The role of poly (ADP-ribose) polymerase in ventilator-induced lung injury

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Oxidative and nitrosative stress in the diaphragm of patients with COPD

COPD is associated with an increased load on the diaphragm. Since chronic muscle loading results in changes in antioxidant capacity and formation of reactive oxygen and reactive nitrogen species, we hypothesized that COPD has a similar effect on the diaphragm, which is related to the severity of COPD. Catalase activity was determined spectrophotometrically. Levels of 4-hydroxy-2-nonenal (HNE)-protein adducts and 3-nitrotyrosine (NT) formation were measured using western blotting. Levels of malondialdehyde (MDA) were assessed by high-performance liquid chromatography. We found that catalase activity was ~89% higher in the diaphragm of severe COPD patients (FEV1 37 ± 5% predicted) compared with non-COPD patients. MDA levels, a marker for lipid peroxidation, were significantly lower in the diaphragm of COPD patients compared with non-COPD patients, whereas the level of HNE-protein adducts was equal in both groups. NT formation was not different between groups. However, increasing hyperinflation and NT formation were inversely correlated. These results indicate that in COPD the diaphragm adapts to a higher work load by increasing catalase activity, resulting in a reduction in oxidative damage to lipids and tyrosine nitration of proteins

The role of calpains in ventilator-induced diaphragm atrophy

Contains fulltext : 178017.pdf (publisher's version ) (Open Access)BACKGROUND: Controlled mechanical ventilation (CMV) is associated with diaphragm dysfunction. Dysfunction results from muscle atrophy and injury of diaphragm muscle fibers. Enhanced proteolysis and reduced protein synthesis play an important role in the development of atrophy. The current study is to evaluate the effects of the calpains inhibitor calpeptin on the development of diaphragm atrophy and activation of key enzymes of the ubiquitin-proteasome pathway in rats under CMV. METHODS: Three groups of rats were studied: control animals (CON, n = 8), rats subjected to 24 h of MV (CMV, n = 8), and rats subjected to 24 h of MV after administration of the calpain inhibitor calpeptin (CMVC, n = 8). The diaphragm was analyzed for calpain activity, myosin heavy chain (MHC) content, and cross-sectional area (CSA) of diaphragmatic muscle fibers as a marker for muscle atrophy. In addition, key enzymes of the ubiquitin-proteasome pathway (MAFbx and MuRF1) were also studied. RESULTS: CMV resulted in loss of both MHCfast and MHCslow. Furthermore, the CSA of diaphragmatic muscle fibers was significantly decreased after 24 h of CMV. However, calpain inhibitor calpeptin prevented loss of MHC and CSA after CMV. In addition, calpeptin prevented the increase in protein expression of calpain1 and calpain2 and reduced calpain activity as indicated by reduced generation of the calpain cleavage product alphaII-spectrin in the diaphragm. CMV-induced upregulation of both MAFbx and MuRF1 protein levels was attenuated by treatment with calpeptin. CONCLUSIONS: The calpain inhibitor calpeptin prevents MV-induced muscle atrophy. In addition, calpeptin attenuated the expression of key proteolytic enzymes known to be involved in ventilator-induced diaphragm atrophy, including MAFbx and MuRF1

Plasma from septic shock patients induces loss of muscle protein

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Levosimendan Efficacy and Safety: 20 years of SIMDAX in Clinical Use

Levosimendan was first approved for clinic use in 2000, when authorisation was granted by Swedish regulatory authorities for the haemodynamic stabilisation of patients with acutely decompensated chronic heart failure. In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitisation and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced heart failure, right ventricular failure and pulmonary hypertension, cardiac surgery, critical care and emergency medicine. Levosimendan is currently in active clinical evaluation in the US. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and non-cardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, UK and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute heart failure arena in recent times and charts a possible development trajectory for the next 20 years

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Oxygen-induced hypercapnia in COPD: myths and facts

During our medical training, we learned that oxygen administration in patients with chronic obstructive pulmonary disease (COPD) induces hypercapnia through the 'hypoxic drive' mechanism and can be dangerous. This mindset frequently results in the reluctance of clinicians to administer oxygen to hypoxemic patients with COPD. However, this fear is not based on evidence in the literature. Here, we will review the impact and pathophysiology of oxygen-induced hypercapnia in patients with acute exacerbation of COPD and recommend a titrated oxygen management