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      Decatecholaminisation during sepsis

      editorial
      1 , , 2
      Critical Care
      BioMed Central

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          Abstract

          Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection [1]. The syndrome is characterised by autonomic dysfunction and increased plasma levels of noradrenaline and adrenaline [2]. These catecholamines originate mainly from the activated sympathetic nervous system, but also originate from the adrenal gland, gut, and immune cells [3]. While necessary and life-saving in the early fight or flight reaction to any insult, prolonged adrenergic stress is detrimental and contributes to organ dysfunction [4]. Strategies to reduce adrenergic stress have been proposed (Table 1) under the umbrella term decatecholaminisation. Table 1 Decatecholaminisation strategies for patients with septic shock Strategy Recommendations Blunt endogenous catecholamine release; avoid compensatory adrenergic stimulation Optimize cardiac preload and vascular filling Assess fluid status by leg-raise test Perform repetitive fluid challenges to a target (e.g. stroke volume) Use cardiac output monitoring and/or echocardiography Treat hypoxia and severe anaemia Target oxygen saturation between 92–96 % Transfuse red blood cells if haemoglobin falls below 70 g/l Optimize sedation and analgesia Avoid over-sedation; use sedation targets Interrupt sedation daily, especially if long-lasting sedatives (e.g. midazolam) are used Use dexmedetomidine (see text for details) Reduce exogenous catecholamine administration Avoid excessive beta-mimetic stimulation Use cardiac output monitoring and/or echocardiography Avoid supra-normal physiological targets Only use inotropes if contractility is impaired Use cardiac output monitoring and/or echocardiography Consider alternative drugs Consider alternative inotropes (e.g. levosimendan) and vasopressors (e.g. vasopressin) Accept abnormal physiological values Adjust therapeutic targets Consider beta-blockers if tachycardia persists Prefer short-acting drugs (e.g esmolol, see text) that can be stopped if adverse effects occur Blunt inflammatory response (to reduce cardiac depression and microvascular dysfunction) Treat underlying infection Use intravenous antibiotics (after sampling for microbiology) Push for urgent surgical/interventional source control Reduce cytokine load Consider low-dose steroids Consider extra-corporeal cytokine removal Evidence and class of recommendations vary between the different interventions Esmolol (Table 2) is a short-acting cardioselective beta-1 adrenergic blocker which has been tested in septic animals and in preliminary studies in human sepsis [5]. In the largest trial to date, Morelli et al. [6] enrolled septic shock patients with tachycardia (>95 beats/min) and an ongoing requirement for high-dose norepinephrine despite 24 h of active resuscitation. In this high-risk population (28-day mortality of 80.5 % in the control group), esmolol titrated to control heart rate was both safe and efficacious, reducing mortality to 49.4 %. The observed decrease in norepinephrine requirements could be mediated by a blunted immune response, resulting in an improved microcirculation [7], or enhanced adrenergic receptor sensitivity [8]. Table 2 Pharmacological properties of the study drugs Dexmedetomidine Esmolol Characteristics Highly selective alpha-2 adrenoreceptor agonist Short-acting, selective beta-1 blocker Mode of action Acts centrally, predominantly in the brain stem (sedation) and in the spinal cord (analgesia) Acts peripherally, predominantly in the heart Effects Short- and long-term sedation in the intensive care unit setting Negative chronotropic, dromotropic, inotropic effects Improves ventricular filling by prolonging diastole Anxiolysis; opioid-sparing effect; anti-delirant effects Sympatholytic activity Sympatholytic activity Route of administration; dose Intravenous infusion: 0.2–1.4 μg/kg/h Loading dose not recommended in clinical practice Infusion: 25 mg/h, up-titration every 20 min in increments of 50 mg/h, to reach the target heart rate of <95beats/min Pharmacokinetics Half-life: 1.5 h Half-life: 9 min Degradation by hepatic metabolism Degradation by unspecific esterases No dose adjustments in renal dysfunction No dose adjustment in renal and/or hepatic dysfunction Adverse haemodynamic effects Hypotension: 25 %, serious 1.7 % Symptomatic hypotension: 12 % Hypertension: 15 % Haemodynamic deterioration in patients with compensatory tachycardia Bradycardia: 13 %, serious 0.9 % Dexmedetomidine is a highly selective alpha-2 adrenoreceptor agonist that has sedative, anxiolytic, and opioid-sparing effects (Table 2) [9, 10]. The use of dexmedetomidine in critically ill patients increased ventilator-free time [11] and decreased the incidence of postoperative complications, delirium, and mortality up to 1 year post-cardiac surgery [12]. In postoperative patients, dexmedetomidine provided sympatholytic activity [13]. It also offers anti-inflammatory and organ protective effects in animal models [14]. The use of dexmedetomidine as an anti-adrenergic strategy in sepsis has been evaluated in a recently completed multicentre Japanese study (‘DESIRE’, https://clinicaltrials.gov/ct2/show/NCT01760967; last accessed 28 August 2016) for which results are still eagerly awaited. In this issue of Critical Care, Hernandez et al. [15] tested both esmolol and dexmedetomidine in a sheep model of endotoxic shock with systemic hypotension, pulmonary hypertension, and hyperlactataemia. After a brief phase of fluid resuscitation and haemodynamic stabilisation with norepinephrine, animals were randomised to receive dexmedetomidine, esmolol, or placebo. Despite the early use of sympatholytic drugs, systemic and regional haemodynamics were maintained in the interventional groups compared to the control group over the 2-h study period. Although heart rate was significantly reduced by esmolol, cardiac output, mean arterial pressure, noradrenaline requirements, and SvO2 did not differ from placebo-treated animals. Dexmedetomidine reduced serum adrenaline levels by almost 40 %. Both esmolol and dexmedetomidine reduced arterial and portal vein lactate levels and improved lactate clearance. In summary, both drugs were well tolerated from a haemodynamic point of view and associated with likely beneficial effects on metabolism. These observations are particularly interesting as dexmedetomidine and esmolol were started very early after shock induction. However, the short duration of the study precludes knowledge of longer term effects and any impact on outcomes. Furthermore, it would have been fascinating to have a fourth experimental group exploring possible synergism between esmolol and dexmedetomidine, as a rationale could be argued for the use of both. Certainly it is premature to translate these findings to clinical practice in septic patients, but this work should encourage further research into the role of alpha-2 agonists in sepsis, with or without beta-blockade.

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          Most cited references12

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          The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).

          Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.
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            Dexmedetomidine: A Review of Its Use for Sedation in the Intensive Care Setting.

            Dexmedetomidine (Dexdor(®)) is a highly selective α2-adrenoceptor agonist. It has sedative, analgesic and opioid-sparing effects and is suitable for short- and longer-term sedation in an intensive care setting. In the randomized, double-blind, multicentre MIDEX and PRODEX trials, longer-term sedation with dexmedetomidine was noninferior to midazolam and propofol in terms of time spent at the target sedation range, as well as being associated with a shorter time to extubation than midazolam or propofol, and a shorter duration of mechanical ventilation than midazolam. Patients receiving dexmedetomidine were also easier to rouse, more co-operative and better able to communicate than patients receiving midazolam or propofol. Dexmedetomidine had beneficial effects on delirium in some randomized, controlled trials (e.g. patients receiving dexmedetomidine were less likely to experience delirium than patients receiving midazolam, propofol or remifentanil and had more delirium- and coma-free days than patients receiving lorazepam). Intravenous dexmedetomidine had an acceptable tolerability profile; hypotension, hypertension and bradycardia were the most commonly reported adverse reactions. In conclusion, dexmedetomidine is an important option for sedation in the intensive care setting.
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              Perioperative dexmedetomidine improves outcomes of cardiac surgery.

              Cardiac surgery is associated with a high risk of cardiovascular and other complications that translate into increased mortality and healthcare costs. This retrospective study was designed to determine whether the perioperative use of dexmedetomidine could reduce the incidence of complications and mortality after cardiac surgery. A total of 1134 patients who underwent coronary artery bypass surgery and coronary artery bypass surgery plus valvular or other procedures were included. Of them, 568 received intravenous dexmedetomidine infusion and 566 did not. Data were adjusted with propensity scores, and multivariate logistic regression was used. The primary outcomes measured included mortality and postoperative major adverse cardiocerebral events (stroke, coma, perioperative myocardial infarction, heart block, or cardiac arrest). Secondary outcomes included renal failure, sepsis, delirium, postoperative ventilation hours, length of hospital stay, and 30-day readmission. Dexmedetomidine use significantly reduced postoperative in-hospital (1.23% versus 4.59%; adjusted odds ratio, 0.34; 95% confidence interval, 0.192-0.614; P<0.0001), 30-day (1.76% versus 5.12%; adjusted odds ratio, 0.39; 95% confidence interval, 0.226-0.655; P<0.0001), and 1-year (3.17% versus 7.95%; adjusted odds ratio, 0.47; 95% confidence interval, 0.312-0.701; P=0.0002) mortality. Perioperative dexmedetomidine therapy also reduced the risk of overall complications (47.18% versus 54.06%; adjusted odds ratio, 0.80; 95% confidence interval, 0.68-0.96; P=0.0136) and delirium (5.46% versus 7.42%; adjusted odds ratio, 0.53; 95% confidence interval, 0.37-0.75; P=0.0030). Perioperative dexmedetomidine use was associated with a decrease in postoperative mortality up to 1 year and decreased incidence of postoperative complications and delirium in patients undergoing cardiac surgery. URL: www.clinicaltrials.gov. Unique identifier: NCT01683448.
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                Author and article information

                Contributors
                +41 44 255 11 11 , alain.rudiger@usz.ch
                m.singer@ucl.ac.uk
                Journal
                Crit Care
                Critical Care
                BioMed Central (London )
                1364-8535
                1466-609X
                4 October 2016
                4 October 2016
                2016
                : 20
                : 309
                Affiliations
                [1 ]Institute of Anaesthesiology, University Hospital Zurich, Raemistrasse 100, CH 8091 Zurich, Switzerland
                [2 ]Bloomsbury Institute of Intensive Care Medicine, University College London, London, WC1E 6BT UK
                Author information
                http://orcid.org/0000-0001-7943-7624
                Article
                1488
                10.1186/s13054-016-1488-x
                5048664
                27716402
                38a62ce4-77a0-4bd2-bbeb-f46fd140047e
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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                Editorial
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                © The Author(s) 2016

                Emergency medicine & Trauma
                Emergency medicine & Trauma

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