SEPSIS

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

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. >38
0
C) or hypothermia (<36
0
C); 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: Pa
O2
/FI
O2
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:
Enterobacteriaceae, pseudomonads, Haemophillus spp.,
other gram-negative bacteria
Diabetes mellitus
Lymphoproliferative diseases
Cirrhosis of the lever
Burns
Invassive procedures or devices
Neutropenia
Indwelling urinary catheter
Diverticulitis, perforated viscus
Gram-positive bacteria:
Staphylococcus aureus, coagulase-negative
staphylococcus, enterococci, Streptococcus pneumoniae,
other streptococci, other gram-positive bacteria
Intravascular catheter
Indwelling mechanical devices
Burns
Neutropenia
Intravenous drug use
Infection with superantigen-producing S. pyogenes
Fungi Neutropenia
Broad-spectrum antimicrobial therapy
Polymicrobial
Classic pathogens:
Neisseria meningitidis, S. pneumoniae, H. influenzae,
Streptococcus pyogenes
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
Mekanisme imunosupresi
CD4 T-cells
Sitokin inflamatori (Th 1): TNF, IFN, IL-2
Sitokin anti-inflamatori (Th 2): IL-4, IL-10
Jenis mikroba,
jumlah koloni,
lokasi infeksi
1. Pergeseran ke arah sitokin anti-inflamasi
2. Anergi
Erat kaitannya dengan kematian
Limfosit, sel epitel usus apoptosis
Apoptotic cell death sitokin anti-inflamasi anergi
3. Kematian sel imun
Sel imun adaptif mengalami apoptosis dalam jumlah besar
Sel B, CD4 T cells, follicular dendritic cells
Produksi antibodi
Aktivitas makrofag/monosit
sebagai APC
Respons patogen dan cross-talk antar sel imun
Adaptasi dari Hotchkiss, 2003, hlm. 140
Infection
Endotoxin and other microbial toxins
Proinflammatory state with cytokine release
and
Other proinflammatory mediators
Sepsis / SIRS
Shock and multiorgan dysfunction and possible death
Old paradigm of sepsis
Adaptasi dari Bone, 1997, hlm 239
Local anti-inflammatory
response
Initial insult
(bacterial, viral,
traumatic, thermal)
Local pro-inflammatory
response
Systemic spillover of pro-
inflammatory mediators
Systemic spillover of anti-
inflammatory mediators
Systemic
reaction:
SIRS (pro-inflammatory)
CARS (anti-inflammatory)
MARS
(mixed)
New paradigm of sepsis
Cardiovascular
compromise
C
(shock)
SIRS
predominates
H
Homeostasis
CARS and
SIRS balanced
A
Apoptosis
(cell death)
SIRS
predominates
O
Organ
dysfunction
SIRS
predominates
S
Suppression
of the
immune system
CARS
predominates
Adaptasi dari Jacobi, 2002, suppl 5

(Adaptasi dari Bone, 1997, hlm 238)
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
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
MCP = monocyte chemoattractant protein
Berbagai jenis molekul pro- dan anti-inflamasi
Proinflammatory molecules Anti-inflammatory molecules
Peran neutrofil pada sepsis
Pisau bermata dua
Eradikasi mikroba patogen
Sekresi protease dan oksidan
Merusak organ
(e.g. ARDS)
Temuan penelitian:
G-CSF produksi nuetrofil survival
Upaya menekan / menstimulasi neutrofil: hasil tak memuaskan
(Hotchkiss, 2003)
?
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/mm
3
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 < 30cmH
2
O
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
Central venous and arterial
catheterization
Sedation, paralysis (if
intubated), or both
Goal achieved
ScvO2
MAP
CVP
Crystalloid
Hospital admission
Colloid
Vasoactive agents
Transfusion of red cells
until hematocrit 30%
Inotropic agents
<8mmHg
<65mmHg
>90mmHg
812mmHg
65 and 90mmHg
70%
<70%
70%
<70%
No
Yes
Protocol for early goal-
directed therapy
Adaptasi dari Rivers, 2001, hlm. 1371
An emerging concept of the nature of the
immune response in sepsis
Hotchkiss, 2003
Tipe respons imun ditentukan oleh:
Mikroba (virulensi, ukuran inokulasi mikroba)
Inang / host (keadaan pasien, nutrisi, umur, polimorfisme gen sitokin,
molekul efektor imun, reseptor)
Pada pasien sepsis yang meninggal:
Sel B
CD4 T cells
Hipoimun berkepanjangan
Kesimpulan:
Anti-inflamasi diberikan pada fase hiperinflamasi
Immune stimulant diberikan pada fase hipoinflamasi
Potential therapies for sepsis
IL-12 (TH-1 inducer)
Ab terhdap aktivasi komplemen C 5a
Bakteri
Apoptosis
Survival
Ab terhadap MMIF peritonitis
Inhibisi produk mikroba toll like receptor (TLR)
PARP - inhibotor
(Adaptasi dari Bochud, 2003, hlm 263)
Potential therapeutic targets for sepsis
(Adaptasi dari Triantafilou, M. and Triantafilou, K. 2004)
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