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      Acetazolamide: a second wind for a respiratory stimulant in the intensive care unit?

      research-article
      1 , , 2 , 1
      Critical Care
      BioMed Central

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          Abstract

          Patients with chronic obstructive pulmonary disease (COPD) are affected by episodes of respiratory exacerbations, some of which can be severe and may necessitate respiratory support. Prolonged invasive mechanical ventilation is associated with increased mortality rates. Persistent failure to discontinue invasive mechanical ventilation is a major issue in patients with COPD. Pure or mixed metabolic alkalosis is a common finding in the intensive care unit (ICU) and is associated with a worse outcome. In patients with COPD, the condition is called post-hypercapnic alkalosis and is a complication of mechanical ventilation. Reversal of metabolic alkalosis may facilitate weaning from mechanical ventilation of patients with COPD. Acetazolamide, a non-specific carbonic anhydrase inhibitor, is one of the drugs employed in the ICU to reverse metabolic alkalosis. The drug is relatively safe, undesirable effects being rare. The compartmentalization of the different isoforms of the carbonic anhydrase enzyme may, in part, explain the lack of evidence of the efficacy of acetazolamide as a respiratory stimulant. Recent findings suggest that the usually employed doses of acetazolamide in the ICU may be insufficient to significantly improve respiratory parameters in mechanically ventilated patients with COPD. Randomized controlled trials using adequate doses of acetazolamide are required to address this issue.

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          Most cited references46

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          Non-invasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis.

          To determine the effectiveness of non-invasive positive pressure ventilation (NPPV) in the management of respiratory failure secondary to acute exacerbation of chronic obstructive pulmonary disease. Systematic review of randomised controlled trials that compared NPPV and usual medical care with usual medical care alone in patients admitted to hospital with respiratory failure resulting from an exacerbation of chronic obstructive pulmonary disease and with PaCO2 >6 kPa. The eight studies included in the review showed that, compared with usual care alone, NPPV as an adjunct to usual care was associated with a lower mortality (relative risk 0.41 (95% confidence interval 0.26 to 0.64)), a lower need for intubation (relative risk 0.42 (0.31 to 0.59)), lower likelihood of treatment failure (relative risk 0.51 (0.38 to 0.67)), and greater improvements at 1 hour in pH (weighted mean difference 0.03 (0.02 to 0.04)), PaCO2 (weighted mean difference -0.40 kPa (-0.78 to -0.03)), and respiratory rate (weighted mean difference -3.08 breaths per minute (-4.26 to -1.89)). NPPV resulted in fewer complications associated with treatment (relative risk 0.32 (0.18 to 0.56)) and shorter duration of stay in hospital (weighted mean difference -3.24 days (-4.42 to -2.06)). NPPV should be the first line intervention in addition to usual medical care to manage respiratory failure secondary to an acute exacerbation of chronic obstructive pulmonary disease in all suitable patients. NPPV should be tried early in the course of respiratory failure and before severe acidosis, to reduce mortality, avoid endotracheal intubation, and decrease treatment failure.
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            Carbonic anhydrases: current state of the art, therapeutic applications and future prospects.

            Carbonic anhydrases (CAs, EC 4.2.1.1) are wide-spread enzymes, present in mammals in at least 14 different isoforms. Some of these isozymes are cytosolic (CA I, CA II, CA III, CA VII, CA XIII), others are membrane-bound (CA IV, CA IX, CA XII and CA XIV), CA V is mitochondrial and CA VI is secreted in the saliva and milk. Three cytosolic acatalytic forms are also known (CARP VIII, CARP X and CARP XI). The catalytically active isoforms, which play important physiological and patho-physiological functions, are strongly inhibited by aromatic and heterocyclic sulfonamides. The catalytic and inhibition mechanisms of these enzymes are understood in great detail, and this greatly helped the design of potent inhibitors, some of which possess important clinical applications. The use of such CA inhibitors (CAIs) as antiglaucoma drugs are discussed in detail, together with the recent developments that led to isozyme-specific and organ-selective inhibitors. A recent discovery is connected with the involvement of CAs and their sulfonamide inhibitors in cancer: many potent CAIs were shown to inhibit the growth of several tumor cell lines in vitro and in vivo, thus constituting interesting leads for developing novel antitumor therapies. Future prospects for drug design of inhibitors of these ubiquitous enzymes are dealt with. Although activation of CAs has been a controversial issue for some time, recent kinetic, spectroscopic and X-ray crystallographic experiments offered an explanation of this phenomenon, based on the catalytic mechanism. It has been demonstrated recently, that molecules that act as carbonic anhydrase activators (CAAs) bind at the entrance of the enzyme active site participating in facilitated proton transfer processes between the active site and the reaction medium. In addition to CA II-activator adducts, X-ray crystallographic studies have been also reported for ternary complexes of this isozyme with activators and anion (azide) inhibitors. Structure-activity correlations for diverse classes of activators is discussed for the isozymes for which the phenomenon has been studied, i.e., CA I, II, III and IV. The possible physiological relevance of CA activation/inhibition is also addressed, together with recent pharmacological/ biomedical applications of such compounds in different fields of life sciences.
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              Predictors of outcome for patients with COPD requiring invasive mechanical ventilation.

              Accurate outcomes data and predictors of outcomes are fundamental to the effective care of patients with COPD and in guiding them and their families through end-of-life decisions. We conducted a retrospective cohort study of 166 patients using prospectively gathered data in patients with COPD who required mechanical ventilation for acute respiratory failure of diverse etiologies. The in-hospital mortality rate for the entire cohort was 28% but fell to 12% for patients with a COPD exacerbation and without a comorbid illness. Univariate analysis showed a higher mortality rate among those patients who required > 72 h of mechanical ventilation (37% vs 16%; p or = 72 h were independent predictors of poor outcome. We conclude that among variables available within the first 6 h of mechanical ventilation, the presence of comorbidity and a measure of the severity of the acute illness are predictors of in-hospital mortality among patients with COPD and acute respiratory failure. The occurrence of extubation failure or the need for mechanical ventilation beyond 72 h also portends a worse prognosis.
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                Author and article information

                Journal
                Crit Care
                Crit Care
                Critical Care
                BioMed Central
                1364-8535
                1466-609X
                2012
                7 August 2012
                7 August 2013
                : 16
                : 4
                : 318
                Affiliations
                [1 ]Medical Intensive Care Unit, European Georges Pompidou Hospital (AP-HP), Université Paris Descartes, Sorbonne Paris Cité, 20 rue Leblanc, 75908 Paris, France
                [2 ]CIC-0109 Cochin-Necker Inserm, Unité de Recherche Clinique, Tarnier Hospital, (AP-HP) and E.A. 3620 Université Paris Descartes, Sorbonne Paris Cité, 27 Rue du Faubourg Saint-Jacques 75014 Paris, France
                Article
                cc11323
                10.1186/cc11323
                3580678
                22866939
                ca453b2d-9754-4e39-9c82-8cdd6d3c54f5
                Copyright ©2012 BioMed Central Ltd
                History
                Categories
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                Emergency medicine & Trauma
                Emergency medicine & Trauma

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