Sepsis Definitions - Changing Perspectives

Abstract

The evolving changes in the “definition” of sepsis reflect both a new emphasis on precision, needed for research, and an ever-expanding knowledge of its pathophysiology. Even with The evolving changes in the “definition” of sepsis reflect both a new emphasis on precision, needed for research, and an ever-expanding knowledge of its pathophysiology. Even with the recent revision of sepsis definitions, identification of patients with early sepsis remains a significant challenge. Newer definitions and clinical criteria should clarify long used descriptors and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing it. This process, however, remains a work in progress.

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Vol. 5 - No.4 Jul-Aug 2018 26 JOURNAL OF PEDIATRIC CRITICAL CARE
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Sepsis Definitions - Changing Perspectives
Vinayak Patki*
*Chief Consultant, Advanced Pediatric Critical Care Centre & Head, Dept of Pediatrics,
Wanless Hospital, Miraj, Maharashtra, India
Received: 28-July-18/Accepted: 08-Aug-18/Published online: 30-Aug-18
Correspondence:
Dr. Vinayak Patki, MB,DNB,FCCP,FIAP.
Chief, Advanced Pediatric Critical are Centre & Head,
Dept of Pediatrics, Wanless Hospital, Miraj, 416410,
Maharashtra, India.
Phone: +919822119314, E-Mail- patkivinayak@gmail.com
Introduction
It is very important for physicians and patients both,
to name or label a specifi c collection of signs and
symptoms. To reach an accurate diagnosis and to
offer optimal medical therapy, precise defi nition
of the disease process is required. Over the years
many disease processes have become well defi ned
and are easy to diagnose with the appropriate set
of symptoms and test results. The ability to form a
specifi c diagnosis and attempt to institute therapies
to benefi t patients is limited by vague or indefi nite
defi nitionsand maysometimes cause harm.
Sepsis is a complex process which can originate from
multiple sites, caused by multiple microorganisms
and can affect any individual. It can present with vast
signs and symptoms, of which many are nonspecifi c
for sepsisand all of which can vary among patients
and within the same patient over time. The severity of
the symptoms can fl uctuate from a mild, short-lived
fever to fatal septic shock. Attempts to provide clear
and accurate defi nitions have been madebut with
poor universal support. Because of its complexity
and variation, a single, simple defi nition for sepsis
will never be possible and we should focus on types
of infection rather than on sepsis per se.
History of the Defi nition of Sepsis
Sepsis is derived from the original Greek
word for the decomposition ofanimal or vegetable
organic matter.1 First used more than 2700 years ago
by Homer, and referenced by Hippocrates, Aristotle,
Plutarch, and Galen, it was only approximately
100 years ago, that the link between bacteria and
systemicsigns of disease was made;2 sepsis then
became almost synonymous with severe infection.
Sepsis Syndrome
Roger Bone and his colleagues introduced the
concept of the “sepsis syndrome” in 1989, which
became the foundation of our systemic infl ammatory
response syndrome (SIRS) criteria.3 Sepsis syndrome
was defi ned as hypothermia (less than 960 F [35.50C])
or hyperthermia (greater than 1010 F [38.30C]);
tachycardia (greater than 90 beat/min); tachypnea
(greater than 20 breath/min); clinical evidence of
an infection site; and the presence of at least one
end-organ demonstrating inadequate perfusion or
dysfunction expressed as poor or altered cerebral
function, hypoxemia (PaO2 less than 75 torr on
room air), elevated plasma lactate, or oliguria (urine
output less than 30 mL/h or 0.5 mL/kg body weight/h
without corrective therapy). However, although it has
been used as an entry criterion for clinical trials,3
sepsis syndrome does not successfully defi ne a
homogeneous group of patients.
1991 International Consensus Conference
(Sepsis 1)
SIRS Criteria
The terminology “sepsis” which is currently used,
was born out of the 1991 International Consensus
Conference: Distinctions in the Defi nition of
ABSTRACT
The evolving changes in the “defi nition” of sepsis refl ect both a new emphasis on precision, needed for research, and
an ever-expanding knowledge of its pathophysiology. Even with the recent revision of sepsis defi nitions, identifi cation
of patients with early sepsis remains a signifi cant challenge. Newer defi nitions and clinical criteria should clarify long-
used descriptors and facilitate earlier recognition and more timely management of patients with sepsis or at risk of
developing it. This process, however, remains a work in progress.
Keywords: Sepsis, Septicshock, PIRO, SOFA, Diagnosis, Infection
DOI-10.21304/2018.0504.00407

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Severe Sepsis (hosted by the Society of Critical
Care Medicine, European Society of Intensive Care
Medicine, the American College of Chest Physicians,
the American Thoracic Society and Surgical
Infection Society)4 Thirty-fi ve experts in the fi eld of
sepsis came together to provide a framework to defi ne
the systemic infl ammatory response to infection
(i.e., sepsis). The result of this conference was the
introduction of the term ‘‘systemic infl ammatory
response syndrome’’ (SIRS). SIRS was an attempt
to differentiate sepsis from the non-infectious causes
that cause the same infl ammatory response, such
as acute pancreatitis, trauma, ischemia/reperfusion
injury and burns. According to the ACCP-SCCM
Consensus Conference,4 infection was defi ned as a
microbial phenomenon characterized by the invasion
of microorganisms or microbial toxins into normally
sterile tissues. SIRS was defi ned, by consensus, as
the presence of at least two of four clinical criteria
(Table 1).
Table 1
•Body temperature >38_C or <36_C
•Heart rate >90 beats/min
•Respiratory rate >20 breaths/min or
hyperventilation with a PaCO2 <32 mmHg
•White blood cell count WBC >12,000/
mm3, <4000/mm3, or with >10%
immatureneutrophils
According to the guidelines, sepsis is SIRS with
suspected or proven infection, while severe sepsis
describes patients who fulfi l the criteria forsepsis and
in addit ion h ave organ dysf unction. In its most severe
manifestation,5 septic shock is defi ned as “acute
circulatory failure characterized by persistent arterial
hypotension [including systolic <90 mmHg, mean
arterial pressure <65 mmHg, or a drop in systolic
blood pressure of >40 mmHg from baseline after
adequate fl uid resuscitation] unexplained by other
causes”6
Shortcomings of the SIRS Criteria
The SIRS criteria are useful because they can
facilitate enrolment for research purposesand have
been adopted for identifi cation of potentially septic
patients. Although the SIRS criteria do have the
prognostic value of defi ning a group of patients who are
at an increased risk of developing complications and
with increased mortality7, they have been criticized
for being too sensitive and nonspecifi c to be of much
clinical use.8 Most ICU patients and many general
ward patients meet the SIRS criteria.
9,10 Sprung CL
et al 11 found up to 90% of patients admitted to the ICU
fi t the criteria for SIRS. Moreover, each of the SIRS
criteria can be present in many different conditions,
so that little or no information about the underlying
disease process is provided by a label of SIRS. Use
of the SIRS criteria to identify patients for enrolment
in clinical trials has been disappointing and has likely
contributed to the negativity of almost all these trials.
Multiple organ dysfunction syndrome
MODS was defi ned as ‘‘the presence of altered organ
function in an acutely ill patientsuch that homeostasis
cannot be maintained without intervention”.4 The
1991 ACCP-SCCM Consensus.The term ‘‘multiple
organ dysfunction syndrome’’ was introduced
with the awareness that severe sepsis is frequently
associated with the development of multiple organ
dysfunction (MODS) and that multiple organ failure
is the most common cause of death in patients who
have severe sepsis.Since then, many systems have
been developed to characterize and quantify MODS,
like the sequential organ failure assessment, which
are increasingly used as measures of morbidity in
clinical trials.12
2001 Sepsis Defi nitions Conference (Sepsis 2)
A Consensus Sepsis Defi nitions Conference of
29 international experts in the fi eld of sepsis was
convened in 2001 under the auspices of SCCM,
the European Society of Intensive Care Medicine,
ACCP, and the Surgical Infection Societies,13 to
give a satisfactory defi nition of sepsis based on
the advanced understanding of its pathogenesis
and pathophysiology. The conference participants
concluded that the defi nitions of sepsis, severe
sepsis, and septic shock, as defi ned in the 1991 North
American Consensus Conference,4 may still be useful
in clinical practice and for research purposes. The
use of the SIRS criteria, which were considered too
sensitive and nonspecifi c was the key change. The
participants suggested that other signs and symptoms
be added to refl ect the clinical response to infection
in better way (Table 2). Sepsis is now defi ned as the
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presence of infection plus some of the listed signs
and symptoms of sepsis. Severe sepsis is now defi ned
as sepsis complicated by organ dysfunction and
septic shock is defi ned as severe sepsis with acute
circulatory failure characterized by persistent arterial
hypotension unexplained by other causes.
Table 2
General signs and symptoms
Fever/hypot herm ia
Tachypnea/respiratory alkalosis
Positive fl uid balance/edema
General infl ammatory reaction
Altered white blood cell count
Increased biomarker (C-reactive protein (CRP), IL- 6, PCT)
concentrations
Hemodynamic alterations
Arterial hypotension
Tac hycard ia
Increased cardiac out put/low systemic vascular resistance
(SVR)/hig h SvO2
Altered skin perfusion
Decreased urine out put
Hyperlactatemia (increased base defi cit)
Signs of organ dysfunction
Hypoxemia
Coagulation abnormalities
Altered mental status
Hyperglycemia
Thrombocytopenia, disseminated intravascular coagulation
Altered liver function (hyperbilirubinemia)
Intolerance to feeding (altered gastrointestinal motility
Abbreviation: PCT, procalcitonin.
PIRO (Predisposition-Infection-Response-Organ
Dysfunction)Model
The overly sensitive nature of SIRS was ack nowledged
by the authorsand PIRO - A hypothetical model for
staging sepsis using premorbid conditions (P), the
causative infection (I), host response (R), and the
severity of organ dysfunction (O) was proposed.(Table
3).The PIRO system helps in forming more similar
subgroups of patients having sepsis, who could then
receive specifi c interventions with the prospect of real
therapeutic advances.
Table 3 : suggested clinical and laboratory variables
for the four components of the PIRO grading system
The PIRO model is a system that allows staging of
sepsis to risk stratify patients for illness and for
potential response to therapy.13 (Figure 1) Similar
to oncologic staging, PIRO staging factors criteria
such as variable genetic susceptibility to illnesses.
It was proposed that this model could also describe
the host response to infectio,
13 for example, a
genetic polymorphism that causes a more aggressive
infl ammatory response to an invading organism.
13 Additionally, early detection of a pathogen
through sensitive assays of microbial genomics or
transcriptomics would allow further characterization
of the host response to infection. Moreno et al
14
used the Simplifi ed Acute Physiology Score (SAPS
3) database to develop a model based on the PIRO
system which could be used to predict mortality in
patients who have sepsis and the PIRO performed
better than the SAPS 3 admission score. It is still
to be seen whether this system is strong enough for
consistent application in the future, even though PIRO
is validated by several studies. The lack of specifi c
genotypic targets that canbe analysed quickly and are
of phenotypic sig nifi cance limit the system further.
Once this tech nology is accessible to most physician s,
it could allow for tailored therapy and prognosticating
ability.
2010 Merinoff Symposium
The 2001 meeting had been notable for giving more
we ight to the h ost re sponse of severe se psis rat her than
the virulence of the specifi c microbe. This was a well-
known concept dating back to William Osler who
said “except on few occasions, the patient appears to
die from the body’s response to infection rather than
from the infection itself”.15 In 2010, the fi rst meeting
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of the Global Sepsis Alliance with representatives
from various national governments and media was
held at the Merinoff symposium to create a “public
defi nition” and a “molecular defi nition” of sepsis that
focuses on the deranged host response to the microbial
insult.16 The results were the following:
1. Defi nition of sepsis: Sepsis is a life-threatening
condition that arises when the body’s response to
an infection injures its own tissues and organs.
Sepsis leads to shock, multiple organ failure,
and death, especially if not recognized early and
treated promptly. 16
2. Molecular defi nition of sepsis: Host-derived
molecules and foreign products of infection
converge on molecular mechanisms that cause
unbalanced activation of innate immunity. Foreign
and endogenous molecules interact with pathogen
recognition receptors expressed on or in cells
of the immune system. Activation of pathogen
recognition receptors culminates in the release of
immune mediators that produce the clinical signs
and symptoms of sepsis.16
2016 The Third International Consensus
Defi nitions for Sepsis and Septic Shock (Sepsis-3)
The most recent defi nition of sepsis stems from
a 2016 task force which resulted in a change in
terminology.17 Simple infection with signs and
symptoms of the infl ammatory response but without
organ dysfunction, formerly defi ned as sepsis, is now
defi ned as infection. Sepsis is now defi ned as infection
with evidence of organ dysfunction (as evidenced by
Sequential Organ Failure Assessment [SOFA] score
> 2). Previously, this was the defi nition of Severe
Sepsis, a term that will no longer be used. This
change was instituted primarily because the fi eld was
already using sepsis to imply a patient deteriorating
with infection and organ dysfunction, leading to
considerable confusion between the terms sepsis and
Predisposition Premorbid illness with reduced
probability of short term survival.
Cultural or regliious beliefs, age,
sex.
Genetic polymorphisms in com-
ponents of inflammatory response
(e.g., TIR, TNF, IL-1, CD14); en-
hanced understanding of specific
interactions between pathogens
and host diseases,
In the present, premorbid factors
impact on the potential attribut-
able mrbidity and mortality of an
acute insult; deleterious conse-
quences of insult heavily depen-
dent on genetic predisposition
(future).
Insult infection culture and sensitivity of infecting
pathogens; detection of disesase
amenable to source control.
Assay of microbial products (LPS,
mannan, bacterial DNA); gene
transcript profiles.
Specific therapies directed against
inciting insult require demonstra-
tion and characterization of that
insult.
Response SIRS, other signs of sepsis,
shock, CRP.
Nonspecific markers of activated
inflammation (e.g., PCT or IL-6)
or impaired host responsiveness
(e.g., HLA-DIR); specific de-
tection of target of therapy (e.g.,
protein C, TNF, PAF)
Both mortality risk and potential
to respond to therapy vary with
nonspecific measures of desease
severity (e.g., shock); specific
mediator-targeted therapy is pred-
icated on presence and activity of
mediator.
Organ dysfunction Organ dysfunction as number of
failing organs or composite score
(e.g., MODS, SOFA, LODS,
PEMOD, PELOD).
Dynamic measures of cellular
response to insult - apoptosis,
cytopathic hyposix,a cell stress.
Response to preemptive therapy
(e.g., targeting microorganism
or early mediator) not possible if
damage already present; therapies
targeting the injurious cellular
process require that it be present.
Figure 1: PIRO system for staging sepsis 13; (adapted from Levy, Crit Care Med 2003;31:1250–6.)
TLR, Toll-like receptor; TNF, tumor necrosis factor; IL, interleukin; LPS, lipopolysaccharide; SIRS, systemic inflammatory response syndrome; CRP,
C-reactive protein; PCT, procalcitonin; HLA-DR, human leukocyte antigen-DR; PAF, platelet-activating factor; MODS, multiple organ dysfunction
syndrome; SOFA, sepsis-related organ failure assessment;LODS, logistic organ dysfunction system; PEMOD, pediatric multiple organ dysfunction;
PELOD, pediatric logistic organ dysfunction.
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severe sepsis. The defi nition of Septic Shock refers
to patients with infection who also have hypotension
(MAP <65 mmHg or systolic < 90 mmHg) and are
receiving vasopressors and with a lactate > 2 mmol/L.
Because SOFA is better known and simpler than the
Logistic Organ Dysfunction System, the guideline
recommends using a change in baseline of the total
SOFA score of 2 points or more to represent organ
dysfunction. The baseline SOFA score should be
assumed to be zero unless the patient is known to
have pr e- exist ing (acut e or c hronic) o rgan d ysf unc tion
before the onset of infection. The overall mortality
risk was approximately 10% in a general hospital
population with presumed infection
18 in patients
with a SOFA score of 2 or more. A SOFA score of
2 or greater identifi ed a 2- to 25-fold increased risk
of dying compared with patients with a SOFA score
less than 2,18 depending on a patient’s baseline level
of risk.
qSOFA (Quick SOFA) Criteria
• Respiratory rate ≥22/min
• Altered mentation
• Systolic blood pressure ≤100 mm Hg
SOFA score is intended to be used to clinically
characterise a septic patient and not as a tool for patient
management (Figure 2). Components of SOFA (such
as creatinine or bilirubin level) require laboratory
testing and thus may not promptly capture dysfunction
in individual organ systems. Neither qSOFA nor
SOFA is considered t o be a stand-alone defi nition of
sepsis. It is crucial, however, that failure to meet 2 or
more qSOFA or SOFA criteria should not lead to a
deferral of investigation or treatment of infection or to
a delay in any other aspect of care deemed necessary
by the practitioners. qSOFA can be rapidly scored at
the bedside without the need for blood tests, and it is
hoped that it will facilitate prompt identifi cation of
an infection that poses a greater threat to life. This
may prompt testing to identify biochemical organ
dysfunction, if appropriate laboratory tests have not
already been done. These data will primarily aid
patient management but will also enable subsequent
SOFA scoring.
Other elements, such as the cardiovascular score, can
be affected by iatrogenic interventions. However,
SOFA has widespread familiarity within the critical
care community and a well-validated relationship to
mortality risk. It can be scored retrospectively, either
manually or by automated systems, from clinical and
laboratory measures often performed routinely as
part of acute patient management.
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Future
The Guidelines noted that there are several novel
biomarkers that can identify renal and hepatic
dysfunction or coagulopathy earlier than the elements
used in SOFA, but these require broader validation
before they can be incorporated into the clinical
criteria describing sepsis. Future repetition of a
process of the sepsis defi nitions should either include
an updated SOFA score with more optimal variable
selection, cut off values, and weighting, or a superior
scoring system.
Confl ict of Interest :Nil
Source of Funding :Nil
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How to cite this article:
Patki V. Sepsis Definitions - Changing Perspectives. J Pediatr Crit Care 2018;5(4):26-32.
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Sepsis Definitions - Changing Perspectives