Lung Fluid Clearance Research Articles

IL-1 promotes α-epithelial Sodium Channel (α-ENaC) expression in murine lung epithelial cells: involvement of NF-κB.

Intra-amniotic exposure to proinflammatory cytokines such as interleukin-1 (IL-1) correlates with a decreased incidence of respiratory distress syndrome (RDS) in infants following premature birth. At birth, inadequate absorption of fluid from the fetal lung contributes to the onset RDS. Lung fluid clearance is coupled to Na+ transport via epithelial sodium channels (ENaC). In this study, we assessed the effects of IL-1 on the expression of ENaC, particularly the α-subunit which is critical for fetal lung fluid clearance at birth. Cultured mouse lung epithelial (MLE-12) cells were treated with either IL-1α or IL-1β to determine their effects on α-ENaC expression. Changes in IL-1-induced α-ENaC levels in the presence of IL-1 receptor antagonist (IL-1ra), cycloheximide, NF-κB inhibitor, and MAP kinase inhibitors were investigated. IL-1α and IL-1β independently induced a significant increase of α-ENaC mRNA and protein after 24h compared to untreated cells. IL-1-dependent increases in α-ENaC protein were mitigated by IL-1ra and cycloheximide. IL-1 exposure induced NF-κB binding activity. Attenuation of IL-1-induced NF-κB activation by its inhibitor SN50 decreased α-ENaC protein abundance. Inhibition of ERK 1,2 MAPK significantly decreased both IL-1α and β-induced α-ENaC protein expression whereas inhibition of p38 MAPK only blocked IL-1β-induced α-ENaC protein levels. In contrast, IL-1-induced α-ENaC protein levels were unaffected by a c-Jun N-terminal kinase (JNK) inhibitor. Our results suggest that in MLE-12 cells, IL-1-induced elevation of α-ENaC is mediated via NF-κB activation and in part involves stimulation of the ERK 1,2 and p38 MAPK signaling pathways.

Postnatal gene expression of airway epithelial sodium transporters associated with birth stress in humans.

Lung fluid clearance is essential for successful postnatal pulmonary adaptation. The epithelial sodium channel (ENaC) and Na-K-ATPase, induced by serum- and glucocorticoid-inducible kinase 1 (SGK1) as well as aquaporins (AQP), represent key players in the switch from fetal lung fluid secretion to absorption and in early postnatal lung fluid balance. Birth stress, including a surge in catecholamines, promotes pulmonary adaptation, likely through the augmentation of epithelial sodium reabsorption. We sought to determine the changes in the airway gene expression of molecules vital to epithelial sodium transport during early pulmonary adaptation, and the association with birth stress reflected in the norepinephrine concentration in the cord blood in humans. We included 70 term newborns: 28 born via vaginal delivery and 42 via elective cesarean section. We determined the norepinephrine concentrations in the cord blood using tandem mass spectrometry and collected nasal epithelial cell samples at 2 min, 1 h, and 24 h postnatally to quantify ENaC, Na-K-ATPase, AQP5, and SGK1 mRNAs using RT-PCR. The molecular gene expression involved in airway epithelium sodium transport changed markedly within the first hour postnatally. Newborns born via elective cesarean section exhibited a lower expression of ENaC, Na-K-ATPase, and SGK1. Significant correlations existed between the expressions of ENaC, Na-K-ATPase, and SGK1, and the concentration of norepinephrine in the cord blood. The association of ENaC, Na-K-ATPase, and SGK1 expression with the cord blood norepinephrine concentration points to the importance of birth stress in promoting lung fluid clearance during early postnatal pulmonary adaptation.

Inhaled procaterol for the treatment of transient tachypnea of the newborn.

Transient tachypnea of the newborn (TTN) is a respiratory disorder that results from inadequate or delayed clearance of fetal lung fluid following delivery. At present, supportive care is generally practiced for the treatment of TTN. In this study, we focused on inhaled beta-agonists for the treatment of TTN, and the aim was to verify the efficacy and the safety of inhaled procaterol for the treatment of TTN. Inhaled procaterol or normal saline solution was administered to infants. Respiratory rate and mixed venous carbon dioxide (PvCO2 ) were evaluated as the primary outcomes. The duration of hospitalization, duration of oxygen therapy, and changes in respiratory support were evaluated as secondary outcomes. Thirty-seven neonates diagnosed with TTN were randomly assigned to the procaterol group (n = 18) or the placebo group (n = 19). There were no differences in PvCO2 or respiratory rate between the two groups before and after intervention. Median duration of oxygen therapy (3 days; IQR, 3-6.5 days vs 2 days, IQR, 2-4.75 days; P = 0.13) and of hospitalization (15 days; IQR, 11.25-20 days vs 11 days, IQR, 8-15.5 days; P = 0.14) were not significantly different. Inhaled procaterol was not effective for the treatment of TTN.

The effect of inhaled salbutamol on the outcomes of transient tachypnea of the newborn

BackgroundTransient tachypnea of the newborn (TTN) is a self-limiting disease that results from a reduction in the rate of lung fluid clearance in neonates. A delay in lung fluid absorption in neonates disrupts the transition from intrauterine to extrauterine life. Use of beta-adrenergic antagonists, such as salbutamol, accelerates lung fluid clearance. The current study aimed to evaluate the effect of inhaled salbutamol on the clinical progression of TTN treatment. MethodsIn the current triple-blind clinical trial, a total of 148 inpatients diagnosed with TTN were randomly divided into 2 groups. The treatment group (n = 74) received inhaled salbutamol and the placebo group (n = 74) received inhaled normal saline. The drug administration was started 6 h after birth and continued in the case of continued respiratory distress and the need for oxygen as adjuvant therapy for up to 72 h maximum after the initiation of treatment. To evaluate the response to treatment with inhaled salbutamol, we assessed the respiratory rate (RR), heart rate (HR), fraction of inspired oxygen (FIO2) level, and O2 saturation at intervals of 30 min as well as 1 h and 4 h after drug administration. The results were compared between the groups. ResultsThe results of the current study indicated a significant difference between the treatment and placebo groups in the treatment duration, hospitalization duration, need for continuous positive airway pressure therapy (CPAP), and time of oral feeding initiation. In addition, no complication was observed during the treatment. It is noteworthy that, following the improvement of disease symptoms and reduction of hospitalization. This reduction may decrease the treatment costs and anxiety of parents, which was associated with proper mental and economic outcomes. ConclusionAlthough, in the current study, drug administration was continued for 72 h maximum, the prescription of at most 4 doses of salbutamol may have had maximum efficiency in the remediation process. To evaluate the therapeutic role of inhaled salbutamol, further studies are recommended.

Providing Ventilation to the Newborn Infant in the Delivery Room

* Abbreviations: BPD: : bronchopulmonary dysplasia CPAP: : continuous positive airway pressure ETT: : endotracheal tube FiO2: : fraction of inspired oxygen NRP: : Neonatal Resuscitation Program PEEP: : positive end-expiratory pressure PIP: : peak inspiratory pressure PPV: : positive pressure ventilation Ventilating the lungs of the newborn is the most important element of neonatal resuscitation. Recognizing and delivering effective ventilation remains a critical skill for all attendants at a newborn delivery. After completing this article, readers should be able to: 1. Recognize the critical role of ventilation in the delivery room. 2. Identify the signs of effective ventilation. 3. Understand devices that deliver positive pressure ventilation. The Neonatal Resuscitation Program (NRP) emphasizes the importance of ventilation in the resuscitation of compromised newborns. (1) The purpose of this review is to explain the physiologic necessity of ventilation in newborn resuscitation and to describe the different methods of providing ventilation in the delivery room. We will also discuss the assessment of ventilation to ensure efficacy. Blood flow during fetal life is focused on perfusion of the brain and major organs with oxygenated blood and avoidance of fluid-filled lungs (Fig 1A). This blood flow is dependent on oxygenated umbilical venous blood from the placenta. Figure 1. A. Fetal circulation path. Only a small amount of blood travels to the lungs. There is no gas exchange in the lung. Blood returning to the right side of the heart from the umbilical vein has the highest oxygen saturation. B. Transitional circulation path. The infant breathes, pulmonary resistance decreases and blood travels to the lungs. Gas exchange occurs in the lungs. Blood returning to the left side of the heart from the lungs has the highest oxygen saturation. (From Textbook of Neonatal Resuscitation, 7th ed. , 2016. Reproduced with permission from the American Academy of Pediatrics.) Normal cardiopulmonary transition of the newborn from intra- to extrauterine life requires a rapid and complex process of fetal lung fluid clearance, expansion of the alveolar spaces with air, and redirection of cardiac output toward the lungs. All of these events take place independent of intervention …

Early rescue Neopuff for infants with transient tachypnea of newborn: a randomized controlled trial

Objective: To examine the efficacy of early continuous positive airway pressure (CPAP), delivered using a T-piece-based infant resuscitator (Neopuff) via a face mask, in reducing the severity and duration of transient tachypnea of the newborn (TTN) as well as testing a hypothesis suggesting that rapid clearance of fetal lung fluid to the circulation via CPAP would increase plasma B-type natriuretic peptide (BNP). Methods: A randomized controlled trial (NCT01859533) was conducted on 64 late preterm/term neonates, delivered by cesarean section and presented by respiratory distress shortly after birth. The Neopuff group included 34 neonates received 20 min of early CPAP and control group included 30 neonates received free flow O2. Plasma BNP was measured baseline and 2 h later. Results: The duration of tachypnea was shorter in Neopuff group with less need of neonatal intensive care unit admission and need of mechanical support (p < .05) with no effect on duration of hospitalization (p > .05). Plasma BNP showed no significant difference between pre- and post-Neopuff levels (p > .05). A positive correlation was found between BNP and duration of tachypnea as well as the length of hospitalization (p < .05) among Neopuff group. Conclusion: Early rescue CPAP reduces the duration and severity of respiratory distress among infants with TTN. Trial registration: ClinicalTrials.gov identifier: NCT01859533.

Influence of Inhaled Amiloride on Lung Fluid Clearance in Response to Normobaric Hypoxia in Healthy Individuals

To investigate the role of epithelial sodium channels (ENaC) on lung fluid clearance in response to normobaric hypoxia, 20 healthy subjects were exposed to 15 hours of hypoxia (fraction of inspired oxygen [FiO2] = 12.5%) on two randomized occasions: (1) inhaled amiloride (A) (1.5 mg/5 mL saline); and (2) inhaled saline placebo (P). Changes in lung fluid were assessed through chest computed tomography (CT) for lung tissue volume (TV), and the diffusion capacity of the lungs for carbon monoxide (DLCO) and nitric oxide (DLNO) for pulmonary capillary blood volume (VC). Extravascular lung water (EVLW) was derived as TV-VC and changes in the CT attenuation distribution histograms were reviewed. Normobaric hypoxia caused (1) a reduction in EVLW (change from baseline for A vs. P, -8.5% ± 3.8% vs. -7.9% ± 5.2%, p < 0.05), (2) an increase in VC (53.6% ± 28.9% vs. 53.9% ± 52.3%, p < 0.05), (3) a small increase in DLCO (9.6% ± 29.3% vs. 9.9% ± 23.9%, p > 0.05), and (4) CT attenuation distribution became more negative, leftward skewed, and kurtotic (p < 0.05). Acute normobaric hypoxia caused a reduction in lung fluid that was unaffected by ENaC inhibition through inhaled amiloride. Although possible amiloride-sensitive ENaC may not be necessary to maintain lung fluid balance in response to hypoxia, it is more probable that normobaric hypoxia promotes lung fluid clearance rather than accumulation for the majority of healthy individuals. The observed reduction in interstitial lung fluid means alveolar fluid clearance may not have been challenged.

Dexmedetomidine enhances human lung fluid clearance through improving alveolar sodium transport.

Accumulating evidence shows that dexmedetomidine can attenuate lung edema with acute lung injury in experimental mouse and rat models, but the mechanisms of dexmedetomidine on human alveolar fluid transport are still unknown. We measured the effects of dexmedetomidine on alveolar fluid clearance in human lung lobes ex vivo. Moreover, we measured the regulation of transepithelial Na+ transport by dexmedetomidine in H441 cells by electrophysiological technique and Western blot method. Our results showed that intratracheal instillation of dexmedetomidine markedly increased the reabsorption of 5% bovine serum albumin instillate (19.8 ± 1.4%, P < 0.01 vs. Control, n = 5). Further studies suggested that dexmedetomidine increased amiloride-sensitive short-circuit currents in permeabilized H441 monolayers and whole cell amiloride-sensitive Na+ currents in a dose-dependent fashion. Real-time PCR and Western blot results showed that dexmedetomidine could enhance the mRNA and protein expression of α-ENaC subunit, while inhibiting the phosphorylation of ERK1/2 . These data demonstrate that dexmedetomidine could improve human lung fluid clearance and lung epithelial Na+ channel activity, and these effects may be mediated through the enhancement of α-ENaC expression and inhibition of ERK1/2 pathway.

Nadph oxidase and epithelial sodium channels regulate neonatal mouse lung development

Background: Epithelial sodium channels (ENaC) play critically important roles in lung fluid clearance at birth. We have previously shown that Nadph oxidase (NOX)-derived reactive oxygen species signaling activates ENaC and promotes alveolar fluid clearance. In this study, we examined a new physiological role for NOX-mediated ENaC activity in mouse lung development. Methods: NOX isoform and ENaC subunit mRNA levels were evaluated in preterm and neonatal C57Bl6 mouse lung using real-time PCR analysis. Newborn mice were intra-nasally treated with 1 mM amiloride, 100 mM NSC 23766, or 300 mM apocynin during postnatal days 1–15 to study development. Lung development was assessed using hematoxylin and eosin (H&E) staining, coupled with radial alveolar counts (RAC) and mean linear intercept (MLI) measurements. Results: ENaC subunits and NOX1-4 mRNA were detected in mouse lung during late gestation, birth, and postnatally. Inhibition of Rac-1-mediated-NOX signaling indicates functional (Rac-dependent) NOX1-3 isoforms in newborn lung, determined by dihydroethidium (DHE) detection of reactive oxygen species production in postnatal (PN) day 7 mouse lung. Amiloride inhibition of ENaC activity, NSC 23766 inhibition of Rac1, and apocynin inhibition of pan NOX activity attenuated normal alveolar development in mouse lung. Conclusion: NOX and ENaC play important roles in mouse lung development.

Nanocurcumin accords protection against acute hypobaric hypoxia induced lung injury in rats.

Decline in oxygen availability experienced under hypobaric hypoxia (HH) mediates imbalance in lung fluid clearance and is a causative agent of acute lung injury. Here, we investigate the pathological events behind acute HH mediated lung injury and assess the therapeutic efficacy of nanocurcumin in its amelioration. We assess the protective efficacy of nanotized curcumin (nanocurcumin) in ameliorating HH induced lung injury and compare to curcumin. Rats exposed to acute HH (6, 12, 24, 48 and 72h) were subjected to histopathology, blood-gas analysis and clinical biochemistry, cytokine response and redox damage. HH induced lung injury was analysed using markers of lung injury due to pulmonary vasoconstriction (ET-1/2/3 and endothelin receptors A and B) and trans-vascular fluid balance mediator (Na+/K+ ATPase). The protective efficacy of nanocurcumin was analysed by examination of Akt/Erk signalling cascade by western blot. HH induced lung injury was associated with discrete changes in blood analytes, differential circulatory cytokine response and severe pulmonary redox damages. Up-regulation of ET-1/2/3 and its receptors along with down-regulation of Na+/K+ ATPase confirmed defective pulmonary fluid clearance which promoted edema formation. Nanocurcumin treatment prevented lung edema formation and restored expression levels of ET-1/2/3 and its receptors while restoring the blood analytes, circulatory cytokines and pulmonary redox status better than curcumin. Modulation in Akt/Erk signalling pathway in rat lungs under HH confirmed the protective efficacy of nanocurcumin.

Real-time X-ray Imaging of Lung Fluid Volumes in Neonatal Mouse Lung.

At birth, the lung undergoes a profound phenotypic switch from secretion to absorption, which allows for adaptation to breathing independently. Promoting and sustaining this phenotype is critically important in normal alveolar growth and gas exchange throughout life. Several in vitro studies have characterized the role of key regulatory proteins, signaling molecules, and steroid hormones that can influence the rate of lung fluid clearance. However, in vivo examinations must be performed to evaluate whether these regulatory factors play important physiological roles in regulating perinatal lung liquid absorption. As such, the utilization of real time X-ray imaging to determine perinatal lung fluid clearance, or pulmonary edema, represents a technological advancement in the field. Herein, we explain and illustrate an approach to assess the rate of alveolar lung fluid clearance and alveolar flooding in C57BL/6 mice at post natal day 10 using X-ray imaging and analysis. Successful implementation of this protocol requires prior approval from institutional animal care and use committees (IACUC), an in vivo small animal X-ray imaging system, and compatible molecular imaging software.

Relationship Between The Change In DLCO With Albuterol And The Change In DLCO With Exercise

Stimulation of the Beta2 Adrenergic Receptors (B2AR) induces lung fluid clearance through Epithelial Sodium channels (ENaC) on alveolar cells. We previously demonstrated that both albuterol and exercise increase the diffusing capacity of the lung (DLCO), alveolar-capillary membrane conductance (DM), and DM corrected for pulmonary capillary blood volume (Vc)(DM/Vc). The improvement in diffusing capacity with exercise could be a direct result of B2AR stimulation or simply an increase in lymphatic drainage due to augmentations in tidal volume (Vt) and minute ventilation (VE). PURPOSE: To investigate the relationship of the change in DLCO (and components, DM and Vc) with albuterol and the change in DLCO and components with exercise to determine B2AR involvement. METHODS: Healthy participants (N=30) completed a maximal VO2 test for baseline capacity, followed by 2 visits measuring lung diffusing capacity for carbon monoxide and nitric oxide, and functional ventilatory parameters. Measurements were taken at rest and 30-minutes post-albuterol administration or at peak exercise. RESULTS: At rest and at peak exercise there were significant relationships in DLCO, DM, and DM/Vc between the albuterol visit and the exercise visit (DLCO: r=0.90 and 0.78, DM: r=0.77 and 0.67, DM/Vc: r=0.58 and 0.48 for rest and peak exercise, respectively, p<0.05 for all). Exercise resulted in a significant increase in DLCO and DM, when compared to albuterol (DLCO=45±16% vs. 0.78±7.6%, DM=40±24% vs. 2.8±13% for exercise and albuterol, respectively, p<0.05). There was no relationship between changes in DLCO and DM with albuterol when compared to changes with exercise, but the change in DM/Vc under the two conditions was trending towards significance (r=0.35, DM/Vc=11.5±8.3% and DM/Vc=6.4±5.2% for exercise and albuterol, respectively, p=0.06). There was a significant relationship (p<0.05) between the change in Vt and DLCO with exercise, but not with albuterol. CONCLUSIONS: The relationship between lung diffusion parameters at peak exercise and following beta-agonist stimulation suggest that at least a portion of this increase is mediated by the B2AR. However, DLCO, considered to be a gross measure of the components of lung diffusion, is influenced by changes in ventilation with exercise. Supported by NIH Grant RO1 HL108962-05.

Albuterol Improves Alveolar-Capillary Membrane Conductance in Healthy Humans.

BACKGROUNDBeta-2 adrenergic receptors (β2ARs) are located throughout the body including airway and alveolar cells. The β2ARs regulate lung fluid clearance through a variety of mechanisms including ion transport on alveolar cells and relaxation of the pulmonary lymphatics. We examined the effect of an inhaled β2-agonist (albuterol) on alveolar-capillary membrane conductance (DM) and pulmonary capillary blood volume (VC) in healthy humans.METHODSWe assessed the diffusing capacity of the lungs for carbon monoxide (DLCO) and nitric oxide (DLNO) at baseline, 30 minutes, and 60 minutes following nebulized albuterol (2.5 mg, diluted in 3 mL normal saline) in 45 healthy subjects. Seventeen subjects repeated these measures following nebulized normal saline (age = 27 ± 9 years, height = 165 ± 21 cm, weight = 68 ± 12 kg, BMI = 26 ± 9 kg/m2). Cardiac output (Q), heart rate, systemic vascular resistance (SVR), blood pressure, oxygen saturation, forced expiratory volume at one-second (FEV1), and forced expiratory flow at 50% of forced vital capacity (FEF50) were assessed at baseline, 30 minutes, and 60 minutes following the administration of albuterol or saline.RESULTSAlbuterol resulted in a decrease in SVR, and an increase in Q, FEV1, and FEF50 compared to saline controls. Albuterol also resulted in a decrease in VC at 60 minutes post albuterol. Both albuterol and normal saline resulted in no change in DLCO or DM when assessed alone, but a significant increase was observed in DM when accounting for changes in VC.CONCLUSIONThese data suggest that nebulized albuterol improves pulmonary function in healthy humans, while nebulization of both albuterol and saline results in an increase in DM/VC.

Microvesicles Derived From Human Mesenchymal Stem Cells Restore Alveolar Fluid Clearance in Human Lungs Rejected for Transplantation

The need to increase the donor pool for lung transplantation is a major public health issue. We previously found that administration of mesenchymal stem cells "rehabilitated" marginal donor lungs rejected for transplantation using ex vivo lung perfusion. However, the use of stem cells has some inherent limitation such as the potential for tumor formation. In the current study, we hypothesized that microvesicles, small anuclear membrane fragments constitutively released from mesenchymal stem cells, may be a good alternative to using stem cells. Using our well established ex vivo lung perfusion model, microvesicles derived from human mesenchymal stem cells increased alveolar fluid clearance (i.e. ability to absorb pulmonary edema fluid) in a dose-dependent manner, decreased lung weight gain following perfusion and ventilation, and improved airway and hemodynamic parameters compared to perfusion alone. Microvesicles derived from normal human lung fibroblasts as a control had no effect. Co-administration of microvesicles with anti-CD44 antibody attenuated these effects, suggesting a key role of the CD44 receptor in the internalization of the microvesicles into the injured host cell and its effect. In summary, microvesicles derived from human mesenchymal stem cells were as effective as the parent mesenchymal stem cells in rehabilitating marginal donor human lungs.

Dopamine treatment does not need speed recovery of newborns from transient tachypnea

Transient tachypnea of the newborn (TTN) results from inadequate neonatal lung fluid clearance. Low-dose dopamine induces natriuresis in the kidneys and it has been assumed that, at this low dosage, dopamine increases renal perfusion in critically ill patients. Medium doses have positive inotropic and chronotropic effects via increased β-receptor activation. Recent studies have demonstrated that dopamine stimulates the clearance of pulmonary edema. Furthermore, β-adrenergic agonists regulate Na+ channels and Na-K-ATPase activity in the pulmonary epithelium. This study investigated the effect of dopamine at different dosages on TTN treatment. A prospective controlled study examined 60 infants with TTN older than 34 weeks of gestation who required at least 24 h of O2 and nasal continuous positive airway pressure (nCPAP) treatment. The infants were randomized into three groups of 20: controls, infants treated with low-dose dopamine (3 μg/kg/min), and infants treated with a medium dose (5 μg/kg/min). The control and study groups were compared in terms of the requirement for mechanical ventilation, and the durations of nCPAP, oxygen requirement, and hospitalization. The requirement for mechanical ventilation, and durations of nCPAP, oxygen requirement, and hospitalization did not differ significantly among the three groups (P=0.54, 0.16 and 0.11, respectively). Dopamine treatment in low-moderate doses does not improve the outcome in TTN. Thus, further studies in this area are needed.

Fluid restriction in the management of transient tachypnea of the newborn

Background Transient tachypnea of the newborn (TTN) is caused by delayed clearance of lung fluid at birth. TTN typically appears within the first two hours of life in term and late preterm neonates and is characterized by tachypnea and signs of respiratory distress. Although it is usually a self-limited condition, admission to a neonatal unit is frequently required for monitoring and providing respiratory support. Restricting intake of fluids administered to these infants in the first days of life might improve clearance of lung liquid, thus reducing the effort required to breathe, improving respiratory distress, and potentially reducing the duration of tachypnea. Objectives To evaluate the efficacy and safety of restricted fluid therapy as compared to standard fluid therapy in decreasing the duration of oxygen administration and the need for noninvasive or invasive ventilation among neonates with TTN. Search methods We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 12), in the Cochrane Library; Ovid MEDLINE and electronic ahead of print publications, in-process & other non-indexed citations, Daily and Versions(R); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), on December 6, 2019. We also searched clinical trial databases and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. Selection criteria We included randomized controlled trials (RCTs), quasi-RCTs, and cluster trials on fluid restriction in term and preterm neonates with the diagnosis of TTN or delayed adaptation during the first week after birth. Data collection and analysis For each of the included trials, two review authors independently extracted data (e.g. number of participants, birth weight, gestational age, duration of oxygen therapy, need for continuous positive airway pressure [CPAP], need for mechanical ventilation, duration of mechanical ventilation) and assessed the risk of bias (e.g. adequacy of randomization, blinding, completeness of follow-up). The primary outcome considered in this review was the duration of supplemental oxygen therapy in hours or days. We used the GRADE approach to assess the certainty of evidence. Main results Four trials enrolling 317 infants met the inclusion criteria. Three trials enrolled late preterm and term infants with TTN, and the fourth trial enrolled only term infants with TTN. Infants were on various methods of respiratory support at the time of enrollment including room air, oxygen, or nasal CPAP. Infants in the fluid-restricted group received 15 to 20 mL/kg/d less fluid than those in the control group for varying durations after enrollment. Two studies had high risk of selection bias, and three out of four had high risk of performance bias. Only one study had low risk of detection bias, with two at high risk and one at unclear risk. The certainty of evidence for all outcomes was very low due to imprecision of estimates and unclear risk of bias. Two trials reported the primary duration of supplemental oxygen therapy. We are uncertain whether fluid restriction decreases or increases the duration of supplemental oxygen therapy (mean difference [MD] -12.95 hours, 95% confidence interval [CI] -32.82 to 6.92; I² = 98%; 172 infants). Similarly, there is uncertainty for various secondary outcomes including incidence of hypernatremia (serum sodium > 145 mEq/L, risk ratio [RR] 4.0, 95% CI 0.46 to 34.54; test of heterogeneity not applicable; 1 trial, 100 infants), hypoglycemia (blood glucose Authors' conclusions We found limited evidence to establish the benefits and harms of fluid restriction in the management of TTN. Given the very low certainty of available evidence, it is impossible to determine whether fluid restriction is safe or effective for management of TTN. However, given the simplicity of the intervention, a well-designed trial is justified.

Empirical Antibiotic Therapy in Transient Tachypnea of the Newborn

Purpose: Transient tachypnea of the newborn (TTN) is a respiratory disorder resulting from delayed clearance of fetal lung fluid. Initiation of empiric antibiotic therapy for possible early-onset sepsis is usually recommended until negative blood cultures for 48 hours. The aim of this study was to compare outcomes of infants with TTN managed with a risk-factor-based restrictive antibiotic use policy. Methods: A single institution retrospective study was conducted on full-term infants admitted with TTN from January, 2008 to December, 2013. Infants were stratified into two groups based on whether they received or did not receive antibiotics. The decision to administer antibiotics depended upon the covering physician at admission. The clinical and laboratory outcomes were evaluated between two groups. Result: A total of 98 full-term infants diagnosed with TTN were admitted to the neonatal intensive care unit; of them 39 (39.8%) received and 59 (60.2%) did not receive antibiotics. Physicians had tendency to start antibiotics in patient with mild-to-moderate chest retraction, need oxygen therapy, high white blood cell count, segmented neutrophil and positive C-reactive protein. All of them had negative blood cultures, no readmission, and no late-onset sepsis. The duration of hospital stay was longer in patients received antibiotics group (10.7±3.0 days vs. 9.0±4.4 days, P=0.04). Conclusion: This study suggests that empiric antibiotic therapy may not be recommended for full-term infants with classic TTN without perinatal risk factors. With the application of strict criteria for classic TTN and the close observation, the empiric use of antibiotics may be avoidable.

Receptor for advanced glycation end-products regulates lung fluid balance via protein kinase C-gp91(phox) signaling to epithelial sodium channels.

The receptor for advanced glycation end-products (RAGE), a multiligand member of the Ig family, may play a crucial role in the regulation of lung fluid balance. We quantified soluble RAGE (sRAGE), a decoy isoform, and advanced glycation end-products (AGEs) from the bronchoalveolar lavage fluid of smokers and nonsmokers, and tested the hypothesis that AGEs regulate lung fluid balance through protein kinase C (PKC)-gp91(phox) signaling to the epithelial sodium channel (ENaC). Human bronchoalveolar lavage samples from smokers showed increased AGEs (9.02 ± 3.03 μg versus 2.48 ± 0.53 μg), lower sRAGE (1,205 ± 292 pg/ml versus 1,910 ± 263 pg/ml), and lower volume(s) of epithelial lining fluid (97 ± 14 ml versus 133 ± 17 ml). sRAGE levels did not predict ELF volumes in nonsmokers; however, in smokers, higher volumes of ELF were predicted with higher levels of sRAGE. Single-channel patch clamp analysis of rat alveolar epithelial type 1 cells showed that AGEs increased ENaC activity measured as the product of the number of channels (N) and the open probability (Po) (NPo) from 0.19 ± 0.08 to 0.83 ± 0.22 (P = 0.017) and the subsequent addition of 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine-N-oxyl decreased ENaC NPo to 0.15 ± 0.07 (P = 0.01). In type 2 cells, human AGEs increased ENaC NPo from 0.12 ± 0.05 to 0.53 ± 0.16 (P = 0.025) and the addition of 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine-N-oxyl decreased ENaC NPo to 0.10 ± 0.03 (P = 0.013). Using molecular and biochemical techniques, we observed that inhibition of RAGE and PKC activity attenuated AGE-induced activation of ENaC. AGEs induced phosphorylation of p47(phox) and increased gp91(phox)-dependent reactive oxygen species production, a response that was abrogated with RAGE or PKC inhibition. Finally, tracheal instillation of AGEs promoted clearance of lung fluid, whereas concomitant inhibition of RAGE, PKC, and gp91(phox) abrogated the response.

Effects of Sustained Lung Inflation, a lung recruitment maneuver in primary acute respiratory distress syndrome, in respiratory and cerebral outcomes in preterm infants

BackgroundSustained Lung Inflation (SLI) is a maneuver of lung recruitment in preterm newborns at birth that can facilitate the achieving of larger inflation volumes, leading to the clearance of lung fluid and formation of functional residual capacity (FRC). AimTo investigate if Sustained Lung Inflation (SLI) reduces the need of invasive procedures and iatrogenic risks. Study design78 newborns (gestational age≤34weeks, weighing≤2000g) who didn't breathe adequately at birth and needed to receive SLI in addition to other resuscitation maneuvers (2010 guidelines). Subjects78 preterm infants born one after the other in our department of Neonatology of Catania University from 2010 to 2012. Outcome measuresThe need of intubation and surfactant, the ventilation required, radiological signs, the incidence of intraventricular hemorrhage (IVH), periventricular leukomalacia, retinopathy in prematurity from III to IV plus grades, bronchopulmonary dysplasia, patent ductus arteriosus, pneumothorax and necrotizing enterocolitis. ResultsIn the SLI group infants needed less intubation in the delivery room (6% vs 21%; p<0.01), less invasive mechanical ventilation (14% vs 55%; p≤0.001) and shorter duration of ventilation (9.1days vs 13.8days; p≤0.001). There wasn't any difference for nasal continuous positive airway pressure (82% vs 77%; p=0.43); but there was less surfactant administration (54% vs 85%; p≤0.001) and more infants received INSURE (40% vs 29%; p=0.17). We didn't found any differences in the outcomes, except for more mild intraventricular hemorrhage in the SLI group (23% vs 14%; p=0.15; OR=1.83). ConclusionSLI is easier to perform even with a single operator, it reduces the necessity of more complicated maneuvers and surfactant without statistically evident adverse effects.

Mechanical stretch induces lung α-epithelial Na+ channel expression

ABSTRACTDuring fetal development physiological stretching helps drive lung growth and maturation. At birth, the α-subunit of the alveolar epithelial sodium channel (α-ENaC) is a critical factor in helping to facilitate clearance of lung fluid during the perinatal period. The effects of stretch, however, on α-ENaC expression in the fetal lung have yet to be elucidated. In an effort to explore this question, we used both an in vitro cell culture model that exposes cells to repetitive cyclic stretch (CS) as well as an in vivo preterm animal model of mechanical ventilation (MV). We found that murine lung epithelial (MLE-12) cells exposed to repetitive CS showed a significant rise in α-ENaC mRNA expression. Total and cell-surface protein abundance of α-ENaC were also elevated after 24 h of CS. Stretch-induced increases in α-ENaC expression were suppressed in the presence of either actinomycin D or cycloheximide. Pharmacological inhibition of the extracellular signal-regulated protein kinase (ERK1/2) did not attenuate stretch-induced increases in α-ENaC protein, whereas inhibition of p38 MAPK or c-Jun NH2-terminal kinase (JNK) did. In 29-day preterm rabbits, alveolar stretching secondary to postnatal MV markedly elevated fetal lung α-ENaC expression compared to spontaneously breathing counterparts. In summary, our findings indicate that mechanical stretch promotes α-ENaC expression.