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2018 sepsis

Third Edition
Guillermo Ortiz-Ruiz
Carmelo Dueñas-Castell



Guillermo Ortiz-Ruiz  •  Carmelo Dueñas-Castell

Third Edition

Guillermo Ortiz-Ruiz

Department of Internal Medicine
Pulmonary Medicine and Critical Care
Hospital Santa Clara
Universidad del Bosque

Carmelo Dueñas-Castell
Department of Critical Care Clínica
Gestión Salud
Universidad de Cartagena

ISBN 978-1-4939-7332-3    ISBN 978-1-4939-7334-7 (eBook)
Library of Congress Control Number: 2017954326
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To my parents to whom I owe everything;
to my family for their self-denial, support,
and sacrifice; and to my patients for their

— (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
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

Guillermo Ortiz-Ruiz
Carmelo Dueñas-Castell


1 Sepsis: A Definition Under Construction. . . . . . . . . . . . . . . . . . . . . . . .    1
Carmelo Dueñas-Castell, Guillermo Ortiz-Ruiz,
and Diana Borré-Naranjo
2 Economic Impact of Infections and Antibiotics. . . . . . . . . . . . . . . . . . .   11
Nelson Alvis-Guzman, Fernando De la Hoz-Restrepo,
and Hernando Pinzon-Redondo
3 Immunity in Sepsis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   25
Nelson Javier Fonseca-Ruiz
4 Biomarkers in Sepsis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   39
Mario Lora-Andosilla, Kevin Cantillo-García, Diana Borré-Naranjo,
Melkis Buelvas-Villalba, Guillermo Ortiz-Ruiz,
and Carmelo Dueñas-Castell
5 Diagnostic Imaging in Sepsis of Pulmonary Origin. . . . . . . . . . . . . . . .   51
Jorge Alberto Carrillo-Bayona and Liliana Arias-Alvarez
6 Multiorgan System Failure in Sepsis. . . . . . . . . . . . . . . . . . . . . . . . . . . .   67
Marco A. Gonzalez and Cristhiaan D. Ochoa
7Resistance Mechanisms: A Problem and an Approach
to the Solution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   73
Gerson Arias-León
8Interpretive Reading of the Antibiogram:
A Tool for Clinical Practice. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   95
Wilfrido Coronell-Rodríguez, Cindy Arteta-Acosta,
and Carmelo Dueñas-Castell
9Sepsis Management: Non-antibiotic Treatment of Sepsis
and Septic Shock. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  117
Manuel Garay-Fernández




10 New Strategies for Training High-Performance Teams. . . . . . . . . . . . .  135
Carolina Martínez-Esparza, Andrea Martínez de la Vega Celorio,
and Rodrigo Rubio-Martínez

Simulation and Sepsis: What Is the Best Evidence?. . . . . . . . . . . . . . .  151
Guillermo Ortiz-Ruiz, José M. Maestre, Demian Szyld,
Ignacio Del Moral, Jenny W. Rudolph, and Germán Díaz

Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  167


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,
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



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,
Hernando Pinzon-Redondo, MD  Health Economics Research Group, Universidad
de Cartagena, Avenida del consulado Campus Piedra de Bolivar, Cartagena, Bolivar,
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

Chapter 1

Sepsis: A Definition Under Construction
Carmelo Dueñas-Castell, Guillermo Ortiz-Ruiz, and Diana Borré-Naranjo

Sepsis generates more than 3,000,000 hospitalizations per year in the United States
[1–3]. Despite advances in modern medicine (vaccines, antibiotics, organ support
therapy), more than 5.3 million people die from sepsis worldwide, and in the United
States, it surpasses the combined deaths from breast cancer, colon cancer, and HIV/
AIDS [1–5]. In addition, sepsis generates a great economic burden due to direct
medical costs and the social repercussions in the medium and long term resulting
from the physical, psychological, and cognitive disability of the survivors [1–5], so
much so that it became the most expensive disease in US hospitals by generating
expenditures of more than $ 20 trillion [6].
Faced with a universal problem of such magnitude, it is essential to have a clear,
objective definition that allows for quantifying the problem, analyzing diagnostic
methods, quantifying the outcomes of therapeutic interventions, standardizing the terminology used, planning multicenter clinical trials, and facilitating communication [2].
Throughout history the definition of sepsis has changed dramatically and has
been a source of reflection [2]. The first description of sepsis appears in some
Egyptian papyri, more than 3500 years ago [7]. The origin of the term sepsis comes
from the Greek; it is found in Homer’s Iliad and was used in the Hippocratic body
C. 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
e-mail: crdc2001@gmail.com
G. Ortiz-Ruiz
Department of Internal Medicine Pulmonary Medicine and Critical Care,
Hospital Santa Clara, Universidad del Bosque, Bogotá, Colombia
D. Borré-Naranjo
Internal Medicine, Critical Medicine and Intensive Care, Universidad de Cartagena,
Cartagena, Colombia
© Springer Science+Business Media LLC 2018
G. Ortiz-Ruiz, C. Dueñas-Castell (eds.), Sepsis,



C. Dueñas-Castell et al.

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 [2].
In 1992, a consensus of sepsis was published, promoted by Dr. Roger Bone, in
which the first universal definition of sepsis was generated [11]. In this consensus, the definition of sepsis was, due to its simplicity, standardized as the host’s
inflammatory response to infection [11]. 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 [14].
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” [15]. 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 [15]. 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 [15].
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,
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 [23].
3. In 2012, a prospective observational study showed that minor variations in the
capture of SIRS data changed the incidence of sepsis [24].
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 [10]. 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 [10].
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 [25]. Strict adherence to SIRS criteria excluded one in eight patients with


C. Dueñas-Castell et al.

severe sepsis. Therefore, they proposed a switch to another definition based on
the presence of infection and organic dysfunction [25].
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 [26]. 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 [26].
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 [29]. 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 [29]. 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
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 [29].
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 [30]. 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 [30]. 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 [30]. 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 [32].
For these new definitions, they considered [32]:
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
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 [33].
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


C. Dueñas-Castell et al.

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,
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

1  Sepsis: A Definition Under Construction


of Chest Physicians (ACCP). The CFCA was one of the societies that p­ romoted the
first consensus in 1992 [36]. 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
Other questionings of the new definition which also have some relation with the
previous ones have been [36]: 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,
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 [37]. 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 [37]. 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 [37].
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


C. Dueñas-Castell et al.

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.

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sepsis definitions conference. Intensive Care Med. 2003;29(4):530–8.
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Chapter 2

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 [1]. 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 [4].

N. Alvis-Guzman, MD, MPH, PhD (*)
Health Economics Research Group, Universidad de Cartagena,
Avenida del consulado Campus Piedra de Bolivar, Cartagena, Bolivar 130001, Colombia
Universidad de la Costa, Barranquilla, Colombia
e-mail: nalvis@yahoo.com
F. De la Hoz-Restrepo, MD, MPH, PhD
Universidad Nacional de Colombia, Bogotá, Colombia
H. Pinzon-Redondo, MD
Health Economics Research Group, Universidad de Cartagena,
Avenida del consulado Campus Piedra de Bolivar, Cartagena, Bolivar 130001, Colombia
© Springer Science+Business Media LLC 2018
G. Ortiz-Ruiz, C. Dueñas-Castell (eds.), Sepsis,



N. Alvis-Guzman et al.

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 [5].
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 [6]. 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 [7].
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
Number of deaths








Communicable, maternal,
neonatal, and nutritional diseases







Non-communicable 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 [11]

2  Economic Impact of Infections and Antibiotics



Millions of DALY





Communicable, maternal,
neonatal, and nutritional diseases







Non-communicable 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 [11]
Table 2.1  Deaths and rate of death per 100,000 persons by group of causes of burden of disease
(1990 and 2015)

maternal, neonatal,
and nutritional
High income
Upper middle income
Lower middle income
Low income
High income
Upper middle income
Lower middle income
Low income
High income
Upper middle income
Lower middle income
Low income

1990 #

death rate

death rate








2015 #








Source: Made by the authors based on [11]

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)
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
World Bank high income
World Bank upper middle income
World Bank lower middle income
World Bank low income







Source: Made by the authors based on [11]
1990 Rank

2015 Rank

1 Diarrhea/LRI/other
2 Neonatal disorders
3 Cardiovascular diseases
4 Other non-communicable
5 Neoplasms
6 Unintentional inj
7 Mental and substance use
8 NTDs and malaria
9 Chronic respiratory
10 Nutritional deficiencies
11 Diabetes/urog/blood/endo
12 Musculoskeletal disorders
13 HIV/AIDS and tuberculosis
14 Transport injuries
15 Neurological disorders
16 Self-harm and violence
17 Digestive diseases
18 Other group I
19 Cirrhosis
20 Maternal disorders
21 War and disaster

1 Cardiovascular diseases
2 Diarrhea/LRI/other
3 Neoplasms
4 Neonatal disorders
5 Other non-communicable
6 Mental and substance use
7 Musculoskeletal disorders
8 Diabetes/urog/blood/endo
9 Unintentional inj
10 HIV/AIDS and tuberculosis
11 Chronic respiratory
12 Neurological disorders
13 NTDs and malaria
14 Nutritional deficiencies
15 Transport injuries
16 Self-harm and violence
17 Digestive diseases
18 Cirrhosis
19 Other group I
20 Maternal disorders
21 War and disaster

Communicable, maternal,
neonatal, and nutritional

Fig. 2.3  DALYs per 100,000, both sexes and all ages in all countries. Source: Made by the
authors based on [11]

2  Economic Impact of Infections and Antibiotics


1990 Rank

2015 Rank

1 Cardiovascular diseases
2 Neoplasms
3 Mental and substance use
4 Musculoskeletal disorders
5 Other non-communicable
6 Neurological disorders
7 Diabetes/urog/blood/endo
8 Unintentional inj
9 Transport injuries
10 Chronic respiratory
11 Self-harm and violence
12 Neonatal disorders
13 Diarrhea/LRI/other
14 Cirrhosis
15 Digestive diseases
16 Nutritional deficiencies
17 HIV/AIDS and tuberculosis
18 Other group I
19 NTDs and malaria
20 Maternal disorders
21 War and disaster

1 Neoplasms
2 Cardiovascular diseases
3 Musculoskeletal disorders
4 Mental and substance use
5 Other non-communicable
6 Diabetes/urog/blood/endo
7 Neurological disorders
8 Chronic respiratory
9 Unintentional inj
10 Self-harm and violence
11 Diarrhea/LRI/other
12 Transport injuries
13 Digestive diseases
14 Cirrhosis
15 Nutritional deficiencies
16 Neonatal disorders
17 HIV/AIDS and tuberculosis
18 Other group I
19 Maternal disorders
20 NTDs and malaria
21 War and disaster

Communicable, maternal,
neonatal, and nutritional

Fig. 2.4  DALYs per 100,000, both sexes and all ages in high-income countries. Source: Made by
the authors based on [11]

1990 Rank

2015 Rank

1 Cardiovascular diseases
2 Diarrhea/LRI/other
3 Neonatal disorders
4 Neoplasms
5 Other non-communicable
6 Unintentional inj
7 Mental and substance use
8 Chronic respiratory
9 Musculoskeletal disorders
10 Transport injuries
11 Diabetes/urog/blood/endo
12 Self-harm and violence
13 Nutritional deficiencies
14 Neurological disorders
15 Digestive diseases
16 HIV/AIDS and tuberculosis
17 Cirrhosis
18 NTDs and malaria
19 Other group I
20 War and disaster
21 Maternal disorders

1 Cardiovascular diseases
2 Neoplasms
3 Other non-communicable
4 Mental and substance use
5 Musculoskeletal disorders
6 Diabetes/urog/blood/endo
7 Unintentional inj
8 Transport injuries
9 Chronic respiratory
10Neurological disorders
11 Diarrhea/LRI/other
12 Neonatal disorders
13 Self-harm and violence
14 HIV/AIDS and tuberculosis
15 Nutritional deficiencies
16 Cirrhosis
17 Digestive diseases
18 NTDs and malaria
19 Other group I
20 War and disaster
21 Maternal disorders

Communicable, maternal,
neonatal, and nutritional

Fig. 2.5  DALYs per 100,000, both sexes and all ages in upper-middle-income countries. Source:
Made by the authors based on [11]

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