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SEPSIS:

Pathophysiology and
Management

Rajani Annamaneni

SEPSIS: DEFINITIONS

The disease spectrum: SIRS


SIRS

Sepsis

Severe
sepsis

A non-specific clinical response including


>2 of the following:

Temperature >38oC or <36oC


Heart rate >90 beats/min
Respiratory rate >20/min
White blood cell count >12,000/mm3 or
<4,000/mm3 or >10% immature neutrophils

As well as infection, SIRS can also be caused by


trauma, burns, pancreatitis and other insults

Death

The disease spectrum: sepsis


SIRS

Sepsis

Severe
sepsis

SIRS with a presumed


or confirmed infectious
process

Death

The disease spectrum: severe sepsis


SIRS

Sepsis

Severe
sepsis

Death

Sepsis with signs of at least one acute


organ dysfunction

Renal
Respiratory
Hepatic
Haematological
Central nervous system
Unexplained metabolic acidosis
Cardiovascular

Septic shock
Severe sepsis
with hypotension
refractory to
adequate volume
resuscitation

SEPSIS: EPIDEMIOLOGY

Admissions to ICU with Severe Sepsis


in the first 24 hours
30

% Admissions to ICU

25
20
15
10
5
0

1996 1997 1998 1999 2000 2001 2002 2003 2004

Year
Harrison DA et al. Epidemiology of severe sepsis in England, Wales
And Northern Ireland,1996-2004. Critical Care 2006;10:R24

Size of the problem


This is the treated incidence
Projected total no.of patients has risen from
18,500 in 1996 to 31,000 in 2004
Projected mortality has risen from 9,000 in
1996 to 14,000 in 2004, though
ICU mortality decreased from 34.3% to 30.8%
Length of stay longer for survivors than nonsurvivors; patients with severe sepsis (27% of
admissions) utilized 46% of critical care bed
days
Harrison DA et al. Epidemiology of severe sepsis in England, Wales
And Northern Ireland,1996-2004. Critical Care 2006;10:R24

The cost burden of severe sepsis


It is estimated that the 1014% of
European ICU patients who
develop severe sepsis account for
2432% of total ICU costs
Sepsis care initiative and Eli Lily

SEPSIS: PATHOPHYSIOLOGY

Sepsis Pathophysiology
An overwhelming inflammatory response of
the organism to injury, not necessarily
infection
A multitude of local and systemic responses
result in tissue damage
Both environmental and genetic influences
However, autopsy studies have not found
major organ pathology in patients who died of
sepsis
Cellular hibernation may explain MODS and
be a protective strategy

An overview
Injury or

Host
responses

Pathogen

Anti-inflammatory
mediators
e.g. IL-10, IL-1ra receptor
antagonists

Pro-inflammatory
mediators

Leukocyte activation

Mitochondrial
dysfunction

Organ
dysfunction

Death

e.g. Tumour necrosis


factor, IL-1, IL-6, IL-8,
nitric oxide

Inflammation
Microvascular
flow
redistribution

Endothelial
dysfunction
Tissue factor expression

Tissue injury

Microvascular
coagulation/
thrombosis

Inhibition of
fibrinolysis

Activation of
coagulation

Sepsis care initiative and Eli Lily

Overview: A manageable summary


Inflammation
Pro-inflammation
Anti-inflammation

Circulatory Defect
Myocardial defect
Microvascular defect
Coagulation defect

Cellular Defect
Endocrine Defects

INFLAMMATION

Pro-inflammation (SIRS)
Toll like receptors are pattern recognition receptors
on innate immune cells such as macrophages,
neutrophils etc
TLRs recognise components of bacteria, viruses etc
to induce nuclear factor B, a transcriptional factor
that induces release of TNF-, IL-1, IL-6 and IL-8
These cytokines further release mediators such as
kinins, complement system, histamine, serotonin,
activate the coagulation system
Neutrophil activation, adhesion and degranulation
releases free oxygen radicals and proteases to
cause local endothelial damage, release NO and
vasodilation
Local tissue damage further releases cytokines: a
cytokine storm

So,
Therapies that block cytokine release
should be beneficial in the management
of severe sepsis
BUT they are not
And patients with features of
immunosuppression are susceptible to
nosocomial infections and death
Initial burst of inflammatory mediators
may be followed by anti-inflammation

Anti-inflammation (CARS)
Anti-inflammatory cytokines are IL-10,4
CD4 T cells may secrete pro-or antiinflammatory mediators. The factors
that determine how CD4 cells respond
is not known
Anergy- a state of nonresponsiveness
to antigen
Apoptosis may induce anergy

Apoptosis
A genetically programmed cell death,
whereby activation of proteases
disassemble the cell (suicidal cells)
Physiologically vital
Large number of lymphocytes and gut
epithelial cells undergo apoptosis in
sepsis leading to anergy
Maybe stimulated by steroids
Necrosis induces pro-inflammation

In Summary
Pathogen

Infection
iNOS,
Cyclo-oxygenase
Activation
Monocyte/
macrophage

Anti-inflammatory
mediators
IL-4, IL-10, IL-11, IL-13,
IL-1r. Mediated by heat
soluble proteins

Pro-inflammatory
Cytokines

Complement
Activation

Tumour necrosis factor, IL-1,


IL-6, IL-8. Mediated by NF-kB

Neutrophil activation,
aggregation, adhesion
degranulation;
release of free oxygen
radicals and proteases

Platelet
activation,
aggregation

T-cell
IL-2,
Interferon-,
GM-CSF

Endothelial
damage
Sepsis care initiative and Eli Lily

VASCULAR DEFECTS

Myocardial Defect-Evidence of
Decreased Contractility: Systolic dysfunction/
low ejection fraction
Decreased Compliance: Diastolic
dysfunction/ high end-diastolic volume
CVP not an accurate estimate of LV preload
in sepsis; RAP and RVP may also not be corelated
Prognostic factors: Decreasing CI, HR and
increasing SVRI at 24 hours
Parker SM et al. Crit Care Med 1987,15:923-29

Myocardial Defect-Mechanisms of
Myocardial hypoperfusion (raised troponin I
levels)
Cytokine mediated myocardial depression
(TNF- and IL-1)
Nitric oxide mediated myocardial
depression
Decreased 1 receptor signal transduction
Decreased responsiveness to
catecholamines

Microvascular Defect
Main site of injury in sepsis
Capillary stopped flow causing stasis
Mis-match of local O2 delivery and
demand and local tissue ischaemia
Main players: endothelium, NO,
coagulation defects, inflammatory
cytokines, RBCs, platelets and
neutrophils

The Endothelium
Interaction with leucocytes

Release of cytokines and inflammatory


mediators
Release of mediators of vasodilatation
and vasoconstriction such as NO and
endothelins
Functional effects on the coagulation
system

Nitric Oxide
Normally,
An ubiquitous molecule
Causes smooth muscle relaxation
Maintains regional blood flow; inhibits platelet
aggregation, involved in neurotransmission
Produced from L-arginine by nitric oxide
synthase, the constitutive form (cNOS)
Produced in a pulsatile manner in response
to rise in intra-cellular Ca

Nitric Oxide
In sepsis
The inducible form, iNOS is involved
Produced in response to proinflammatory cytokines by endothelium,
platelets, macrophages, lung epithelium
No production is now Ca independent,
occurs in large quantities in a nonpulsatile manner

Nitric Oxide: Effects in Sepsis


Vaso-paralysis and refractory
hypotension
Reacts with superoxide to produce
peroxynitrite, a potent oxidant on
cellular components
Impairs mitochondrial function, slows
rate of glycolysis electron transport and
ATP generation

Coagulation Defect
Endothelial dysfunction
Tissue factor
Common coagulation pathway

Thrombin generation

Inflammation
Leucocyte
aggregation/
adhesion

Fibrin clot
formation and
platelet activation

Tissue Hypoperfusion
Organ failure

Reduced
fibrinolysis

Procoagulant state

Microvascular
thrombosis, DIC
Sepsis care initiative and Eli Lily

Coagulation Defect
Activated Protein C
Pro-fibrinolytic properties by inactivating
plasminogen-activator inhibitor produced by platelets
and endothelium in the presence of thrombin
Inhibits thrombin generation by inhibiting factors V
and VIII a
Anti-inflammatory: inhibits secretion of inflammatory
mediators
Improves regional flow
In sepsis endogenous protein C is insufficiently
activated by the damaged endothelium

Therapies aimed at coagulation


dysfunction
ATIII treatment: no benefit in mortality
in a large PRCT with placebo. Warren
BL et al. JAMA 2001; 286:1869-78
APC: Absolute risk reduction 6.1%,
Relative risk reduction 19%. Risk of
serious bleeding 3.5% vs 2%. Less
benefit in patients with lower APACHEII
scores. Bernard GR et al. NEJM
2001,344:699-709

CELLULAR DEFECT

Mitochondrial Dysfunction
Dysfunctional cellular oxygen utilization
NO inhibited electron transport chain:
competition between O2 and NO for
binding sites on mitochondria
Inhibition of cytochrome oxidase by NO
Formation peroxynitrite, a potent
cellular toxin
Other mechanisms: PARS, pyruvate
dehydrogenase inhibition

ENDOCRINE DEFECTS

Endocrine Defects
Relative adrenal insufficiency
resulting in vascular hyporeactivity
and modulation of inflammatory
response
Relative vasopressin deficiency
Relative thyroid deficiency
Insulin Resistance

Relative adrenal insufficiency


Glucocorticoids inhibit the production & function
of pro-inflammatory mediators (IL-1,2,3,6,
TNF-, complement system)
Enhance the function of anti-inflammatory
mediators (IL-10, IL-1 receptor antagonist)
Inhibit major inflammatory cells
Control vascular tone by increased production of
catecholamines, adrenergic receptors; improved
reactivity of receptors
Inhibit NO production
Maintain blood sugar levels

Cortisol production in sepsis


Tissue injury, pain, cytokines stimulate
the HPA axis
Negative feedback
Inflammatory mediators and
corticostatin directly inhibit adrenal
cortex and HPA axis
Cytokine induced inhibition of
glucocorticoid receptors

Diagnosis of relative adrenal insufficiency


What is adequate steroid response
Serum cortisol as an indicator of
prognosis
High cortisol levels (>1302 nmol/L) early
in disease process and low levels (<350
nmol/L) in late stages indicative of poor
prognosis
Short synacthen test: what is appropriate
dose of ACTH and response

Prognosis based on cortisol response


Annane et al JAMA2000;283:1038-45
Prognosis

Good

Intermediate

Baseline
</=940 =940
>940
Cortisol
nmol/L
Maximal
>250
</=250 >250
Response to
ACTH 250mcg
nmol/L
28 day
26%
67%
mortality

Poor
>940

<250

82%

Vasopressin
Vasopressin acts on V1 (vascular) and
V2 (renal) receptors. V1 produces
vasoconstriction
Inhibits K+ channels; cytokine IL-1 and
hence NO
Exhaustion of hypothalmic and pituitary
stores of vasopressin in sepsis
Impaired autonomic function and baroreceptor reflexes

Relative Vasopressin Deficiency


Exhaustion of hypothalmic and pituitary
stores of vasopressin
Impaired autonomic function and baroreceptor reflexes
BUT, effects incompletely understood
and hence not routinely recommended
Indicated in vasopressor resistant shock
and only in replacement doses

SEPSIS MANAGEMENT

Surviving Sepsis Campaign


guidelines for management of
severe sepsis and septic shock

Dellinger RP, Carlet JM, Masur H, et al.


Critical Care Medicine. 2004;32(3):858-873.

Surviving Sepsis Campaign


A concerted international effort to
reduce mortality from sepsis by 25% by
2009
Participating organisations: SCCM,
ESICM, ISF and others
Experts in critical care and infectious
diseases developed guidelines
To be used by clinicians at the bedside

Grading of Recommendations
Modified Delphi methodology
Grading indicates levels of literature
support
A: atleast 2 level I investigations
B: one level I investigation
C: level II investigations only
D: atleast one level III investigation
E: level IV or V evidence

Grading of Evidence
I: large RCT with clear cut results; low risk of
and errors
II: Small RCT with uncertain results ; moderate
to high risk of and errors
III: Non-randomised, contemporaneous
controls
IV: Non-randomised, historical controls and
expert opinion
V: Case series, uncontrolled studies, expert
opinion

Recommendations: A to R

A: Initial Resuscitation
Goal directed resuscitation: Grade B
Rivers E, Nguyen B, Havstad S, et al. New England
Journal of Medicine. 2001;345(19):1368-1377.
CVP: 8-12 mm Hg
MAP >/=65 mm Hg
Urine >/= 0.5ml/kg/hr
ScvO2 > /= 70%
If in 6 hours ScvO2 is not achieved
Transfuse PRBCs to haematocrit of >/=30%
And/or dobutamine (max 20mcg/kg/min)

B: Diagnosis
Appropriate cultures before antibiotics
Atleast 2 blood cultures, if possible one
peripheral and the other from a vascular
device
Grade D

Diagnostic studies to locate source of


sepsis
Grade D

C: Antibiotic Therapy
IV antibiotics after appropriate cultures
and within an hour of presentation
Grade E

Choice guided by susceptibility patterns


in the community and hospital.
Spectrum as broad as possible
Grade D

C: Antibiotic Therapy
Antimicrobial regime reassessed at 4872 hours based on clinical and
microbiological data

If presenting clinical syndrome is found


to be non-infectious antibiotics should
be stopped
Both grade E

D: Source Control
Focus of infection must be sought
Risk/benefit analysis of the method of
diagnosis must be assessed
Source must be controlled if found,
In the presence of intravascular devices
and undiagnosed source, they must be
removed
All Grade E

E: Fluid Therapy
May consist of colloid or crystalloid
Grade C
Fluid challenge of 500-1000ml
crystalloid or 300-500 ml colloid over 30
minutes
Grade E

F: Vasopressors
When appropriate fluid challenge fails
to establish BP or organ perfusion,
vasopressors should be started
Grade E
Either norepinephrine or dopamine is
the first choice
Grade D

F: Vasopressors
Low dose dopamine should not be used for
renal protection
Grade B
All patients requiring vasopressors should
have an arterial line inserted
Grade E
Vasopressin may considered in refractory
shock in doses 0.01-0.04 units/min
Grade E

G: Inotropes
In low output states despite adequate
filling, dobutamine may be used
Grade E

A strategy of increasing cardiac index to


arbitrary levels is not recommended
Grade A

H: Steroids
IV hydrocortisone 200-300mg/day for 7
days in patients who require
vasopressors despite adequate filling
Grade C
Doses >300mg/day should not be used
Grade A
Should not wait for ACTH stimulation
results to administer steroids
Grade E

H: Steroids
Decrease dose of steroids after
resolution of septic shock
Taper the dose of steroids at the end of
therapy
Add fludrocortisone
All grade E

I: Activated Protein C
Recommended in patients at high risk
of death (APACHE II score>25) and no
absolute contra-indication
Grade B

J: Blood Products
Red blood cell transfusion should occur
only when Hb<7.0gm/dl, in the absence
of acute hage, significant coronary
disease, and high lactate
Erythropoietin not recommended in the
absence of other causes anaemia such
as renal failure
Antithrombin III not recommended
All grade B

J: Blood Products
Routine FFP in the absence of bleeding
or planned invasive procedures not
recommended
Platelets < 5,000 should be replaced;
5000-30,000 transfusion should be
considered, if significant risk of
bleeding; >/= required for
surgery/procedures
Both grade E

K: Mechanical Ventilation
Protective lung ventilation
Grade B
Permissive hypercapnia
Grade C
Prone position
Grade E
Head up 45o degrees
Grade C
Weaning protocol
Grade A

L: Sedation, Analgesia, Paralysis


Sedation Protocols
Daily sedation hold
Both grade B
Neuromuscular blockade avoided
Grade E

M: Glucose Control
Following stabilization, maintain blood
sugar at 8.3 mmol/l with frequent
monitoring
Grade D
Nutrition protocol, preferably enteral
nutrition
Grade E

N: Renal Replacement
In ARF, in the absence of
haemodynamic instability CCH and
intermittent dialysis are considered
equivalent
Grade B

O: Bicarbonate Therapy
Not recommended for treatment of
hypoperfusion related lactate acidosis if
pH >/= 7.15
Grade C

P: DVT Prophylaxis
Prophylaxis with LMWH or
unfractionated heparin is recommended
If heparin is contraindicated,
mechanical devices should be used
Very high risk patients both
pharmacological and mechanical
devices should be used
All grade A

Q and R:
Q: Stress ulcer prophylaxis should be
given to all patients; H2 receptor
inhibitors are the preferred choice
Grade A
R: Consideration for therapy limitation
should be discussed with the family
Grade E