Curriculum Vitae

Name
: Lie Khie Chen
Birth
: Jakarta
Graduates
MD
: FMUI 1994
Internist
: FMUI 2003
Consultant : FMUI 2006
PhD
: FMUI 2014
Occupation
Internal Medicine Department
Tropical Medicine and Infectious Diseases Division
Interest
Sepsis
Antimicrobial Treatment
Antimicrobial Resistance
Fungal Infection
HIV and opportunistic infections

Workshop PIN PAPDI 2014

Diagnosis dan Penatalaksanaan

Sepsis
Khie Chen

Tropical Medicine and Infectious Disease Division

Internal Medicine Department
Medical Faculty University of Indonesia

Sepsis

Clinical syndrome
Host response to infection
Systemic process
Multi organ system affected

Konsep Disfungsi dan Gagal Organ pada Sepsis

The Major Networks of

the Host Response
Following Microbial
Challenge by PAMPs
(Pathogen Associated
Molecular Patterns) or
Tissue Injury by DAMPs
(Danger Associated
Molecular Patterns)

Definisi Sepsis
SCCM/ESICM/ACCP/ATS/SIS 2001

Infeksi :
terdokumentasi atau suspek

Parameter umum:
Suhu (temperatur rectal/core >38,3oC)
Hipotermia (temperatur rektal/core <36oC)
Frekuensi jantung >90x/menit atau
>2SD diatas nilai normal menurut umur
Takipnu >30x/menit
Perubahan status mental/kesadaran
Edema atau balan cairan positif (>20ml/kg/24jam)
Hiperglikemia (glukosa plasma>110 mg/dl) tanpa diabetes

Parameter inflamasi:
Lekositosis (Lekosit>12.000/ul)
Lekopenia (Lekosit<4.000/ul)
Lekosit normal dengan lekosit imatur/batang>10%
Peningkatan CRP > 2SD nilai normal
Peningkatan PCT > 2SD nilai normal

Parameter hemodinamik:
Hipotensi arterial
(tekanan sistolik <90 mmHg, MAP<70
atau tekanan sistolik turun >40mmHg pada dewasa)
Saturasi vena oksigen campuran (SmcvO2) >70%
Indeks kardiak >3.5 l/menit/m2

Levy MM, Fink MF, Marshall JC, et al. 2001

SCCM/ESICM/ACCP/ATS/SIS international sepsis definition
confrences. Intensive Care Med 2003; 29: 530-8.

Parameter disfungsi organ:

Hipoksemia arterial (PaO2/FiO2 <300)
Oliguria akut (produksi urin <0.5 ml/kg/jam)
Peningkatan kreatinin >0.5 mg/dl
Abnormalitas koagulasi (INR>0,5 atau APTT>60 detik)
Masa tromboplastin > 60 detik
Ileus
Trombositopenia (trombosit<100.000/ul)
Hiperbilirubin (bilirubin total>4 mg/dl)
Hiperlakatemia (>3mmol/L)
Penurunan pengisian kapiler

Levy MM, Fink MF, Marshall JC, et al. 2001

SCCM/ESICM/ACCP/ATS/SIS international sepsis definition
confrences. Intensive Care Med 2003; 29: 530-8.

Pyramid of Sepsis Demonstrating Increased

Mortality with Increasing Severity of Sepsis

Therapy Across the Sepsis Continuum

Infection

SIRS

Microorganism
invading
sterile tissue

A clinical
response arising
from a nonspecific
insult, with 2 of
the following:
T >38oC or
<36oC
HR >90
beats/min
RR >20/min
WBC
>12,000/mm3
or <4,000/mm3
or >10% bands

Sepsis

Severe Sepsis Septic Shock

SIRS with a
presumed
or confirmed
infectious
process

Sepsis with
organ failure
Vascular collapse
Renal
Hemostasis
Lung
LA

Refractory
hypotension

Chest 1992;101:1644

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.

Initial Management of Suspected

Serious Infection
PRIMARY STEPS (FIRST HOUR)
1. Clinical awareness
2. Assessing severity (1): vital signs. Proceed to resuscitate if indicated
3. Focused history and physical examination
4. Initial imaging studies (only in selected cases)
- Plain chest X-ray (pneumonia)
- Ultrasound (urosepsis, acute cholecystitis, infective endocarditis)
- CT imaging (central nervous system, abdomen, soft tissues)
5. Blood samples:
- Blood cultures
- Lactate
- Sepsis profile (including renal [creatinine], hepatic [bilirubin], hematologic
[platelet count] function, and metabolic status [glucose, lactate, bicarbonate])
- Serum markers (procalcitonin, C-reactive protein, others)
6. Initiate empiric antibiotic therapy, based on:
- Probable focus of infection
- Local microbiologic and susceptibility profile

Initial Management of Suspected

Serious Infection
SECONDARY STEPS
1. Additional microbiological samples for stains and cultures
2. Secondary (systemic) history and physical examination
3. Additional imaging, as indicated
4. Hemodynamic monitoring, in case of:
- Non responding hypotension
- Vasoactive drugs
- Severe hypoperfusion (blood lactate > 4 mmol/dL)
5. Assessing severity (2):
- Organ dysfunction
- Serum markers (prognostic value)
- Blood lactate (lactate clearance)
6. Consider drainage of focus

7. Rapid microbiological techniques (Gram and other stains, PCR techniques, rapid
antibiogram [E test])
- Early antibiotic adjustment

Therapy Across the Sepsis Continuum

Infection

SIRS

Sepsis

Severe Sepsis Septic Shock

CVP > 8-12 mm Hg
MAP > 65 mm Hg
Urine Output > 0.5 ml/kg/hr
ScvO2 > 70%
SaO2 > 93%
Hct > 30%

* Early Goal Directed Therapy

Antibiotics and Source Control
Early Goal-Directed Therapy (EGDT): involves adjustments of cardiac preload, afterload, and contractility to
balance O2 delivery with O2 demand: Fluids, Blood, and Inotropes
Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. NEJM 2001;345:1368.

SUMMARY: SEPSIS GUIDELINES 2008

Strong Recommendation : Recommended
A

DVT Prophylaxis

Antibiotics within 1 hr
for Septic Shock

EGDT and Protocolized

Resuscitation

Glycemic Control

Fluid Challenge

Crystalloid = Colloid

BC prior to Abx

PPI PUD Prophylaxis

Source Control

Low VT for ALI

Dopamine or
Norepinephrine

H2 Blocker PUD
Prophylaxis
No Routine Use
of SGC
No Renal Dose
Dopamine
No High Dose
Steroids

HOB >45
Limited Transfusion
No Antithrombin II

No Erythropoietin
Intermittent =
Continuous sedation
Weaning Protocol/SBT

Avoid NMB

Limit P plateau <30

cm H2O
PEEP
De-escalation
Antibiotic Therapy
Conservative Fluid in
ALI with no Shock

Antibiotics within 1
hr in No septic
Shock Patients
7-10 day Antibiotic
Duration
Consider Limiting
Support

Protocol for Early Goal-Directed Therapy.

Rivers E. N Engl J Med 2001;345:1368-77

Goals of Resuscitation

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 transport and utilization

parameters

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

ScvO2/SmvO2

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 treatment in septic shock

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

Fluid Treatment SSC 2012

Vasopressor in septic shock

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

Vasopressor SSC 2012

Practical Use of vassopressor

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 5-10ug/kg/min increased gradually
Epinephrin:
Start dose 0.05ug/kg/min increase 0.05ug/kg/min

De-escalation approach to antimicrobial utilization

Serious hospital acquired infection suspected
Obtain appropriate microbial
sample for culture and special stain
Begin empirical antibacterial treatment with
a combination agents targeting the most common
pathogen based on local data
Follow clinical parameter : Temp, WBC, CXR
PaO2/FiO2, haemodynamic, organ function
De-escalating antibacterial based on
results of clinical microbiology data
Search for superinfection
Abscess formation
Non infectious caused
of fever

Significant clinical improvement

after 48-96 hours
Y
Discontinue antibacterial after 7-14 days course based
on site of infection and clinical response
Kollef, Drugs 2003;63 (20): 2157

Empiric Therapeutic Regimens

CLASS

SPECIFIC DRUGS

ANTI-STAPHYLOCOCCAL
AGENTS

Glycopeptide
Oxazolidine
Lipopeptide

Vancomycin
Linezolid
Daptomycin

BROAD SPECTRUM DRUG

WITH GRAM-POSITIVE AND
GRAM-NEGATIVE ACTIVITY

Carbapenem

Imipenem
Meropenem
Ertapenem
Levofloxacin
Moxifloxacin
Ciprofloxacin
Piperacilin-Tazobactam
Ampicillin-Sulbactam
Ticarcillin-Clavulanate

Quinolone

Beta lactam-Beta lactamase inhibitor

ANTI-PSEUDOMONAL

Carbapenem
Aminoglycoside
Beta lactam-Beta lactamase inhibitor
Quinolone

Imipenem or Meropenem
Gentamicin, Tobramycin, Amikacin
Piperacillin-Tazobactam
Ciprofloxacin

ANTI-ANAEROBE

Nitroimidazole
Carbapenem
Quinolone
Beta lactam-Beta lactamase inhibitor

Metronidazole
Imipenem, Meropenem
Moxifloxacin
Piperacillin-Tazobactam

ANTI-CANDIDAL

Echinocandin

Caspofungin
Micafungin
Anidulafungin
Fluconazole
Voriconazole

Azole

SEPSIS
MORTALITAS 20-30%
BROAD SPECTRUM
NON CARBAPENEM

SEPSIS BERAT
MORTALITAS 50-80%
BROAD SPECTRUM
MONOTERAPI/KOMBINASI

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

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

Glucose control

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-ofcare testing of capillary blood be interpreted with caution, as
such measurements may overestimate arterial blood or plasma
glucose values (grade 1B).

Intensive Insulin Therapy in Critically Ill Patients

Randomization
Conventional

Intensive

Blood glucose level

when insulin infusion
was started

>215 mg/dL

>110 mg/dL

Infusion adjusted to
maintain blood
glucose

180 to 200 mg/dL

(10.0 and 11.1
mmol/L)

80 to 110 mg/dL
(4.4 to 6.1
mmol/L)

39 % Received insulin

99% Received Insulin

van den Berghe G, et al. NEJM 2001;345:1359-1367.

Tight Glucose Control Improved Survival

Van den Burghe, NEJM 2001;345:1359-1367.

Hemoglobin levels in Severe sepsis

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

Indication for Extended Ampiric Antibiotic

Therapy of Severe Sepsis / Septic Shock
GRAM-NEGATIVE COVERAGE

1. Nosocomial infection
2. Neutropenic or immunosuppresed
3. Immunocompromised due to chronic organ
failure (liver, renal, lung, heart, etc)

GRAM-POSITIVE COVERAGE
(vancomycin)

1. High level endemic MRSA* (community or

nosocomial)
2. Neutropenic patient

3. Intravascular catheter infection

4. Nosocomial infection
FUNGAL/YEAST COVERAGE
(fluconazole, caspofungin, amphotericin B)

1. Neutropenic fever or other immunosuppressed

patient unresponsive to standard antibiotic
therapy
2. Prolonge broad spectrum antibiotic therapy
3. Positive relevant fungi cultures
4. Consider empiric therapy if high risk patient
with severe shock

Crit Care Med 2008; 36:296

DVT Prophylaxis SSC 2012

Multiple Variables of Prognosis

Pathogenicity of causative organism

Quantity of causative organism
Availability of tolerable antimicrobial agents that are active at the
site of infection
Co-morbidities in the host such as neutropenia, severe cardiac
dysfunction, renal or hepatic dysfunction, or diabetes
Immune competence of host
Removal of foreign body or drainable focus
Promptness and adequacy of resuscitation and empiric
antimicrobial regimen