IMMUN-SEPSIS

Prof. Dr. Djoni Djunaedi, dr, SpPD, KPTI,

FINASIM

Definitions used to describe the condition of septic patients

Bacteriemia

Presence of bacteria in blood (positive blood cultures)

Septicemia

Presence of microbes or their toxins in blood

SIRS

2 of these conditions: fever (oral temp. >380C) or hypothermia (<360C); tachypnea (>24 breath/min);
tachycardia (heart rate > 90 beats/min); leukocytosis (> 12.000/L); leukopenia (< 4.000/L) or > 10%
bands; may have a noninfectious etiology

Sepsis

SIRS that has a proven or suspected microbial etiology

Severe sepsis

= sepsis syndrome: sepsis with 0ne or more signs of organ dysfunction, e.g:
1. Cadiovascular: arterial systolic blood pressure 90mmHg or mean arterial pressure 70mmHg that
respons to administration of intravenous fluid
2. Renal: urine output < 0,5mL/kg per hour for 1 h despite adequate fluid resuscitation
3. Respiratory: PaO2/FIO2 250 or, if the lung is the only dysfunction organ, 200
4. Hematologic: platelet count < 80.000/L or 50% decrease in platelet count from highest value
ercorded over previous 3 days
5. Unexplained metabolic acidosis: a pH 7,30 or a base deficit 5,0mEq/L and a plasma lactate level
> 1,5 times upper limit of normal for reporting lab
6. Adequate fluid resuscitation: pulmonary artery wedge pressure 12mmHg or CVP 8mmHg

Septic shock

Sepsis with hypotention (arterial blood pressure < 90mmHg systolic, or 40mmHg less than patients
normal blood pressure) for at least 1 h despite adequate fluid resuscitation; or need for vasopressors to
maintain systolic blood pressure 90mmHg or mean arterial pressure 70mmHg

Refractory
septic shock

Septic shock that last for > 1 h and does not respond to fluid or pressor administration

MODS

Dysfunction of mor than one organ, requiring intervention to maintain homeostasis

SIRS: systemic inflammatory response syndrome

MODS: multiple-organ dysfunction syndrome

Etiology
Microorganism and condition that may predispose to infection
Microorganism

Condition

Gram-negative bacteria:

Diabetes mellitus
Lymphoproliferative diseases
Cirrhosis of the lever
Burns
Invassive procedures or devices
Neutropenia
Indwelling urinary catheter
Diverticulitis, perforated viscus

Enterobacteriaceae, pseudomonads, Haemophillus spp.,

other gram-negative bacteria

Gram-positive bacteria:
Staphylococcus aureus, coagulase-negative
staphylococcus, enterococci, Streptococcus pneumoniae,
other streptococci, other gram-positive bacteria

Fungi
Polymicrobial
Classic pathogens:
Neisseria meningitidis, S. pneumoniae, H. influenzae,
Streptococcus pyogenes

Intravascular catheter
Indwelling mechanical devices
Burns
Neutropenia
Intravenous drug use
Infection with superantigen-producing S. pyogenes

Neutropenia
Broad-spectrum antimicrobial therapy

Epidemiology

Incidence of sepsis and septic shock over the past 20 years

Annual number of cases: > 300.000

2/3 of cases occur in pts hospitalized for other illnesses

The increasing incidence of severe sepsis is attributable to:

The aging of the population

The increasing longevity of pts with chronic diseases

The relatively high frequency with which sepsis develops in pts with AIDS

The wide spread use of antimicrobial agents, glucocorticoids, indwelling

catheter and mechanical devices and mechanical ventilation

Imunopatogenesis

Sistem imun pada pasien sepsis:

Immunosuppressive
Delayed hypersensitivity (-)
Kemampuan menghilangkan infeksi (-)
Predisposisi infeksi nosokomial

(Adaptasi dari Bochud, 2003, hlm 263)

Respons patogen dan cross-talk antar sel imun

Adaptasi dari Hotchkiss, 2003, hlm. 140

Old paradigm of sepsis

Infection

Endotoxin and other microbial toxins

Proinflammatory state with cytokine release

and
Other proinflammatory mediators

Sepsis / SIRS

Shock and multiorgan dysfunction and possible death

Adaptasi dari Bone, 1997, hlm 239

New paradigm of sepsis

Local pro-inflammatory
response

Initial insult
(bacterial, viral,
traumatic, thermal)

Systemic spillover of proinflammatory mediators

Local anti-inflammatory
response

Systemic spillover of antiinflammatory mediators

Systemic
reaction:
SIRS (pro-inflammatory)
CARS (anti-inflammatory)
MARS
(mixed)

Adaptasi dari Jacobi, 2002, suppl 5

Cardiovascular
compromise
(shock)

Homeostasis

Apoptosis
(cell death)

Organ
dysfunction

Suppression
of the
immune system

SIRS
predominates

CARS and
SIRS balanced

SIRS
predominates

SIRS
predominates

CARS
predominates

Berbagai jenis molekul pro- dan anti-inflamasi

Proinflammatory molecules
TNF-
IL-1
IL-2
IL-6
IL-8
IL-15
Neutrophil elastase
IFN-
Protein kinase
MCP-1*
MCP-2
Leukemia inhib.factor
(D-factor

Thromboxane
Platelet activating factor
Soluble Adhesion mol.
Vasoactive neuropeptides
Phospholipase
Tyrosine kinase
Plasminogen activator inhib.-1
Free radical generation
Neopterin
CD14
Prostacyclin
Prostaglandins

MCP = monocyte chemoattractant protein

(Adaptasi dari Bone, 1997, hlm 238)

Anti-inflammatory molecules

IL-1 ra
IL-4
IL-10
IL-13
Type II IL-1 receptor
Transforming growth factor-
Epinephrine
Soluble TNF- receptors
Leukotriene B4-receptor
antagonism
Soluble recombinant CD-14
LPS binding protein

Otopsi

Limfosit, epitel sel usus: menghilang (apoptosis)

Sel imun adaptif turun secara progresif dan dalam

jumlah besar

Penyebab kematian (gagal organ), secara

histologis: tidak sesuai

?
cell hibernation
(cell stunning)

Konsep baru dalam penatalaksanaan sepsis

(Dellinger, 2004: Evidence-based)

1. Initial resuscitation and fluid therapy

Tujuan: memperbaiki oksigenasi jaringan (keseimbangan oxygen

delivery demand)

Follow up: konsentrasi, base defisit, pH, saturasi oksigen vena

sentral 6 jam pertama sangat menentukan keberhasilan tindakan

2. Diagnosis

Penting menentukan sumber dan mikroba penyebab infeksi

Bahan yang diperiksa: darah, urin, cairan serebrospinal, luka, sputum, dll

3. Antibiotic therapy
sebelum tersedia hasil kultur: sesuai pola antibiotika se-tempat

4. Source control

Drainase abses, debridement jaringan nekrosis

Alat bantu (kateter, dll), benda potensial sumber infeksi disingkirkan

5. Vasopressors

Diberikan selama pemberian fluid chalengge dan hipovolemik belum

teratasi

Pemberian dopamin harus dalam dosis teurapetik

6. Inotropic therapy

Bagi pasien dengan isi semenit rendah: beri dopamin

Bagi pasien dengan tekanan darah rendah: kombinasi dengan

vasopresor

7. Steroid

Pemberian dosis tinggi memperjelek kondisi (infeksi sekunder)

Temuan penelitian: pemberian hidrokortison 200- 300mg/hr selama 1

minggu perbaikan kondisi

Perlu pemberian dosis rendah kortikosteroid (Dellinger, 2004; Hotchkiss, 2003)

Kortikosteroid tidak direkomendasikan (Chambers, 2003)

8. Activated protein C

Pemberian Rh APC

Relative risk of death 19,4%; absolut risk of death 6,1%

Harus memenuhi sistem scoring APACHE

Rh APC:

Menghambat faktor Va dan VIIIa trombin tak terbentuk

penghambatan aktivitas trombosit, pematangan neutrofil,
degranulasi sel mast

Pumya kemampuan direct anti-inflammatory

Dosis 24 g/kgBB/jam selama 96 jam

Efek samping: perdarahan (intrakranial: 3,4%)

9. Blood production administration

Target kadar hemoglobulin optimum 7 9 gr% (dalam keadaan darurat)

Transfusi trombosit jika kadar trombosit 5.000 30.000/mm3 dan

ada dugaan resiko perdarahan

10. Mechanical ventilation of sepsis-induced acute lung injury

(ALI / ARDS)

Tidal volume rendah (6 ml/kgBB)

End respiratory plateau pressure < 30cmH2O

Angka kematian 9%

11. Sedation, analegik, neuromuscular blockade in sepsis

Harus memenuhi standar subjective sedation scale

Dapat menurunkan durasi pemakaian ventilasi mekanik dan rawat

inap, menurunkan tracheostomy rates

12. Glucosa control

Mortalitas pasien dengan kadar gula darah normal < pasien dengan
kadar gula darah tinggi

Mekanisme protektif insulin belum dikerahui secara pasti

Koreksi hiperglikemia daya fagositosis + efek anti-apoptotic

Insulin mencegah apoptotic cell death melalui aktivasi

phosphatidylinositol 3-kinase-Akt pathway (Siegel, 2002)

13. Renal replacement

Melalui continuous hemofiltration, intermittent hemodialysis
gagal ginjal akut

14. Bicarbonate therapy (masih memerlukan penelitian)

15. Deep vein thrombosis (DVT) prophylaxis

Pasien dengan kemungkinana DVT: beri low-dose unfractionated

heparin / low-molecular weight heparin

Pasien dengan resiko perdarahan:pakai intermittent compression

device e.g.

Trombositopenia

Koagulasi

Perdarahan aktif

16. Stress ulcer prophylaxis

Diberikan kepada semua pasien sepsis parah

Preparat: H2 receptor inhibitor

Efektivitas proton pump inhibitor belum pasti

Supplemental oxygen endotracheal

intubation and mechanical ventilation

Protocol for early goaldirected therapy

Central venous and arterial

catheterization
Sedation, paralysis (if
intubated), or both

CVP

<8mmHg

Colloid

812mmHg

MAP
65 and 90mmHg
ScvO2

70%

No

Crystalloid

<65mmHg

Vasoactive agents

>90mmHg
<70%

Transfusion of red cells

until hematocrit 30%

70%
<70%

Inotropic agents

Goal achieved

Yes
Hospital admission

Adaptasi dari Rivers, 2001, hlm. 1371

Kesimpulan

Terjadi pergeseran besar dalam sikap peneliti mengenai

masalah sepsis

Sepsis tidak sekedar immune system gone haywire

melainkan kemungkinan severely compromised immune
system (mikroba patogen )

Hasil otopsi menunjukkan focal necrosis

Evidence-based recommendation: initial resuscitation

stress ulcer prophylaxis

Future therapy: enhance / inhibit the patients immune

response, depending on genetic polymorphisms, duration of
disease, characteristic of particular pathogen

Terimakasih