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Pathophysiology and
Management
Rajani Annamaneni
SEPSIS: DEFINITIONS
Sepsis
Severe
sepsis
Death
Sepsis
Severe
sepsis
Death
Sepsis
Severe
sepsis
Death
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
25
20
15
10
5
0
Year
Harrison DA et al. Epidemiology of severe sepsis in England, Wales
And Northern Ireland,1996-2004. Critical Care 2006;10:R24
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
Inflammation
Microvascular
flow
redistribution
Endothelial
dysfunction
Tissue factor expression
Tissue injury
Microvascular
coagulation/
thrombosis
Inhibition of
fibrinolysis
Activation of
coagulation
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
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
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
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
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
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
SEPSIS MANAGEMENT
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
C: Antibiotic Therapy
IV antibiotics after appropriate cultures
and within an hour of presentation
Grade E
C: Antibiotic Therapy
Antimicrobial regime reassessed at 4872 hours based on clinical and
microbiological data
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
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
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