Charalambos Roussos

Tracheal gas insufflation reduces the tidal volume while PaCO2 is maintained constant

ObjectiveThe aims of the present study were two-fold: first, to confirm the effect of tracheal gas insufflation (TGI) throughout the respiratory cycle on alveolar ventilation at various catheter flows and constant total inspired VT as an adjunct to conventional volume cycled mechanical ventilation in patients with acute lung injury; second, to test the efficacy of TGI in the reduction of toal VT, peak and mean airway pressure while maintaining PaCO2 in its baseline value. The hemodynamic effect and the consequences on oxygenation as result of the reduction of VT, were also estimated.DesignProspective study of patients with acute lung injury requiring mechanical ventilation.Setting: 12 bedded, adult polyvalent intensive care unit in a teaching hospital.Patients7 paralyzed and sedated patients with acute respiratory failure were studied. All patients were clinically and hemodynamically stable without fluctuation of the body temperature. All patients were orally intubated with cuffed endotracheal tubes, and mechanically ventilated with a standard circuit of known compliance.InterventionsContinuous flows (4 and 6 l/min) were delivered through a catheter positioned 1 cm above carina while tidal volume or PaCO2 were maintained constant at their baseline value.ResultsIn this study a modest level of TGI significantly enhanced CO2 elimination in patients with acute respiratory failure. Improved ventilatory efficiency resulted from the functional reduction of dead space during TGI allowing the same PaCO2 to be maintained at the same frequency with lower tidal volume and lower airway pressure requirement. Tidal volume, peak and mean airway pressure decreased linearly with catheter flow, without significant changes in oxygenation, while PaCO2 remained stable.ConclusionThe results of this study suggest that TGI may be an useful adjunct mode of mechanical ventilation that limits alveolar pressure and minute ventilation requirements.

Inhaled activated protein C protects mice from ventilator-induced lung injury

IntroductionActivated Protein C (APC), an endogenous anticoagulant, improves tissue microperfusion and endothelial cell survival in systemic inflammatory states such as sepsis, but intravenous administration may cause severe bleeding. We have thus addressed the role of APC delivered locally by inhalation in preventing acute lung injury from alveolar overdistention and the subsequent ventilator-induced lung injury (VILI). We also assessed the effects of APC on the activation status of Extracellular- Regulated Kinase 1/2 (ERK) pathway, which has been shown to be involved in regulating pulmonary responses to mechanical stretch.MethodsInhaled APC (12.5 μg drotrecogin-α × 4 doses) or saline was given to tracheotomized C57/Bl6 mice starting 20 min prior to initiation of injurious mechanical ventilation with tidal volume 25 mL/Kg for 4 hours and then hourly thereafter; control groups receiving inhaled saline were ventilated with 8 mL/Kg for 30 min or 4 hr. We measured lung function (respiratory system elastance H), arterial blood gases, surrogates of vascular leak (broncho-alveolar lavage (BAL) total protein and angiotensin-converting enzyme (ACE)-activity), and parameters of inflammation (BAL neutrophils and lung tissue myeloperoxidase (MPO) activity). Morphological alterations induced by mechanical ventilation were examined in hematoxylin-eosin lung tissue sections. The activation status of ERK was probed in lung tissue homogenates by immunoblotting and in paraffin sections by immunohistochemistry. The effect of APC on ERK signaling downstream of the thrombin receptor was tested on A549 human lung epithelial cells by immunoblotting. Statistical analyses were performed using ANOVA with appropriate post-hoc testing.ResultsIn mice subjected to VILI without APC, we observed hypoxemia, increased respiratory system elastance and inflammation, assessed by BAL neutrophil counts and tissue MPO activity. BAL total protein levels and ACE activity were also elevated by VILI, indicating compromise of the alveolo-capillary barrier. In addition to preserving lung function, inhaled APC prevented endothelial barrier disruption and attenuated hypoxemia and the inflammatory response. Mechanistically, we found a strong activation of ERK in lung tissues by VILI, which was prevented by APC, suggestive of pathogenetic involvement of the Mitogen-Activated Kinase pathway. In cultured human lung epithelial cells challenged by thrombin, APC abrogated the activation of ERK and its downstream effector, cytosolic Phospholipase A2.ConclusionsTopical application of APC by inhalation may effectively reduce lung injury induced by mechanical ventilation in mice.

A critical role for gelsolin in ventilator-induced lung injury.

Mechanical ventilation, an essential life-support modality of patients with acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS), exerts its detrimental effects through largely unknown mechanisms. Gelsolin (GSN), an actin-binding protein and a substrate of caspase-3, was recently shown to play a major role in bleomycin- or lipopolysaccharide-induced lung injury. To dissect a possible role of GSN in the pathogenesis of ventilator-induced lung injury (VILI), genetically modified mice lacking GSN expression and wild-type controls underwent mechanical ventilation with high tidal volumes. GSN was found up-regulated in the airways upon VILI, and its genetic ablation led to almost complete disease protection as manifested by reduced edema formation, reduced lung injury, attenuated epithelial apoptosis, diminished cytokine expression, and impaired neutrophil infiltration. GSN fragmentation was shown to be an effector mechanism in VILI-induced apoptosis, while GSN expression was shown to be necessary for efficient neutrophil infiltration, which was found to be a prerequisite for VILI induction in this model. Therefore, intracellular GSN and GSN-mediated responses were shown to be an important player in the pathogenesis of VILI.

Role of caveolin-1 expression in the pathogenesis of pulmonary edema in ventilator-induced lung injury

Caveolin-1 is a key regulator of pulmonary endothelial barrier function. Here, we tested the hypothesis that caveolin-1 expression is required for ventilator-induced lung injury (VILI). Caveolin-1 gene-disrupted (Cav-1−/−) and age-, sex-, and strain-matched wild-type (WT) control mice were ventilated using two protocols: volume-controlled with protective (8 mL/kg) versus injurious (21 mL/Kg) tidal volume for up to 6 hours; and pressure-controlled with protective (airway pressure = 12 cm H2O) versus injurious (30 cm H2O) ventilation to induce lung injury. Lung microvascular permeability (whole-lung 125I-albumin accumulation, lung capillary filtration coefficient [Kf, c]) and inflammatory markers (bronchoalveolar lavage [BAL] cytokine levels and neutrophil counts) were measured. We also evaluated histologic sections from lungs, and the time course of Src kinase activation and caveolin-1 phosphorylation. VILI induced a 1.7-fold increase in lung 125I-albumin accumulation, fourfold increase in Kf, c’ significantly increased levels of cytokines CXCL1 and interleukin-6, and promoted BAL neutrophilia in WT mice. Lung injury by these criteria was significantly reduced in Cav-1−/− mice but fully restored by i.v. injection of liposome/Cav-1 cDNA complexes that rescued expression of Cav-1 in lung microvessels. As thrombin is known to play a significant role in mediating stretch-induced vascular injury, we observed in cultured mouse lung microvascular endothelial cells (MLECs) thrombin-induced albumin hyperpermeability and phosphorylation of p44/42 MAP kinase in WT but not in Cav-1−/− MLECs. Thus, caveolin-1 expression is required for mechanical stretch-induced lung inflammation and endothelial hyperpermeability in vitro and in vivo.

Acid-induced acute lung injury in mice is associated with P44/42 and c-Jun N-terminal kinase activation and requires the function of tumor necrosis factor α receptor I.

ABSTRACT Aspiration of hydrochloric acid (HCl)–containing gastric juice leads to acute lung injury (ALI) and hypoxemic respiratory failure due to an exuberant inflammatory response associated with pulmonary edema from increased vascular and epithelial permeability. The aim of this study was to determine the role and signaling mechanisms of tumor necrosis factor &agr; (TNF-&agr;) in experimental ALI from HCl aspiration using a combination of genetic animal models and pharmacologic inhibition strategies. To this end, HCl was instilled intratracheally to mice, followed by respiratory system elastance measurement, bronchoalveolar lavage, and lung tissue harvesting 24 h after injection. Hydrochloric acid instillation induced an inflammatory response in the lungs of wild-type mice, evidenced as increased bronchoalveolar lavage total cells, neutrophils, and total protein; histologic lung injury score; and respiratory system elastance, whereas TNF-&agr; receptor I mRNA levels were maintained. These alterations could be prevented by pretreatment with etanercept or genetic deletion of the 55-kd TNF-&agr; receptor I, but not by deletion of the TNF-&agr; gene. Hydrochloric acid induced a 6-fold increase in apoptotic, caspase 3–positive cells in lung sections from wild-type mice, which was abrogated in mice lacking TNF-&agr; receptor I. In immunoblotting and immunohistochemistry studies, HCl stimulated signaling via p44/42 and c-Jun N-terminal kinase, which was blocked in TNF-&agr; receptor I knockout mice. In conclusion, ALI induced by HCl requires TNF-&agr; receptor I function and associates with activation of downstream proinflammatory signaling pathways p44/42 and c-Jun N-terminal kinase.

Comparative analysis of phase difference estimation methods quantifying asynchronies between compartmental chest wall volume signals

Asynchronous breathing movements may be observed in the presence of pulmonary disease, such as chronic obstructive pulmonary disease (COPD). This study was undertaken in an attempt to propose a reliable methodology to quantify this asynchrony. Five methods for estimating phase differences between two signals, based on the phase angle of the Fourier Transform (PhDFT), paradoxical motion (PhDPM), the Lissajous figure (PhDLF), maximal linear correlation (PhDP) and least-squares filtering (PhDLS), were compared. Frequency-modulated signals, simulating compartmental chest wall volumes, were used to evaluate the methods. Breathing asynchrony was quantified in two ways; by estimating (a) a single PhD value for the entire recording and (b) time-varying PhDs, representing non-stationarities of human breathing. PhDPM and PhDLF had the lowest average errors (4%), and PhDLS had a slightly higher error. PhDFT had zero error when estimating a single PhD value but a considerable error when estimating time-varying PhDs. PhDP presented the highest errors in all cases. An application of this methodology is proposed in real compartmental chest wall volume signals of normal and COPD subjects. Preliminary results indicate that the methodology is promising in quantifying differences in asynchronous breathing between thoracic volumes of COPD patients and healthy controls.

Mediastinal Mass with Dysphagia in an Elderly Patient

Abstract.We report the use of endoscopic techniques for successful diagnosis in a case of atypical esophageal tuberculosis. Tuberculosis of the esophagus is an unusual presentation of this disease, having been estimated to occur in 0.15% of the people who die of tuberculosis. A few cases of possible primary tuberculous esophagitis have been described. This report describes a patient with dysphagia who appeared to have esophageal tuberculosis without HIV and in the absence of other signs of tuberculosis. The patient responded promptly to treatment with tuberculostatics.

Multiple organ failure

Longterm prognosis of patients with cirrhosis depends on the occurence of ascltes, jaundice or GI-bleeding. Inhospital outcome depends on the occurence of additional complications. In a retrospective andlysis we studied the outcome of 78 patients with decompensated cirrhosis admitted to the medical ICU of our clinic because of the occurence of additional organ failure. Patients : n-7B (age 51±12years) male=57, female-21, ICU survival 19% (overall ICU survival Bt%). Studyperiod: 1.1.81 -31.12.90. On admission 51 patients showed renal failure (survival 191) 24 patients had a respiratory failure (survival 13%) and 14 patients were in circulatory shock (survival 21%). In 56 patients severe bleeding led to the admission (survival lit), in 53 patients Clinical symptoms of sepsis were found on admission (survival 19%). Most of the patients with bleeding or sepals showed addition[ complications (Table 1).