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      Milrinone Attenuates Arteriolar Vasoconstriction and Capillary Perfusion Deficits on Endotoxemic Hamsters

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          Abstract

          Background and Objective

          Apart from its inotropic property, milrinone has vasodilator, anti-inflammatory and antithrombotic effects that could assist in the reversal of septic microcirculatory changes. This paper investigates the effects of milrinone on endotoxemia-related microcirculatory changes and compares them to those observed with the use of norepinephrine.

          Materials and Methods

          After skinfold chamber implantation procedures and endotoxemia induction by intravenous Escherichia coli lipopolysaccharide administration (2 mg.kg-1), male golden Syrian hamsters were treated with two regimens of intravenous milrinone (0.25 or 0.5 μg.kg-1.min-1). Intravital microscopy of skinfold chamber preparations allowed quantitative analysis of microvascular variables. Macro-hemodynamic, biochemical, and hematological parameters and survival rate were also analyzed. Endotoxemic non-treated animals, endotoxemic animals treated with norepinephrine (0.2 μg.kg-1.min-1), and non-endotoxemic hamsters served as controls.

          Results

          Milrinone (0.5 μg.kg-1.min-1) was effective in reducing lipopolysaccharide-induced arteriolar vasoconstriction, capillary perfusion deficits, and inflammatory response, and in increasing survival. Norepinephrine treated animals showed the best mean arterial pressure levels but the worst functional capillary density values among all endotoxemic groups.

          Conclusion

          Our data suggests that milrinone yielded protective effects on endotoxemic animals’ microcirculation, showed anti-inflammatory properties, and improved survival. Norepinephrine did not recruit the microcirculation nor demonstrated anti-inflammatory effects.

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          Most cited references39

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          Clinical use of lactate monitoring in critically ill patients

          Increased blood lactate levels (hyperlactataemia) are common in critically ill patients. Although frequently used to diagnose inadequate tissue oxygenation, other processes not related to tissue oxygenation may increase lactate levels. Especially in critically ill patients, increased glycolysis may be an important cause of hyperlactataemia. Nevertheless, the presence of increased lactate levels has important implications for the morbidity and mortality of the hyperlactataemic patients. Although the term lactic acidosis is frequently used, a significant relationship between lactate and pH only exists at higher lactate levels. The term lactate associated acidosis is therefore more appropriate. Two recent studies have underscored the importance of monitoring lactate levels and adjust treatment to the change in lactate levels in early resuscitation. As lactate levels can be measured rapidly at the bedside from various sources, structured lactate measurements should be incorporated in resuscitation protocols.
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            The disconnect between animal models of sepsis and human sepsis.

            Frequently used experimental models of sepsis include cecal ligation and puncture, ascending colon stent peritonitis, and the i.p. or i.v. injection of bacteria or bacterial products (such as LPS). Many of these models mimic the pathophysiology of human sepsis. However, identification of mediators in animals, the blockade of which has been protective, has not translated into clinical efficacy in septic humans. We describe the shortcomings of the animal models and reasons why effective therapy for human sepsis cannot be derived readily from promising findings in animal sepsis.
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              Lactate versus non-lactate metabolic acidosis: a retrospective outcome evaluation of critically ill patients

              Introduction Acid–base abnormalities are common in the intensive care unit (ICU). Differences in outcome exist between respiratory and metabolic acidosis in similar pH ranges. Some forms of metabolic acidosis (for example, lactate) seem to have worse outcomes than others (for example, chloride). The relative incidence of each type of disorder is unknown. We therefore designed this study to determine the nature and clinical significance of metabolic acidosis in critically ill patients. Methods An observational, cohort study of critically ill patients was performed in a tertiary care hospital. Critically ill patients were selected on the clinical suspicion of the presence of lactic acidosis. The inpatient mortality of the entire group was 14%, with a length of stay in hospital of 12 days and a length of stay in the ICU of 5.8 days. Results We reviewed records of 9,799 patients admitted to the ICUs at our institution between 1 January 2001 and 30 June 2002. We selected a cohort in which clinicians caring for patients ordered a measurement of arterial lactate level. We excluded patients in which any necessary variable required to characterize an acid–base disorder was absent. A total of 851 patients (9% of ICU admissions) met our criteria. Of these, 548 patients (64%) had a metabolic acidosis (standard base excess < -2 mEq/l) and these patients had a 45% mortality, compared with 25% for those with no metabolic acidosis (p < 0.001). We then subclassified metabolic acidosis cases on the basis of the predominant anion present (lactate, chloride, or all other anions). The mortality rate was highest for lactic acidosis (56%); for strong ion gap (SIG) acidosis it was 39% and for hyperchloremic acidosis 29% (p < 0.001). A stepwise logistic regression model identified serum lactate, SIG, phosphate, and age as independent predictors of mortality. Conclusion In critically ill patients in which a measurement of lactate level was ordered, lactate and SIG were strong independent predictors of mortality when they were the major source of metabolic acidosis. Overall, patients with metabolic acidosis were nearly twice as likely to die as patients without metabolic acidosis.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                2015
                3 February 2015
                : 10
                : 2
                : e0117004
                Affiliations
                [1 ]Department of Internal Medicine, Division of Critical Care, Faculty of Medical Sciences, Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil
                [2 ]Pediatric Cardiac Intensive Care Unit, Perinatal Barra, Rio de Janeiro, RJ, Brazil
                [3 ]Institute Fernandes Figueira, Oswaldo Cruz Foundation—FIOCRUZ, Rio de Janeiro, RJ, Brazil
                [4 ]Department of Surgery, Division of Anesthesiology, Faculty of Medical Sciences, Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil
                [5 ]Department of Internal Medicine, Division of Endocrinology, Faculty of Medical Sciences, Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil
                [6 ]Laboratory for Clinical and Experimental Research in Vascular Biology—BioVasc, Biomedical Center, Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil
                Indian Institute of Science, INDIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SJP AOMTS LGKA EB. Performed the experiments: SJP AOMTS. Analyzed the data: MLM SJP NRV LGKA. Contributed reagents/materials/analysis tools: MLM EB. Wrote the paper: MLM EB. Critically revised the manuscript: NRV EB. Supervised the study: LGKA EB.

                Article
                PONE-D-14-45808
                10.1371/journal.pone.0117004
                4315607
                25646813
                2bd9fdf6-ec6e-4b6c-b273-62544a54435f
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 2 November 2014
                : 17 December 2014
                Page count
                Figures: 7, Tables: 2, Pages: 17
                Funding
                This study was supported by grants from CNPq (National Council for Scientific and Technological Development, Brasilia, Brazil, http://www.cnpq.br/; grant number 303836/2010-5) and FAPERJ (State of Rio de Janeiro Agency for Research Support, Rio de Janeiro, Brazil, http://www.faperj.br/; grant number E26/110.754/2012). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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