Nadir Yehya

Cyclic Stretch–Induced Oxidative Stress Increases Pulmonary Alveolar Epithelial Permeability

Mechanical ventilation with high tidal volumes has been associated with pulmonary alveolar flooding. Understanding the mechanisms underlying cyclic stretch-induced increases in alveolar epithelial permeability may be important in designing preventive measures for acute lung injury. In this work, we assessed whether cyclic stretch leads to the generation of reactive oxygen species in type I-like alveolar epithelial cells, which increase monolayer permeability via activation of NF-κB and extracellular signal-regulated kinase (ERK). We cyclically stretched type I-like rat primary alveolar epithelial cells at magnitudes of 12, 25, and 37% change in surface area (ΔSA) for 10 to 120 minutes. High levels of reactive oxygen species and of superoxide and NO specifically were detected in cells stretched at 37% ΔSA for 10 to 120 minutes. Exogenous superoxide and NO stimulation increased epithelial permeability in unstretched cells, which was preventable by the NF-κB inhibitor MG132. The cyclic stretch-induced increase in permeability was decreased by the superoxide scavenger tiron and by MG132. Furthermore, tiron had a dramatic protective effect on in vivo lung permeability under mechanical ventilation conditions. Cyclic stretch increased the activation of the NF-κB signaling pathway, which was significantly decreased with the ERK inhibitor U0126. Altogether, our in vitro and in vivo data demonstrate the sensitivity of permeability to stretch- and ventilation-induced superoxide production, suggesting that using antioxidants may be helpful in the prevention and treatment of ventilator-induced lung injury.

Characterizing degree of lung injury in pediatric acute respiratory distress syndrome.

Objective: Although all definitions of acute respiratory distress syndrome use some measure of hypoxemia, neither the Berlin definition nor recently proposed pediatric-specific definitions proposed by the Pediatric Acute Lung Injury Consensus Conference utilizing oxygenation index specify which PaO2/FIO2 or oxygenation index best categorizes lung injury. We aimed to identify variables associated with mortality and ventilator-free days at 28 days in a large cohort of children with acute respiratory distress syndrome. Design: Prospective, observational, single-center study. Setting: Tertiary care, university-affiliated PICU. Patients: Two-hundred eighty-three invasively ventilated children with the Berlin-defined acute respiratory distress syndrome. Interventions: None. Measurements and Main Results: Between July 1, 2011, and June 30, 2014, 283 children had acute respiratory distress syndrome with 37 deaths (13%) at the Children’s Hospital of Philadelphia. Neither initial PaO2/FO2 nor oxygenation index at time of meeting acute respiratory distress syndrome criteria discriminated mortality. However, 24 hours after, both PaO2/FIO2 and oxygenation index discriminated mortality (area under receiver operating characteristic curve, 0.68 [0.59–0.77] and 0.66 [0.57–0.75]; p < 0.001). PaO2/FIO2 at 24 hours categorized severity of lung injury, with increasing mortality rates of 5% (PaO2/FIO2, > 300), 8% (PaO2/FIO2, 201–300), 18% (PaO2/FIO2, 101–200), and 37% (PaO2/FIO2, ⩽ 100) across worsening Berlin categories. This trend with 24-hour PaO2/FIO2 was seen for ventilator-free days (22, 19, 14, and 0 ventilator-free days across worsening Berlin categories; p < 0.001) and duration of ventilation in survivors (6, 9, 13, and 24 d across categories; p < 0.001). Similar results were obtained with 24-hour oxygenation index. Conclusions: PaO2/FIO2 and oxygenation index 24 hours after meeting acute respiratory distress syndrome criteria accurately stratified outcomes in children. Initial values were not helpful for prognostication. Definitions of acute respiratory distress syndrome may benefit from addressing timing of oxygenation metrics to stratify disease severity.

MicroRNA Modulate Alveolar Epithelial Response to Cyclic Stretch

BackgroundMicroRNAs (miRNAs) are post-transcriptional regulators of gene expression implicated in multiple cellular processes. Cyclic stretch of alveoli is characteristic of mechanical ventilation, and is postulated to be partly responsible for the lung injury and inflammation in ventilator-induced lung injury. We propose that miRNAs may regulate some of the stretch response, and therefore hypothesized that miRNAs would be differentially expressed between cyclically stretched and unstretched rat alveolar epithelial cells (RAECs).ResultsRAECs were isolated and cultured to express type I epithelial characteristics. They were then equibiaxially stretched to 25% change in surface area at 15 cycles/minute for 1 hour or 6 hours, or served as unstretched controls, and miRNAs were extracted. Expression profiling of the miRNAs with at least 1.5-fold change over controls revealed 42 miRNAs were regulated (34 up and 8 down) with stretch. We validated 6 of the miRNAs using real-time PCR. Using a parallel mRNA array under identical conditions and publicly available databases, target genes for these 42 differentially regulated miRNAs were identified. Many of these genes had significant up- or down-regulation under the same stretch conditions. There were 362 down-regulated genes associated with up-regulated miRNAs, and 101 up-regulated genes associated with down-regulated miRNAs. Specific inhibition of two selected miRNAs demonstrated a reduction of the increased epithelial permeability seen with cyclic stretch.ConclusionsWe conclude that miRNA expression is differentially expressed between cyclically stretched and unstretched alveolar epithelial cells, and may offer opportunities for therapeutic intervention to ameliorate stretch-associated alveolar epithelial cell dysfunction.

Improved oxygenation 24 hours after transition to airway pressure release ventilation or high-frequency oscillatory ventilation accurately discriminates survival in immunocompromised pediatric patients with acute respiratory distress syndrome*.

Objectives: Children with an immunocompromised condition and requiring invasive mechanical ventilation have high risk of death. Such patients are commonly transitioned to rescue modes of nonconventional ventilation, including airway pressure release ventilation and high-frequency oscillatory ventilation, for acute respiratory distress syndrome refractory to conventional ventilation. Our aim was to describe our experience with airway pressure release ventilation and high-frequency oscillatory ventilation in children with an immunocompromised condition and acute respiratory distress syndrome refractory to conventional ventilation and to identify factors associated with survival. Design: Retrospective cohort study. Setting: Tertiary care, university-affiliated PICU. Patients: Sixty pediatric patients with an immunocompromised condition and acute respiratory distress syndrome refractory to conventional ventilation transitioned to either airway pressure release ventilation or high-frequency oscillatory ventilation. Interventions: None. Measurements and Main Results: Demographic data, ventilator settings, arterial blood gases, oxygenation index, and PaO2/FIO2 were recorded before transition to either mode of nonconventional ventilation and at predetermined intervals after transition for up to 5 days. Mortality in the entire cohort was 63% and did not differ between patients transitioned to airway pressure release ventilation and high-frequency oscillatory ventilation. For both airway pressure release ventilation and high-frequency oscillatory ventilation, improvements in oxygenation index and PaO2/FIO2 at 24 hours expressed as a fraction of pretransition values (oxygenation index24/oxygenation indexpre and PaO2/FIO224/PaO2/FIO2pre) reliably discriminated nonsurvivors from survivors, with receiver operating characteristic areas under the curves between 0.89 and 0.95 (p for all curves < 0.001). Sensitivity-specificity analysis suggested that less than 15% reduction in oxygenation index (90% sensitive, 75% specific) or less than 90% increase in PaO2/FIO2 (80% sensitive, 94% specific) 24 hours after transition to airway pressure release ventilation were the optimal cutoffs to identify nonsurvivors. The comparable values 24 hours after transition to high-frequency oscillatory ventilation were less than 5% reduction in oxygenation index (100% sensitive, 83% specific) or less than 80% increase in PaO2/FIO2 (91% sensitive, 89% specific) to identify nonsurvivors. Conclusions: In this single-center retrospective study of pediatric patients with an immunocompromised condition and acute respiratory distress syndrome failing conventional ventilation transitioned to either airway pressure release ventilation or high-frequency oscillatory ventilation, improved oxygenation at 24 hours expressed as PaO2/FIO224/PaO2/FIO2pre or oxygenation index24/oxygenation indexpre reliably discriminates nonsurvivors from survivors. These findings should be prospectively verified.

Alveolar Dead Space Fraction Discriminates Mortality in Pediatric Acute Respiratory Distress Syndrome.

Objectives: Physiologic dead space is associated with mortality in acute respiratory distress syndrome, but its measurement is cumbersome. Alveolar dead space fraction relies on the difference between arterial and end-tidal carbon dioxide (alveolar dead space fraction = (PaCO2 – PetCO2) / PaCO2). We aimed to assess the relationship between alveolar dead space fraction and mortality in a cohort of children meeting criteria for acute respiratory distress syndrome (both the Berlin 2012 and the American-European Consensus Conference 1994 acute lung injury) and pediatric acute respiratory distress syndrome (as defined by the Pediatric Acute Lung Injury Consensus Conference in 2015). Design: Secondary analysis of a prospective, observational cohort. Setting: Tertiary care, university affiliated PICU. Patients: Invasively ventilated children with pediatric acute respiratory distress syndrome. Interventions: None. Measurements and Main Results: Of the 283 children with pediatric acute respiratory distress syndrome, 266 had available PetCO2. Alveolar dead space fraction was lower in survivors (median 0.13; interquartile range, 0.06–0.23) than nonsurvivors (0.31; 0.19–0.42; p < 0.001) at pediatric acute respiratory distress syndrome onset, but not 24 hours after (survivors 0.12 [0.06–0.18], nonsurvivors 0.14 [0.06–0.25], p = 0.430). Alveolar dead space fraction at pediatric acute respiratory distress syndrome onset discriminated mortality with an area under receiver operating characteristic curve of 0.76 (95% CI, 0.66–0.85; p < 0.001), better than either initial oxygenation index or PaO2/FIO2. In multivariate analysis, alveolar dead space fraction at pediatric acute respiratory distress syndrome onset was independently associated with mortality, after adjustment for severity of illness, immunocompromised status, and organ failures. Conclusions: Alveolar dead space fraction at pediatric acute respiratory distress syndrome onset discriminates mortality and is independently associated with nonsurvival. Alveolar dead space fraction represents a single, useful, readily obtained clinical biomarker reflective of pulmonary and nonpulmonary variables associated with mortality.

High-frequency percussive ventilation improves oxygenation and ventilation in pediatric patients with acute respiratory failure☆

PURPOSE High-frequency percussive ventilation (HFPV) in pediatrics has been described predominantly in burned patients. We aimed to describe its effectiveness and safety in noninhalational pediatric acute respiratory failure (ARF). METHODS We conducted an observational study in a tertiary care pediatric intensive care unit on 31 patients with ARF failing conventional ventilation transitioned to HFPV. Demographics, ventilator settings, oxygenation index, oxygen saturation index, oxygen saturation as measured by pulse oximetry/fraction of inspired oxygen (Fio2), and Pao2/Fio2 were recorded before and during HFPV. RESULTS Initiation of HFPV was associated with improvements in oxygenation index, oxygen saturation index, Pao2/Fio2, and oxygen saturation as measured by pulse oximetry/Fio2 as early as 12 hours (P < .05), which continued through 48 hours after transition. Improved oxygenation occurred without an increase in mean airway pressures. Reductions in Paco2 occurred 6 hours after initiation of HFPV and continued through 48 hours (P < .01). Improved gas exchange was accompanied by reduced peak-inflating pressures at all time intervals after initiation of HPFV (P < .01). Vasopressor scores were similar before and after initiation of HFPV in patients requiring vasoactive support. Twenty-six (83.9%) of 31 patients survived to hospital discharge. CONCLUSIONS In a heterogeneous population of pediatric ARF failing conventional ventilation, HFPV efficiently improves gas exchange in a lung-protective manner.

Relevant Outcomes in Pediatric Acute Respiratory Distress Syndrome Studies

Despite distinct epidemiology and outcomes, pediatric acute respiratory distress syndrome (PARDS) is often managed based on evidence extrapolated from treatment of adults. The impact of non-pulmonary processes on mortality as well as the lower mortality rate compared to adults with acute respiratory distress syndrome (ARDS) renders the utilization of short-term mortality as a primary outcome measure for interventional studies problematic. However, data regarding alternatives to mortality are profoundly understudied, and proposed alternatives, such as ventilator-free days, may be themselves subject to hidden biases. Given the neuropsychiatric and functional impairment in adult survivors of ARDS, characterization of these morbidities in children with PARDS is of paramount importance. The purpose of this review is to frame these challenges in the context of the existing pediatric literature, and using adult ARDS as a guide, suggest potential clinically relevant outcomes that deserve further investigation. The goal is to identify important areas of study in order to better define clinical practice and facilitate future interventional trials in PARDS.

High frequency oscillation and airway pressure release ventilation in pediatric respiratory failure

Airway pressure release ventilation (APRV) and high frequency oscillatory ventilation (HFOV) are frequently used in acute lung injury (ALI) refractory to conventional ventilation. Our aim was to describe our experience with APRV and HFOV in refractory pediatric ALI, and to identify factors associated with survival.

Cecal ligation and puncture accelerates development of ventilator-induced lung injury

Sepsis is a leading cause of respiratory failure requiring mechanical ventilation, but the interaction between sepsis and ventilation is unclear. While prior studies demonstrated a priming role with endotoxin, actual septic animal models have yielded conflicting results regarding the role of preceding sepsis on development of subsequent ventilator-induced lung injury (VILI). Using a rat cecal ligation and puncture (CLP) model of sepsis and subsequent injurious ventilation, we sought to determine if sepsis affects development of VILI. Adult male Sprague-Dawley rats were subject to CLP or sham operation and, after 12 h, underwent injurious mechanical ventilation (tidal volume 30 ml/kg, positive end-expiratory pressure 0 cmH2O) for either 0, 60, or 120 min. Biochemical and physiological measurements, as well as computed tomography, were used to assess injury at 0, 60, and 120 min of ventilation. Before ventilation, CLP rats had higher levels of alveolar neutrophils and interleukin-1β. After 60 min of ventilation, CLP rats had worse injury as evidenced by increased alveolar inflammation, permeability, respiratory static compliance, edema, oxygenation, and computed tomography. By 120 min, CLP and sham rats had comparable levels of lung injury as assessed by many, but not all, of these metrics. CLP rats had an accelerated and worse loss of end-expiratory lung volume relative to sham, and consistently higher levels of alveolar interleukin-1β. Loss of aeration and progression of edema was more pronounced in dependent lung regions. We conclude that CLP initiated pulmonary inflammation in rats, and accelerated the development of subsequent VILI.

Positive End-Expiratory Pressure Lower Than the ARDS Network Protocol Is Associated with Higher Pediatric Acute Respiratory Distress Syndrome Mortality

&NA; Rationale: The ARDS Network (ARDSNet) used a positive end‐expiratory pressure (PEEP)/FiO2 model in many studies. In general, pediatric intensivists use less PEEP and higher FiO2 than this model. Objectives: To evaluate whether children managed with PEEP lower than recommended by the ARDSNet PEEP/FiO2 model had higher mortality. Methods: This was a multicenter, retrospective analysis of patients with pediatric acute respiratory distress syndrome (PARDS) managed without a formal PEEP/FiO2 protocol. Four distinct datasets were combined for analysis. We extracted time‐matched PEEP/FiO2 values, calculating the difference between PEEP level and the ARDSNet‐recommended PEEP level for a given FiO2. We analyzed the median difference over the first 24 hours of PARDS diagnosis against ICU mortality and adjusted for confounding variables, effect modifiers, or factors that may have affected the propensity to use lower PEEP. Measurements and Main Results: Of the 1,134 patients with PARDS, 26.6% were managed with lower PEEP relative to the amount of FiO2 recommended by the ARDSNet protocol. Patients managed with lower PEEP experienced higher mortality than those who were managed with PEEP levels in line with or higher than recommended by the protocol (P < 0.001). After adjustment for hypoxemia, inotropes, comorbidities, severity of illness, ventilator settings, nitric oxide, and dataset, PEEP lower than recommended by the protocol remained independently associated with higher mortality (odds ratio, 2.05; 95% confidence interval, 1.32‐3.17). Findings were similar after propensity‐based covariate adjustment (odds ratio, 2.00; 95% confidence interval, 1.24‐3.22). Conclusions: Patients with PARDS managed with lower PEEP relative to FiO2 than recommended by the ARDSNet model had higher mortality. Clinical trials targeting PEEP management in PARDS are needed.