SEPSIS

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

Definitions used to describe the condition of septic patients

Bacteriemia Septicemia SIRS
Presence of bacteria in blood (positive blood cultures) Presence of microbes or their toxins in blood 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 SIRS that has a proven or suspected microbial etiology = 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 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 Septic shock that last for > 1 h and does not respond to fluid or pressor administration Dysfunction of mor than one organ, requiring intervention to maintain homeostasis

Sepsis Severe sepsis

Septic shock

Refractory septic shock MODS

SIRS: systemic inflammatory response syndrome MODS: multiple-organ dysfunction syndrome

Etiology
Microorganism and condition that may predispose to infection
Microorganism
Gram-negative bacteria:
Enterobacteriaceae, pseudomonads, Haemophillus spp., other gram-negative bacteria

Condition
Diabetes mellitus Lymphoproliferative diseases Cirrhosis of the lever Burns Invassive procedures or devices Neutropenia Indwelling urinary catheter Diverticulitis, perforated viscus Intravascular catheter Indwelling mechanical devices Burns Neutropenia Intravenous drug use Infection with superantigen-producing S. pyogenes Neutropenia Broad-spectrum antimicrobial therapy

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

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

1. Pergeseran ke arah sitokin anti-inflamasi

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

2. Anergi
Erat kaitannya dengan kematian Limfosit, sel epitel usus Apoptotic cell death apoptosis 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

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 Local anti-inflammatory response

Initial insult (bacterial, viral, traumatic, thermal)

Systemic spillover of proinflammatory mediators Systemic reaction: SIRS (pro-inflammatory) CARS (anti-inflammatory) MARS (mixed)

Systemic spillover of antiinflammatory mediators

Adaptasi dari Jacobi, 2002, suppl 5

C
Cardiovascular compromise (shock) SIRS predominates

H
Homeostasis

A
Apoptosis (cell death) SIRS predominates

O
Organ dysfunction SIRS predominates

S
Suppression of the immune system CARS predominates

CARS and SIRS balanced

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

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

MCP = monocyte chemoattractant protein

(Adaptasi dari Bone, 1997, hlm 238)

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 Menghambat faktor Va dan VIIIa trombin tak terbentuk penghambatan aktivitas trombosit, pematangan neutrofil, degranulasi sel mast Pumya kemampuan direct anti-inflammatory

Rh APC:

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

Central venous and arterial catheterization Sedation, paralysis (if intubated), or both

Protocol for early goaldirected therapy

CVP 812mmHg

<8mmHg

Crystalloid Colloid

MAP 65 and 90mmHg ScvO2

<65mmHg >90mmHg <70%

Vasoactive agents

Transfusion of red cells until hematocrit 30% Inotropic agents

70%
<70%

70%

No

Goal achieved

Yes
Hospital admission
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