Angiotensin II type 2 receptor agonist Compound 21 attenuates pulmonary inflammation in a model of acute lung injury.

PURPOSE: Although the role of the angiotensin II type 2 (AT2) receptor in acute lung injury is not yet completely understood, a protective role of this receptor subtype has been suggested. We hypothesized that, in a rodent model of acute lung injury, stimulation of the AT2 receptor with the direct agonist Compound 21 (C21) might have a beneficial effect on pulmonary inflammation and might improve pulmonary gas exchange. MATERIALS AND METHODS: Male adult rats were divided into a treatment group that received pulmonary lavage followed by mechanical ventilation (LAV, n=9), a group receiving pulmonary lavage, mechanical ventilation, and direct stimulation of the AT2 receptor with C21 (LAV+C21, n=9), and a control group that received mechanical ventilation only (control, n=9). Arterial blood gas analysis was performed every 30 min throughout the 240-min observation period. Lung tissue and plasma samples were obtained at 240 min after the start of mechanical ventilation. Protein content and surface activity of bronchoalveolar lavage fluid were assessed and the wet/dry-weight ratio of lungs was determined. Transcriptional and translational regulation of pro- and antiinflammatory cytokines IL-1ß, tumor necrosis factor-alpha, IL-6, IL-10, and IL-4 was determined in lungs and in plasma. RESULTS: Pulmonary lavage led to a significant impairment of gas exchange, the formation of lung edema, and the induction of pulmonary inflammation. Protein content of lavage fluid was increased and contained washed-out surfactant. Direct AT2 receptor stimulation with C21 led to a significant inhibition of tumor necrosis factor-alpha and IL-6 expressions in the lungs, whereas the expressions of IL-1, IL-10, and IL-4 remained unchanged. During the 240-min observation period, AT2 receptor stimulation did not improve pulmonary gas exchange or lung edema. CONCLUSION: In this rodent model of acute lung injury after repeated pulmonary lavage, AT2 receptor stimulation attenuates pulmonary inflammation but does not improve gas exchange.

Closed-loop mechanical ventilation for lung injury: a novel physiological-feedback mode following the principles of the open lung concept.

Adherence to low tidal volume (VT) ventilation and selected positive end-expiratory pressures are low during mechanical ventilation for treatment of the acute respiratory distress syndrome. Using a pig model of severe lung injury, we tested the feasibility and physiological responses to a novel fully closed-loop mechanical ventilation algorithm based on the "open lung" concept. Lung injury was induced by surfactant washout in pigs (n = 8). Animals were ventilated following the principles of the "open lung approach" (OLA) using a fully closed-loop physiological feedback algorithm for mechanical ventilation. Standard gas exchange, respiratory- and hemodynamic parameters were measured. Electrical impedance tomography was used to quantify regional ventilation distribution during mechanical ventilation. Automatized mechanical ventilation provided strict adherence to low VT-ventilation for 6 h in severely lung injured pigs. Using the "open lung" approach, tidal volume delivery required low lung distending pressures, increased recruitment and ventilation of dorsal lung regions and improved arterial blood oxygenation. Physiological feedback closed-loop mechanical ventilation according to the principles of the open lung concept is feasible and provides low tidal volume ventilation without human intervention. Of importance, the "open lung approach"-ventilation improved gas exchange and reduced lung driving pressures by opening atelectasis and shifting of ventilation to dorsal lung regions.

Efficacy and safety of argatroban in patients with acute respiratory distress syndrome and extracorporeal lung support.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) or pumpless extracorporeal lung assist (pECLA) requires effective anticoagulation. Knowledge on the use of argatroban in patients with acute respiratory distress syndrome (ARDS) undergoing ECMO or pECLA is limited. Therefore, this study assessed the feasibility, efficacy and safety of argatroban in critically ill ARDS patients undergoing extracorporeal lung support. METHODS: This retrospective analysis included ARDS patients on extracorporeal lung support who received argatroban between 2007 and 2014 in a single ARDS referral center. As controls, patients who received heparin were matched for age, sex, body mass index and severity of illness scores. Major and minor bleeding complications, thromboembolic events, administered number of erythrocyte concentrates, thrombocytes and fresh-frozen plasmas were assessed. The number of extracorporeal circuit systems and extracorporeal lung support cannulas needed due to clotting was recorded. Also assessed was the efficacy to reach the targeted activated partial thromboplastin time (aPTT) in the first consecutive 14 days of therapy, and the controllability of aPTT values is within a therapeutic range of 50-75 s. Fisher's exact test, Mann-Whitney U tests, Friedman tests and multivariate nonparametric analyses for longitudinal data (MANOVA; Brunner's analysis) were applied where appropriate. RESULTS: Of the 535 patients who met the inclusion criteria, 39 receiving argatroban and 39 matched patients receiving heparin (controls) were included. Baseline characteristics were similar between the two groups, including severity of illness and organ failure scores. There were no significant differences in major and minor bleeding complications. Rates of thromboembolic events were generally low and were similar between the two groups, as were the rates of transfusions required and device-associated complications. The controllability of both argatroban and heparin improved over time, with a significantly increasing probability to reach the targeted aPTT corridor over the first days (p < 0.001). Over time, there were significantly fewer aPTT values below the targeted aPTT goal in the argatroban group than in the heparin group (p < 0.05). Both argatroban and heparin reached therapeutic aPTT values for adequate application of extracorporeal lung support. CONCLUSIONS: Argatroban appears to be a feasible, effective and safe anticoagulant for critically ill ARDS patients undergoing extracorporeal lung support.

Respiratory Failure and Mechanical Ventilation in the Pregnant Patient.

Fewer than 2% of all peripartal patients need intensive care unit admission. But due to some anatomic and physiologic changes in pregnancy, respiratory failure can be promoted. This article reviews several obstetric and nonobstetric diseases that lead to respiratory failure and the treatment of these. Furthermore, invasive and noninvasive ventilation in pregnancy is discussed and suggestions of medication during ventilation are given.

Characterization of inflammation in a rat model of acute lung injury after repeated pulmonary lavage.

AIM OF THE STUDY: Repeated pulmonary lavage allows to reliably reproduce failure of gas exchange and major histological findings of acute lung injury (ALI). However, because the capacity of pulmonary lavage to induce pulmonary inflammation is not well established in rodents, this study aims to characterize the induction of pulmonary inflammation in a rat model of ALI. MATERIALS AND METHODS: Male adult rats were divided into a treatment group (n = 9) that received pulmonary lavage with consecutive mechanical ventilation, and a control group that received mechanical ventilation only (n = 9). Arterial blood gas analyses were performed every 30 min throughout the study. Pressure-volume curves, and lung tissue and plasma samples, were obtained at 240 min after the start of mechanical ventilation. Protein content and surface activity of bronchoalveolar lavage fluid was assessed. Transcriptional and translational regulation of pro- and anti-inflammatory cytokines IL-1ß, TNF-α, IL-6, and IL-10 was determined in lungs and plasma. Markers of cellular stress were measured in lung tissue. RESULTS: Pulmonary lavage significantly decreased lung compliance, induced hypoxia and hypercapnia, and mediated respiratory acidosis. Protein content of lavage fluid was significantly increased and contained washed out surfactant. Expression of IL-1ß, TNF-α, and IL-6 mRNA and protein expression of IL-1ß and TNF-α was significantly induced in lavaged lungs, without spillover into the systemic circulation. Markers of cellular stress were significantly upregulated in lavaged lungs. CONCLUSIONS: This model of ALI applied in rats can induce pulmonary inflammation. The model might be used to develop therapeutic strategies that target pulmonary inflammation in ALI.

Stimulation of the Angiotensin II AT2 Receptor is Anti-inflammatory in Human Lipopolysaccharide-Activated Monocytic Cells.

Recently, AT2 receptors have been discovered on the surface of human immunocompetent cells such as monocytes. Data on regulative properties of this receptor on the cellular immune response are poor. We hypothesized that direct stimulation of the AT2 receptor mediates anti-inflammatory responses in these cells. Human monocytic THP-1 and U937 cells were stimulated with lipopolysaccharide (LPS) and the selective AT2 receptor agonist Compound 21 (C21). Expression of pro- and anti-inflammatory cytokines IL-6, IL-10, tumor necrosis factor-α (TNFα), and IL-1ß were analyzed on both the transcriptional and the translational level over course of time. Treatment with C21 attenuated the expression of TNFα, IL-6, and IL-10 after LPS challenge in both cell lines in a time- and dose-dependent manner. We conclude that selective AT2 receptor stimulation acts anti-inflammatory in human monocytes. Modulation of cytokine response by AT2 receptor activation might be a beneficial and novel treatment concept in inflammatory conditions.

Automatic protective ventilation using the ARDSNet protocol with the additional monitoring of electrical impedance tomography.

INTRODUCTION: Automatic ventilation for patients with respiratory failure aims at reducing mortality and can minimize the workload of clinical staff, offer standardized continuous care, and ultimately save the overall cost of therapy. We therefore developed a prototype for closed-loop ventilation using acute respiratory distress syndrome network (ARDSNet) protocol, called autoARDSNet. METHODS: A protocol-driven ventilation using goal-oriented structural programming was implemented and used for 4 hours in seven pigs with lavage-induced acute respiratory distress syndrome (ARDS). Oxygenation, plateau pressure and pH goals were controlled during the automatic ventilation therapy using autoARDSNet. Monitoring included standard respiratory, arterial blood gas analysis and electrical impedance tomography (EIT) images. After 2-hour automatic ventilation, a disconnection of the animal from the ventilator was carried out for 10 seconds, simulating a frequent clinical scenario for routine clinical care or intra-hospital transport. RESULTS: This pilot study of seven pigs showed stable and robust response for oxygenation, plateau pressure and pH value using the automated system. A 10-second disconnection at the patient-ventilator interface caused impaired oxygenation and severe acidosis. However, the automated protocol-driven ventilation was able to solve these problems. Additionally, regional ventilation was monitored by EIT for the evaluation of ventilation in real-time at bedside with one prominent case of pneumothorax. CONCLUSIONS: We implemented an automatic ventilation therapy using ARDSNet protocol with seven pigs. All positive outcomes were obtained by the closed-loop ventilation therapy, which can offer a continuous standard protocol-driven algorithm to ARDS subjects.

A mathematical model for carbon dioxide elimination: an insight for tuning mechanical ventilation.

PURPOSE: The aim is to provide better understanding of carbon dioxide (CO2) elimination during ventilation for both the healthy and atelectatic condition, derived in a pressure-controlled mode. Therefore, we present a theoretical analysis of CO2 elimination of healthy and diseased lungs. METHODS: Based on a single-compartment model, CO2 elimination is mathematically modeled and its contours were plotted as a function of temporal settings and driving pressure. The model was validated within some level of tolerance on an average of 4.9% using porcine dynamics. RESULTS: CO2 elimination is affected by various factors, including driving pressure, temporal variables from mechanical ventilator settings, lung mechanics and metabolic rate. CONCLUSION: During respiratory care, CO2 elimination is a key parameter for bedside monitoring, especially for patients with pulmonary disease. This parameter provides valuable insight into the status of an atelectatic lung and of cardiopulmonary pathophysiology. Therefore, control of CO2 elimination should be based on the fine tuning of the driving pressure and temporal ventilator settings. However, for critical condition of hypercapnia, airway resistance during inspiration and expiration should be additionally measured to determine the optimal percent inspiratory time (%TI) to maximize CO2 elimination for treating patients with hypercapnia.

Acute respiratory failure complicating advanced liver disease.

Advanced liver disease is associated with hypoxemia and respiratory failure by various mechanisms. Patients with cirrhosis are especially prone to episodes of decompensation requiring intensive care unit admission and management. Such patients may already be in acute liver failure or have decompensated due to a concurrent illness such as spontaneous bacterial peritonitis, sepsis, encephalopathy, varices, or hepatorenal syndrome. Acute respiratory distress syndrome is one of the main reasons for intensive care unit admission and mortality. Overall, critically ill cirrhotic patients frequently progress to multiorgan failure requiring mechanical ventilation. Caring for such patients is therefore understandably complex and extremely challenging. Patients with end-stage liver disease are especially at risk for developing acute respiratory failure and hypoxemia secondary to hepatopulmonary syndrome, portopulmonary hypertension, and hepatic hydrothorax. They should therefore be screened for these conditions because failure to recognize and adequately treat these serious complications of cirrhosis may have devastating consequences. This article is based on a review of the current literature on how to approach and manage acute respiratory failure in advanced liver disease, which is important to intensivists, anesthesiologists, and physicians as a whole.

Lungs in critical care: new look at old practices.

There has been a marked increase in the volume of critical care services throughout the world in the last few years with the wide addition of intensive care units in developing nations. Despite extensive efforts in research and some progress in treatment, mortality and morbidity have not significantly decreased. Recent research has demonstrated that modifying standard practices of mechanical ventilation and sedation may contribute to improved patient outcomes. This article discusses how new aspects of physiologically based mechanical ventilation with minimal intravenous sedation may help decrease the incidence of nosocomial pneumonia, modulate systemic inflammatory response, and reduce the incidence of delirium. These interlinked modalities may someday contribute to decreased length of stay and a reduction in treatment-related complications. These concepts may also open new avenues to improve patient care and stimulate ongoing investigation in other areas related to physiologically based critical care practices.