Patterns of recruitment and injury in a heterogeneous airway network model

In respiratory distress, lung airways become flooded with liquid and may collapse due to surface-tension forces acting on air-liquid interfaces, inhibiting gas exchange. This pa- per proposes a mathematical multiscale model for the mechanical ventilation of a network of occluded airways, where air is forced into the network at a fixed tidal volume, allowing investigation of optimal recruitment strategies. The temporal response is derived from mechanistic models of individual airway reopening, incorporating feedback on the airway pressure due to recruitment. The model accounts for stochastic variability in airway di- ameter and stiffness across and between generations. For weak heterogeneity, the network is completely ventilated via one or more avalanches of recruitment (with airways recruited in quick succession), each characterised by a transient decrease in the airway pressure; avalanches become more erratic for airways that are initially more flooded. However, the time taken for complete ventilation of the network increases significantly as the network becomes more heterogeneous, leading to increased stresses on airway walls. The model predicts that the most peripheral airways are most at risk of ventilation-induced damage. A positive-end-expiratory pressure (PEEP) reduces the total recruitment time but at the cost of larger stresses exerted on airway walls

Excess Circulating Angiopoietin-2 May Contribute to Pulmonary Vascular Leak in Sepsis in Humans

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a devastating complication of numerous underlying conditions, most notably sepsis. Although pathologic vascular leak has been implicated in the pathogenesis of ARDS and sepsis-associated lung injury, the mechanisms promoting leak are incompletely understood. Angiopoietin-2 (Ang-2), a known antagonist of the endothelial Tie-2 receptor, was originally described as a naturally occurring disruptor of normal embryonic vascular development otherwise mediated by the Tie-2 agonist angiopoietin-1 (Ang-1). We hypothesized that Ang-2 contributes to endothelial barrier disruption in sepsis-associated lung injury, a condition involving the mature vasculature. METHODS AND FINDINGS: We describe complementary human, murine, and in vitro investigations that implicate Ang-2 as a mediator of this process. We show that circulating Ang-2 is significantly elevated in humans with sepsis who have impaired oxygenation. We then show that serum from these patients disrupts endothelial architecture. This effect of sepsis serum from humans correlates with measured Ang-2, abates with clinical improvement, and is reversed by Ang-1. Next, we found that endothelial barrier disruption can be provoked by Ang-2 alone. This signal is transduced through myosin light chain phosphorylation. Last, we show that excess systemic Ang-2 provokes pulmonary leak and congestion in otherwise healthy adult mice. CONCLUSIONS: Our results identify a critical role for Ang-2 in disrupting normal pulmonary endothelial function

Computer-aided ventilator resetting is feasible on the basis of a physiological profile.

BACKGROUND: Ventilator resetting is frequently needed to adjust tidal volume, pressure and gas exchange. The system comprising lungs and ventilator is so complex that a trial and error strategy is often applied. Comprehensive characterization of lung physiology is feasible by monitoring. The hypothesis that the effect of ventilator resetting could be predicted by computer simulation based on a physiological profile was tested in healthy pigs. METHODS: Flow, pressure and CO2 signals were recorded in 7 ventilated pigs. Elastic recoil pressure was measured at postinspiratory and post-expiratory pauses. Inspiratory and expiratory resistance as a function of volume and compliance were calculated. CO2 elimination per breath was expressed as a function of tidal volume. Calculating pressure and flow moment by moment simulated the effect of ventilator action, when respiratory rate was varied between 10 and 30 min(-1) and minute volume was changed so as to maintain PaCO2. Predicted values of peak airway pressure, plateau pressure, and CO2 elimination were compared to values measured after resetting. RESULTS: With 95% confidence, predicted pressures and CO2 elimination deviated from measured values with < 1 cm H2O and < 6%, respectively. CONCLUSION: It is feasible to predict effects of ventilator resetting on the basis of a physiological profile at least in health

Partial liquid ventilation for preventing death and morbidity in adults with acute lung injury and acute respiratory distress syndrome (Review)

Background: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are syndromes of severe respiratory failure that are associated with substantial mortality and morbidity. Artifical ventilatory support is commonly required and may exacerbate lung injury. Partial liquid ventilation (PLV) has been proposed as a less injurious form of ventilatory support for these patients. Although PLV has been shown to improve gas exchange and to reduce inflammation in experimental models of ALI, a previous systematic review did not find any evidence to support or refute its use in humans with ALI and ARDS. Objectives: The primary objective of this review was to assess whether PLV reduced mortality (at 28 d, at discharge from the intensive care unit (ICU), at discharge from hospital and at one, two and five years) in adults with ALI or ARDS when compared with conventional ventilatory support. Secondary objectives were to determine how PLV compared with conventional ventilation with regard to duration of invasive mechanical ventilation, duration of respiratory support, duration of oxygen therapy, length of ICU stay, length of hospital stay, incidence of infection, long-term cognitive impairment, long-term health related quality of life, long- term lung function, long-term morbidity costs and adverse events. The following adverse events were considered: hypoxia (arterial P

Choosing a control intervention for a randomised clinical trial

BACKGROUND: Randomised controlled clinical trials are performed to resolve uncertainty concerning comparator interventions. Appropriate acknowledgment of uncertainty enables the concurrent achievement of two goals : the acquisition of valuable scientific knowledge and an optimum treatment choice for the patient-participant. The ethical recruitment of patients requires the presence of clinical equipoise. This involves the appropriate choice of a control intervention, particularly when unapproved drugs or innovative interventions are being evaluated. DISCUSSION: We argue that the choice of a control intervention should be supported by a systematic review of the relevant literature and, where necessary, solicitation of the informed beliefs of clinical experts through formal surveys and publication of the proposed trial's protocol. SUMMARY: When clinical equipoise is present, physicians may confidently propose trial enrollment to their eligible patients as an act of therapeutic beneficence

Inhalation Therapy in Patients Receiving Mechanical Ventilation: An Update

Incremental gains in understanding the influence of various factors on aerosol delivery in concert with technological advancements over the past 2 decades have fueled an ever burgeoning literature on aerosol therapy during mechanical ventilation. In-line use of pressurized metered-dose inhalers (pMDIs) and nebulizers is influenced by a host of factors, some of which are unique to ventilator-supported patients. This article reviews the impact of various factors on aerosol delivery with pMDIs and nebulizers, and elucidates the correlation between in-vitro estimates and in-vivo measurement of aerosol deposition in the lung. Aerosolized bronchodilator therapy with pMDIs and nebulizers is commonly employed in intensive care units (ICUs), and bronchodilators are among the most frequently used therapies in mechanically ventilated patients. The use of inhaled bronchodilators is not restricted to mechanically ventilated patients with chronic obstructive pulmonary disease (COPD) and asthma, as they are routinely employed in other ventilator-dependent patients without confirmed airflow obstruction. The efficacy and safety of bronchodilator therapy has generated a great deal of interest in employing other inhaled therapies, such as surfactant, antibiotics, prostacyclins, diuretics, anticoagulants and mucoactive agents, among others, in attempts to improve outcomes in critically ill ICU patients receiving mechanical ventilation