial, we tested the hypothesis that high-frequency ventilation (HFV) with a high lung volume strategy results in fewer treatment failures than intermittent positive pressure ventilation (IPPV) with high rates and low peak inspiratory pressures. STUDY DESIGN Infants with a gestational age between >/=24 weeks and <30 weeks, requiring mechanical ventilation within 6 hours of birth, were randomly assigned to receive either IPPV or HFV until 240 hours after randomization, extubation, or meeting treatment failure criteria. Treatment failure, the primary end point, was determined when air leaks, an oxygenation index >35 to 45 (depending on gestational age), death, or chronic lung disease occurred. Chronic lung disease was defined as persistent requirement of mechanical ventilation, continuous positive airway pressure, or supplemental oxygen at a postmenstrual age of 36 weeks. Secondary end points included the incidence of intracranial hemorrhage. RESULTS The third scheduled interim analysis led to termination of the trial after recruitment of 284 infants. Treatment failure criteria were met by 46% of infants receiving IPPV and 54% of infants receiving HFV (1-tailed primary hypothesis, P =.92; 2-tailed chi2 test, P =.15). Air leaks occurred in 31% and 42% (P =.042), CLD in 23% and 25%, and grade 3-4 intracranial hemorrhage in 13% and 14% of IPPV-treated and HFV-treated patients, respectively. The mortality rate before discharge was 10% in both groups. CONCLUSION HFV with a high lung volume strategy did not cause less lung injury in preterm infants than IPPV with a high rate and low peak inspiratory pressures.

Outcome of extremely preterm infants randomized at birth to different PaCO2 targets during the first seven days of life.

Background: Ventilation with higher PaCO2 goals may reduce lung injury and bronchopulmonary dysplasia (BPD). The effect may be enhanced by using a higher PaCO2 goal than in previous trials. Objective: To determine the clinical benefits and safety of higher PaCO2 goals for ventilated preterm infants. Study Design: Preterm infants with a gestational age between 23 and 28 completed weeks receiving mechanical ventilation within 6 h of birth were randomized to be managed with either a PaCO2 target between 55 and 65 mm Hg (7.3– 8.7 kPa, minimal ventilation) or 35 and 45 mm Hg (4.7– 6.0 kPa, routine ventilation) for the first 7 days of life. The primary outcome measure was BPD, defined as need for mechanical ventilation or supplemental oxygen at 36 weeks postmenstrual age, or death. The neurodevelopmental status was assessed at 18–22 months corrected age. Results: The trial was stopped early after enrolling 31% of the projected sample size. Enrolled infants had a median birth weight of 640 g. BPD or death occurred in 21/33 (64%) infants after minimal ventilation and 19/32 (59%) infants after routine ventilation. Minimal ventilation was associated with trends towards higher mortality and higher incidence of neurodevelopmental impairment, and a significantly increased combined outcome of mental impairment or death (p < 0.05). Conclusion: Minimal ventilation as performed in this study did not improve clinical outcome, and may have been associated with a worse neurodevelopmental outcome.

Syntaxin 1A is expressed in airway epithelial cells, where it modulates CFTR Cl– currents

The CFTR Cl(-) channel controls salt and water transport across epithelial tissues. Previously, we showed that CFTR-mediated Cl(-) currents in the Xenopus oocyte expression system are inhibited by syntaxin 1A, a component of the membrane trafficking machinery. This negative modulation of CFTR function can be reversed by soluble syntaxin 1A peptides and by the syntaxin 1A binding protein, Munc-18. In the present study, we determined whether syntaxin 1A is expressed in native epithelial tissues that normally express CFTR and whether it modulates CFTR currents in these tissues. Using immunoblotting and immunofluorescence, we observed syntaxin 1A in native gut and airway epithelial tissues and showed that epithelial cells from these tissues express syntaxin 1A at >10-fold molar excess over CFTR. Syntaxin 1A is seen near the apical cell surfaces of human bronchial airway epithelium. Reagents that disrupt the CFTR-syntaxin 1A interaction, including soluble syntaxin 1A cytosolic domain and recombinant Munc-18, augmented cAMP-dependent CFTR Cl(-) currents by more than 2- to 4-fold in mouse tracheal epithelial cells and cells derived from human nasal polyps, but these reagents did not affect CaMK II-activated Cl(-) currents in these cells.

Ventilation strategies and outcome in randomised trials of high frequency ventilation

Objective: Randomised controlled trials comparing elective use of high frequency ventilation (HFV) with conventional mechanical ventilation (CMV) in preterm infants have yielded conflicting results. We hypothesised that the variability of results may be explained by differences in study design, ventilation strategies, delay in initiation of HFV, and use of permissive hypercapnia. Methods: Randomised controlled trials comparing the elective use of HFV with any form of CMV were identified. Trials were classified according to the ventilation strategies used for HFV and CMV and oscillator device employed. For cumulative meta-analyses, trials were arranged by the following covariables: mean duration until randomisation, Paco2 limits, publication date, and sample size. Odds ratios (OR) and 95% confidence intervals were calculated using fixed and random effects models. Results: Seventeen randomised trials enrolling 3776 patients were included. Unlike previous meta-analyses, there was no significant difference in the incidence of bronchopulmonary dysplasia or death (OR 0.87, 0.75–1.00) and severe intraventricular haemorrhage grade 3–4 (1.14, 0.96–1.37). The incidence of air leaks (OR 1.23, 1.06–1.44) was significantly increased with HFV. Subgroup analyses and cumulative meta-analyses demonstrated that trial results were related to the ventilation strategies used for HFV and CMV. No influence was found for mean time to randomisation, degree of permissive hypercapnia, or sample size. Conclusions: Heterogeneity among trials of elective HFV compared to CMV in preterm infants is mainly due to differences in ventilatory strategies. Optimising CMV strategy appeared to be as effective as using HFV in improving pulmonary outcome in preterm infants.

Comparison of pulmonary inflammatory mediators in preterm infants treated with intermittent positive pressure ventilation or high frequency oscillatory ventilation.

Ventilated preterm infants prone to the development of bronchopulmonary dysplasia have been shown to have increased inflammatory mediators in their tracheal aspirates. High frequency oscillatory ventilation (HFOV) is thought to be less traumatic than intermittent positive pressure ventilation (IPPV) in premature infants with surfactant deficiency, and therefore may reduce the inflammatory response in tracheobronchial aspirates. We randomized 76 premature infants requiring mechanical ventilation (birth weight 420-1830 g, median 840 g, gestational age 23 3/7 to 29 2/7 wk, median 26 4/7 to receive either an IPPV with a high rate (60-80/min) and low peak pressures, or an HFOV aiming at an optimization of lung volume, within 1 h of intubation. Tracheal aspirates were systematically collected during the first 10 d of life and analyzed for albumin, IL-8, leukotriene B4 (LTB4), and the secretory component (SC) for IgA as a reference protein. Bacterially colonized samples were excluded. On the treatment d 1, 3, 5, 7, and 10, the resulting median values of albumin (milligrams/mg of SC) were 28, 23, 24, 18, and 10, in IPPV-ventilated infants, and 33, 28, 18, 25, and 39 in HFOV-ventilated infants, respectively. Median IL-8 values (nanograms/mg of SC) were 671, 736, 705, 1362, and 1879 (IPPV) and 874, 1713, 1029, 1426, and 1823 (HFOV), respectively, and median LTB4 values (nanograms/mg of SC) were 26, 13, 27, 22, and 11 (IPPV) and 15, 12, 7, 12, and 16 (HFOV), respectively. Values were similar in IPPV- and HFOV-ventilated infants, and no significant differences were noted. We conclude that HFOV, when compared with a high rate low pressure IPPV, does not reduce concentrations of albumin, IL-8, and LTB4 in tracheal aspirates of preterm infants requiring mechanical ventilation.

Prenatal Estrogen and Progesterone Deprivation Impairs Alveolar Formation and Fluid Clearance in Newborn Piglets

Exposure to high levels of estradiol (E2) and progesterone (P) derived from the fetoplacentomaternal unit during the last trimester of pregnancy may play a crucial role in prenatal lung development and immediate postnatal alveolar fluid clearance (AFC). To measure prenatal alveolar formation and postnatal amiloride-sensitive AFC after pharmacological deprivation of E2 and P in utero, fetuses from five sows received an intramuscular depot injection of the E2 receptor blocker ICI 182.780 (ICI) and the P receptor blocker RTI 3021-022 (RTI) and fetuses of five other sows received a placebo injection (control group) during a laparotomy at 90 d of gestation (term gestation, 115 d). Piglets were delivered by cesarean section on d 114 of gestation. Of 95 live-born piglets, 35 were mechanically ventilated. The airways of the right lower lobe were isolated by a balloon catheter wedged in the bronchus and 5% albumin in 0.9% NaCl with or without 1 mmol/L amiloride was instilled. Amiloride-sensitive AFC was calculated from the protein concentration changes in fluid recovered after 120 min as the percentage of absorbed fluid. Lungs were removed under standardized conditions to perform alveolar counts. Prenatal treatment with ICI and RTI resulted in a significantly lower amiloride-sensitive AFC (median, 31%; min-max, –4–58) than placebo (74%, 18–231). Median alveolar counts per visual field were significantly lower in piglets that were exposed to ICI and RTI (38, 21–78) compared with placebo (56, 32–113). We conclude that prenatal E2 and P deprivation significantly impaired alveolar formation and amiloride-sensitive AFC.

Modulation of Sodium Transport in Alveolar Epithelial Cells by Estradiol and Progesterone

The effects of estradiol (E2) and progesterone (P) on alveolar epithelial Na+ transport were studied in isolated alveolar epithelial cells from 18- to 19-d GA rat fetuses, grown to confluence in serum-free media supplemented with E2 (0–1 μM) and P (0–2.8 μM). Short-circuit currents (ISC) were measured, showing an increase by E2 and P in a dose-dependent manner. The Na,K-ATPase subunits -α1 and -β1 were detected by Western blotting, but total expression was not significantly altered. Furthermore, all three epithelial Na+ channel (ENaC) subunits -α, -β, and -γ were detected, with trends toward a higher expression in the presence of E2 and P. Real-time PCR revealed an increase of α- and β-ENaC expression but no alteration of γ-ENaC. In addition, the mRNA expression of cystic fibrosis transmembrane conductance regulator (CFTR) and Na,K-ATPase-β1 subunit were elevated in the presence of E2 and P. Single-channel patch clamp analysis demonstrated putative highly selective and nonselective cation channels in the analyzed cells, with a higher percentage of responsive patches under the influence of E2 and P. We conclude that E2 and P increased Na+ transport in alveolar epithelial cells by enhancing the expression and activity of ENaC and Na,K-ATPase.

Comparison of lung volume measurements by antero-posterior chest X-ray and the SF6 washout technique in mechanically ventilated infants†

While anterior/posterior chest x‐rays (CXR) are routinely performed to estimate lung volume (LV) and adjust ventilator settings, the precise measurement of LV requires additional sophistication. In 31 infants ventilated because of surfactant deficiency (n = (23), bronchopulmonary dysplasia (n = 7), or pulmonary hypoplasia (n = 1) with either intermittent positive pressure (n = 18) or high frequency oscillation (n = 13) gestational age 23–39 weeks (median 26 weeks); birthweight 550–2780 g (median 840 g); age at measurement 1–91 days (median 6 days); weight at study time (WST) 675–3000 g (median 938 g), we investigated whether LV, as measured by the sulfur hexafluoride (SF6) washout technique, could by estimated from CXR by: (1) the sum (A+B) of the right (A) and left (B) lung fields areas; 2) the product (LxW) of the distances from the right apex to the right costophrenic angle (L) and between both costophrenic angles (W); (3) the diaphragm position relative to the posterior parts of the ribs (DP); and (4) the lung radiolucency (RL, grades 0–4). Correlations between A+B (r = 0.44) or LxW (r = 0.37) and LV were poor, but improved when A+B, LxW, and LV were normalized to WST: (A+B)/WST vs. LV/WST (r = 0.74), and LxW/WST vs. LV/WST (r = 0.67). DP (r = 0.13) and RL (Spearmans rho = 0.17) did not correlate with LV/WST. A multiple linear regression analysis led to the following best‐fit equation: LV/WST = 2.58 (A+B)/WST − 5.47 DP + 42.2 (r = 0.83). We concluded that an estimate of LV from CXR lacked sufficient accuracy. DP and RL did not correlate with LV measured by SF6 washout. Pediatr Pulmonol. 1998; 26:265–272.

Dynamics of Breathing during Partial Liquid Ventilation in Spontaneously Breathing Rabbits Supported by Elastic and Resistive Unloading

Partial liquid ventilation (PLV) has been shown to improve gas exchange in paralyzed animals and in humans with lung disease. This study tests the hypothesis that PLV combined with respiratory mechanical unloading results in stable ventilation and gas exchange in spontaneously breathing animals. Ten adult anesthetized, intubated, and spontaneously breathing rabbits received ventilatory support by respiratory mechanical unloading (FiO2 1.0). Minute ventilation, respiratory rate, esophageal pressure, heart rate, and arterial blood pressure were recorded continuously during gas ventilation for 1 h. Next, 30 mL/kg of perfluorocarbon was instilled into the endotracheal tube. Thereafter, data were recorded again for 1 h (PLV). Arterial blood gases were obtained at the end of each period. Variability of recorded data was assessed by calculating coefficients of variation using data obtained each minute. Compared with gas ventilation, minute ventilation was larger during PLV (275 ± 93 versus 368 ± 89 mL/kg/min.;p < 0.01). This was because of a higher respiratory rate during PLV (58 ± 23 versus 74 ± 18 breaths/min;p < 0.05), while tidal volume was similar. Compared with gas ventilation, PaO2 was lower during PLV (61.31 ± 5.32 versus 47.35 ± 8.38 kPa;p < 0.05). PaCO2, peak esophageal pressure deflections, heart rate, mean arterial blood pressure, and coefficients of variation for minute ventilation, tidal volume, respiratory rate, and peak esophageal pressure were not significantly different between modes. Compliance was decreased and resistance and work of breathing were increased during PLV. We conclude that stable ventilation and gas exchange may be achieved during PLV combined with mechanical unloading in spontaneously breathing animals without lung disease.

Novel SIN-1 reactive intermediates modulate chloride secretion across murine airway cells

We examined the effects of reactive oxygen-nitrogen intermediates on chloride (Cl-) currents across murine tracheal epithelial (MTE) cells isolated from CD-1 mice. MTE cells were cultured on permeable supports until they formed water-tight monolayers with transepithelial resistances (Rt)>500 Omega/cm2 and then were mounted in Ussing chambers. Baseline short-circuit current (ISC) values, prior to and following the addition of 10 microM amiloride (an inhibitor of sodium-transport pathways) into the apical side, were 65 +/- 1.9 microA/cm2 and 7.6 +/- 0.51 microA/cm2, respectively (X +/- 1 SE, n=32). The addition of 3-morpholinosydnominine (SIN-1, 1 mM), which generates both superoxide and nitric oxide anions, to amiloride-treated monolayers resulted in a transient increase of ISC to a peak value of 35 +/- 1.3 microA/cm2 (X +/- SE, n=14) within the next 30-60 min. After this, the ISC decreased gradually and returned to its pre-SIN-1 value. These changes were blocked by glibenclamide (200 microM), an inhibitor of cystic fibrosis transmembrane regulator, or reduced by glutathione (GSH, 5 mM), a scavenger of peroxynitrite. Forskolin (10 microM) augmented the SIN-1 effect when added at the peak of the SIN-1 response but not when ISC had returned to its baseline value. Perfusion of MTE cells with SIN-1 also increased whole cell Cl- currents 4-fold and the open probability of CFTR-type single-channel currents from 0.041 to 0.92 in a transient fashion. Decomposed SIN-1, but not pure SIN-1c (the stable decomposition product of SIN-1), also increased ISC with an EC50 of 5 microM. Electrospray mass spectroscopy revealed several unique and uncharacterized compounds formed during the decomposition of SIN-1 as well as the reaction of SIN-1c with peroxynitrite. Formation of these compounds was inhibited by GSH. We conclude that compounds formed by the reaction of peroxynitrite with by-products of SIN-1, rather than reactive oxygen-nitrogen species per se, were responsible for the modulation of Cl- secretion across primary cultures of MTE cells.