SEPSIS

RISNA HALIM MUBIN

BAG. ILMU PENYAKIT DALAM
FAK. KEDOKTERAN

SEPSIS
Affects 700,000 people and accounts for 210,000
deaths annually (in US)
Incidence rate is rising 1.5% - 8% per year survival
rate is only 55%-65% despite technical developments
in ICU & advanced supportive treatment
Before 1987 the predominant pathogens: gram- negative
bacteria, after 1987: gram positive (52%), in the 22-year
period the rate of fungal infections 207%

SEPSIS
One of the most common causes of death in ICUs
Over past 2 decades, advances in understanding of
pathophysiology of (severe) sepsis & septic shock, and
numerous new approaches to treatment total number
of deaths continued to
Possible reasons for the in incidence of sepsis:
increased use of invasive procedures,
immunosuppressants, chemotherapy, transplantation,
HIV infection, and microbial resistance

CLINICAL DEFINITION

(SCCM-ACCP 1992)

SIRS: 2 of this conditions: temperature >38.3oC or <36oC, HR >90

bpm, RR > 20/m or PaCO2 < 32 mmHg, WBC >12000/mm3 or
<4000/mm3 or >10% immature band forms

SEPSIS: SIRS + evidence of infection

Severe sepsis: Sepsis associated with organ dysfunction,
hypoperfusion, or hypotension, including lactic acidosis, oliguria, or
acute alteration in mental state

Septic shock: Sepsis-induced hypotension despite adequate fluid

resuscitation (SBP <90 mmHg or of >40 mmHg from baseline

MODS: presence of altered organ function in an acutely ill patient

such that homeostasis cannot be maintained without intervention

EXTENDED CRITERIA FOR THE

DIAGNOSIS OF SEPSIS
(SCCM/ESICM/ACCP/ATS/SIS 2001)

1. General variables

2. Inflammatory variables
3. Hemodynamic variables
4. Organ dysfunction
5. Tissue perfusion

General
variables

Fever or hypothermia (temperature > 38.3C or < 36C

Heart rate > 90 bpm or > 2 SD above the normal value for age
Tachypnea, altered mental state
Significance edema or positive fluid balance (> 20 ml/kg over 24 h)
Hyperglycemia (PG > 120 mg/dl or > 7.7 mmol/l) while diabetes absents

Inflammatory
variables

Leukocytosis (> 12000/mm3) or leukopenia (<4000/mm3)

Normal WBC count with > 10% immature forms
Plasma C-reactive protein level > 2 SD above the normal value
Plasma procalcitonin level > 2 SD above the normal value

Hemodynamic Arterial hypotension (SBP < 90 mmHg, MAP < 70 mmHg, or SBP
decrease > 40 mmHg in adults or < 2 SD below normal for age
variables
SvO2 > 70%
Cardiac index > 3.5 l/min x M-2

Organ
dysfunction

Arterial hypoxemia (PaO2/FiO2 < 300)

Acute oliguria (urine output < 0.5 ml/kg/h or 45 mmol/l for at least 2 h)
Creatinine increase > 0.5 mg/dl
Coagulation abnormalities (INR > 1.5 or aPTT > 60 s)
Ileus (absent bowel sounds)
Thrombocytopenia (platelet count < 100000/mm3
Hyperbilirubinemia (total bilirubin > 4 mg/dl or > 70 mmol/l)

Tissue
perfusion

Hyperlactatemia ( > 2 mmol/l)

Decreased capillary refill

Sepsis: Defining a Disease Continuum

Insult

SIRS

Sepsis Severe Sepsis

Infection
Bacterial,
viral,
trauma,
heat, etc

Sepsis with 1 sign of organ

failure
Cardiovascular (refractory
hypotension)
Renal
Respiratory
Hepatic
Hematologic
CNS
Metabolic acidosis

Shock

Bone et al. Chest. 1992;101:1644; Wheeler and Bernard. N Engl J Med. 1999;340:207.

PATHOPHYSIOLOGY
Sepsis is a complex interaction between microorganisms,
toxins,and the immune system, which results in activation
of the SIRS, characterized by cytokine production
(inflammatory mediators) and activation of the coagulation
cascade

The resultant effects to the host are generalized

endothelial injury, increased capillary permeability,
distributive hemodynamic compromise, coagulopathy,
tissue anoxia, and ischemia, all of which can lead to the
development of multiorgan system failure

PATHOPHYSIOLOGY

Molecules proinflammation & antiinflammation

Proinflammation
TNF-
IL-1, IL-1
IL-2
IL-6
IL-8
IL-15
IFN-
Neutrophil
elastase
Protein kinase
MCP-1 & 2
Leukemia
inhibitory factor

Antiinflammation

Thromboxane
Platelet activating
factor
Soluble adhesion
molecules
Vasoactive
neuropeptides
Phospholipase A2
Tyrosin kinase
PAI-1
Free radical generation
Neopterin
CD 14
Prostacyclin,
Prostaglandin

IL-1 ra
IL-4, IL-6
IL-10, IL-11
IL-13
Type II IL-1 receptor
TGF-
Epinephrine
Soluble TNF- receptors
Leukotriene 4-rec.
antagonism
Soluble recombinant CD
14
LPS binding protein
(LBP)

Hotchkiss et al N Engl J Med 2003;348:2

Pathophysiology of Severe Sepsis

COAGULATION
CASCADE

Endothelium

Tissue Factor

Factor VIIIa

PAI-1

IL-6
IL-1
TNF-

Organisms
Monocyte

Factor Va
Suppressed
fibrinolysis
THROMBIN
Neutrophil

Fibrin

IL-6

Fibrin clot

Tissue Factor

Inflammatory Response
to Infection

TAFI

Thrombotic Response
to Infection

Fibrinolytic Response
to Infection

MANAGEMENT
Management of Sepsis
Diagnosis
Lab routine
Culture
Radiologic exam
Biochemical
markers: LBP, PCT,
CRP, IL

Therapy
Supportive
lnitial resuscitation

Specific

Fluid therapy

Antimicrobials

Steroids

APC

Vasopressors/inotropic

Source control

Mechanical ventilation

Modification of
inflammation

Blood tranfusion
Dialysis, glucose
control, RRT

Identification of High-Risk Severe Sepsis

GRAPH:

SPECIFIC
THERAPY

Insert continuum, p. 4, elxi 8291, see attached.

MANAGEMENT
Based on Surviving Sepsis Campaign guidelines for
management of severe sepsis and septic shock 2003

Supportive therapy

initial resuscitation, fluid administration, vasopressors and

inotropic agents, steroids, blood transfusion, mechanical
ventilation, glucose control, dialysis, prevention of DVT and
stress ulcer, bicarbonate, and renal replacement

Specific therapy

antimicrobial agents, activated protein C, source control, and

modification of inflammatory response

Initial Resuscitation (early goal directed

therapy)
Manipulate of cardiac preload, afterload, & contractility to
achieve a balance between oxygen delivery & demand
Administration of colloid/crystalloid fluid, vasoactive, and
transfusion of PRC
The first 6-hours endpoints:
CVP: 8 - 12 mmHg
MAP 65 and 90 mmHg
Urine output 0.5 ml/kg/h
SvO2 (central/mixed O2 saturation) 70%

Vasopressors and Inotropic Agents

Started when appropriate fluid challenge fails to restore
adequate BP & organ perfusion
Norepinephrine or dopamine is the first choice to correct
hypotension in shock
In low CO despite adequate fluid administration, use
dobutamine, if low BP, combine with vasopressors
Increasing cardiac index to supranormal levels not
recommended goal of resuscitation is to achieve
adequate levels of O2 delivery or avoid flow-dependent
tissue hypoxia

Vasopressor and inotropic agents

Drug

Pharmacologic Role

Clinical Effect

Usual Dose
Range

Epinephrine

- & -adrenergic
agonist

chronotropism,
inotropism,
vasoconstriction

5-20 g/min

Norepinphrine

& adrenergic agonist

(- is greater than -)

chronotropism,
inotropism,
vasoconstriction

5-20 g/min

Dopamine

Dopamine & adrenergic agonist,

progressive - effect
with increased dose

chronotropism,
inotropism,
vasoconstriction

2-20 g/kg of
BW/min

Dobutamine

-adrenergic agonist

chronotropism,
inotropism, vasodilation

5-15 g/kg/min

Phenylephrine

-adrenergic agonist

vasoconstriction

2-20 g/min

Steroids
In patient with septic shock require vasopressors, despite
adequate fluid therapy, can be given i.v hydrocortisone
200-300 mg/day for 7 days
Doses of > 300 mg/day hydrocortisone should not be used
for treating septic shock
In the absence of shock no recommended
No contraindication to continuing maintenance steroid
therapy or using stress dose, if needed for patient with
prior history of steroid therapy or adrenal dysfunction

Blood product administration

Once tissue hypoperfusion has resolved, no CAD, no acute
hemorrhage, no lactic acidosis PRC transfusion only
when Hb <7 g/dl to target 7-9 g/dl
EPO is not recommended for anemia associated with
severe sepsis
Routine use of FFP in the absence of bleeding or invasive
procedures is not recommended
Antithrombin administration is not recommended
Administer platelets when counts <5000/mm3, consider
when counts 5000-30000/mm3 and high risk of bleeding

Intensive Insulin Therapy in the Critically ill

Hyperglycemia and insulin resistance are common
van den Berghe et al conducted a RCT of 1548 patients to evaluate
role of intensive (BG 80-110) vs conventional (BG 180-200)
glycemic control in critically ill (incl. severe sepsis/shock)
Intensive insulin resulted in
34% decrease in-hospital mortality
46% reduction in bloodstream infection
41% reduction in renal failure requiring RRT
50% decrease in median RBC transfusions
Van den Berghe et al NEJM 2001: 345; 1359-67

Antimicrobial agents
Intravenous antibiotic should be started within the 1st hour of
severe sepsis, after appropriate cultures be obtained
Initial empirical anti-infective agents should include 1 drug
against the likely pathogens. The choice of drugs is guided
by susceptibility patterns in the community & hospital
Assessment should be done after 48-72 hrs based on
microbiological & clinical data. If causative pathogen is
identified no reason for combination therapy
If the presenting clinical syndrome is not due to infectious
cause stop antimicrobial therapy

Activated Protein C
Activated Protein C (an endogenous anticoagulant)
has anti-thrombotic, anti-inflammatory and profibrinolytic properties
Efficacy recently studied in the PROWESS study
(2001) improved survival in patients with sepsis induced
organ dysfunction

Drotrecogin alfa (recombinant human APC), continuous

infusion administration over 96 h approved by FDA

The Role of Activated Protein C In Severe Sepsis

Activated Protein C

COAGULATION
CASCADE

Tissue Factor

Factor VIIIa

IL-6
IL-1
TNF-

Organisms

Inhibition

Factor Va
Inactivation

Activated
Protein C

THROMBIN
Neutrophil
Inhibition

PAI-1

Inactivation

Monocyte

IL-6

Tissue Factor

Inflammatory Response
to Infection

Activated Protein C

Prevention of activation

Endothelium

Inactivation

Suppressed
fibrinolysis

TAFI

Fibrin
tion
Reduclling
o
of R

Activated Protein C

Thrombotic Response
to Infection

Fibrin clot

Fibrinolytic Response
to Infection

Short-term Mortality in Overall Population

Drotrecogin Alfa (Activated)
Placebo

p = 0.005

34.6%

Percent Mortality

35

30.8%

30
25

p = 0.023
29.4%

24.7%

20
15
10
5
0

28-Day

In-Hospital
PROWESS, 2001

Source Control
Evaluation for a focus on infection include: drainage of
abscess or focus infection, debridement, removal of
potentially infected device
Selection of methods must weigh benefits & risks of the
specific intervention: bleeding, fistulas, organ injury
When a focus of infection has been identified as the cause
of severe sepsis/shock, source control measures as soon
as possible after initial resuscitation
If i.v devices are potentially as source promptly removed
after establishing other i.v access

SUMMARY
Sepsis remains a serious cause of morbidity and
mortality, while the pathophysiology of the disease is
unclear.

The syndrome of sepsis is a complex interaction between

microorganisms, toxins, and the immune system, which
results in SIRS activation characterized by cytokines
production, activation of prostaglandin, and coagulation
cascade.

SUMMARY
The resultant effects to the host are generalized endothelial
injury, increased capillary permeability, distributive
hemodynamic compromise, coagulopathy, tissue hypoxia,
and ischemia, all of which can lead to the development of
multiorgan system dysfunction or failure.

The definition of clinical manifestations of sepsis and the

searching efforts for effective therapeutic interventions are
ever evolving.

Thank You

Levinson, 2003

SEPSIS AND BACTEREMIA

Bradikinin

DIC

Tissue
factor

PMN
activation

Factors XII
LPS-binding
protein
Macrophage
TNF-
Nitric
oxide

C5a

Complement
ENDOTOXIN

Phospholipase A2

CRF

CNS
Endorphin

Stress
hormones

IL-1
Lypoxygenase
(leukotriens)

PAF

Cyclooxygenase
(prostanoids)
Mandell G, 2002; Essential Atlas
of Infectious Diseases

PMN

Gram
negative
bacteria

Liver

Lipopolysaccharide
(LPS)
BACTERICIDAL
Permeability-increasing
protein (BPI)

LPS-binding
protein (LBP)

LPS/LBP
Complex

LPS/BPI
Complex

LPS
degradation

CD14

G
protein

Kinase activation
NF kB
Macrophage

Nuclear
translocation
Increased transcription

TNF IL-1

IL-2 IL-6 IL-8 PAF IFN

LPS
Bacterial
lysis

+
LPS
binding
protein

LPS binding
protin complex

CD14
Macrophage
ARDS

TNF, IL-1, IL-6, IL-8,

pletelet-activating factor
Activation of
coagulation
cascade

Prostaglandin
leukotriens

DIC
Endothelial
damage
MOF

Activation
of
complement
cascade

ANTIBIOTIC SELECTION BASE ON

Site of infection : pulmonary infection, intra abdominal infections,

intravascular infections, genitourinary infections, wound and skin-related
infections

Antimicrobial dosing

Combination antibiotic treatment

Mechanisms of antibiotic resistance

Discontinue antibiotics at the point when the infection has cleared

ANTIBIOTIC-INDUCE ENDOTOXIN RELEASE

Early biochemical events in sepsis

SEPSIS, SIRS, CARS, MARS

(Bone,

1997)
Old paradigm for sepsis:

infection

endotoxin & other microbial toxins

proinflammatory state with cytokine release and other

proinflammatory mediators

sepsis / SIRS

shock & MODS & possible death

SEPSIS, SIRS, CARS, MARS

Local
proinflammatory
response

(Bone, 1997)

Initial insult (bacterial, viral,

traumatic, thermal)

Systemic spillover of
pro-inflammatory
mediators

Systemic reaction
SIRS/pro-infl

Local
antiinflammatory
response

Systemic spillover of
anti-inflammatory
mediators

CARS/anti-infl
MARS/mixed
Cardiovascular
compromise
(shock)
SIRS
predominate

Homeostasis

Apoptosis

CARS - SIRS
balance

Death with
minimal
inflammation

Organ
dysfunction
SIRS
predominates

Suppression
of immune
system
CARS >>

SEPSIS, SIRS, CARS, MARS (Bone, 1997)

Stages of the development of Sepsis-MODS:
1. Local reaction at the site of injury or infection
2. Initial systemic response
3. Massive systemic inflammation
4. Excessive immunosuppression
5. Immunologic dissonance

Not beneficial
Anti TNF (dose dependent increase in 28 day mortality)
Anti Endotoxin antibodies
Anti IL-1 receptor antagonist
Greatest benefit in patients with higher mortality
Most animal studies use pre-treatment protocols

Norepinephrine
Potent -adrenergic activity
Less but significant -1 activity
Little or no chronotropic effect due to effect of
increased venous capacitance on baroreceptors in
right side of heart
No large clinical trials comparing outcomes with
different pressors
Preferred agent for sepsis

Dopamine
Variable physiologic effects depending on dose
<2mcg/kg/min stimulates dopamine receptors resulting
in vasodilation
5-10 mcg/kg/min stimulates 1 receptors, increasing
cardiac output
>10 mcg/kg/min stimulates receptors increasing SVR

Dopamine
Dose response variable in septic patients
May decrease PO2 by increasing CI and perfusion
to poorly ventilated lung units
Continuous low dose dopamine to at risk patients
no effect on decreasing renal failure

Bellomo et al Lancet 2000;356:2139-43

Phenylephrine
Selective 1 agonist
In theory no effect on heart rate or CI but CO can
decrease

Vasopressin
Acting via V1 receptors it acts as potent
vasoconstrictor in vitro, less potent in vivo
Serum concentrations rise in cardiogenic and
hypovolemic shock and are inappropriately low in
septic shock
While systemic blood pressure may rise may get a
significant fall in splanchnic blood flow

Vasopressin
Double blind placebo controlled study of 10 patients
Primary endpoint was hemodynamic response
Vasopressin infusion at 0.04U/min
Significant increase in MAP (65+6 to 80+8, p<0.05)
SVR increased from (878+218 to 1190+213, p<0.05)

Malay et al J Trauma 1999;47:699

Trial design (intensive insulin therapy)

Patients admitted to surgical ICU, mechanically ventilated
All patients received 200-300 g glucose/day on admission
TPN or parenteral fluid within 24 hours of admission with
60-80% glucose calories
Conventional: titrate glucose to 180-200 mg/dL
Intensive: titrate glucose to 80-110 mg/dL
Van den Berghe et al NEJM 2001: 345; 1359-67

Role of Intensive Insulin

Intensive insulin resulted in
34% decrease in-hospital mortality
46% reduction in bloodstream infection
41% reduction in renal failure requiring RRT
50% decrease in median RBC transfusions
Van den Berghe et al NEJM 2001: 345; 1359-67

Role of Intensive Insulin

Conventional

Intensive

Insulin
(median units/day)

33

71*

Duration of Insulin
use (% ICU days)

67

100*

AM glucose
(all patients)

153

103*

AM glucose
(Insulin patients)

173

103*

VandenBergheetalNEJM2001:345;1359-67

*P<0.001