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 Sepsis Severe Sepsis Septic Shock

Microorganism  A clinical SIRS with a Sepsis with Refractory

invading response arising presumed organ failure hypotension
sterile tissue from a nonspecific or confirmed Vascular collapse
insult, with 2 of infectious
Renal
the following: process
Hemostasis
 T >38oC or
<36oC Lung
 HR >90 LA
beats/min
 RR >20/min
 WBC
>12,000/mm3
or <4,000/mm3
or >10% bands

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 B C D

DVT Prophylaxis Antibiotics within 1 hr EGDT and Protocolized Antibiotics within 1

for Septic Shock Resuscitation hr in No septic
H2 Blocker PUD Shock Patients
Glycemic Control Fluid Challenge
Prophylaxis
Crystalloid = Colloid 7-10 day Antibiotic
BC prior to Abx Duration
No Routine Use
of SGC PPI PUD Prophylaxis Source Control Consider Limiting
Low VT for ALI Dopamine or Support
No Renal Dose
Dopamine HOB >45 Norepinephrine
Limited Transfusion Limit P plateau <30
No High Dose cm H2O
Steroids No Antithrombin II
PEEP
No Erythropoietin
De-escalation
Intermittent =
Antibiotic Therapy
Continuous sedation
Weaning Protocol/SBT Conservative Fluid in
ALI with no Shock
Avoid NMB
 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?  Criteria for effectiveness
Adequate cardiac filling : MAP > 60-70 mmHg
CVP/PCWP : 12-15 mmHg No decrease in CI or ScvO2
Cardiac index>3-4 l/min/m2 reestablishment of urine flow
ScvO2 >65-70 % decreased blood lactate level
MAP <70 mmHg 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 N Significant clinical improvement
Non infectious caused after 48-96 hours
of fever
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 Glycopeptide Vancomycin
AGENTS Oxazolidine Linezolid
Lipopeptide Daptomycin
BROAD SPECTRUM DRUG Carbapenem Imipenem
WITH GRAM-POSITIVE AND Meropenem
GRAM-NEGATIVE ACTIVITY Ertapenem
Quinolone Levofloxacin
Moxifloxacin
Ciprofloxacin
Beta lactam-Beta lactamase inhibitor Piperacilin-Tazobactam
Ampicillin-Sulbactam
Ticarcillin-Clavulanate
ANTI-PSEUDOMONAL Carbapenem Imipenem or Meropenem
Aminoglycoside Gentamicin, Tobramycin, Amikacin
Beta lactam-Beta lactamase inhibitor Piperacillin-Tazobactam
Quinolone Ciprofloxacin
ANTI-ANAEROBE Nitroimidazole Metronidazole
Carbapenem Imipenem, Meropenem
Quinolone Moxifloxacin
Beta lactam-Beta lactamase inhibitor Piperacillin-Tazobactam
ANTI-CANDIDAL Echinocandin Caspofungin
Micafungin
Anidulafungin
Azole Fluconazole
Voriconazole
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-of-
care 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 >215 mg/dL >110 mg/dL
was started

Infusion adjusted to 180 to 200 mg/dL 80 to 110 mg/dL

maintain blood (10.0 and 11.1 (4.4 to 6.1
glucose mmol/L) 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 1. High level endemic MRSA* (community or
(vancomycin) nosocomial)
2. Neutropenic patient
3. Intravascular catheter infection
4. Nosocomial infection
FUNGAL/YEAST COVERAGE 1. Neutropenic fever or other immunosuppressed
(fluconazole, caspofungin, amphotericin B) 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