 Sindroma komplek

 Respons inflamasi sistemik terhad

ap infeksi (bakteri, jamur, protozo
a, virus)
 → syok, MODS → †
 Mordibitas : - Indonesia ?
- USA 100.000 – 300.000
bakteriemi / tahun
50% jadi syok septik
 Mortalitas :
+ 40- 60 % pada syok septik
+ 28 – 50% pada sepsis
 Morbiditas ~ usia, status imun, prosedur inf
asif
 INFEKSI : invasi m.o
 BAKTERIEMI : m.o hidup di darah
 SIRS
Severe Clinical Insults → Respons I
nflamasi sistemik
S < 38oC, 36oC
N < 90/mnt
R <20/mnt; Pa CO2 < 32 Torr
Lekosit < 12.000; < 4.000/mm3
10% imatur
 SEPSIS: SIRS pada infeksi
 Severe Sepsis : sepsis + disfungsi organ,
hifoperfusi
 Septic shock
◦ Resusilasi adekuat cairan → hipotensi
◦ hipoperfusi
 Hipotensi : < 90 mmHg atau ↓40 mmHg
 Mods

Pemahaman Sepsis↑ → Pengelolaan↑

CHANGE
Surviving Sepsis Campaign: International Guidelines
for Management of Sepsis and Septic Shock: 2016
 Sepsis: Life-threatening organ dysfunction ca
used by dysregulated host response to infecti
on
 Septic Shock: Subset of sepsis with circulatory
and cellular/metabolic dysfunction associated
with higher risk of mortality

JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.02

87
 QuickSOFA adalah pemeriksaan bedside cepat
yg dapat mengidentifikasi pasien dengan dug
aan infeksi yang berisiko lebih besar untuk ha
sil yang buruk di luar unit perawatan intensif
(ICU).
 Menggunakan tiga kriteria, menetapkan masi
ng masing satu poin untuk
◦ Tekanan darah sistolik ≤100 mmHg
◦ Respirasi ≥22 napas per menit
◦ Perubahan kesadaran (Glasgow koma skala <15) htt
p://www.qsofa.org/calculator.php
 PATOFISIOLOGI
 INTERAKSI : M.O : Host
•VIRULENSI Status imun
•INOCULUM

 START : pengenalan m.o

atau komponennya
oleh sistem imun
PENGENALAN M.O
Endotoxin
LPS al. Peptidoglycan
Gr - Gr +

LPS & LPB

CD4
TLR 4
Sel imun

Sitokin/mediator

Kaskade Sepsis
 Kaskade
I Sitokin Sitokin
N LPS
T
E
R Sel Lain : Lekosit, Tr
A
K ombosit, Endotel
S
I
Sistim Mediator Lainnya
Koagulasi •Metabolat arachidonic acid
Komplemen •NO
Kinimi •Elastase
•PAF
•Oksigen radikal

Gangguan Hemodinamik
Gangguan Metabolisme
Gangguan Organ/sistem → MODS/DIC
 Proinflamasi : PAF, NO, Oksigen R
adikal, TNF, IL1, IL2, IL6, IL8, IFN
 Antiinflamasi : Soluble TNF recept
or IL1 receptor antagonis, IL4, IL1
0, IL11
 MEDIASI
Phospholifase A2

Lipoxygenase Cycloxygenase
pathway pathway

Leukotrienes Prostoglandin
Tromboxane
 Leukotrienes
LTB4 → Kemotaxis
LTC4 → Vasokonstriksi, broncho konstrik
si
 Protaglanicin
PGI2 → Vasodilator
PGE2 → Vasodilatasi, agrega trombosit
 Tromboxane → Vasokonskriksi
agregasi trombosit
Mediator Lain
PAF : * Phosfolifaseface A2 → lekosit
endotel
* - Oxigen radikal → merusak jaringan
- Aktivasi Platelet
- permeabelitas vasculer ↑

EDRF(NO) : - Neutrofil, endotel, sel kupter

- agregasi nombosit
Aktivasi Sistem
• Komplemen
• Kinin
• Koagulasi
 Hageman factor
XII
Collagen or other
activators

XIIa Prekallikrein activator

Coagulation Prekallikrein Kallikrein

cascade
Kininogen Bradykinin

Vasadilation
Vascular permeability
Pain
Extrinsic Pathway Intrinsic Pathway
Injured cells Collagen other activators

XIIa XII

X Xa

Va
Phospholipid

Prothrombin Thrombin

Fibrino + Fibrinopeptide
Fibrinogen
monomer
Clotting

Fibrin polymer
 CLOTTING SYSTEM
Hageman factor KININ SYSTEM
Instrinsic XII
pathway
Prekallikrein
Plasminogen
Kininogen
XIIa
Prothrombin
Kallikrein

Fibrinogen Plasmin Bradykinin

Prekallikrein
Thrombin activator

Fibrin Fibrinopeptides

C1 C1
COMPLEMENT SYSTEM

C4, 2 C4b, 2a

C3 C3b + C3a

C5 C5b + C5a

C6, C7, C8, C9 C5b - 9

 INFEKSI

Aktifasi jalur Inflamasi

Kerusakan Endotel Vasodilatasi-Permeabilita

s Meningkat Depresi Myocard

Aktifasi jalur koagul TPR turun

CO Turun
asi

Maldistribusi Aliran drh

Koagulopati
Hipoperfusi-Isemik

Mikrovaskular endot
el disfungsi Kerusakan Jaringan

Gagal Organ

Meninggal
“Sepsis and septic shock ar
e medical emergencies an
d we recommend that trea
tment and resuscitation b
egin immediately.”
Best Practice Statement
 We recommend that a specific anatomic di
agnosis of infection requiring emergent so
urce control be identified or excluded as ra
pidly as possible in patients with sepsis or
septic shock, and that any required source
control intervention be implemented as so
on as medically and logistically practical af
ter the diagnosis is made.
(Best Practice Statement).
 We recommend that administration of IV
antimicrobials be initiated as soon as poss
ible after recognition and within 1 h for b
oth sepsis and septic shock.
(strong recommendation, moderate quality
of evidence).
 We recommend empiric broad-spectrum t
herapy with one or more antimicrobials to
cover all likely pathogens.
(strong recommendation, moderate quality
of evidence).
 We recommend that in the resuscitation f
rom sepsis-induced hypoperfusion, at le
ast 30ml/kg of intravenous crystalloid flu
id be given within the first 3 hours.
(Strong recommendation; low quality of evi
dence)

 We recommend that following initial fluid

resuscitation, additional fluids be guided
by frequent reassessment of hemodynam
ic status.
(Best Practice Statement)
 We recommend crystalloids as the fluid
of choice for initial resuscitation and su
bsequent intravascular volume replacem
ent in patients with sepsis and septic sh
ock
(Strong recommendation, moderate qualit
y of evidence).

 We suggest using albumin in addition to

crystalloids when patients require subst
antial amounts of crystalloids
(weak recommendation, low quality of evi
dence).
 We recommend norepinephrine as the fir
st choice vasopressor
(strong recommendation, moderate quality
of evidence).

 We suggest adding either vasopressin (up

to 0.03 U/min) or epinephrine to norepin
ephrine with the intent of raising MAP to t
arget, or adding vasopressin (up to 0.03
U/min) to decrease norepinephrine dosag
e.
(weak recommendation, low quality of evid
ence)
 We recommend further hemodynamic assess
ment (such as assessing cardiac function) to
determine the type of shock if the clinical ex
amination does not lead to a clear diagnosis.
(Best Practice Statement)

 We suggest that dynamic over static variable

s be used to predict fluid responsiveness, wh
ere available.
(Weak recommendation; low quality of evidenc
e)
We suggest guiding resuscitation to normali
ze lactate in patients with elevated lactate lev
els as a marker of tissue hypoperfusion.
(Weak recommendation; low quality of evidence
)
 Start resuscitation early with source control,
intravenous fluids and antibiotics.
 Frequent assessment of the patients’ volum
e status is crucial throughout the resuscitati
on period.
 We suggest guiding resuscitation to normali
ze lactate in patients with elevated lactate l
evels as a marker of tissue hypoperfusion.
 We suggest empiric combination therapy (
using at least two antibiotics of different a
ntimicrobial classes) aimed at the most lik
ely bacterial pathogen(s) for the initial ma
nagement of septic shock.
◦ (Weak recommendation; low quality of evidence)
 We suggest that combination therapy not
be routinely used for on-going treatment
of most other serious infections, including
bacteremia and sepsis without shock.
◦ (Weak recommendation; low quality of evidence)
.

 We recommend against combination ther

apy for the routine treatment of neutropen
ic sepsis/bacteremia.
◦ (Strong recommendation; moderate quality of ev
idence).
 We recommend that empiric antimicrobial therapy be narr
owed once pathogen identification and sensitivities are es
tablished and/or adequate clinical improvement is noted.
 (BPS)
 We suggest that an antimicrobial treatment duration of 7-
10 days is adequate for most serious infections associated
with sepsis and septic shock.
 (Weak recommendation; low quality of evidence)
 We recommend daily assessment for de-escalation of anti
microbial therapy in patients with sepsis and septic shock.
 (BPS)
 We suggest that measurement of procalcitonin levels can
be used to support shortening the duration of antimicrobi
al therapy in sepsis patients.
 (Weak recommendation; low quality of evidence)
We suggest against using intravenous hyd
rocortisone to treat septic shock patients i
f adequate fluid resuscitation and vasopre
ssor therapy are able to restore hemodyna
mic stability. If this is not achievable, we s
uggest intravenous hydrocortisone at a do
se of 200 mg per day.
(Weak recommendation; low quality of evidence)
 We suggest using higher PEEP over lower P
EEP in adult patients with sepsis-induced
moderate to severe ARDS.
◦ Weak recommendation; moderate quality of evid
ence
 We recommend using prone over supine p
osition in adult patients with sepsis-induc
ed ARDS and a PaO2/FIO2 ratio <150.
◦ (Strong recommendation; moderate quality of ev
idence)
 We recommend against the use of HFOV in
adult patients with sepsis-induced ARDS.
◦ (Strong recommendation; moderate quality of ev
idence)
 We recommend against the use of beta-2
agonists for the treatment of patients with
sepsis- induced ARDS without bronchospa
sm.
◦ (Strong recommendation; moderate quality of ev
idence)
 We suggest using lower tidal volumes over
higher tidal volumes in adult patients with
sepsis-induced respiratory failure without
ARDS.
◦ (Weak recommendation; low quality of evidence)
We recommend a protocolized approach to blood
glucose management in ICU patients with sepsis,
commencing insulin dosing when 2 consecutive b
lood glucose levels are <180 mg/dL. This approa
ch should target an upper blood glucose level ≤1
80 mg/dL rather than an upper target blood gluc
ose ≤110 mg/dL. (Strong recommendation; high
quality of evidence)
We recommend that blood glucose values be mo
nitored every 1 to 2 hrs until glucose values and i
nsulin infusion rates are stable, then every 4 hrs t
hereafter in patients receiving insulin infusions. (
BPS)
3. We recommend that glucose levels obtained
with point-of-care testing of capillary blood
be interpreted with caution, as such measure
ments may not accurately estimate arterial bl
ood or plasma glucose values. (BPS)
4. We suggest the use of arterial blood rather t
han capillary blood for point of care testing u
sing glucose meters if patients have arterial c
atheters. (Weak recommendation; low quality
of evidence)
 We suggest against the use of renal replacem
ent therapy in patients with sepsis and acute
kidney injury for increase in creatinine or olig
uria without other definitive indications for di
alysis.
◦ (Weak recommendation; low quality of evidence)
1. Kegawatan ginjal
 a. Klinis: keadaan uremik berat, overhidrasi
 b. Oligouria (produksi urine <200 ml/12 jam)
 c. Anuria (produksi urine <50 ml/12 jam)
 d. Hiperkalemia (terutama jika terjadi perubahan ECG, biasanya K
<6,5
 mmol/l )
 e. Asidosis berat ( pH <7,1 atau bikarbonat <12 meq/l)
 f. Uremia ( BUN <150 mg/dL)
 g. Ensefalopati uremikum
 h. Neuropati/miopati uremikum
 12
 i. Perikarditis uremikum
 j. Disnatremia berat (Na <160 atau <115 mmol/L)
 k. Hipertermia

2. Keracunan akut (alkohol, obat-obatan) yang bisa melewati mem

bran dialisis
 Keadaan pasien yang mempunyai GFR <15ml/me
nit tidak selalu sama, sehingga dialisis dianggap
baru perlu dimulai jika dijumpai salah satu dari h
al tersebut di bawah ini (Daurgirdas et al., 2007):
 a. GFR <15 ml/menit, tergantung gejala klinis
 b. Gejala uremia meliputi; lethargy, anoreksia, na
usea, mual dan muntah.
 c. Adanya malnutrisi atau hilangnya massa otot.
 d. Hipertensi yang sulit dikontrol dan adanya kele
bihan cairan.
 e. Komplikasi metabolik yang refrakter.
 We recommend against the administration
of early parenteral nutrition alone or paren
teral nutrition in combination with enteral
feedings (but rather initiate early enteral n
utrition) in critically ill patients with sepsis
or septic shock who can be fed enterally. (
Strong recommendation; moderate quality
of evidence)
 We recommend against the administration of
parenteral nutrition alone or in combination
with enteral feeds (but rather to initiate IV glu
cose and advance enteral feeds as tolerated)
over the first 7 days in critically ill patients wi
th sepsis or septic shock in whom early enter
al feeding is not feasible. (Strong recommend
ation; moderate quality of evidence).
 We suggest the early initiation of enteral feedi
ng rather than a complete fast or only IV gluco
se in critically ill patients with sepsis or septic
shock who can be fed enterally. (Weak recomm
endation; low quality of evidence)
 We suggest either early trophic/hypocaloric or
early full enteral feeding in critically ill patients
with sepsis or septic shock; if trophic/hypocal
oric feeding is the initial strategy, then feeds s
hould be advanced according to patient tolera
nce. (Weak recommendation; moderate quality
of evidence)
 We suggest against routinely monitoring g
astric residual volumes in critically ill patie
nts with sepsis or septic shock. (Weak reco
mmendation; low quality of evidence). Ho
wever, we suggest measurement of gastric
residuals in patients with feeding intoleran
ce or who are considered to be high risk f
or aspiration. (Weak recommendation; ver
y low quality of evidence)
 Nutrition
 We suggest the use of prokinetic agents in cri
tically ill patients with sepsis or septic shock
and feeding intolerance. (Weak recommendati
on; low quality of evidence)
 We recommend that goals of care and pro
gnosis be discussed with patients and fam
ilies. (BPS)
 We recommend that the goals of care be i
ncorporated into treatment and end-of-lif
e care planning, utilizing palliative care pri
nciples where appropriate. (Strong recom
mendation; moderate quality of evidence)
 We suggest that goals of care be addresse
d as early as feasible, but no later than wit
hin 72 hours of ICU admission. (Weak rec
ommendation; low quality of evidence)
 DIC
 Definisi : Heterogen, komplek → sindrome
Hemoragis & Trombosis
Kontroversi & Konfus
No Perfect Definition
International Society on Trombosis and hemo
stasis acquired syndrome characterized by
innovascular activation of coagulation with los
e of localization arising from different causes
Microvasculatur DIC
 Infeksi

DIC •Cytokines Direct tissue injury :

•Endotoxin •Syok
•Sitotoksik

Endothelial
damage

XIIa TF
Sistem
Sistem Koagulasi
Kinin Plasma Sistem Oklusi
Sistem Komplemen •Fibrin clo
ts vaskuler
Syok Trombosit
Konsumsi
faktor clotting
Oklusi
Hemoragis dysfusi
 Pathophysiology of disseminated intravascular
coagulation (DIC).
Cytokines
(TNF, ILs, PAF, IF) Direct tissue
Endotoxin injury
Antecedent

XIIa Endothelial Mechanical

Prekallikrein Activation/ Tissue Venom
injury damage
tPA Ag/Ab complex
Kallikrein Monocyte/endotoxin complex
Malignant cells
Plasminogen TF (Coagulation
Cell Lysis
Cascade)
lysis VIIa
Bradykinin X XA F1 + 2 Coagulation
factors
Plasmin Complement Prothrombin Thrombin Antithrombin
Shock
TAT
Fibrinogen complex
Platelets
Vasodilation
↑vascular FPA
permeability Fibrin Accelerated
Aggregation clots Consumption of
Lysis
Clotting factors

↓Capillary
Blood flow Micro
thrombi FDPs Hemorrhage
Platelet Thrombocytopenia D-dimer
dysfunction Vascular
occlusion

TAT = thrombin antithrombin complex

Ischemia, TF = tissue factor
Infarction FDP = fibrin degradation products
Necrosis of TNF = Tumor necrosis factor
Tissues/organs ILs = inter leukins (IL-6, IL-8, IL-1)
IF = interferon
PAF = platelet activating factor
tPA = tissue plasminogen factor
MODS MODS = multiple organ dysfunction syndrome
 Hubungan gangguan Hemodinamik MODS, DIC

•Endotoxin
•Kinin •Sitokin
•Perdarahan •Non Syok
Syok •DIC •Tissue injury

•Tissue Injury
•Organ Dysfu a/l - HVS
nction/Mods - Sitotoksik
 Gangguan Hemodinamik
 Khas : Hiper dinamik : CO↑, DO2↑, SVR↓
 Hipotensi
Takhikardi
 Syok : → hipotensi, tanda perifer
 PVR ↑
 Tonus Vena ↓ →hipovolemi relatif
permeabilitas vasculer ↑ →transdusi cairan
↓
Hipovolemi
Hipovalemi → pre load ↓ ← pooling sirkulasi
 Gangguan performa jantung :
ventricular ejection fraction↓, dilatasi ventrikel
 Perifer : DO2 lokal ↓
VO2↓
A-V oxy content Difference↓
mixed venous oxy Sa↑
 ~ lama, berat sepsis
 Metabolic nutrisi dan imunologi premorbid
 Metabolic rate ↑
 Resistensi insulin → Hiperglikei←gluconegenesis
↑
 Sintesa hati↓ → Trigliserid↑
 Protein turn over ↑, balans protein (-) (penghanc
uran otot, jaringan ikat, viseral) albumin↓, tranfe
rin↓
 Mekanisme ? ( - kerusakan/gangguan mikr
ovaskuler
- inflamasi)
 Sistim/organ : semua
 Mortalitas ~ jumlah organ
 Paling sering : paru
ginjal
hati
 Hipertensi Pulmonal
cairan extra vaskuler paru ↑
 Keletihan otot respirasi
kontraksi diafragma↓
HATI
•INTRA HEPATIC CHOLESTATIS
•MINIMAL NECROSIS

GINJAL
•ARF
•Syok atau tanpa syok

SISTIM HEMATOLOGI
•Trombositofeni : 50% sepsis
•AT3 ↓, aPC↓

STRESS ULCER
 FIBRINOGEN; Hipofibrinogenemia
 D-Dimer (FDP): meningkat pada <85% kasus
 Kultur darah
 LDH: meningkat pada semua keadaan yang meny
ebabkan kerusakan sel
 CRP: protein sbagai penanda non spesifik adanya
inflamasi atau infeksi atau trauma pada jaringan (
meingkat pada bakteri <virus)
 Prokalsitonin: meningkat secara cepat dalam 6-1
2 jam setelah infeksi bakterial sistemik, menurun
stelah infeksi berkurang
 Laktat; penting untuk target terapi sepsis
 D-Dimer adalah suatu fragmen degradasi fibr
in yang dihasilkan setelah berlangsung fibrin
olisis. Kadar D-dimer digunakan untuk memb
antu mendiagnosis trombosis.

 Pengukuran D-Dimer diindikasikan apabila ad

a dugaan trombosis vena dalam (deep vein tr
ombosis, DVT), emboli paru (pulmonary emb
olus/embolism, PE), pembekuan intravaskuler
menyeluruh (disseminated intravascular coag
ulation, DIC), arterial thromboemboli, infark
myocard,
 Bila vena atau arteri yang terluka dan darah m
ulai bocor, maka faktor-faktor pembekuan di
aktifkan dalam urutan langkah-langkah pemb
ekuan (disebut kaskade koagulasi) untuk me
mbatasi pendarahan dan menciptakan gumpa
lan yang menyumbat luka. Gumpalan tersebut
adalah benang protein yang disebut fibrin.
 Setelah tubuh memiliki waktu untuk menyembuh
kan daerah cedera tersebut, tubuh menggunakan
protein yang disebut plasmin untuk memecahkan
gumpalan (thrombus) menjadi bagian-bagian kec
il sehingga dapat dibersihkan. Proses tersebut di
namakan fibrinolisis yang menghasilkan fragmen
-fragmen yang disebut produk degradasi fibrin (f
ibrin degradation product, FDP). Salah satu produ
k degradasi fibrin tersebut adalah D-dimer. Peng
ukuran D-dimer dapat memberitahu bahwa telah
terjadi proses yang abnormal pada mekanisme p
embekuan darah
 Infeksi Sepsis
factor ? predisposisi
 Sepsis : overaktif, uncontrole reaction
failure of immune system
 Pemotongan proses/kaskade sepsis ?
 Selama proses sepsis : gangguan
◦ Stadium ~ terapi
◦ Marker untuk diagnosa/prognosa
◦ Proses immune (perubahan)
 Mediator belum dikenal ?
 Pengetahuan Patofisiologi

Terapi
 Proses Sepsis : - komplek
- masih ?
- interaksi sitokin
mediator, sistem
- Fungsi setiap mediator
- Mediator sentral !
 Pemilihan Antibiotik
Penghilangan fokus infeksi
Terapi Suportif
Intervensi Kaskade Sepsis