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SEPSIS IN INTENSIVE CARE PATIENTS: CHALLENGES IN DIAGNOSIS AND PROGNOSTICATION Peter Klein Klouwenberg Sepsis in intensive care patients: challenges in diagnosis and prognostication PhD thesis, University of Utrecht, the Netherlands ISBN: 978-94-6182-528-5 Lay-out: Off Page, www.offpage.nl Printing: Off Page, www.offpage.nl © Peter Klein Klouwenberg, Utrecht, the Netherlands. All rights reserved. No parts of this thesis may be reproduced, stored in a retrieval system or transmitted in any form or by any means without permission of the author. The copyright of articles that have been published or accepted for publication has been transferred to the respective journals. The research presented in this thesis was performed within the framework of CTMM, the Center for Translational Molecular Medicine (ctmm.nl), project MARS (grant 04I-201). The printing of this thesis was kindly supported by Immunexpress, SAS Institute BV, Chipsoft BV, Pfizer, and Astellas Pharma BV. SEPSIS IN INTENSIVE CARE PATIENTS: CHALLENGES IN DIAGNOSIS AND PROGNOSTICATION Sepsis in intensive care patiënten: uitdagingen in diagnostiek en prognostiek (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan, ingevolgde het besluit van het college voor promoties in het openbaar te verdedigen op vrijdag 23 januari 2015 des middags te 4.15 uur door Peter Marius Cornelis Klein Klouwenberg geboren op 7 mei 1976 te Bergeijk Promotor: Prof.dr. M.J.M. Bonten Copromotor: Dr. O.L. Cremer TABLE OF CONTENTS PART I: INTRODUCTION Chapter 1 General introduction 9 PART II: CHALLENGES IN THE DIAGNOSIS OF SEPSIS Chapter 2 Classification of sepsis, severe sepsis and septic 17 shock: the impact of minor variations in data capture and definition of SIRS criteria Chapter 3 Interobserver agreement of CDC criteria for 33 classifying infections in critically ill patients Chapter 4 Presence of infection in patients with presumed 45 sepsis at the time of intensive care unit admission Chapter 5 Electronic implementation of a novel surveillance 61 paradigm for ventilator-associated events: easibility and validation PART III: CHALLENGES IN THE PROGNOSTICATION OF PATIENTS WITH SEPSIS Chapter 6 Intensive care unit-acquired infections after 83 admission for sepsis or non-infectious disease: incidence and attributable mortality Chapter 7 The attributable mortality of delirium in critically 101 ill patients: a prospective cohort study Chapter 8 Incidence and outcomes of new-onset atrial 123 fibrillation in critically ill patients with sepsis: a cohort study Chapter 9 Predicting evolution of disease severity in critically 135 ill patients with severe sepsis or septic shock PART IV: DISCUSSION AND SUMMARY Chapter 10 General discussion 153 Nederlandse samenvatting 165 Dankwoord 171 About the author List of publications 173 Curriculum vitae 175 PART I INTRODUCTION 1 GENERAL INTRODUCTION Peter M.C. Klein Klouwenberg HISTORICAL PERSPECTIVE OF SEPSIS Sepsis is a syndrome that arises when the body’s response to a severe infection injures its 1 own tissues. It is a major and increasing cause of in-hospital morbidity and mortality 1 2. GENERAL INTRODUCTION Most patients with severe sepsis and septic shock are admitted to intensive care units and are on mechanical ventilation, and the annual costs for the treatment of patients with sepsis are estimated to exceed US$17 billion in the United States alone 3. The word “sepsis” was first introduced by Hippocrates (ca. 460-370 BC) and is derived from the Greek word σηψις, which means “rotten flesh and putrefaction”4 . Celsus, a Roman encyclopaedist, described the cardinal clinical signs of localized acute inflammation, rubor, calor, dolor, and tumor in his extensive book De Medicina. Somewhat later, Galen of Pergamon, added a fifth manifestation: functio laesa, or loss of function. Not until the late 17th century, Leeuwenhoek made some of the first descriptions of bacteria, “animalcules”. Around the same time another Dutch physician, Boerhave, thought that toxic substances in the air were the cause for sepsis. However, it took another two centuries before some of the founders of modern microbiology, including Koch, Pasteur, Semmelweis, and Lister postulated the link between bacteria and infection 5. Finally, in 1914, Schottmüller reported that the release of pathogenic germs into the bloodstream was responsible for systemic symptoms and signs 6, changing our modern understanding of the term “sepsis”. Nonetheless, it has only been recently appreciated that the morbidity of sepsis is not solely a consequence of the virulent activity of the microorganism itself, but that its’ deleterious consequences are, as importantly, also caused by the indirect effects of the host response to the microbial invasion. In 1967 Ashbaugh observed a severe lung disease which developed in critically ill patients with severe shortness of breath, loss of lung compliance, and diffuse alveolar infiltration7 . It was soon understood that particularly patients with sepsis suffered from this so-called Adult Respiratory Distress Syndrome (ARDS) and that its development was a result of an inflammatory reaction. In the 1980s it was discovered that this inflammatory reaction was not only apparent in the lungs but in the whole body 8. More than 30 years ago, a group of experts proposed a clinical definition for sepsis to improve uniform inclusion in clinical trials. They introduced the concept of a “systemic inflammatory response syndrome” (SIRS), involving alterations in body temperature, heart rate, respiration rate and leukocyte counts 9. The panel defined sepsis as SIRS caused by clinically suspected infection, “severe sepsis” as sepsis complicated by acute organ dysfunction and “septic shock” as sepsis complicated by hypotension refractory to fluid resuscitation. These definitions, generally referred to as the “Bone criteria”, have been used as inclusion criteria in many clinical sepsis trials, and until today have remained largely unchanged 10. 11 THESIS AIM AND OUTLINE 1 Despite recent advances in the management of sepsis, the morbidity and mortality caused by sepsis remain unacceptably high. Patient populations with sepsis are GENERAL INTRODUCTION heterogeneous with regard to the implicated pathogen, the underlying infectious disease and their genetic profile, which makes it demanding to improve the outcome of sepsis. In particular, the diagnosis of sepsis and the prognostication of sepsis patients remain challenging. For these reasons, the Molecular Diagnosis and Risk Stratification of Sepsis (MARS) data collection initiative and biobank study was started in two Dutch tertiary intensive care units in 2010 11,12 . Its aim is to provide solutions for the current shortcomings in the diagnosis and prognostication of critically ill patients with presumed sepsis. This thesis describes some of the results of this initiative. The first part of this thesis focuses on the diagnostic challenges in critically ill patients with sepsis. Chapter 2 describes the influence of minor variations in the definition and measurement of SIRS criteria and organ failure on the observed incidences of sepsis, severe sepsis and septic shock. The interobserver agreement for classifying infections of various subtypes according to Centers for Disease Control and Prevention criteria in a mixed ICU population is described in Chapter 3. Chapter 4 provides an assessment of the likelihood of infection in patients who were treated for sepsis upon admission to the ICU, and quantified the association between plausibility of infection and mortality. Chapter 5 presents a validation study of a novel surveillance system for complications of mechanical ventilation as an alternative to the current surveillance of ventilator-associated pneumonia. In the second part of this thesis, the prognosis of important complications of sepsis in critically ill patients is described. In Chapter 6 we present a comparative analysis of the incidence and attributable mortality of secondary infections in patients admitted to the ICU with or without sepsis. Chapter 7 presents the attributable mortality caused by an important complication of sepsis, delirium, in critically ill patients. The incidence and outcomes of atrial fibrillation in a cohort of critically ill patients with sepsis is provided in Chapter 8. Chapter 9 present a model that predicts the evolution of disease for individual patients admitted for sepsis, by estimating daily probabilities of progression to death or multiple organ failure after one week in the ICU, using routinely available parameters. A synthesis of the results and general discussion is provided in Chapter 10. 12 REFERENCES 1. Martin GS, Mannino DM, Eaton S, Moss M. primary role of lymphoreticular cells in the 1 The epidemiology of sepsis in the United mediation of host responses to bacterial States from 1979 through 2000. N Engl J endotoxim. J Infect Dis 1980;141(1):55-63. GENERAL INTRODUCTION Med 2003;348(16):1546-54. 9. Bone RC, Balk RA, Cerra FB, Dellinger RP, 2. WHO. The world health report, changing Fein AM, Knaus WA, et al. Definitions for history: Deaths by cause, sex and mortality sepsis and organ failure and guidelines for stratum in WHO regions estimates for 2002, the use of innovative therapies in sepsis. 2004. The ACCP/SCCM Consensus Conference 3. Angus DC, Linde-Zwirble WT, Lidicker Committee. American College of Chest J, Clermont G, Carcillo J, Pinsky MR. Physicians/Society of Critical Care Medicine. Epidemiology of severe sepsis in the United Chest 1992;101(6):1644-55. States: analysis of incidence, outcome, and 10. Angus DC, van der Poll T. Severe sepsis and associated costs of care. Crit Care Med septic shock. N Engl J Med 2013;369(9):840- 2001;29(7):1303-10. 51. 4. Marshall JC. Sepsis: rethinking the 11. Klein Klouwenberg PM, Ong DS, Bonten MJ, approach to clinical research. J Leukoc Biol Cremer OL. Classification of sepsis, severe 2008;83(3):471-82. sepsis and septic shock: the impact of minor 5. Vincent JL, Abraham E. The last 100 years variations in data capture and definition of SIRS of sepsis. Am J Respir Crit Care Med criteria.