ACE I/D but not AGT (-6)A/G polymorphism is a risk factor for mortality in ARDS
ABSTRACT The intrapulmonary renin-angiotensin system via tissue concentration of angiotensin II or bradykinin may have multiple effects on pulmonary pathophysiology. Therefore, it was investigated whether the presence of the D allele of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism or the A allele of angiotensinogen (AGT) promoter polymorphism (-6)A/G are independent risk factors for 30-day survival in acute respiratory distress syndrome (ARDS) patients. In a prospective study, adults (Germans of Caucasian ethnicity) with ARDS (n = 84) were recruited from the current authors' intensive care unit and genotyped for the ACE I/D and the AGT (-6)A/G polymorphisms, as were 200 healthy Caucasian controls. Mortality was increased in the ACE DD genotype compared with the I allele, and the ACE I/D polymorphism was an independent prognostic factor for 30-day survival. Patients with a homozygous DD genotype were at highest risk for death (hazard ratio 5.7; 95% confidence interval 1.7-19.2) compared with the II genotype. In contrast, the AGT (-6)A/G polymorphism was neither associated with an increased risk for development of ARDS nor with outcome. In patients with acute respiratory distress syndrome, the angiotensin-converting enzyme insertion/deletion polymorphism but not the angiotensinogen (-6)A/G promoter polymorphism is an independent risk factor with a pronounced effect on 30-day survival.
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ABSTRACT: This article describes the methodology used for the Pediatric Acute Lung Injury Consensus Conference. Consensus conference of international experts in pediatric acute respiratory distress syndrome using the Research ANd Development/University of California, Los Angeles appropriateness method and an expert recommendations process developed by the French-speaking intensive care society. Topics related to pediatric acute respiratory distress syndrome were divided into nine subgroups with a review of the literature. A group of 27 experts met three times over the course of 2 years and collaborated in their respective subgroups to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and future research priorities. The consensus conference resulted in summary of recommendations published in Pediatric Critical Care Medicine, the present Pediatric Acute Lung Injury Consensus Conference methodology article, articles on the nine pediatric acute respiratory distress syndrome subtopics, and a review of pediatric acute respiratory distress syndrome pathophysiology published in this supplement of Pediatric Critical Care Medicine. The methodology described involved experts from around the world and the use of modern information technology. This resulted in recommendations for pediatric acute respiratory distress syndrome management, the identification of current research gaps, and future priorities.Pediatric Critical Care Medicine 06/2015; 16(5_suppl Suppl 1):S1-S5. DOI:10.1097/PCC.0000000000000420 · 2.33 Impact Factor
Article: Future therapies for ARDS[Show abstract] [Hide abstract]
ABSTRACT: IntroductionDespite more than 150 randomized clinical trials (RCTs) of multiple potential therapies, the only interventions for acute respiratory distress syndrome (ARDS) that reduce mortality are those that minimize ventilator-induced lung injury . This ‘translational failure’ may have a number of explanations. Firstly, ARDS is a syndrome, and interventional trials in ARDS generally include a heterogenous patient group with a wide spectrum of disease etiology and disease severity. Second, deficits exist in our understanding of key aspects of the pathogenesis of ARDS. Notwithstanding these challenges, a number of promising therapies are currently under investigation for ARDS, and offer hope for the future.Future therapies for ARDSAspirinPlatelets are important in ARDS pathogenesis. In pre-clinical studies, aspirin reduces thromboxane A2, P-selectin, and platelet-derived chemokine (e.g., CCL5 and CXCL4) production, reduces platelet–neutrophil aggregates and neutrophil extracellular t ...Intensive Care Medicine 12/2014; 41(2). DOI:10.1007/s00134-014-3578-z · 5.54 Impact Factor
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ABSTRACT: The physiological responses to hypoxaemia and cellular hypoxia are poorly understood, and inter-individual differences in performance at altitude and outcome in critical illness remain unexplained. We propose a model for exploring adaptation to hypoxia in the critically ill: the study of healthy humans, progressively exposed to environmental hypobaric hypoxia (EHH). The aim of this study was to describe the spectrum of adaptive responses in humans exposed to graded EHH and identify factors (physiological and genetic) associated with inter-individual variation in these responses. Observational cohort study of progressive incremental exposure to EHH. University human physiology laboratory in London, UK (75 m) and 7 field laboratories in Nepal at 1300 m, 3500 m, 4250 m, 5300 m, 6400 m, 7950 m and 8400 m. 198 healthy volunteers and 24 investigators trekking to Everest Base Camp (EBC) (5300 m). A subgroup of 14 investigators studied at altitudes up to 8400 m on Everest. Exercise capacity, exercise efficiency and economy, brain and muscle Near Infrared Spectroscopy, plasma biomarkers (including markers of inflammation), allele frequencies of known or suspected hypoxia responsive genes, spirometry, neurocognitive testing, retinal imaging, pupilometry. In nested subgroups: microcirculatory imaging, muscle biopsies with proteomic and transcriptomic tissue analysis, continuous cardiac output measurement, arterial blood gas measurement, trans-cranial Doppler, gastrointestinal tonometry, thromboelastography and ocular saccadometry. Of 198 healthy volunteers leaving Kathmandu, 190 reached EBC (5300 m). All 24 investigators reached EBC. The completion rate for planned testing was more than 99% in the investigator group and more than 95% in the trekkers. Unique measurements were safely performed at extreme altitude, including the highest (altitude) field measurements of exercise capacity, cerebral blood flow velocity and microvascular blood flow at 7950 m and arterial blood gas measurement at 8400 m. This study demonstrates the feasibility and safety of conducting a large healthy volunteer cohort study of human adaptation to hypoxia in this difficult environment. Systematic measurements of a large set of variables were achieved in 222 subjects and at altitudes up to 8400 m. The resulting dataset is a unique resource for the study of genotype:phenotype interactions in relation to hypoxic adaptation.BMC Medical Research Methodology 10/2010; 10:98. DOI:10.1186/1471-2288-10-98 · 2.17 Impact Factor