SEPSIS

RISNA HALIM MUBIN

BAG. ILMU PENYAKIT DALAM
FAK. KEDOKTERAN
UNIV. HASANUDDIN
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

Possible reasons for the  in incidence of sepsis:

increased use of invasive procedures,
immunosuppressants, chemotherapy, transplantation,
HIV infection, and microbial resistance
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 Antiinflammation
TNF- Thromboxane IL-1 ra
IL-1, IL-1 Platelet activating factor IL-4, IL-6
IL-2 Soluble adhesion IL-10, IL-11
IL-6 molecules IL-13
IL-8 Vasoactive neuropeptides Type II IL-1 receptor
IL-15 Phospholipase A2 TGF-
IFN- Tyrosin kinase Epinephrine
Neutrophil elastase PAI-1 Soluble TNF- receptors
Protein kinase Free radical generation Leukotriene 4-rec.
MCP-1 & 2 Neopterin antagonism
Leukemia inhibitory CD 14 Soluble recombinant CD 14
factor Prostacyclin, Prostaglandin LPS binding protein (LBP)
Pathophysiology of Severe Sepsis

Endothelium COAGULATION
CASCADE
Tissue Factor
Factor VIIIa
PAI-1
IL-6
IL-1
Organisms TNF-
Monocyte
Factor Va

Suppressed
fibrinolysis
THROMBIN TAFI

Neutrophil
Fibrin

IL-6
Fibrin clot
Tissue Factor

Inflammatory Response Thrombotic Response Fibrinolytic Response

to Infection to Infection to Infection
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 Fever or hypothermia (temperature > 38.3C or < 36C
variables 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 Leukocytosis (> 12000/mm3) or leukopenia (<4000/mm3)

variables 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
variables decrease > 40 mmHg in adults or < 2 SD below normal for age
SvO2 > 70%
Cardiac index > 3.5 l/min x M-2

Organ Arterial hypoxemia (PaO2/FiO2 < 300)

dysfunction 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 Hyperlactatemia ( > 2 mmol/l)

perfusion Decreased capillary refill
Sepsis: Defining a Disease Continuum

Insult SIRS Sepsis Severe Sepsis

Infection
Bacterial,
viral, Sepsis with 1 sign of organ
failure
trauma,
Cardiovascular (refractory
heat, etc hypotension)
Renal

Shock
Respiratory
Hepatic
Hematologic
CNS
Metabolic acidosis

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

Management of Sepsis

Diagnosis Therapy

Supportive
Lab routine
lnitial resuscitation Specific
Culture
Fluid therapy
Antimicrobials
Radiologic exam
Steroids
APC
Biochemical
Vasopressors/inotropic
markers: LBP, PCT, Source control
CRP, IL Mechanical ventilation
Modification of
Blood tranfusion inflammation
Dialysis, glucose
control
Identification of High-Risk Severe Sepsis

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

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

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 chronotropism, 5-20 g/min
agonist inotropism,
vasoconstriction
Norepinphrine  &  adrenergic agonist chronotropism, 5-20 g/min
(- is greater than -) inotropism,
vasoconstriction
Dopamine Dopamine & - chronotropism, 2-20 g/kg of
adrenergic agonist, inotropism, BW/min
progressive - effect vasoconstriction
with increased dose
Dobutamine -adrenergic agonist chronotropism, 5-15 g/kg/min
inotropism, vasodilation

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
 Penatalaksanaan
Antibiotik empiris pada jam pertama
Pertimbangan Nama Obat
Pneumonia Tanpa factor resiko infeksi pseudomonas:
Komunitas Seftriakson IV 1-2g/12jam + Gentamisin IV 7 mg/KgBB/8jam
Dengan factor risiko infeksi pseudomonas:
Sefepim IV 1-2 g/8-12 jam +Siprofloksasi IV 400 mg/8jam

Pneumonia Sefepim IV 1-2g/8-12 jam + Gentamisin 7mg/KgBB/8jam

Nosokomial
Urosepsis Levofloksasin IV 750mg/24jam + Ampisilin sulbaktam IV 1,5
g/6-8jam
Infeksi Monoterapi: imipenem IV 1-2g/12jam / Monifloksasi IV
Intraabdomen 400mg/24jam atau Ampisilin sulbaktam IV 1,5 g/6-8jam
Kombinasi: Metronidazol IV 500mg/8jam + Aztreonam IV 2g/6-
8jam

Infeksi system Metronidazol IV 500mg/8jam + Levofloksasin IV 750mg/24jam

saraf pusat
Sumber infeksi Sefotaksim IV 3 g/6jam + Gentamisin 7mg/KgBB/8jam
tidak jelas
Activated Protein C
Activated Protein C (an endogenous anticoagulant)
has anti-thrombotic, anti-inflammatory and pro-
fibrinolytic 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
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.
Thank You
Levinson, 2003
SEPSIS AND BACTEREMIA

Bradikinin DIC Tissue PMN

factor activation C5a

Factors XII
Complement
LPS-binding ENDOTOXIN
protein CNS CRF

Macrophage Phospholipase A2 Endorphin

Stress
TNF- IL-1 hormones
Lypoxygenase PAF Cyclooxygenase
(leukotriens) (prostanoids)
Nitric
oxide Mandell G, 2002; Essential Atlas
of Infectious Diseases
 Gram
negative
PMN
bacteria
Liver

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

LPS/BPI LPS/LBP
Complex Complex

CD14
LPS G
degradation protein

Kinase activation
NF kB
Nuclear translocation
Macrophage

Increased transcription

TNF IL-1 IL-2 IL-6 IL-8 PAF IFN

 LPS +
Bacterial lysis
LPS binding LPS binding protin
complex
protein

CD14
Macrophage
TNF, IL-1, IL-6, IL-8,
pletelet-activating factor
ARDS

Activation of Prostaglandin Activation of

coagulation complement
cascade leukotriens cascade
DIC

Endothelial damage

MOF
 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 (Bone, 1997)

Local Local
proinflammatory antiinflammatory
response Initial insult (bacterial, viral, response
traumatic, thermal)

Systemic spillover of Systemic reaction Systemic spillover of

pro-inflammatory anti-inflammatory
mediators SIRS/pro-infl mediators
CARS/anti-infl
MARS/mixed

Cardiovascular Homeostasis Apoptosis Organ Suppression

compromise dysfunction of immune
(shock) CARS - SIRS Death with
system
balance minimal SIRS
SIRS
predominate
inflammation predominates 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 33 71*
(median units/day)
Duration of Insulin 67 100*
use (% ICU days)
AM glucose 153 103*
(all patients)
AM glucose 173 103*
(Insulin patients)

Van den Berghe et al NEJM 2001: 345; 1359-67 *P<0.001