Definition

Infeksi

adalah istilah untuk menamakan

keberadaan berbagai kuman yang masuk ke
dalam tubuh manusia.
Bila kuman berkembang biak menyebabkan
kerusakan jaringan disebut penyakit infeksi,
menyebabkan jejas.

Inflamasi ialah reaksi jaringan vaskuler terhadap

semua bentuk jejas. Pada dasarnya inflamasi
adalah suatu proses pertahanan tubuh.
Inflamasi : Lokal
Sistemik Sistemic Inflamasi
Response Syndrome (SIRS)

BACTEREMIA
OTHER
INFECTION

INFECTION
SEPSIS

FUNGEMIA
PARASITEMIA

BURNS

VIREMIA
OTHER

PANCREATITIS

SIRS
TRAUMA

Genetic Susceptibility
Resistance to Antimicrobial
Coexisting health complications

Predisposition

Pathogen, toxicity and immunity

Location and compartmentalization

Infection
Response
Organ Dysfunction

Increased biomarkers / biomediators

Manifested physiologic symptoms

Number of failing organs

Optimum Individualized Treatment

Epidemiologic sepsis in US period 1979 2000 :

Centers for Disease Control in the United States the incidence of
septicaemia :
1979 73.6 / 100 000 patients
- 1987 175.9 / 100 000 patients

US and European surveys have estimated that severe sepsis

accounts for 2-11 % of all admissions to hospital or ICU.
Sepsis is the 11th leading couse of death.
US Increase of 13,7 % / year
Culture identified in 51 %
- gram positive
= 52,1 %
- gram negative
= 37,5 %
- polymicrobial
= 4,7 %
- fungal
= 4,6 %
- anaerobic bacteri = 1,0 %
Gram positive infection increase of 26,3 % / year MRSA

Estimates of the Impact of Sepsis

Syndromes Annually in U.S.
Mortality
Septic
shock
200,000
Severe sepsis
200,000

Sepsis
200,000

600,000 cases/yr

Deaths

46%

92,000

20%

40,000

16%

32,000
164,000 death/yr

Rekapitulasi Sepsis Berdasarkan Kekerapan

Etiologi di Indonesia
1. Pseudomonas aeruginosa
2. Stafilokok aureus :
(MSSA)
3. Stafilokok aureus :
(MRSA)
4. Klebsiella spp
5. E.coli
6. Enterobacter
7. Acinetobacter
8. Lain-lain

Rekapitulasi Semi Nasional

Sepsis Menurut Sumber Organ :
1. Pulmonal
2. Tr. Urinarius
3. Dermal
4. Gastrointestinal
5. Abdominal
6. Lain-lain

FAKTOR BERPERAN ATAS PENINGKATAN

SEPSIS
1. meningkatnya chemoterapi onkologi dan terapi radiasi,
2. meluasnya pemakaian kortikosteroid dan terapi
imunosupresi pada transplantasi organ dan penyakit
inflamasi,
3. meningkatnya survival pasien yang mempunyai
predisposisi sepsis (misalnya neonatus; usia lanjut,
diabetes mellitus, kanker, kegagalan organ penting;
atau granulositopenia),
4. pemakaian alat invasif (misalnya protesis surgical,
peralatan inhalasi; kateter intra vena dan kateter urine),
5. pemakaian secara sembarangan obat antimikroba
yang menyebabkan overgrowth, kolonisasi dan disusul
infeksi oleh kuman patogen resistan terhadap
antimikroba

ETIOLOGI SEPSIS :
Bakteri gram (-) : 6070%
Solo (1997)
50%
Corigan (2004) 52.5%

gram (+) : 2040%

50%
37.5%

Bakteri gram (-) :

LPS (Lipopolisakarida)

Lipid A

(Peradangan jaringan, demam, SEPSIS

SYOK SEPTIK)

Bakteri gram (+) :

Eksotoksin yang dapat merusak integritas
membran sel imun.
Virus, parasit dan jamur

BACTERIAL SEPSIS
Gram negative bacilli : Enterobacteriaceae
Escherichia coli, Klebsiella species, and Pseudomonas
aeruginosa
Lung, abdomen,
bloodstream, or urinary tract.
Gram positive cocci : Staphylococci aureus, and
streptococci : pyogenes, viridans, pneumoniae. Skin,
soft tissue, intravasculer devices, primary bloodstrem
infections, or respiratory infections.
Fungi, mostly Candida, account for only about 5% of
all cases of severe sepsis.
Bochud Y. P. and Calandra T., 2003

PERAN RESPONS IMUN

FACTOR
:

External :
- Endotoxin
- superantigen
. Eksotoxin
. Virus
. Parasite
- Tissue Damage

Internal :
- Immune humoral
- Immune cellular
. Interleukin
. IL - 1, TNF - a
. IL - 6
. IL - 8
. IL - 10

SYSTEMIC INFLAMMATORY RESPONSE

Inflammatory trigger (s)
Local pro inflammatory & anti inflammatory
reactions
Mediator pro
inflammatory

Mediator anti
inflammatory

Systemic circulation

SEPSIS

SIRS

MARS

CARS

IMMUNOLOGIC DISSONANCE
CHAOS

CV Septic shock
OD/MODS - Apoptosis

Home
ostasi
s

Suppression immune
system / AnergyInfection

OD/MODS

(Carrigan et. al., 2004)

CYTOKINES & RELATED FACTORS

IMMUNO
REGULATORY

IFN
IL- 2
IL- 4
IL- 5
IL- 7
IL-11

PRO
INFLAMMATORY

IL-1
IL- 6
IL- 8
IL-12
IL-15
IL-18
PAF
PGs

Thromboxane
Endotheline
GF
Adhesion Mol
Elastase

ANTI
INFLAMMATORY

IL - 4
IL- 10
IL-11
IL-13
IL ra
Leptin
TGF

The Systemic Inflammatory

Cascade

ENDOTHELIAL SLOUGHING
Triggers by:
Acidosis
Hypoxia
Endotoxin
Circulating antigen-antibody complexes
exposure of blood to subendothelial
collagen/basement membrane

Bick RL, 2002

VASCULAR LEAKAGE SYNDROME

NO

PAI-1
ICAM-1

1. NO
SYOK SEPTIK

2. Tonus pembuluh darah tepi .

3. Permeabilitas kapiler
4. DIC / PERDARAHAN

Sepsis

Diffuse activation of coagulation

Deposition of fibrin Consumption coagulation

(disseminated)

Microvascular thrombosis
In various organs
Multiorgan failure

factors and platelets

Bleeding

PATHOGENETIC
MECHANISMS IN DIC

TF
TF-VIIa

IXa-VIIIa

Cytokines pro-inflammatory

Xa-Va

1- Activation of
coagulation
(TF mediated)

Thrombine

2- Dysfunctional
anticoagulant
mechanisme
(AT, PC)

Fibrin
formation

3- Impaired Fibrinolysis
(hyperactivite PAI-1)

Thrombus
Microvasculaire

Platelet

inhibitor
Thrombosis

Ve
ss
els

els
ss
Ve

Coagulation

Fibrinolysis

Body

Bleeding

Role of LPS in ARDS

LBP
LPS

TNF-
IL 1
PG

Neutralization
I2

ELAM-1 / ICAM - 1

AT III
ROS
O2
H2O2

ELAM-1 / ICAM - 1

ROS
O2
H2O2

Endothelial
injury

Microvascular damage

Exudate

ARDS

Exudate

Proposed Actions of Activated Protein C in Modulating

the Systemic Inflammatory, Procoagulant, and
Fibrinolytic Host Responses to Infection.

( Bernard et al, 2001 )

FOUR THERAPEUTIC GOALS FOR SEPSIS

TO TREAT UNDERLYING INFECTION
(elimination of the infecting microorganisms through control of the source of
infection and effective antimicrobial therapy)

TO PRESERVE ORGAN PERFUSION

(aggressive and targeted shock resuscitation and cardiovascular
support)

TO MAINTAIN TISSUE OXYGENATION

(supportive care of multiple organs at risk for dysfunction)

TO AVOID COMPLICATIONS
(selective modification of the hosts adaptive and maladaptive
responses to infection)

INDEKS KAMPANYE PENYELAMATAN

SEPSIS (SSC)
1.
2.
3.
4.
5.
6.
7.
8.
9.

Resusitasi awal
Diagnosis
Terapi antibiotik
Pengendalian sumber
infeksi
Terapi cairan
Vasopresor
Terapi inotropik
Steroid
RhAPC
(Recombinant human activated protein
C)

10. Pemberian produk darah

11. Ventilasi mekanik / oksigenisasi
12. Sedasi, analgesi, blokade neuromuskuler
pada sepsis
11. Pengendalian glukosa
12. Mengganti faal ginjal
15. Terapi bikarbonat
16. Profilaksis thrombosis
vena dalam (DVT)
17. Profilaksis Stress ulcer
18. Membatasi support

Fluid Therapy: Choice of

Fluid

Fluid resuscitation may consist

of natural or artificial colloids
or crystalloids

Grade C

No evidenced-based support for

one type of fluid over another

Crystalloids have a much larger

volume of distribution compared to
colloids
Crystalloid resuscitation requires
more fluid to achieve the same
endpoints as colloid Choi PTL. Crit care Med 1999;27:200-210
Cook D. Ann Intern Med 2001;135:205-208
Crystalloids result in Scierhout
more G.
edema
BMJ 1998;316:961-964

Fluid Therapy: Fluid

Challenge
Grade E

Fluid challenge in patients with suspected

hypovolemia may be given
500 - 1000 mL of crystalloids over 30 mins
300 - 500 mL of colloids over 30 mins
Repeat based on response and tolerance
Input is typically greater than output due to
venodilation and capillary leak
Most patients require continuing aggressive
fluid resuscitation during the first 24 hours
of management

SUPPORT NUTRISI
Salah satu indeks SSC adalah suport nutrisi,
dengan tujuan :
1. Deteksi dan koreksi adanya malnutrisi
yang
sudah ada sebelumnya
2. Mencegah malnutrisi energi-protein
3. Optimalisasi kondisi metabolik
4. Mengurangi morbiditas dan lama
konvalesen

PEMBERIAN NUTRISI PADA SEPSIS

Calory ; 25-30 kCcal/kg;
Protein : 1.3 - 2.0 g/kg
Glucose : 30-70% of total non protein ( BS <225 mg%)
Lipid 15 - 30 % of total non protein

PROGNOSIS

1.
2.
3.

Resiko mortalitas :
Tiga sistem 85%
Empat sistem 95%
Lima sistem 99%
Lebih sedikit : ARF : 30-50% ; Toxic metabolic : 12%
Fulminant
N meningitidis : Waterhause Frederickson syndrome
S aureus
: Toxic shock syndrome
S pyogenes
: necrotizing fasciitis, streptococcal shock
syndrome

Mortality Associated With Initial

Inadequate Therapy In Critically Ill
Patients With Serious Infections in the ICU
Initial appropriate
therapy

Alvarez-Lerma,1996
Rello, 1997

Initial inadequate
therapy

Kollef, 1999
Kollef, 1998
Ibrahim, 2000
Luna, 1997
Mortality*

0%

20%

40%

*Mortality refers to crude or infection-related mortality

Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394.
Ibrahim EH et al. Chest 2000;118L146-155.
Kollef MH et al. Chest 1999; 115:462-474
Kollef MH et al. Chest 1998;113:412-420.
Luna CM et al. Chest 1997;111:676-685.
Rello J et al. Am J Resp Crit Care Med 1997;156:196-200.

60%

80%

100%

Appropriate antimicrobial
therapy (correct regimen,
timing, dosage, route, and
duration) saves lives!!!

Source Control: Examples of Potential

Sites
Drainage
-

Intra-abdominal abscess
Thoracic empyema
Septic arthritis
Pyelonephritis, cholangitis

Debridement
- Necrotizing fasciitis
- Mediastinitis
- Infected pancreatic
necrosis
- Intestinal infarction

Device Removal
- Infected vascular
catheter
- Urinary catheter
- Colonized endotracheal
tube

Definitive Control
- Sigmoid resection for
diverticulitis
- Amputation for clostridial
myonecrosis
- Cholecystectomy for
gangrenous cholecystitis

Steroids
Intravenous corticosteroids are
recommended in patients with septic
shock who require vasopressor therapy
to maintain blood pressure

Grade C

Administer intravenous hydrocortisone

200-300 mg/day for 7 days in three or
four divided doses or by continuous
infusion
Shown to reduce mortality rate in patients
with relative adrenal insufficiency

Annane D. JAMA 2002;288:862-871

Recombinant human Activated Protein

C

Recombinant human Activated Protein C [Drotrecogin

alfa (activated)] is recommended in patients at a high
risk of death

Grade B

APACHE II score 25, or

Sepsis-induced multiple organ failure, or
Septic shock, or
Sepsis induced acute respiratory distress syndrome

Treatment with drotrecogin alfa (activated) should begin

as soon as possible once a patient has been identified
as being at high risk of death

Patients should have no absolute or relative

contraindication related to bleeding risk that outweighs
the potential benefit of rhAPC

Bernard GR. N Engl J Med 2001;344:699-709

MANAGEMENT OF DIC
Treatment of underlying disease
(sepsis)
Plasma and platelet substitution
therapy
Anticoagulants
Restoration of anticoagulant
pathways

(Takala et.al., 2002)

Evidence based medicine (EBM) interventions in sepsis, severe sepsis

and septic shock from Emergency Department (ED) to Intensive Care
Unit (ICU)

ED

Lab monitoring
CRP
Procalcitonin
Coagulation
monitoring

Microbiological
monitoring
Immune
monitoring

24 hours

48 hours

Microbiological monitoring
Immune monitoring
Coagulation monitoring

72 hours

INTENSIVECARE
CAREUNIT
UNITSTAY
STAY
INTENSIVE
TIGHTCONTROL
CONTROLOF
OFBLOOD
BLOODSUGAR
SUGARWITH
WITHINSULIN
INSULIN
TIGHT
Earlydiagnosis
diagnosisofofSEPSIS
SEPSIS
Early
Severesepsis
sepsisand
andseptic
septicshock
shock
Severe

EGDT
EGDT

Searchofoffoci,
foci,surgery,
surgery,abscess
abscessdrainage
drainage
Search

Early,adequate,
adequate,appropriate
appropriateempiric
empiricantibiotic
antibiotictherapy
therapy
Early,

Definitiveantibiotic
antibiotictherapy
therapy
Definitive

Drotrecoginalfa
alfa(activated)
(activated)
Drotrecogin
refractoryseptic
septicshock,
shock,
IfIfrefractory
Moderatedose
dosecorticosteroids
corticosteroids
Moderate

High risk patient

APACHE II >25
Fever
Tachycardia BP
Tachypnea

symptoms

INFECTION
Specific
care

Oxygenation

SEPSIS

Cultures,source
sourcecontrol
control, ,
Cultures,

Supportive
care

antibiotics,
antibiotics,

Oxygenation
Oliguria

SEVERE SEPSIS SEPTIC SHOCK

Empiric
antibiotic therapy
Source control

BP

Drotecogin

MODS

(activated)

intensiveinsulin
insulin therapy
therapy
intensive

*Fluids *oxygen therapy * vasopressors

*mechanical
*EGDT *pressure support * inotropes
ventilation
ventilation
* moderate
*low TV
*NIV
corticosteroids *recruitment
* vasopressin
manovreus
*prone
position
*CVVH etc

ROC Analysis for various Biomarker

Marker

Age

Cutoff range

Sensitivity - %

Specificity - %

TNF

Adults

11,5 ng/L

55

66

Neonatus

12 - 20 ng/L

67 / 79 / 88

43 / 71 / 86

Adults

50 - 200 ng/L

51 / 67 / 86

53 / 65 / 79

Neonatus

10 160 ng/L

71 / 84 / 100

43 / 71 / 96

Children

NA

33

89

Neonatus

10,9 ug/L

93

92

Adults

30 340 ng/L

57 / 63 / 68

57 / 76 / 93

Neonatus

50 ng/L

92

70

Adults

4 150 mg/L

35 / 69 / 89

18 / 61 / 81

Neonatus

1 23 mg/L

43 / 65 / 96

80 / 90 / 100

Adults

0,4 8,1 ug/L

65 / 81 / 97

48 / 73 / 94

Neonatus

1,0 6,1 ug/L

77 / 85 / 99

62 / 83 / 91

IL-6
IL-ra
IL-8
CRP
PCT

Carrigan et al. 2004