To my parents to whom I owe everything; to my family for their self-denial, support, and sacrifice; and to my patients for their
teachings. — (Carmelo Dueñas) To my patients, my students, and my family. — (Guillermo Ortiz)
Sepsis is a global public health problem; it generates more than 3,000,000 hospitalizations per year. Despite the advances in modern medicine, more than 5.3 million people die from sepsis annually. It remains the leading cause of death in critically ill patients in noncoronary intensive care units, with an estimated overall mortality of about 30%. In order to face a problem of such magnitude, it is essential to have an objective, a clear and universal definition. Although the first description dates back to more than 3,500 years, it was only in 1992 that an effort was made to reach a consensus on a definition. From a definition by a consensus of experts in 1992, a switch was made to another one based on a compilation of clinical studies that included a large number of patients. We present a historical summary of the changes that the definition of sepsis and septic shock has undergone and the fundamentals of these changes. The latest publication in 2016, despite being a gigantic achievement, has been the subject of ample questions that show that the definition of sepsis is still under construction. The present text aims to review the basic aspects of sepsis from its definition, the immunity in sepsis, and the implementation of biomarkers and their actual usefulness. We also reviewed the cost and overall impact of sepsis as well as the total economic cost of antibiotic resistance. Estimates vary but have ranged as high as $20 billion in excess direct healthcare costs, with additional costs to society for lost productivity as high as $35 billion a year (2008 dollars). We present the extent of diagnostic imaging in the workup of sepsis, organ dysfunction, and mechanisms of resistance. The information we obtain and extract from the antibiogram has a great clinical and epidemiological impact, because, on one hand, it serves as a guide to choose the antimicrobial treatment in an infectious process and, on the other hand, it avoids the use of other antibiotics in an unnecessary way, thus leading to a reduction in the ecological impact.
In one chapter, we develop the antibiogram and its objective, importance, and interpretation in the health environment. Finally we review the n on-antibiotic management of sepsis and septic shock, the new strategies for training high-performance teams, and the role of simulation in sepsis. We hope that this text will be useful to the kind readers and generates such a concern that will allow us all to diminish the great uncertainty existing about a pathology as old as not yet known. Bogotá, Colombia Cartagena, Colombia
Liliana Arias-Alvarez Hospital Universitario San Ignacio, Bogotá, Colombia Nelson Alvis-Guzman, MD, MPH, PhD Health Economics Research Group, Universidad de Cartagena, Avenida del consulado Campus Piedra de Bolivar, Cartagena, Bolivar, Colombia Universidad de la Costa, Barranquilla, Colombia Mario Lora-Andosilla Internal Medicine, Critical Medicine and Intensive Care, Universidad de Cartagena, Cartagena, Colombia Cindy Arteta-Acosta MPH Epidemiology, Universidad del Norte, Barranquilla, Colombia Medicine Universidad de Cartagena, Cartagena, Colombia Jorge Alberto Carrillo-Bayona Department of Diagnostic Imaging, Universidad Nacional de Colombia, Bogotá, Colombia Diana Borré-Naranjo Internal Medicine, Critical Medicine and Intensive Care, Universidad de Cartagena, Cartagena, Colombia Wilfrido Coronell-Rodríguez Pediatrician, Universidad del Valle, Cali, Colombia Infectious disease Universidad Autonoma de Mexico, Mexico City, Mexico Professor of Universidad de Cartagena, Tropical Medicine Universidad de Cartagena, Cartagena, Colombia Germán Díaz Hospital Santa Clara, Universidad el Bosque, Bogotá, Colombia Carmelo Dueñas-Castell Postgraduate Program in Critical Medicine and Intensive Care, Universidad de Cartagena, Intensive Care Unit, Gestion Salud, Cartagena, Bolivar, Colombia Universidad del Bosque, Bogotá, Colombia Critical Care Medicine, Universidad de la Sabana, Cundinamarca, Colombia Carolina Martínez-Esparza ABC Medical Center, Mexico City, Mexico xi
Manuel Garay-Fernández, MD Department of Critical Care, Hospital Santa Clara, Bogotá, Colombia Nelson Javier Fonseca-Ruiz Department of Critical Care, Clínica Medellín, Universidad CES, Medellín, Colombia Kevin Cantillo-García Internal Medicine, Critical Medicine and Intensive Care, Universidad de Cartagena, Cartagena, Colombia Marco A. Gonzalez, MD, MS, FCCM Division of Critical Care Medicine, Universidad Pontificia Bolivariana and Clinica Sagrado Corazon, Medellín, Antioquia, Colombia Torre Médica Ciudad del Río, Medellín, Antioquia, Colombia Fernando De la Hoz-Restrepo, MD, MPH, PhD Universidad Nacional de Colombia, Bogotá, Colombia Gerson Arias-León Clinica Shaio, Internal Medicine, Department of Infectious Diseases, National University, Bogotá, Colombia José M. Maestre Hospital Virtual Valdecilla, Santander, Spain Rodrigo Rubio-Martínez Anesthesia Department, ABC Medical Center, UNAM School of Medicine, Mexico City, Mexico Ignacio Del Moral Hospital Virtual Valdecilla, Santander, Spain Cristhiaan D. Ochoa, MD, PhD Physician-Scientist Training Program, Division of Pulmonary and Critical Care and Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, TX, USA Guillermo Ortiz-Ruiz, MD, PhD Department of Internal Medicine, Pulmonary Medicine and Critical Care Hospital Santa Clara, Universidad del Bosque, Bogotá, Colombia Hernando Pinzon-Redondo, MD Health Economics Research Group, Universidad de Cartagena, Avenida del consulado Campus Piedra de Bolivar, Cartagena, Bolivar, Colombia Jenny W. Rudolph Center for Medical Simulation, Boston, MA, USA Demian Szyld Center for Medical Simulation, Brigham and Women’s Hospital, Boston, MA, USA Andrea Martínez de la Vega Celorio ABC Medical Center, Mexico City, Mexico Melkis Buelvas-Villalba Internal Medicine, Universidad Libre Barranquilla, Barranquilla, Colombia
Sepsis: A Definition Under Construction Carmelo Dueñas-Castell, Guillermo Ortiz-Ruiz, and Diana Borré-Naranjo
about 2400 years ago [7–9]. The Greeks used the term sepsis to describe decay or putrefaction. Centuries later, the signs of inflammation were described and organ dysfunction was reported [2, 3, 7–10]. When microorganisms were identified, sepsis was considered an infection associated with these germs . In 1992, a consensus of sepsis was published, promoted by Dr. Roger Bone, in which the first universal definition of sepsis was generated . In this consensus, the definition of sepsis was, due to its simplicity, standardized as the host’s inflammatory response to infection . By then the criteria that defined systemic inflammatory response syndrome (SIRS) were four: temperature, heart rate, respiratory rate, and white blood cell count. The SIRS was defined by the presence of at least two of the following criteria: 1 . Temperature >38 or <36°°C 2. Heart rate >90 min−1 3. Respiratory rate >20 min−1 or hyperventilation with a PaCO2 <32 mm Hg 4. Leukocytes >12,000 or <4000 or with more than 10% immature neutrophils Over the years, pathophysiology and symptomatology have made the diagnosis of sepsis increasingly difficult. Additionally, the high mortality led to the need for an early diagnosis that would allow for the implementation of more timely interventions. This has forced the scientific community to make it easier for the doctor to think about sepsis and to make the clinical diagnosis early. This explains why, over the years, the criteria for considering such diagnosis have been broadened, improving sensitivity despite losing accuracy [3, 7–10, 12, 13]. Although there are about 2000 biomarkers, there is no standard diagnostic test for sepsis. This makes sepsis one of the most complex diagnostic challenges. The gigantic advance made in 1992 made it possible to unify criteria and to standardize protocols and epidemiological and research studies, as well as improve the detection. Clinical criteria should help make quick decisions and even guide diagnostic testing and therapy, guide in the identification of infected patients with an increased risk of complications and death, and monitor response to treatment. However, in a qualitative survey of 1000 physicians (including 529 intensivists) conducted in 2000 by telephone interview, it was found that less than 20% of the respondents gave a consistent definition of sepsis. Many physicians had the mistaken idea that fever or hypotension should be present to diagnose sepsis . Since 1991 it is accepted that sepsis is a heterogeneous clinical syndrome, and since then there have been serious questions about the sensitivity and specificity of the proposed criteria. However, the definition prevailed for more than 10 years, focusing on the septic syndrome as a simplified excess of inflammation. A second consensus effort was made in 2001, and sepsis was considered as “a clinical syndrome defined by the presence of both infection and systemic inflammatory response syndrome” . The committee accepted the poor specificity of SIRS in identifying patients with sepsis. Therefore, they expanded the list of clinical and para-clinical criteria in order to optimize the clinician’s approach . This improved the sensitivity, but with a deterioration of specificity in the diagnosis.
1 Sepsis: A Definition Under Construction
As every intensivist has suffered, many critically ill patients with SIRS do not have sepsis, and some septic patients do not have SIRS [12, 13]. By then sepsis was defined as infection plus some of the following criteria: hyperthermia or hypothermia, tachycardia or tachypnea, altered mental status, edema or positive fluid balance, hyperglycemia (no history of diabetes), leukocytosis or leukopenia, elevated C-reactive protein or procalcitonin, hypotension, low mixed venous saturation or high cardiac index, hypoxia, oliguria or elevated creatinine, coagulation abnormalities, ileus, thrombocytopenia, elevated bilirubin, elevated lactate, and slow capillary filling . This has caused large variations in case definitions, with very different results in terms of the epidemiology of sepsis. Thus, recent estimates have reported an annual incidence between 300 and 1000 cases of sepsis per 100,000 inhabitants [1, 2, 4, 7, 8]. The 1992 consensus defined sepsis, identified severe sepsis, and established septic shock as the potential progression from sepsis to multiple organ failure and death. The basic structure of the 1992 consensus, with the definitions of SIRS, sepsis, severe sepsis, and septic shock, remained unchanged in the 2003, 2008, and 2012 guidelines [16–18]. The definition and criteria were actually based on the opinion of experts who attempted to provide simple, universal, easy-to-obtain tools at the foot of the patient’s bed and to allow the clinician to establish that the patient looked septic. The experts acknowledged that these criteria were not specific for infection and should therefore be interpreted in the light of the relevant clinical situation to determine if there was actually an infection and whether infection was the cause of such alterations [14–18]. However, in parallel, several publications raised serious doubts about the real diagnostic utility of such definitions: 1. This was a much broader definition than that used in large studies and research on sepsis [19–22]. 2. In 2006, a European survey showed that SIRS criteria were 100% responsive but only 18% specific for severe infections . 3. In 2012, a prospective observational study showed that minor variations in the capture of SIRS data changed the incidence of sepsis . 4. In 2013, Dr. Vincent and colleagues argued that SIRS has been less sensitive and non-specific. They further stated that the SIRS approach has three main problems . Firstly, SIRS criteria are so sensitive that up to 90% of patients admitted to an intensive care unit (ICU) meet them; secondly, they can be caused by many noninfectious clinical processes (trauma, severe burns, pancreatitis); and, thirdly, almost all patients with acute disease meet SIRS criteria . 5. A retrospective study found that, of the 109,663 patients with organ failure and infection, 13,278 (12.1%) did not meet the traditional SIRS criteria for defining sepsis . Strict adherence to SIRS criteria excluded one in eight patients with
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severe sepsis. Therefore, they proposed a switch to another definition based on the presence of infection and organic dysfunction . 6. It is clear that sepsis cannot be simplified as a state of hyperinflammation, since pro-inflammatory and anti-inflammatory responses may occur in some patients, while other septic patients show signs of impaired immunity . Moreover, the fact that a patient presents a hyperimmune or hypoimmune response depends on a wide range of pathogen or host factors, and these can change in the same patient during the course of the disease. This is much more unpredictable in elderly and renal patients with renal replacement therapy . 7. Some publications have suggested that clinicians often disagree with the diagnosis of sepsis performed with rigorous consensus definitions [27, 28]. 8. A recent publication reported a survey completed by 94 physicians . The majority (88%) were specialists in critical care: pulmonologists (39%), anesthesiologists (19%), surgeons (9%), and emergency specialists (9%). They had an average of 8 years of practice. The majority (83%) felt able to apply the definitions of sepsis. However, the agreement with respect to the five classification levels (SIRS, sepsis, severe sepsis, septic shock, or none of the above) was poor. In addition, when sepsis is diagnosed, it is very subjective to decide whether infection is present, whether acute organ dysfunction is present, and whether this dysfunction is attributable to infection . The subjectivity in diagnosing sepsis should be taken into account when interpreting initiatives or studies that evaluate the quality of care or when making public reports, measuring adherence to the bundles of measures, or for epidemiological studies or investigations. Therefore, they stated the need to have objective criteria and a standardized methodology in order to improve the consistency and comparability of research, surveillance, quality of care, and reporting . 9. In a cohort of patients with infection and organ dysfunction, Churpek and colleagues found that two or more SIRS criteria were unable to differentiate the probability of death . In 269,951 patients admitted to five US hospitals between 2008 and 2013, nearly half met two or more SIRS criteria upon admission to the ICU . On the other hand, the presence of dysfunction of one or more organs occurred less frequently (14%); however, organ dysfunction was associated with higher mortality (5.3% vs. 1.1%) and increased sequentially to a greater number of compromised organs . Therefore, they suggested that organic dysfunction is a better choice to identify patients at higher risk of death [30, 31]. This change in the approach to the patient is consistent with ideas presented by members of the Third International Consensus for the Definition of Sepsis and Septic Shock [30, 31]. In 2014, the North American (SCCM) and European Critical Care and Intensive Care Societies (ESICM) convened in a group of 19 experts to generate an update and/or consensus on the definition of sepsis, in order to standardize the terminology used, improve early detection of sepsis, and increase consistency in
1 Sepsis: A Definition Under Construction
the inclusion of patients in clinical trials. After several meetings, using the Delphi method, based on the review and analysis of electronic database records and through a voting system, in 2016 they published a new definition of sepsis and septic shock . For these new definitions, they considered : 1. Sepsis is the primary cause of death from infection, especially when it is not recognized and treated properly. 2. Sepsis is a syndrome generated by pathogen and host factors that differs from infection by an aberrant or unregulated host response and by the presence of organic dysfunction. 3. The organic dysfunction induced by sepsis may be hidden, and therefore its presence should be considered in any patient with infection. In addition, as an unrecognized infection can cause organic dysfunction, any organ dysfunction should warn about possible underlying infection. 4. The clinical and biological phenotype of sepsis may be altered by pre-existing disease, comorbidities, medications, or interventions. 5. Specific infections can lead to localized organ dysfunction without generating an unregulated host response. In a predictive validation comparing SIRS, sequential organic failure assessment (SOFA), and logistic system of organic dysfunction (LODS) among patients with suspected infection (n = 7932), the predictive value for hospital mortality of SOFA is 0.74 (95% CI, 0.73–0.76) but was higher than the SIRS [AUROC, 0.64 (95% CI, 0.62–0.66)]. This supported the use of SOFA for sepsis. Considering that SOFA was less complicated and more widely used, they proposed to define organ dysfunction. Thus, patients with two or more points would be classified as organ dysfunction. The SOFA scale includes: respiration (PaO2/FiO2 low), coagulation (thrombocytopenia), liver (high bilirubin), cardiovascular (hypotension), central nervous system (altered mental status), and renal (elevated creatinine or oliguria). This definition generated a dramatic change over the period from 1992 to 2001. The new definition of sepsis is: “life-threatening organic dysfunction caused by an unregulated response to infection.” This underscores the widely held view that the presence of a systemic response does not necessarily reflect an inappropriate, unregulated host response and that nonregulation is best identified by organ dysfunction. The authors emphasized that sepsis without organic dysfunction, hypotension, or hypoperfusion is a very different entity from septic shock and may not require an aggressive approach. SOFA score is well recognized as a valuable method for characterizing organ dysfunction, but it is somewhat complex for the early identification of the patient with sepsis outside an ICU . Seymour and colleagues derived a new scale called quick SOFA (qSOFA) in a primary cohort and then in a confirmatory analysis reported that, in patients with suspected infection, out of the ICU (n = 66,522), qSOFA had a high predictive value
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for mortality [AUROC, 0.81 (95% CI, 0.80–0.82)] similar to SOFA and statistically superior to SIRS [AUROC, 0.76 (95% CI, 0.75–0.77)]. They therefore selected it as a quick method for identifying adults with suspected infection and with a high probability of having worse outcomes. In addition, they suggested that SIRS should not be used to evaluate patients with suspected sepsis. The quick SOFA (qSOFA) is composed of three variables: 1 . Respiratory rate >22 min−1 2. Systolic blood pressure <100 mm Hg 3. Mental state, Glasgow <15 It is a very specific and relevant tool for the recognition of patients with suspected infection, which has the advantages of being easy to remember, quickly obtained, and only by clinical evaluation of the patient [3, 33]. It should not be ignored that the presence of these variables could be related to some comorbidities, interventions, or previous medications and that hypotension in the context of infection does not necessarily define the presence of shock. It is important to note that SOFA and qSOFA reflect the score of both acute and chronic alterations in organ function, so changes in the score over time are more useful than a static value. The presence of two or more of these criteria should encourage the healthcare team to evaluate the presence of infection and/or organ dysfunction, initiate or adjust therapy, and consider referral of the patient to an intensive care unit [3, 32, 33]. Clinical criteria are an early warning system. However, although clinically valuable markers are still imperfect, a patient with less than two criteria may remain a concern for the healthcare team or vice versa. As well as SIRS criteria, the criteria of qSOFA may be present in a patient without infection, due to other acute conditions such as hypovolemia, severe heart failure, or massive pulmonary thromboembolism. Thus, these scales are tools designed to help improve patient care and as such should never replace clinical judgment [3, 34]. Similarly, to define septic shock, the Delphi method was followed, a systematic review and a meta-analysis of the literature. Ninety-two publications were found, with great variability in the definitions used [13, 32, 35]. After reviewing three databases and evaluating six different criteria, the following definition was reached, “a subgroup of septic patients with circulatory disorders and cell metabolism so profound that they substantially increase mortality”, and it was agreed that patients with septic shock could be clinically identified by the following criteria [32, 35]: 1.The requirement for vasopressors to maintain an average arterial pressure of 65 mm Hg or greater 2. Serum lactate levels greater than 2 mmol/L (>18 mg/dL) 3. In the absence of hypovolemia Despite the great international support received by the new definitions, there have been comments against them. Probably the most important opposition has been an editorial published in Chest, an official publication of the American College
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of Chest Physicians (ACCP). The CFCA was one of the societies that p romoted the first consensus in 1992 . In the editorial there are several reasons for not agreeing with the new definitions of sepsis: 1. There are insufficient arguments to change previous definitions that had been shown to predict mortality and that had been used in studies to apply interventions that had reduced overall mortality. 2. Failure to use SIRS criteria may result in failure to recognize the onset of a continuum of sepsis until the patient has progressed to dysfunction of organs. Thus the CFCA states that this could lead to a failure to recognize the signs of potentially lethal infections until it is too late. 3. A consensus on this subject should have a greater representation of emergency and hospice medicine to address concern about the principle that the new definition underestimates intervention at earlier stages of sepsis. 4. The syndrome is actually mostly treatable. 5. Record the concern that doctors from different specialties have expressed their disagreement with the application of the new definition as this could cost the lives of patients and therefore state emphatically that they could not support their adoption. Other questionings of the new definition which also have some relation with the previous ones have been : the cutoff points used; the chosen variables; the fact that the cause of the organic dysfunction may not be directly related to the infection, which does not integrate the chronology of the infectious process with organ dysfunction; and the obvious differences in pathophysiology related to innate immunity, comorbidities, and infection characteristics (source, inoculum, microorganism). Some of the members of the group that created these new definitions have stated that, despite being the best summary of current knowledge, they are not in themselves definitions and therefore do not allow us to say with absolute certainty that a given patient has sepsis and another one does not . They do not offer a gold standard to make the diagnosis accurate and totally reliable. The new definition of sepsis proposes a sequence of events in which an infection can generate an unregulated response that causes dysfunction of organs, which in its turn can threaten the patient’s life. It is not clear whether this logical sequence of events always happens like this, and, in addition, there are other noninfectious pathological conditions that can generate that same cascade of events attributable to infection which today we call sepsis . Another challenge to the definition is that it still considers the predominant anomaly to be immunological, as it was more than two decades ago, despite the fact that investigations about that immune pathway have not borne the expected results . It is clear that constructing a definition of sepsis is very complex and difficult, especially when there are still aspects about sepsis that we do not fully understand [38, 39]. In a complete review, Angus and colleagues [38, 39] present the difficulties and outline a frame of reference for future proposals while proposing that the criteria for operationalizing a definition can be judged by six areas or
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domains of utility (reliability, construct and criterion of validity, measurement load, and punctuality). The relative importance of these six domains depends on the purpose of the criteria (clinical care, basic and clinical research, monitoring, quality improvement, and auditing). Using that frame of reference to identify the purpose and apply the domains can help with the evaluation of existing diagnostic criteria for sepsis and provide a roadmap for future work aimed at improving this definition that is still under construction.
References 1. Sun A, Mikkelsen M. The evolution of sepsis performance metrics: from mortality to hospital readmission. Crit Care Med. 2015;43(9):2031–2. 2. Marshall J. Sepsis-3: what is the meaning of a definition? Crit Care Med. 44:1459–60. 3.Vincent J, Mira P, Antonelli M. Sepsis: older and newer concepts. Lancet Respir Med. 2016;4:237–40. 4. Scott MC. Defining and diagnosing sepsis. Emerg Med Clin N Am. 2017;35:1–9. 5.Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, Angus DC, Reinhart K. Assessment of global incidence and mortality of hospital-treated sepsis. current estimates and limitations. Am J Respir Crit Care Med. 2016;193:259–72. 6. Torio C, Andrews R. National inpatient hospital costs: the most expensive conditions by payer, 2011. Washington, DC: Agency for Health Care Policy and Research (US); 2013. 7.Kempker JA, Martin GS. The changing epidemiology and definitions of sepsis. Clin Chest Med. 2016;37:165–79. 8.Moss M. Epidemiology of sepsis: race, sex, and chronic alcohol abuse. Clin Infect Dis. 2005;41(Suppl 7):S490–7. 9.Botero JSH, Pe’rez MCF. The history of sepsis from ancient Egypt to the XIX century. 2012. http://www.intechopen.com/books/export/citation/End Note/sepsis-an-ongoing-and-significant-challenge/the-history-of-sepsis-from-ancient-egypt-to-the-xixcentury. Accessed 2 Jan 2017. 10.Vincent JL, Opal SM, Marshall JC, Tracey KJ. Sepsis definitions: time for change. Lancet. 2013;381(9868):774–5. 11.Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM. Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644–55. 12.Shankar-Hari M, Deutschman C, Singer M. Do we need a new definition of sepsis? Intensive Care Med. 2015;41:909–11. 13.Abraham E. New definitions for sepsis and septic shock continuing evolution but with much still to be done. JAMA. 2016;315(8):757. 14. Poeze M, Ramsay G, Gerlach H, Rubulotta F, Levy M. An international sepsis survey: a study of doctors’ knowledge and perception about sepsis. Crit Care. 2004;8(6):R409–13. 15.Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Intensive Care Med. 2003;29(4):530–8. 16.Dellinger RP, Carlet JM, Masur H, et al. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004;32(3):858–73. 17. Dellinger RP, Levy MM, Carlet JM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1):296–327.
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18.Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165–228. 19.Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368–77. 20.ProCESS Investigators. Randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683–93. 21. ARISE Investigators, ANZICS Clinical Trials Group, Peake S, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496–506. 22. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372(14):1301–11. 23.Vincent J-L, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006;34(2):344–53. 24. Klein Klouwenberg PM, Ong DS, Bonten MJ, et al. Classification of sepsis, severe sepsis and septic shock: the impact of minor variations in data capture and definition of SIRS criteria. Intensive Care Med. 2012;38(5):811–9. 25. Kaukonen KM, Bailey M, Pilcher D, et al. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med. 2015;372(17):1629–38. 26. Drewry AM, Hotchkiss RS. Revising definitions of sepsis. Nat Rev Nephrol. 2015;11(6):326–8. 27.Weiss SL, Fitzgerald JC, Maffei FA, Kane JM, Rodriguez-Nunez A, Hsing DD, et al.
Discordant identification of pediatric severe sepsis by research and clinical definitions in the SPROUT international point prevalence study. Crit Care. 2015;19:325. 28.Brown T, Ghelani-Allen A, Yeung D, Nguyen HB. Comparative effectiveness of physician diagnosis and guideline definitions in identifying sepsis patients in the emergency department. J Crit Care. 2015;30(1):71–7. 29. Rhee C, Kadri SS, Danner RL, Suffredini AF, et al. Diagnosing sepsis is subjective and highly variable: a survey of intensivists using case vignettes. Crit Care. 2016;20:89. 30.Churpek MM, Zadravecz FJ, Winslow C, Howell MD, Edelson DP. Incidence and prognostic value of the systemic inflammatory response syndrome and organ dysfunctions in ward patients. Am J Respir Crit Care Med. 2015;192(8):958–64. 31. Smyth M, Daniels R, Perkins G. Identification of sepsis among ward patients. Am J Respir Crit Care Med. 2015;192(8):910–1. 32.Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):801–10. 33.Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, et al. Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):762–74. 34.Vincent J, Martin G, Levy M. qSOFA does not replace SIRS in the definition of sepsis. Crit Care. 2016;20:210. 35. Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, et al. Developing a new definition and assessing new clinical criteria for septic shock: for the third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):775–87. 36. Simpson SQ. New sepsis criteria: a change we should not make. Chest. 2016;149(5):117–8. 37. Deutschman CS. Imprecise medicine: the limitations of sepsis-3. Crit Care Med. 2016;44:857–8. 38.Angus DC, Seymour CW, Coopersmith CM, Deutschman CS, et al. A framework for the development and interpretation of different sepsis definitions and clinical criteria. Crit Care Med. 2016;44:e113–21. 39. Seymour CW, Coopersmith CM, Deutschman CS, Gesten F, et al. Application of a framework to assess the usefulness of alternative sepsis criteria. Crit Care Med. 2016;44:e122–30.
Economic Impact of Infections and Antibiotics Nelson Alvis-Guzman, Fernando De la Hoz-Restrepo, and Hernando Pinzon-Redondo
Burden of Diseases and Epidemiologic Transition Epidemiologists have described disease’s impact in different ways. Mortality analysis was the most important approach until the 1980s decade. In the 1990s, the World Bank commissioned the original Global Burden of Disease (GBD) study which was published in the World Development Report 1993: “Investing in Health.” This GBD study served as the most comprehensive effort to systematically measure the world’s health problems, generating estimates for 107 diseases and 483 sequelae . The GBD is a measurement of impact of disease combining years of life lost to premature mortality plus years of life lost to time lived in states of less than full health, measured by disability-adjusted life years (DALY). “One DALY can be thought of as one lost year of ‘healthy’ life. The sum of these DALYs across the population, or the burden of disease, can be thought of as a measurement of the gap between current health status and an ideal health situation where the entire population lives to an advanced age, free of disease and disability” [2, 3]. The causes of disease were grouped into three by the Global Burden of Disease study: (a) communicable, perinatal, maternal, and nutritional conditions, (b) noncommunicable diseases, and (c) injuries .
Furthermore, in 1972, Abdel R. Omran posited the theory of epidemiologic transition, which described the complex change in patterns of health and disease and the interactions between those patterns and their demographic, economic, and sociologic determinants and consequences. One of the five basic propositions that support the theory is that pandemics of infection are gradually displaced by degenerative and man-made diseases as the chief form of morbidity and primary cause of death . Despite the evident predominance of chronic diseases as a cause of death in 2015, infectious diseases still persist among the top ten causes. In 2015, for instance, lower respiratory infections caused 3.2 million deaths out of the 56.4 million deaths registered worldwide in that year. The death rate from diarrheal diseases almost halved between 2000 and 2015, but still caused 1.4 million deaths in 2015. Similarly, tuberculosis killed fewer people during the same period, but is still among the top ten causes with a death toll of 1.4 million. HIV/AIDS is no longer among the world’s top ten causes of death when all countries are considered, but is still among the top ten in developing countries, killing 1.1 million people in 2015 . The GBD 2015 showed that progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders . It is possible that environmental factors, like warmer temperatures, produce an increase in the importance of other infectious diseases such as those transmitted by mosquitoes. Dengue already produces more than 390 million cases every year around the world, and its burden of disease is probably underestimated due to constraints in the resources used for surveillance in developing countries. Malaria continues to ravage some developing countries especially in Africa, Asia, and South America, and emerging resistance to treatment with artesunates may hamper control efforts in the future. Recently, it has been estimated that there are around 400 million cases of malaria every year [8–10]. Figures 2.1 and 2.2 show the evolution of deaths and DALYs in the world between 1990 and 2015. Table 2.1 describes the relationship between the income level of the countries and the mortality profile. In the low-income countries, the 45,000,000 40,000,000 35,000,000 Number of deaths
Communicable, maternal, neonatal, and nutritional diseases
Fig. 2.1 Deaths by three groups of causes for the burden of disease in the world (1990–2015). Source: Made by the authors based on 
2 Economic Impact of Infections and Antibiotics
Millions of DALY
1,200.0 1,000.0 800.0 600.0 400.0 200.0 -
Communicable, maternal, neonatal, and nutritional diseases
Fig. 2.2 DALYs (disability-adjusted life years), number by three groups of causes for the burden of disease in the world (1990–2015). Source: Made by the authors based on  Table 2.1 Deaths and rate of death per 100,000 persons by group of causes of burden of disease (1990 and 2015)
Causes Communicable, maternal, neonatal, and nutritional diseases High income Upper middle income Lower middle income Low income Noncommunicable diseases High income Upper middle income Lower middle income Low income Injuries High income Upper middle income Lower middle income Low income Total
causes of death from infectious diseases predominate, while chronic and degenerative diseases are most frequent in high-income countries. However, in both groups of countries, there is a decrease in the proportion of communicable or infectious diseases as causes of death between 1990 and 2015.
N. Alvis-Guzman et al.
Taking into account two of the most important groups of infectious diseases (diarrhea, lower respiratory infections, other common infectious diseases, and meningitis), the percentage of change (decrease) is variable with the level of income, and as expected, the changes in developed countries (high income) were much lower during the period (see Table 2.2 and Figs. 2.3, 2.4, 2.5, 2.6, and 2.7). Table 2.2 DALYs, rate of death per 100,000 persons by group of causes of burden of disease and income countries (1990 and 2015) Diseases Diarrhea, lower respiratory infections, and other common infectious diseases World Bank high income World Bank upper middle income World Bank lower middle income World Bank low income Global Meningitis World Bank high income World Bank upper middle income World Bank lower middle income World Bank low income Global