SEPSIS

OUTLINE
Introduction
Definitions
SIRS
Sepsis
Severe sepsis
Septic shock

Pathophysiology
Protocols for treatment
SURVIVING SEPSIS CAMPAIGN

INTRODUCTION
Major cause of morbidity and mortality
worldwide.
Leading cause of death in noncoronary ICU.
11th leading cause of death overall.

Mortality
Sepsis: 30% - 50%
Septic Shock: 50% - 60%

For every hour delay in the

administration of treatment, there is an
associated 6% rise in mortality.

SIRS
Widespread inflammatory response
to a variety of severe clinical insults.
Clinically recognized by the presence
of 2 or more of the following:
Temperature >38C or < 36C
Heart Rate >90
Respiratory Rate > 20 or PaCO2 <32
WBC > 12,000, < 4000 or > 10%
immature forms

Stages In the Development of

SIRS (Bone, 1996)
Stage 1. In response to injury / infection,
the local environment produces cytokines.
Stage 2. Small amounts of cytokines are
released into the circulation:
Recruitment of inflammatory cells.
Acute Phase Response.
Normally kept in check by endogenous antiinflammatory mediators (IL-10, PGE2,
Antibodies, Cytokine receptor antagonists).

Stages In the
Development of SIRS
Stage 3. Failure to control
inflammatory cascade:
Loss of capillary integrity.
Stimulation of Nitric Oxide Production.
Maldistribution of microvascular blood
flow.
Organ injury and dysfunction.

SEPSIS
SIRS criteria + evidence of infection,
or:
White cells in normally sterile body fluid
Perforated viscus
Radiographic evidence of pneumonia
Syndrome associated with a high risk of
infection

SEVERE SEPSIS
Sepsis criteria + evidence of organ dysfunction or tissue
hypoperfusion, including:
CV: Systolic BP < 90 mmHg, MAP < 70 mm Hg for at least 1 hour
despite volume resuscitation, or the use of vasopressors.
Renal: Urine output < 0.5 ml/kg body weight/hr for 1 hour despite
volume resuscitation
Pulmonary: PaO2/FiO2 < 250 in absence of pneumonia as infection
source or < 200 in presence of pneumonia as infection source.
Hematologic: Platelet count < 1L or decreased by 50% in 3 days
Metabolic: pH < 7.3 and plasma lactate > upper normal
INR > 1.5, S. Bil > 2 mg/dl, S. Creat >2 mg/dl

SEPTIC SHOCK
Septic Shock

Hypotension secondary to Sepsis that is

resistant to adequate fluid
administration.

PATHOPHYSIOLOGY

Pathophysiology of SepsisInduced Organ Injury

Multiple Organ Dysfunction (MODS) and
Multiple Organ Failure (MOF) result from
diffuse cell injury / death resulting in
compromised organ function.
Mechanisms of cell injury / death:

Cellular Necrosis (ischemic injury).

Apoptosis.
Leukocyte-mediated tissue injury.
Cytopathic Hypoxia

Pathophysiology of SepsisInduced Ischemic Organ Injury

Cytokine production leads to massive
production of endogenous vasodilators.
Structural changes in the endothelium result in
extravasation of intravascular fluid into
interstitium and subsequent tissue edema.
Plugging of select microvascular beds with
neutrophils, fibrin aggregates, and
microthrombi impair microvascular perfusion.
Organ-specific vasoconstriction.

Pathogenesis of Vasodilation in
Sepsis
Loss of Sympathetic Responsiveness:
Down-regulation of adrenergic receptor number
and sensitivity, possible altered signal
transduction.

Vasodilatory Inflammatory Mediators.

Endotoxin has direct vasodilatory effects.
Increased Nitric Oxide Production.

Infection

Vasodilation

Inflammatory
Mediators

Hypotension Microvascular Plugging

Endothelial
Dysfunction

Vasoconstriction

Maldistribution of Microvascular Blood Flow

Ischemia

Cell Death

Organ Dysfunction

Edema

MANAGEMENT

PIRO staging for sepsis

Aims to describe the sepsis
considering the relationship amongst
premorbid factors, infection insult &
host response and how it impacts on
development of organ dysfuction &
prognosis of septic patients

SEPSIS SIX
TheSepsis Sixis the name given to a bundle of
medical therapies designed to reduce the mortality
of patients withsepsis.
The Sepsis Six consists of three diagnostic and
three therapeutic steps all to be delivered within
one hour of the initial diagnosis of sepsis.
1.
2.
3.
4.
5.
6.

Deliver high-flowoxygen.
Takeblood cultures.
Administer empiric intravenousantibiotics.
Measure serumlactate and sendfull blood count.
Startintravenous fluidresuscitation.
Commence accurateurineoutput measurement.

Daniels et al. The sepsis six and the severe sepsis resuscitation bundle: a prospective observational
cohort study. Emerg Med J (2011) vol. 28 (6) pp. 507-12

 TheSurviving Sepsis
Campaign(SSC) - global initiative
to bring together professional
organizations in reducing mortality
from sepsis.
The Surviving Sepsis Campaign and
the Institute for Healthcare
Improvement teamed up to achieve
a 25 percent reduction in sepsis
mortality by 2009.

History of the guideline

2004
The initial SSC guidelines incorporated the
evidence available through the end of 2003

2008
Publication analyzed evidence available
through the end of 2007

2012
The most current iteration is based on
updated literature search incorporated into
the evolving manuscript through fall 2012

Selection and Organization of

Committee Members
Appointed by the Society of Critical
Care Medicine and European Society
of Intensive Care Medicine
Sepsis expertise
Four clinicians with experience in the
GRADE process application (referred
as GRADE group or Evidence-Based
Medicine [EBM] group)

GRADING
Grading of Recommendations Assessment,
Development and Evaluation (GRADE) system
Quality of evidence
High (grade A)
Moderate (grade B)
Low (grade C)
Very low (grade D)

Classification of recommendations
Strong (grade 1)
Weak (grade 2)

GRADING
Strength of recommendation and
quality of evidence assessed using
GRADE criteria, presented in brackets
after each guideline. For added clarity:
Indicates a strong recommendation or we
recommend.
o Indicates a weak recommendation or we
suggest.
UG means the evidence is ungraded

MANAGEMENT OF SEVERE
SEPSIS
Initial Resuscitation and Infection
Issues
Hemodynamic Support and
Adjunctive Therapy
Supportive Therapy of Severe Sepsis

WORLD SEPSIS DAY 13

SEPTEMBER

Initial Resuscitation and

Infection Issues

Initial Resuscitation and Infection

Issues
A. Initial Resuscitation
B. Screening for Sepsis and
Performance Improvement
C. Diagnosis
D. Antimicrobial Therapy
E. Source Control
F. Infection Prevention

A. Initial Resuscitation
Resuscitation of patients with sepsis- induced
tissue hypoperfusion
defined as hypotension persisting after initial fluid
challenge or blood lactate concentration 4 mmol/L

1.EGDT (first 6 hrs of resuscitation)

a) Central venous pressure (CVP) 812 mm Hg
b) Mean arterial pressure (MAP) 65 mm Hg
c) Urine output 0.5 mL/kg/hr
d) Scvo2 or Svo2 70% or 65%, respectively- 1C

2. If Elevated Lactate- target resuscitation to

normalize lactate 2C

How to Resuscitate
Resuscitate with IVF to reduce lactate
Resuscitate early ( if <6h- mortality by
16%)
If Hypotension + Lactate mortality 16%
if ScvO2 <70% / SvO2 <65% despite
adequate intravascular volume repletion
with persisting tissue hypoperfusionDobutamine @ max 20 g/kg/min
OR
PRBC- to achieve Hct >= 30%

How to Resuscitate
Target CVP 12-25mm Hg if known
Ventricular compliance
Dont Use CVP guided IVF if known PAH
SEVERE SEPSIS

INCIDENCE

MORTALITY

Hypotension +
Lactate >4mmol/l

16%

46

Hypotension Only

49%

36%

Only Lactate
>4mmol/l

5.4%

30%

B. Screening for Sepsis and

Performance Improvement
Routine screening of seriously ill
patients for severe sepsis to
increase the early identification of sepsis
(1C)
allow implementation of early sepsis
therapy

Performance improvement efforts to

improve patient outcomes and
decrease sepsis-related mortality.

B. Screening for Sepsis and

Performance Improvement*
The SSC guidelines and bundles as
the basis of a sepsis performance
improvement program
A bundle is a selected set of
elements of care derived
fromevidence based practice
guidelines
effect on outcomes beyond
implementing the individual elements

SEVERE SEPSIS

SEPTIC SHOCK

2016- not
mandatory if early
recognition of
sepsis & timely Ab
given

How to Screen
Use Sepsis screening tools
Many tools eg. St. Joseph Mercy,
Sepsis Surv Campaign etc
Any can be used as per hospital
requirements/equipment

C. Diagnosis
Cultures before antibiotic therapy
Without causing significant delay

At least 2 blood cultures (both aerobic and

anaerobic)
percutaneous
drawn through each lumen of each vascular access device
(if >48 hrs)

Imaging studies in attempts to confirm a potential

source of infection
Balancing risks & benefits

C. Diagnosis
o Other Cultures if indicated- Urine, CSF,
sputum etc
o Vol of blood sample > 10ml
o Adjunct Methods- PCR, Mass Spectroscopy,
Microarrays
o Procalcitonin & CRP cant differentiate
b/w Sepsis & other Inflammatory States
(Not Recommended)
o 1,3 -d-glucan assay (2B), mannan and
anti-mannan antibody assays
If invasive candidiasis suspected

D. Antimicrobial Therapy
Goal - Administration of effective i/v
antibiotics within the first hour of
recognition of septic shock (grade 1B) and
severe sepsis (grade 1C).

? Premixed Abx Solutions

Abx Bolus vs Infusions
Initial empiric anti-infective therapy
one or more drugs
activity against all likely pathogens (bacterial
and/or fungal or viral) presumed to be the
source of sepsis (grade 1B)

D. Antimicrobial Therapy
Reassessed daily for potential deescalation (grade 1B)
prevent the development of resistance
to reduce toxicity
to reduce costs

o Combination empiric therapy (>=2

classes of Abx)o neutropenic patients with severe sepsis (grade
2B)
o difficult-to-treat, multidrug-resistant bacterial
pathogens such as Acinetobacter and
Pseudomonas spp.

D. Antimicrobial Therapy
o Extended spectrum beta-lactam +
AGS/FQs for P. aeruginosa bacteremia
o Beta-lactam and macrolide for
bacteremic Streptococcus
pneumoniae infections
o Not for more than 35 days
o De-escalation to the most appropriate
single therapy as per susceptibility

D. Antimicrobial Therapy
o Duration of therapy 710 days
o Longer courses
o slow clinical response
o undrainable foci of infection
o bacteremia with S. aureus
o some fungal and viral infections
o immunologic deficiencies, including
neutropenia (grade 2C).

D. Antimicrobial Therapy
o Antiviral therapy suspected to be
viral origin (grade 2C).
Should not be used in severe
inflammatory states determined to
be of non-infectious cause (UG)

How to Give Antibiotics

Choice- based on
History
Previous Ab usage
Clinical Features
Community pathogenic susceptibility
Renal/ Hepatic function

M/C Organisms- G+ > G- > Mixed

E. Source Control
Specific anatomical diagnosis of
infection requiring emergent source
control- Imaging
Intervention for source control within
the first 12 hr of diagnosis.
Source control with least
physiological insult in severe sepsis.

E. Source Control
Intravascular access suspected to be
source of severe sepsis or septic shock
remove promptly after other vascular
access has been established (UG).
Surgical intervention done when
minimally invasive approaches are
inadequate / when diagnostic
uncertainty persists despite imaging

F. Infection Prevention
o Selective Oral decontamination(SOD)- 2%
gentamicin, 2% colstin, and 2% vancomycin
paste has been shown to reduce VAP
o Oral CHG be used (2B)
o Selectivedigestivedecontamination(SDD)o oralcavity paste + GI tract solution, and IV
antibiotics x 4 days.
o Eliminates harmful bacteria & allows native flora to
thrive. CONTOVERSIAL

HAEMODYNAMIC SUPPORT
& ADJUNCTIVE THERAPY

HAEMODYNAMIC SUPPORT &

ADJUNCTIVE THERAPY
FLUID THERAPY
VASOPRESSORS
INOTROPIC SUPPORT
CORTICOSTEROIDS

FLUID THERAPY
Crystalloids*
Against the use of hydroxyethyl starches
o Albumin for fluid resuscitation when
patients require substantial amounts of
crystalloids
Initial fluid challenge in patients with
sepsis-induced tissue hypoperfusion &
suspected of hypovolemia @ 30 mL/kg
of crystalloids (minimum)*

VASOPRESSORS
Target a mean arterial pressure (MAP) of 65 mm Hg
Norepinephrine* as the first choice vasopressor
o Epinephrine added when an additional agent is
needed to maintain adequate B.P.
Vasopressin 0.03 U/min added to NE for raising
MAP or decreasing NE dosage (UG)
Low dose vasopressin not recommended as the
single initial vasopressor for sepsis-induced
hypotension (UG)
Vasopressin doses > 0.03-0.04 U/min reserved for
salvage therapy (UG)

VASOPRESSORS
Dopamine as an alternative vasopressor
agent to NE only in highly selected patients
with low risk of tachyarrhythmias
absolute or relative bradycardia

Phenylephrine not recommended except

when
NE associated with serious arrhythmias
cardiac output high and BP persistently low
as salvage therapy when combined
inotrope/vasopressor drugs and low dose
vasopressin have failed to achieve MAP

VASOPRESSORS
Low dose dopamine should not be
used for renal protection

INOTROPIC THERAPY
Trial of dobutamine infusion up to 20
mcg/kg/min be administered or added
to vasopressor (if in use) (grade 1C)
myocardial dysfunction suggested by
elevated cardiac filling pressures and low
cardiac output
ongoing signs of hypoperfusion, despite
achieving adequate intravascular volume
and adequate MAP.

CORTICOSTEROID
o Not indicated if adequate fluid
resuscitation and vasopressor therapy
able to restore hemodynamic stability
o In case not achievable, iv
hydrocortisone at a dose of 200 mg per
day
Corticosteroids not be administered for
treatment of sepsis in the absence of
shock

CORTICOSTEROID
o Not using the ACTH stimulation test
to identify adults with septic shock
who should receive hydrocortisone
(grade 2B).
o In treated patients hydrocortisone
tapered when vasopressors are no
longer required
o Low-dose hydrocortisone to be given
as continuous infusion rather than
repetitive bolus injections

OTHER SUPPORTIVE
THERAPY

OTHER SUPPORTIVE
THERAPY

Blood products administration

Immunoglobulins*
Selenium*
Mechanical ventilation of sepsis induced ARDS
rhAPC*
Sedation, anaelgesia & neuromuscular blockade
Glucose control
Renal replacement therapy
Bicarbonate therapy
DVT prophylaxis
Stress ulcer prophylaxis
Nutrition*
Setting goals of care

BLOOD PRODUCT ADMINISTRATION

PRBC transfusion only when Hb <7.0 g/dl
Target Hb of 7.0 9.0 g/dl

EPO not be used as specific treatment of

anemia associated with severe sepsis
o FFP not be used to correct laboratory
clotting abnormalities in the absence of
bleeding or planned invasive procedures
Not using antithrombin for the treatment
of severe sepsis and septic shock

BLOOD PRODUCT ADMINISTRATION

o Platelet transfusion
<10,000/mm3 in the absence of
apparent bleeding*
< 20,000/mm3 if the patient has a
significant risk of bleeding
Higher platelet counts (50,000/mm3)
advised for active bleeding, surgery, or
invasive procedures

IMMUNOGLOBULINS*

SELENIUM*

MECHANICAL VENTILATION OF
SEPSIS INDUCED ARDS
Target tidal volume of 6 mL/kg predicted body
weight in patients with sepsis-induced ARDS
Positive end-expiratory pressure (PEEP) be
applied to avoid alveolar collapse at end
expiration
Mechanically ventilated sepsis patients be
maintained with the head end elevation of 3045o
limit aspiration risk
prevent the development of VAP

MECHANICAL VENTILATION OF
SEPSIS INDUCED ARDS
Weaning protocol to be in place
Spontaneous breathing trials regularly to evaluate
the ability to discontinue mechanical ventilation if
arousable
hemodynamically stable (without vasopressor agents)
no new potentially serious conditions
low ventilatory and end-expiratory pressure
requirements
low Fio2 requirements which can be met safely
delivered with a face mask or nasal cannula.

If the spontaneous breathing trial is successful,

consideration should be given for extubation

MECHANICAL VENTILATION OF
SEPSIS INDUCED ARDS
Beta 2-agonists not be used for sepsisinduced ARDS, in absence of
bronchospasm
Pulmonary artery catheter not to be used
routinely for patients with sepsis-induced
ARDS
Conservative fluid strategy for patients
with established sepsis-induced ARDS
without evidence of tissue hypoperfusion

rhAPC (drotecogin alpha)*

PROWESS trial (2001)
Included in 2004 SSC

Downgraded to suggestion in 2008

SSC
PROWESS SHOCK trial (2011)
No benefit
Drug withdrawn from market
No recommendation in SSC 2012

SEDATION, ANAELGESIA &

NEUROMUSCULAR BLOCKADE
Continuous or intermittent sedation be
minimized in mechanically ventilated sepsis
patients
Morphine vs morphine + propofol/midazolam

NMBAs avoided if possible in the septic

patient without ARDS
risk of prolonged neuromuscular blockade
following discontinuation.
If required, either intermittent bolus or
continuous infusion with monitoring of the depth
of blockade

GLUCOSE CONTROL
Protocolised approach
Insulin when two consecutive blood
glucose > 180 mg/dL
upper target blood glucose 180 mg/dL
rather than 110 mg/dL*

Blood glucose values every 12 hrs

until glucose values and insulin
infusion rates stable and then every
4 hrs thereafter

RENAL REPLACEMENT
THERAPY
o Continuous renal replacement
therapies and intermittent
hemodialysis equivalent in patients
with severe sepsis and acute renal
failure (grade 2B).
o Continuous therapies to facilitate
management of fluid balance in
hemodynamically unstable septic
patients (grade 2D).

BICARBONATE THERAPY
o NaHCO3 therapy not useful for the
purpose of improving hemodynamics
or reducing vasopressor
requirements in patients with
hypoperfusion-induced lactic
acidemia.

DVT PROPHYLAXIS
VTE prophylaxis required using daily
subcutaneous LMWH*
If creatinine clearance <30 mL/min, use
dalteparin or UFH
o Combination of pharmacologic therapy and
intermittent pneumatic compression
devices whenever possible
o C/I for heparin use mechanical
prophylaxis. Start pharmacological Rx
when risk decreases.

STRESS ULCER
PROPHYLAXIS
Stress ulcer prophylaxis using H2
blocker or proton pump inhibitor in
patients with GI bleeding risk factors
Coagulopathy
Mechanical ventilation for at least 48 hrs
Hypotension

o PPIs > H2RA*

o Patients without risk factors do not
receive prophylaxis

NUTRITION*
o Oral or enteral feeding, as tolerated, rather than
complete fasting or only i/v glucose within the first
48 hours after diagnosis of severe sepsis/septic
shock
o Low dose feeding > full caloric feeding in the first
week (upto 500 Calories/day, advancing as
tolerated)
o Use i/v glucose + enteral nutrition rather than TPN
alone or parenteral nutrition + enteral feeding in the
first 7 days
Nutrition without specific immunomodulating
supplementation

SETTING GOALS OF CARE

Discuss goals of care and prognosis
with patients and families
Goals of care to be incorporated into
treatment and end-of-life care
planning

KEY TAKE HOME POINTS

Recongnize Sepsis EARLY and determine SEVERITY

EARLY Antibiotics are critical to resolution of shock
RESUSCITATE severe sepsis and septic shock ASAP
EARLY GOAL DIRECTED THERAPY

REFERENCES
1.

Dellinger RP, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis
and Septic Shock:. Critical Care Medicine and Intensive Care Medicine. 2012;41:580637

2.

Courtney M. Townsend J, Beauchamp RD, Evers BM, Mattox KL. Sabiston textbook of surgery : the
biological basis of modern surgical practic. 20 ed. Philadelphia: Elsevier, Inc; 2017.

3.

Ortiz-Ruiz G, Perafn MA, Faist E, Castell CD. Sepsis. 2 ed. United States of America: Springer
Science+Business Media, Inc; 2006.

THANK YOU