sepsis

1. Sepsis

2. 1. Early sepsis
a. Infection and Bacteremia
b. Identification of Early sepsis (qSOFA, NEWS)
2. Sepsis
3. Septic shock
4. Others
1. Multiple organ dysfunction syndrome (MODS)
2. Systemic inflammatory response syndrome
(SIRS)
Sepsis

3. 1- Early sepsis
Infection and bacteremia may be
early forms of infection that can
progress to sepsis.
 No formal definition of early sepsis.
Despite the lack of definition,
monitoring those suspected of
having sepsis is critical for its
Prevention.

4. 1- Early sepsis
a. Infection and Bacteraemia
 All patients with infection or bacteraemia
are at risk of developing sepsis and
represent early phases in the continuum of
sepsis severity:
1. Infection is defined as the invasion of
normally sterile tissue by pathogenic
microorganisms that proliferate, resulting
in tissue injury that can progress to
disease.
2. Bacteremia is the presence of viable

5. 1- Early Sepsis
b. Identification of early sepsis (qSOFA, NEWS)
Societal guidelines place emphasis on the early
identification of infected patients who may go on to
develop sepsis as a way to decrease sepsis-associated
mortality.
The two most commonly used scores are :
1. The quick Sequential (Sepsis-related) Organ Failure
Assessment score (qSOFA) score
2. The National Early Warning Score (NEWS) score.

6. 1- Early Sepsis
b.Identification of early sepsis (qSOFA, NEWS)
1. qSOFA score is easy to calculate since it only has three
components, each of which are readily identifiable at the bedside
and are allocated one point:
1. Respiratory rate ≥22/minute
2. Altered mentation
3. Systolic blood pressure ≤100 mmHg
This qSOFA score is a modified version of the SOFA score.
A score ≥2 is associated with poor outcomes due to sepsis.

7. 1- Early Sepsis
2. NEWS score is an aggregate scoring
system derived from six physiologic
parameters:
1. Respiration rate
2. Oxygen saturation
3. Systolic blood pressure
4. Pulse rate
5. Level of consciousness or new confusion
6. Temperature
The aggregate score represents the risk of
death from sepsis and indicates the urgency
of the response:
1. 0 to 4 – low risk (a score of 3 in any individual
parameter is low-medium)
2. 5 to 6 – medium risk
3. 7 or more – high risk

8. Sepsis is a clinical
syndrome that has
physiologic, biologic,
and biochemical
abnormalities caused by
a dysregulated host
response to infection.
Sepsis and the
inflammatory response
that ensues can lead to
multiple organ
dysfunction syndrome
2- Sepsis
1. Early sepsis
a. Infection and bacteremia
b. Identification of early sepsis (qSOFA,
NEWS)
2. Sepsis
3. Septic shock
4. Others
1. Multiple organ dysfunction syndrome
2. Systemic inflammatory response
syndrome

9. 2- Sepsis
• A 2016 SCCM/ESICM task force has defined sepsis as life-threatening
organ dysfunction caused by a dysregulated host response to
infection (Sepsis-3):

10. Pathogenesis of sepsis
(a) Sepsis is defined as a dysregulated host
response to infection, leading to life-threatening
organ dysfunction.
(b) Once a pathogen has succeeded to cross the
mucosal barrier of the host, it can cause sepsis
depending on its load and virulence.
(c) Sepsis is by definition a disease with organ
failure.
 The clinical manifestation can be heterogeneous.

11. Sepsis exists on a
continuum of severity
ranging from infection
and bacteraemia to
sepsis and septic
shock, which can lead
to MODS and death.

12. A clinical syndrome characterized by
systemic inflammation caused by
infection.
In the USA, over 1.6 million cases of
Sepsis occur every year, with a
mortality rate of 20– 50%.
Mortality of Septic Shock is 40– 50%.

13.  The definitions of Sepsis and Septic Shock have rapidly evolved since the early 1990s

14. The SIRS is no longer included in the definition since it is not always
caused by infection.

15. The Center for Medicare and Medicaid Services (CMS) still
continues to support the previous definition of SIRS, Sepsis, and
Severe Sepsis.

16. Sepsis
Organ dysfunction
Organ dysfunction is defined by the 2016
SCCM/ESICM task force as an increase of
two or more points in the SOFA score .
 The predictive validity of the SOFA score
for in-hospital mortality was superior to
that for the SIRS criteria .
Importantly, the SOFA score is an organ
dysfunction score.
It is not diagnostic of sepsis nor does it
identify those whose organ dysfunction
is truly due to infection but rather helps
identify patients who potentially have a
high risk of dying from infection.

17. Septic shock
Septic shock is a type of Vasodilatory or
distributive shock.
Septic shock is defined as sepsis that has
circulatory, cellular, and metabolic
abnormalities that are associated with a
greater risk of mortality than sepsis alone .
Clinically, this includes patients who fulfill
the criteria for sepsis who, despite
adequate fluid resuscitation, require
vasopressors to maintain a MAP ≥65
mmHg and have a lactate >18 mg/dL.
Per predictions from the SOFA score ,
patients who fulfill these criteria for septic
shock have a higher mortality than those
who do not (≥40 versus ≥10 %).

18. Severe Sepsis
• The term severe sepsis, which originally referred to sepsis that was
associated with tissue hypoperfusion (eg, elevated lactate, oliguria)
or organ dysfunction (eg, elevated creatinine, coagulopathy), and
the term SIRS are no longer used since the 2016 sepsis and septic
shock definitions include patients with evidence of tissue
hypoperfusion and organ dysfunction.

20. Sepsis

21. 1. Early sepsis
a. Infection and bacteremia
b. Identification of early sepsis (qSOFA,
NEWS)
2. Sepsis
3. Septic shock
4. Others
1. Multiple organ dysfunction syndrome
2. Systemic inflammatory response
Sepsis

22. Multiple Organ Dysfunction Syndrome (MODS)
MODS refers to progressive organ dysfunction in an acutely ill patient, such that homeostasis cannot be
maintained without intervention.
It is at the severe end of the severity of illness spectrum of both infectious (sepsis, septic shock) and
noninfectious conditions (eg, SIRS from pancreatitis).
MODS can be classified as primary or secondary:
1. Primary MODS is the result of a well-defined insult in which organ dysfunction occurs early and can be directly
attributable to the insult itself (eg, renal failure due to rhabdomyolysis).
2. Secondary MODS is organ failure that is not in direct response to the insult itself, but is a consequence of the host's
response (eg, acute respiratory distress syndrome in patients with pancreatitis).
There are no universally accepted criteria for individual organ dysfunction in MODS.
However, progressive abnormalities of the following organ-specific parameters are commonly used to diagnose
MODS and are also used in scoring systems (eg, SOFA or LODS) to predict ICU mortality :
1. Respiratory – Partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio
2. Hematology – Platelet count
3. Liver – Serum bilirubin
4. Renal – Serum creatinine (or urine output)
5. Brain – Glasgow coma score
6. Cardiovascular – Hypotension and vasopressor requirement
In general, the greater the number of organ failures, the higher the mortality, with the greatest risk being
associated with respiratory failure requiring mechanical ventilation.

23. 1. Early sepsis
a. Infection and bacteremia
b. Identification of early sepsis (qSOFA,
NEWS)
2. Sepsis
3. Septic shock
4. Others
1. Multiple organ dysfunction syndrome
2. Systemic inflammatory response
Sepsis

24. The use of SIRS criteria to identify those with sepsis has fallen out of
favor since it is considered by many experts that SIRS criteria are
present in many hospitalized patients who do not develop infection,
and their ability to predict death is poor when compared with other
scores such as the SOFA score .
SIRS is considered a clinical syndrome that is a form of dysregulated
inflammation.
It was previously defined as two or more abnormalities in temperature, heart rate,
respiration, or WBC count .
SIRS may occur in several conditions related, or not, to infection.
Noninfectious conditions classically associated with SIRS include autoimmune
disorders, pancreatitis, vasculitis, thromboembolism, burns, or surgery.
Systemic Inflammatory Response Syndrome (SIRS)

26. Definitions
The definitions of sepsis are constantly evolving. ‘Sepsis-3’, published in February 2016, moved away from the use of
SIRS in the identification of sepsis focussing instead on life-threatening organ dysfunction.
• Fever— defined as ‘a state of elevated core temperature which is often, but not necessarily, part of the defensive
responses of a multicellular organism (the host) to the invasion of live (microorganisms) or inanimate matter recognized
as pathogenic or alien to the host’.
• Infection— the presence of organisms in a normally sterile site, usually accompanied by a host inflammatory
response.
• Bacteraemia— the presence of bacteria in the blood; may be transient.
• Systemic inflammatory response syndrome (SIRS)— response to a widevariety of clinical insults which include
infectious and non- infectious causes.
• Sepsis— a clinical syndrome defined as life-threatening organ dysfunction caused by a dysregulated immune
response to infection.
• Septic shock— that subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound
enough to increase
mortality.

28. Fever has been recognized as a clinical
syndrome since the sixth century BC.
Several centuries later, Hippocratic physicians
proposed that body temperature was a balance
between the four corporal humours— blood,
phlegm, black bile, and yellow bile.
Devices to measure body temperature have been
around since the first century BC.
Thermometry became a part of clinical practice in
1868, when Wunderlich declared 37.4°C (98.6°F)
to be the normal body temperature and described
the diurnal variation of body temperature.

30. Clinical Features
‘Sepsis-3’ proposes using the Sequential (sepsis-related) Organ Failure Assessment (SOFA) score
to assess organ dysfunction in the presence of infection.

31. Clinical Features
At present most hospitals will use these clinical definitions:
 Sepsis is defined as the presence of infection with systemic
manifestations, including:
(i) physiological variables, e.g. temperature >38.3°C or <36°C,
pulse >90 beats/ min, systolic blood pressure <90mmHg,
respiratory rate >20/ min, altered mental state, significant oedema
or positive fluid balance, hyperglycaemia;
(ii) inflammatory variables, e.g. leucocytosis >12 000 cells/
microlitre, leucopenia <4000 cells/ microlitre, C- reactive protein
(CRP) >2 standard deviations above normal, plasma procalcitonin
> 2 standard deviations above normal value;
(iii) organ dysfunction, e.g. arterial hypoxaemia, acute oliguria,
creatinine increase >44.2 micromoles/ L, coagulation abnormalities,
ileus, thrombocytopenia, hyperbilirubinaemia;

32. Severe sepsis refers to sepsis- induced tissue hypoperfusion or organ dysfunction with any of the
following thought to be due to the infection:
(i) sepsis- induced hypotension;
(ii) lactate above ULN;
(iii) urine output <0.5mL/ kg/ h for 2h, despite adequate fluid resuscitation;
(iv) acute lung injury with PaO2/ FiO2 ratio <250 in the absence of pneumonia as
infection source;
(v) acute lung injury with PaO2/ FiO2 ratio <200 in the presence of pneumonia as
infection source;
(vi) serum creatinine >176.8 micromoles/ L;
(vii) serum bilirubin >34.2 micromoles/ L;
(viii) platelet count <100 000/ microlitre;
(ix) coagulopathy INR >1.5.
Clinical Features

33. Pathogenesis of sepsis
(a) Sepsis is defined as a dysregulated host response to infection,
leading to life-threatening organ dysfunction.
 The normally careful inflammatory balance is disturbed,
and this dysregulation is associated with a failure to return
to homeostasis.
 Hyperinflammation and immune suppression ensue, to an
extent that is detrimental to the host.
(b) Once a pathogen has succeeded to cross the mucosal barrier of
the host, it can cause sepsis depending on its load and virulence.
 The host defense system can recognize molecular
components of invading pathogens (PAMPs) with
specialized receptors (PRRs).
 Stimulation of PRRs has proinflammatory and immune
suppressive consequences.
 It leads to activation of target genes coding for
proinflammatory cytokines (leukocyte activation),
inefficient use of the complement system, activation of
the coagulation system, and concurrent downregulation of
anticoagulant mechanisms and necrotic cell death.
 This starts a vicious cycle with further progression to
sepsis, due to the release of endogenous molecules by
injured cells (DAMPs or alarmins), which can further
stimulate PRRs.
 Immune suppression is characterized by massive
apoptosis and thereby depletion of immune cells,
reprogramming of monocytes and macrophages to a state
of a decreased capacity to release proinflammatory
cytokines and a disturbed balance in cellular metabolic
processes.
(c) Sepsis is by definition a disease with organ failure. The clinical

34. Laboratory diagnosis
•
Routine investigations may show a number of abnormalities, as
•
described in E Clinical features above.
•
• BCs and samples from suspected sites of infection (e.g. sputum, urine,
•
stool, pus) should be taken for culture, ideally prior to administration of
•
antimicrobial therapy.

35. Management
• Therapeutic priorities— these include early initiation of supportive care to correct physiological abnormalities and
institution of appropriate therapy for sepsis.
• Stabilize respiration— supplemental oxygen should be given to all patients with sepsis, and oxygen saturations
monitored. Intubation and mechanical ventilation may be required. A CXR and arterial blood gas (ABG) should be
obtained.
• Assess perfusion— blood pressure should be assessed early and often.
An arterial line may be required in patients who are shut down or have labile blood pressures.
• Establish central venous access— a CVC is inserted in most patients with severe sepsis, in order to infuse fluids
and medications and to collect blood samples.
• Initial resuscitation— goals during the first 6h, as suggested by the
Surviving Sepsis Campaign Guidelines, include: (i) central venous pressure 8– 12mmHg; (ii) central venous
(superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively; (iii) mean arterial pressure
≥65mmHg; (iv) urine output ≥0.5mL/ kg/ h.
• Restoration of perfusion— rapid infusion of large volumes of IV fluid are administered, often in 500mL boluses.
Careful monitoring is required, as patients may develop non- cardiogenic pulmonary oedema. Vasopressors, e.g.
noradrenaline, may be required in patients who remain hypotensive, despite adequate fluid resuscitation.
Additional therapies, such as inotropic therapy (e.g. dobutamine) or red cell transfusions, are sometimes given.

36. Management
• Identification of septic focus— prompt identification and treatment of the focus of infection are
essential. Biomarkers of sepsis, e.g. procalcitonin, TREM- 1 (triggering receptor expressed on myeloid
cells- 1), and CD64 expression on neutrophils, may be useful to suggest bacterial infection.
• Antimicrobial therapy— this should be instigated promptly; the empirical regimen will depend on the
likely source of infection, local antibiotic policies, and antibiotic resistance profiles.
Poor outcome is associated with delayed or inappropriate therapy.
• Additional therapies— glucocorticoid therapy may be of benefit in patients with severe septic shock.
Nutritional support improves nutritional outcomes in critically ill patients, but its impact on clinical
outcomes from sepsis is uncertain. Intensive insulin therapy is helpful in diabetic patients with
hyperglycaemia and insulin resistance.
One study has suggested that external cooling may be helpful in patients with severe sepsis. Sepsis
treatment protocols also appear to improve outcome.

37. Sepsis and septic shock
• Sepsis is a life-threatening organ dysfunction that results
from the body’s response to infection.
• It requires prompt recognition, appropriate antibiotics, careful
hemodynamic support, and control of the source of infection.
• With the trend in management moving away from protocolized
care in favor of appropriate usual care, an understanding of
sepsis physiology and best practice guidelines is critical.

38. Sepsis and septic shock
• Sepsis and particularly septic shock should be recognized as
medical emergencies in which time matters, as in stroke and
acute myocardial infarction.
• Early recognition and rapid institution of resuscitative measures
are critical.

39. DEFINITIONS HAVE EVOLVED
In 1991, sepsis was first defined as a systemic
inflammatory response syndrome (SIRS) due to a
suspected or confirmed infection with 2 or more of the
following criteria4:
•
Temperature below 36°C or above 38°C
•
Heart rate greater than 90/minute
•
Respiratory rate above 20/minute, or arterial partial
pressure of carbon dioxide less than 32 mm Hg
•
White blood cell count less than 4 × 109/L or greater than
12 × 109/L, or more than 10% bands.
Severe sepsis was defined as the progression of sepsis to
organ dysfunction, tissue hypoperfusion, or hypotension.
Septic shock was described as hypotension and organ
dysfunction that persisted despite volume resuscitation,
necessitating vasoactive medication, and with 2 or more
of the SIRS criteria listed above.
In 2001, definitions were updated with clinical and
laboratory variables.5
In 2004, the Surviving Sepsis Campaign guidelines
adopted those definitions, which led to the development of
a protocol-driven model for sepsis care used
worldwide.6 The US Centers for Medicare and Medicaid
Services (CMS) followed suit, defining sepsis as the
presence of at least 2 SIRS criteria plus infection; severe
sepsis as sepsis with organ dysfunction (including serum
lactate > 2 mmol/L); and septic shock as fluid-resistant
hypotension requiring vasopressors, or a lactate level of at
least 4 mmol/L.7
In 2016, the Sepsis-3 committee8 issued the following new
definitions:
•
Sepsis—A life-threatening condition caused by a
dysregulated host response to infection, resulting in organ
dysfunction
•
Septic shock—Circulatory, cellular, and metabolic
abnormalities in septic patients, presenting as fluid-
refractory hypotension requiring vasopressor therapy with

40. Multiple definitions create confusion
Both the CMS and international consensus definitions are currently used in clinical practice,
with distinct terminology and different identification criteria, including blood pressure and lactate
cutoff points.
The CMS definition continues to recommend SIRS for sepsis identification, while Sepsis-3 uses
sequential organ failure assessment (SOFA) or the quick version (qSOFA) to define sepsis
(described below).
This has led to confusion among clinicians and has been a contentious factor in the
development of care protocols.

41. TOOLS FOR IDENTIFYING HIGH RISK:
SOFA AND qSOFA
• SOFA is cumbersome
• SOFA is an objective scoring system to determine major organ
dysfunction, based on oxygen levels (partial pressure of oxygen
and fraction of inspired oxygen), platelet count, Glasgow Coma
Scale score, bilirubin level, creatinine level (or urine output), and
mean arterial pressure (or whether vasoactive agents are required).
• It is routinely used in clinical and research practice to track
individual and aggregate organ failure in critically ill patients.9
• But the information needed is burdensome to collect and not usually
available at the bedside to help with clinical decision-making.

42. TOOLS FOR IDENTIFYING HIGH RISK:
SOFA AND qSOFA
qSOFA is simpler…
Singer et al8 compared SOFA and SIRS and identified 3 independent
predictors of organ dysfunction associated with poor outcomes in sepsis to
create the simplified qSOFA:
Respiratory rate at least 22 breaths/minute
Systolic blood pressure 100 mm Hg or lower
Altered mental status (Glasgow Coma Scale score < 15).
A qSOFA score of 2 or more with a suspected or confirmed infection was
proposed as a trigger for aggressive treatment, including frequent
monitoring and ICU admission.
qSOFA has the advantage of its elements being easy to obtain in clinical
practice.

43. TOOLS FOR IDENTIFYING HIGH RISK: SOFA AND qSOFA
• …but has limitations
• Although qSOFA identifies severe organ dysfunction and predicts risk of death in sepsis, it
needs careful interpretation for defining sepsis.
• One problem is that it relies on the clinician’s ability to identify infection as the cause of
organ dysfunction, which may not be apparent early on, making it less sensitive than
SIRS for diagnosing early sepsis.10
• Also, preexisting chronic diseases may influence accurate qSOFA and SOFA
measurement.11
• In addition, qSOFA has only been validated outside the ICU, with limited utility in patients
already admitted to an ICU.12
• Studies have suggested that the SIRS criteria be used to detect sepsis, while qSOFA
should be used only as a triaging tool.1