dr.

Khomimah, SpPD
RS Islam Jakarta Pondok Kopi
Sepsis :
 Kondisi yang ditandai oleh sindroma respons
inflamasi sistemik / systemic inflammatory
respon syndrome (SIRS) sebagai akibat proses
infeksi seperti bakteri, viral, jamur
SIRS:
 Respos inflamasi dapat disebabkan proses non-
infeksi (trauma berat, komplikasi
operasi__insufiseensi adrenal, infark miokard,
luka bakar, pankreatitis akut
Bone et al. Chest 1992;101:1644
 Sepsis berat
 Sepsis yang disertai disfungsi organ.
 hipoperfusi  hipoksemia jaringan

 Syock sepsis
 Hipoperfusi yang diakibatkan sepsis yang
menetap meskipun sudah dilakukan resusitasi
cairan dengan adekuat
 Akibat sepsis berat yang tidak teratasi
/ SIRS

 Levy et al 2005
 Angka kematian: tinggi
 Insidensi sepsis meningkat:
 Populasi tua meningkat
 Penurunan sistem imun akibat kmoterapi
 Transplantasi organ
 Tindakan invasif
 ko-morbid : DM, HIV, CHF

 Inggris:
 Insidensi sepsis berat yg masuk ICU 1,5 % /tahun
 Angka kematian 23  30 kematian per 100.000 populasi
 1/3 pasien CU sepsis (25%-nya sepsis pada saat di bangsal
rawat)
Martin et al, NEJM 2003; 348:1546
Clinical conditions associated with sepsis
Gastrointestinal Intravascular
Liver Central iv line
Gallbladder Infected prostetic device
Colon Septic thrombophlebitis
Intraabdominal abscess Lower respiratory tract
Intestinal obstruction Community acquired pneumonia
Intraabdominal instrumentation Nosocomial pneumonia
Genitourinary Empyema
Acute pyelonephritis Lung abscess
Renal abscess Cardiovascular
Renal calculi Acute bacterial endocarditis
Urinary tract obstruction Myocardial abscess
Prostatic abscess Central nervous system
Instrumentation Bacterial meningitis
Pelvic Brain abscess
Pelvic abscess, peritonitis Perimeningeal infection
Cuncha B. In : Conn Current Therapy 2003
 • Respon fisiologi pada sepsis
• Tujuan: mengeliminir patogen atau toksin
• Keseimbangan homeostasis
• Sepsis  efek sistemik

Gambar 2. Perkembangan sepsis

 Hipoperfusi jaringan/sel  hipoksia  respirasi anaerobik
selular  produksi laktat meningkat  penurunan PH
darah /asidosis (keseimbangan asam basa berubah) 
stimulasi medulla oblongata  peningkatan frekuensi
napas
 Vasodilatasi sistemik (pasien tampak merah dan flushed).
Peningkatan sirkulasi perifer dan permeabilitas
mikrovaskular  ekstravasasi cairan dari sirkulasi 
volume intravaskular turun  disfungsi organ
 Peningkatan frekuensi napas dan heart rate, perubahan
status mental, produksi urin turun, TD turun, dan perubahan
temperatur
 Fase awal sepsis: vasodilatasi  venous
return dan cardiac output turun  heart
rate dan kadar adrenalin meningkat
(kompensasi)  perbaikan cardiac out put
dan tonus vaskular

 Respons penurunan aliran darah: Aktivasi

sistem RAA  tonus vaskular meningkat
dan penurunan produksi urin
(mempertahankan volume cairan tubuh)
 Tahap lanjut:
 sebagai dampak hilangnya venous return dan
volume sirkulasi darah  suplai oksigen tidak
adekuat, hipoksia selular dan disfungsi organ.
 Gejala perburukan ini dalam beberapa jam
sebelum sepsis berat

 keluhan awal terlewat  sepsis berat/shock

septik
Systemic Inflammatory Response Syndrome (SIRS)

Host response to
Inflammation include 2 of:

1. Temp >38oC or <36oC

2. Heart rate >90x/’
3. Respiratory rate >20x/’
or PaCO2<32mmHg
4. White blood cells count
>12.000/mm3, < 4.000
or bands >10%
Bone et al. Chest 1992;101:1644
 tanda sepsis yang
Sepsis
berat
= Sepsis +
berhubungan
dengan disfungsi
organ

 Fungsi paru (hypoksia)

 Fungsi ginjal (peningkatan serum
kreatinin)
 Koagulasi ( trombosit turun, DIC)
 Fungsi hati (hiperbilirubinemia)
 Status mental
 Status hemodinamik -shock septik
 Syok septik
 Dampak lanjut respon inflamasi sistemik terhadap
suplai oksigen jaringan
 Harus diterapi sebelum kerusakan organ
menetap
 Tidak berespon terhadap terapi pengganti cairan
 Syok refrakter
 Tekanan darah tidak berespon terhadap obat
vasoaktif  kematian
 Systemic Inflammatory Response syndrome (SIRS)
 Sepsis
 Severe sepsis
 Septic shock
 Multiple Organ Dysfunction Syndrome (MODS)

Bone RC, et al (1992): American College of Chest Physician / Society of Critical care
medicine Consensus Conference
 Platelet count
> 100.000 = 0 < 50.000 - 100.000 = 1 < 50.000 = 2
 D-dimer
0.5-1 = 1 1-2 = 2 > 2 ug/ml = 3
 PT/APTT
Prolong PT 3-6 sec = 1 >6 sec=2
 Fibrinogen < 100 = 1

ISTH 2001
 Elimination source of infections
Antibiotic treatment
 Supportive care : Stabilized the patient
Maintain oxygenization and perfusion
Nutrition, renal function, coagulation, etc
 Modulation the immune response
Hyperimmune state or immunoparalysis
 Strategy in Management of Sepsis

Supportive

Immunosupresion Immunostimulation
Antimicrobial
Outcome
Sepsis

Underlying diseases and risk factor days

 L. Sedation, Analgesia, and
A. Initial Resuscitation Neuromuscular Blockade in
B. Diagnosis Sepsis
C. Antibiotic therapy M. Glucose Control
D. Source Control N. Renal Replacement
E. Fluid Therapy O. Bicarbonate therapy
F. Vasopressors P. Deep Vein Thrombosis
G. Inotropic Therapy Prophylaxis
H. Steroids Q. Stress Ulcer Prophylaxis
I. Recombinant Human Activated R. Consideration for Limitation of
Protein C Support
J. Blood Product Administration S. Pediatric consideration
K. Mechanical Ventilation of
Sepsis-Induced Acute Lung
Injury

Dellinger RP - Crit Care Med 2004; 32(3): 858-73

Factors that determine the outcome of
sepsis treatment
• Virulence of the pathogens
• Early management and appropriate treatment
of primary causes (source of infections and
antimicrobial treatment)
• Early management and quality of supportive
treatment
• Underlying diseases
• Host response to infection
Opal, Shock 2003
 Resucitation

 In case of severe sepsis, hypotension

or shock
 Early in 6 hour period
 Fluid therapy, oxygenization, vasopressor
Transfusion if needed
 Monitoring

Rivers E, Nguyen B, Havstad S, et al. N Eng J Med 2001;345:1368-77

 Monitoring in Sepsis

 Monitoring is essential in unstable

conditions (severe sepsis or shock)
 Clinical examination and assessment
can’t be substituted by invasive monitoring
 Minimal requirement include
blood pressure, continuous cardiac
monitoring, central venous pressure,
rapid blood gas analysis

Lynn WA. In: Amstrong D, Cophen J. Infectious Diseases, 1999.

 Central venous pressure 8-12 mmHg
 MAP > 65 mmHg
 Urine output > 0.5mg/kg/hours
 ScvO2>70%

Surviving sepsis campaign guidelines for management of severe sepsis

and septic shock. Crit Care Med 2004; 32(3): 858-73
 Oxygen delivery (DO2)
CO x CaO2 x 10
CaO2= 0.0031 x PaO2 + 1.38 x Hb x SaO2

 Oxygen consumption (VO2)

VO2=CO x Hb x 1.38 x (SaO2-SmvO2) x 10
 Central venous/mixed venous oxygen saturation
 Oxygen saturation from central venous catheter
or pulmonary artery catheter (Swan Ganz)
 Reflects physiologic efforts to meet oxygen
demand
 Normal value : 65-75%
 SmvO2 <50% : body limit of aerobic metabolism
lactic acidosis
 Fluid resuscitation may consist natural or artificial
colloids or crystalloids
 There are no evidence-based support for one type
of fluid over another
 Resuscitation with crystalloids require more volume
to achieve the same end point
 For fluid challenge need 500-1000 ml of crystalloids
or 300-500 ml colloids over 30 minute and repeated
based on response

Surviving sepsis campaign guidelines for management of severe sepsis

and septic shock. Crit Care Med 2004; 32(3): 858-73
 When to start?
Adequate cardiac filling :
CVP/PCWP : 12-15 mmHg
Cardiac index>3-4 l/min/m2
ScvO2 >65-70 %
MAP <70 mmHg
 Criteria for effectiveness
MAP > 60-70 mmHg
No decrease in CI or ScvO2
reestablishment of urine
flow
decreased blood lactate
level
adequate skin perfusion
adequate level of
consciousness
 Either norepinehprine or dopamine is the first choice
vasopressor to correct hypotension in septic shock
 Norepinephrine has vassoconstrictive effect, increase
MAP more potent than dopamine, less effect to heart
rate and splanic circulation.
 Dopamine increase MAP and CO primarily due to
increase stroke volume and heart rate.
 Epinephrine and is least agent suggested
 Norepinephrin:
Start dose 0.05ug/kg/min, increase step of
0.05ug/kg/min up to MAP 70mm Hg
If NE > 0.1-0.2 ug/kg/min need invasive monitoring
with pulmonary arteri catether
 Dopamine :
Initial dose 5-10 ug/kg/min increased gradually
 Epinephrin:
Start dose 0.05ug/kg/min increase 0.05ug/kg/min
Rivers E. N Engl J Med 2001;345:1368-77
 IV antibiotic therapy should be started within
1 hour
GRADE E
 Initial empiric anti-infective therapy should
have activity against the likely pathogen (see
local susceptibility pattern)
GRADE D
General Concept in Emprical Antibiotics
Therapy

 Spectrum of antibiotics
 Organ system involved
 Pharmacokinetics
 Safety profile
 Cost

Cuncha B. In : Conn Current Therapy 2003

Spectrum of antimicrobial
• Pathogen possible (most likely)
Gram positive, negative, anaerobe, mixed,
parasite, fungal
• Community or nosocomial infections
• Resistance pattern
• Host condition and Immunological status
• Risk of antimicrobial failure
Organ system involved
• Site infections
Pulmonary, abdominal, genitourinary,
cns, multiple, no obvious site
• Focal infection
Prosthetic, abscess
Antimicrobial Pharmacokinetics
• Antimicrobial blood levels
• Antimicrobial tissue levels
• Antimicrobial combination interaction
• Drugs interaction
Safety profile
• Organ dysfunction or failure
• Side effect
• Allergic potential
• Drug induce fever
• Resistance potential
Appropriate Antimicrobial Treatment
• Initial treatment will improve survival
• Decreased development of shock
• Essential but others factor involved
on significant mortality decreasing.

Simon D, Crit Care Clin 2000;16(2):215

Single or Combination Antimicrobial Treatment

• Covered potential pathogen

• Synergistic activities
• Special cases :
Endocarditis caused by Enterococcus
Nosocomial pneumonia by gram negative rods
(P. aeruginosa)
Chronic osteomyelitis
Prosthetic material (prosthetic valve endocarditis)
Neutropenic

Bouza E, Munoz P. Med Clin North Am. 2000;84(6):1357-87

 Patient

Outpatient Hospitalized

Stable condition Severe or high risk

Escalation Deescalation

Antibiotic selection based on

• Susceptibility and resistance pattern
• Immunity status, co morbidity and organ dysfunction

Antibiotic monotherapy or combination

Pohan HT, 2005
 General Concept in
Management of Sepsis

 Elimination source of infection

 Antimicrobial treatment
 Supportive treatment
 Modification the maladaptive
immune response

Sessler CN, Shepherd W. Curr Opin in Crit Care 2002;8:465-72.

 Supportive Therapy in Sepsis

Oxygenization
Fluid and volume resucitation
Vasopresor and inotropic
Albumine
Blood trasfusion
Nutrition
Blood glucose controlled
Renal dysfuction
Bicarbonate therapy
Corticosteroids
Coagulation disorders

Jindal N, Hollenberg SM, Dellinger RP. Crit Care Clin 2000;16(2):233-49

 Nutritional support is important in septic patients
 Early nutritional support seems to be beneficial in all
acutely ill patients.
 Enteral route is preffered to maintain integrity of
gut mucosa and avoid possibly harmful effect of
parenteral nutrition
 Immunonutrition have beneficial effect improving
host response in acute disease, but further study is
needed to better define which constituents should
be included
 Daily intake 25-30 kcal/kg usual body weight
 Protein 1.5-2.0g/kg/day
 Carbohydrate fat ratio of 60:40 to 70:30

Perez J. Intensive Care Med. 2001;27 Suppl 1:S116-27

 Following initial stabilization, patients with severe sepsis and
hyperglycemia who are admitted to the ICU receive
intravenous insulin therapy to reduce blood glucose levels
(grade 1B).
 Validated protocol for insulin dose adjustments and
targeting glucose levels to the <150 mg/dL range (grade 2C).
 We recommend that all patients receiving intravenous
insulin receive a glucose calorie source and that blood
glucose values be monitored every 1-2 hrs until glucose
values and insulin infusion rates are stable and then every 4
hrs thereafter (grade 1C).
 We recommend that low glucose levels obtained with point-
of-care testing of capillary blood be interpreted with caution,
as such measurements may overestimate arterial blood or
plasma glucose values (grade 1B).
Van den Berghe G - Clin Cornerstone - 01-JAN-2003; 5(2): 56-63
 The optimum hemoglobin levels in severe sepsis has
not been specifically investigated.
 Transfusion requirement in trial suggested
Hb > 7-9 g/dl
 Transfusion for septic shock (ScvO2<70%)
require Hematocrit levels > 30%

Surviving sepsis campaign guidelines for management of severe sepsis

and septic shock. Crit Care Med 2004; 32(3): 858-73
 Renal replacement Renal support

Purpose Replace renal function Support other organs

Based on level of Based on individualized

Timing of intervention
biochemical markers need

Indications for dialysis Narrow Broad

Targeted for overall

Dialysis dose Extrapolated from ESRD
support

Abdeen O. Crit Care Clin 2002;(2):223-47

 Metabolic acidosis in sepsis

Metabolic acidosis  mortality:

Hemodynamics instability

 inducible nitric oxide synthase (iNOS)

 ekspression cytokine proinflamatory

Pedoto A. Am J Respir Crit Care Med 1999; 159:397–402

Jensen JC. J Surg Res 1990; 49:350 –353
 Immunotherapy in Sepsis
• Immunosupression or immunomodulation ?
• When to start the treatment ?
• Target to treat (endotoxin ?)
• One agent of combination ?
 SIRS CARS
Inflammation Anti-inflammation
 Some Immunomodulatory Therapy in Sepsis

Antiendotoxin therapy
Monoclonal or polyconal antibodies
LPS analog, LPS elimination
Specific mediators Immunostimulation
anti TNF Immunoglobulins
TNF receptors G-CSF
IL-1 RA IFN g
Coagulants (AT, activated protein C) Immunonutrition
Tissue factor pathway inhibitors Non specific
PAF Corticosteroids
Arachidonic metabolites Pentoxifillin
Bradikinin antagonist Hemofiltration
Nitric oxide synthase inhibitors

Vincent JL, Sun Q, Duboid MJ. Clin Infec Dis 2002;34:1084-93

Pathway Mediators Treatment RCT result

Exo/endotoxin Superantigen TSS1 Anti TSS Not evaluated

Streptococcal endotoxin Anti Strep endotx Not evaluated
Lipoplysacharide Anti LPS Negative
Innate immunity TLR2 TLR4 TLR agonis Not evaluated
Monocyte- macrophge GM-CSF, IFNg Not evaluated
Neutrophyl GCSF Not evaluated
B cell (and Ig) IgG Not evaluated
CD4 (Th1-Th2)
Proinflammatory TNF-a Anti TNFa Negative
Pathway IL1b IL-1b agonist Negative
IL-6 IL-6 agonist Not evaluated
PG. Leucotrien Ibuprofen
High dose Corticos Negative
Bradikinin Bradikinin agonist Negative
PAF PAF hydrolyse Negative
NO NO synthase inhibitor Negative

Russel, 2006
Pathway Mediators Treatment RCT result
Procoagulant Decreased Prot C Activated Prot C Positive

Decreased AT3 Antitrombin III Negative

Decreased TFPI TFPI Negative
Increased-PAI-1 tPA Not evaluated
Antiinflammatory IL-10 IL-10 Not evaluated
TNF a receptor TNF a receptor Not evaluated
Hypoxia Hypoxiea induce factor EGDT Positive
vasc growth factor Supra normal delivery Negative
Eritorpoitin Not evaluated
Immunosupression Lymphocyte apoptosis Anticaspases Not evaluated
Apoptosis Apotosis of intestinal Anticaspases Not evaluated
epithelial cells
Endocrine Adrenal insufficiency Corticostroids Mixed results
Vassopresin deficiency Vassopresin Not evaluated
Hyperglycemia Intensive insulin th Not evaluaed

Russel, 2006
Failed in Clinical trial of Immune-modulator
Therapy
 The experimental agent are ineffective
 Doses are inadequate
 Timing of intervention is inadequate
 Patient population is too heterogeneous
(variability in genetic polymorphism)
 Single therapies may be ineffective

Vincent JL, Sun Q, Duboid MJ. Clin Infec Dis 2002;34:1084-93

Group Patient Intervention group Control Motality NNT

ARDS 861 Low tidal vlume High tidal vol 31 vs 40 11

Severe sepsis 263 EGDT Usual therapy 33 vs 49 6
and septic shock
Severe sepsis 1690 Activated Prot C Placebo 25 vs 31 16
and septic shock
Septic shock 299 Hydrocortisone+ Placebo 53 vs 63 10
fludrocortisone
Crit ill surgical 1548 Intensive insulin usual glucose
thrapy control
(glucose lev 4.4-6.1) (glucose lev 10-11.1) 46 vs 8 29
Medical ICU 1200 Intensive insulin usual glucose
therapy control 37 vs 48 NA

Russel, 2006
Applicable Immunotherapy
• Corticosteroids
• Activated Protein C
• Granulocyte (G-CSF)
• IvIg
• Immune nutrition

* Not available in Indonesia

70 P =0.02
P =0.001
60

50

40
placebo
30 63 corticosteroid
57
53
20 40

10

0
mortality Vasopressor withdrawn
Annane D. JAMA. 2002 Aug 21;288(7):862-71
Bernard gr. N Engl J Med 2001;344:699-709