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What is Sepsis ?

Main causative organisms


70% Septic patients : Blood culture (-)

Martin GS, et al. NEJM 2003;348:1546-54

Annane D, et al. Lancet 2005;365:63-78

Sepsis versus SIRS

From Infection to Septic Shock

Nguyen HB, et al. AnnEmergMed 2006;48:28-54

SIRS to Septic Shock


Insult

SIRS

Sepsis

Severe Sepsis

SIRS + presumed or
confirmed infectious process
2 of the following:

BT >38 or <36
HR > 90bpm
RR > 20bpm or PaCO2 <32mmHg
WBC >12,000, <4,000, or >10% bands

Sepsis + 1 organ dysfunction


Cardiovascular (Refractory low BP)
Adrenal
Hematologic
Coagulation
Renal
Respiratory
Hepatic
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CNS
Unexplained metabolic acidosis

Septic
Shock

Bone RC, et al. Chest 1992;101:1644

Severe Sepsis
Sepsis-induced
tissue hypoperfusion or organ dysfunction

Septic shock
Sepsis-induced hypotension persisting
despite adequate fluid resuscitation

Epidemiology of Sepsis in US (1979-2000)

N Engl J Med 2003; 348: 1546-54.

Organ dysfunction is a major


outcome parameter
Septic shock (n=1134)

Severe Sepsis (n=827)

Sepsis (n=1063)
Infection no SIRS (n584)
Total n=3608

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Alberti et al. Am J Respir Crit Care Med. 2003;168:77-84

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Crit Care Med 2008; 36: 1394 1396

International Sepsis Definition:


GIHOT
General variables

Fever (core temperature > 38.3C)


Hypothermia (core temperature < 36C)
Heart rate > 90 bpm or >2 SD above the normal value
Tachypnea
Altered mental status
Significant edema or positive fluid balance (>20 mL/kg
over 24 hrs)
Hyperglycemia (plasma glucose >140 mg/dL) in the
absence of diabetes

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Crit Care Med 2008; 36: 1394 1396

International Sepsis Definition:


GIHOT
Inflammatory variables
Leukocytosis (WBC count > 12,000/L)
Leukopenia (WBC count < 4000/L)
Normal WBC count with > 10% immature forms
Plasma C-reactive protein > 2 SD above the
normal value
Plasma procalcitonin > 2 SD above the normal
value
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Crit Care Med 2008; 36: 1394 1396

International Sepsis Definition:


GIHOT
Hemodynamic variables
Arterial hypotension
SBP < 90 mm Hg,
MAP < 70 mm Hg, or
an SBP decrease > 40 mm Hg in adults or < 2 SD
below normal for age

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Crit Care Med 2008; 36: 1394 1396

International Sepsis Definition:


GIHOT
Organ dysfunction variables
Arterial hypoxemia (PaO2/FiO2 < 300)
Acute oliguria (urine output < 0.5 mL/kg/hr for at least
2 hrs despite adequate fluid resuscitation)
Creatinine increase > 0.5 mg/dL
Coagulation abnormalities (INR > 1.5 or aPTT > 60 secs)
Ileus (absent bowel sounds)
Thrombocytopenia (platelet count < 100,000 /L)
Hyperbilirubinemia (plasma total bilirubin > 4 mg/dL)

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Crit Care Med 2008; 36: 1394 1396

International Sepsis Definition:


GIHOT
Tissue perfusion variables
Hyperlactatemia (> upper limit of lab normal)
Decreased capillary refill or mottling

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2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definition Conference. CCM 2003;31:1250-1256

Sepsis Management: VIPs


Surviving Sepsis Campaign 2008 guidelines

Ventilation
Infection
Perfusion
Supportive care
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Index

Activated Protein C (rhAPC)

//

Bicarbonate

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A Problematic Measurement
It should be recognized that
systemic hypo-perfusion
usually precedes
hypotension, especially in
patients with sepsis
Rackow, JAMA, 1991

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20

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Serum Lactate as a Mortality


Predictor in Severe Sepsis
Mortality Rate (%)

0.3

28.4%

Death within 3 days

0.3
28 Day In-hospital Mortality

22.4%

0.2
0.2
9.0%

0.1
4.9%

0.1

4.5%

1.5%

0.0
0.0-2.4

2.5-3.9

Lactate Level ( mmol/L)

>4.0

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Shapiro NI, et al. Ann Emerg Med 2005;45:524-528

Early lactate clearance is


associated with improved outcome

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Nguyen HB, et al. CCM 2004;32:1637-1642

SvO2 versus ScvO2

Where to measure ?

Normal value ?

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What does ScvO2 mean ?


Low ScvO2 (<< 70%)

High ScvO2 (>> 70%)

Low DO2

High VO2

High DO2

Low VO2

Hypoxia, Suctioning
(low SaO2)

Exercise

Hyperoxia
(high FiO2)

Hypothermia

Pain

Erythrocytosis
(high Hb)

Anesthesia,
Pharmacologic
paralysis

Anemia,
Hemorrhage
(low Hb)
Cardiac dysfunction,
Hypovolemia, Shock,
Arrythmia
(low CO)

Hyperthermia,
Shivering, Seizure

Arterio-venous
shunting,
Hyperdynamic state
Mitochondrial defect,
(high CO)
Terminal Shock
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How do we treat global tissue hypoxia


in severe sepsis/septic shock

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Approach to Hemodynamic Optimization

27

Hollenberg SM, et al. CCM 2004;32:1928-1948

DO2
Cardiac Output
Heart Rate

Oxygen Content

Stroke Volume
Afterload

Preload
Contractility

Oxygen content = (1.34 x Hb x SaO2) + (0.0031 x PaO2)

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Early Goal-Directed Therapy

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EGDT Results
28-day Mortality
60
50

49.2%

40

P = 0.01*
33.3%

30
20
10
0

Standard Therapy
n=133

EGDT
n=130
.

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

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EGDT in ER

sepsis induced hypotension or Lactate 4 mmol/L

6
1.
2.
3.
4.

CVP: 8-12 mmHg (12-15 in ventilator pts)


MAP: > 65 mmHg
Urine output: > 0.5mL/kg/hr
ScvO2 or SvO2: 70%
6 Rivers E. N Engl J Med 2001;345:1368-77.
PRBCHct >30% /
dobutamine (max 20g/kg/min)
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2


(48hr)
(
):

Weinstein MP. Rev Infect Dis 1983;5:35-53


Blot F. J Clin Microbiol 1999; 36: 105-109.

32


1
()




Kreger BE. Am J Med 1980;68:344-355.
Ibrahim EH. Chest 2000;118:146-155.
Hatala R. Ann Intern Med 1996;124-717-725.

33

48-72

Optimize efficacy
Prevent resistance
Avoid toxicity
Minimize costs

7-10

Ali MZ. Clin Infect Dis 1997;24:796-809

34


Maximal efficacy & minimal physiologic upset
Jimenez MF. Intensive Care Med 2001;27:S49-S62.
Bufalari A. Acta Chir Belg 1996;96:197-200.

35

Moss RL. J Pediatr Surg 1996;31:1142-1146.


CDC. MMWR 2002;51:1-29.

36


Drainage
- Intra-abdominal abscess
- Thoracic empyema

- Septic arthritis
- Pyelonephritis, cholangitis

Debridement
- Necrotizing fasciitis
- Infected pancreatic necrosis

- Mediastinitis
- Intestinal infarction

Device Removal
- Infected vascular catheter
- Urinary catheter
- Colonized endotracheal tube

Definitive Control
- Sigmoid resection for diverticulitis
- Amputation for clostridial myonecrosis
- Cholecystectomy for gangrenous cholecystitis
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Fluid resuscitation in ICU

Total n=6997

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SAFE study. NEJM 2004;350:2247-56

:
colloidscrystalloids


(volume of distribution)


Choi PTL. Crit Care Med 1999;27:200-210.
Cook D. Ann Intern Med 2001;135:205-208.
Schierhout G. BMJ 1998;316:961-964.

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:

Goal: CVP 8 mmHg ( or 12 mmHg)
500 - 1000 mL of crystalloids over 30 mins
300 - 500 mL of colloids over 30 mins


24


40


Goal: MAP 65 mmHg

norepinephrine
dopamine

Norepinephrinedopamine
Dopa ;

LeDoux D. Crit Care Med 2000;28:2729-2732.


Martin C. Chest 1993;103:1826-1831.
DeBacker D. Crit Care Med 2003;31:1659-1667.

Regnier B. Intensive Care Med 1977;3:47-53.


Martin C. Crit Care Med 2000;28:2758-2765. 41
Hollenberg SM. Crit Care Med 1999; 27: 639-660.


dopamine

Vasopressin

: 0.01-0.04 units/min
(stroke volume)
Hollenberg SM. Crit Care Med 1999; 27:639-660.
Bellomo R. Lancet 2000; 356: 2139-2143.
Kellum J. Crti Care Med 2001; 29: 1526-1531.

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dobutamine

dobutamine

Gattinoni L. N Eng J Med 1995;333:1025-1032.


Hayes MA. N Eng J Med 1994;330:1717-1722.

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(ACTH Test Non-responders)


(77%)

100%

(ACTH Test Responders)


(23%)

100%

28-day Mortality

P=0.04

80%

P=0.96

80%
63%

60%
40%

53%
N=114

61%
53%

60%
N=115

40%

20%

20%

0%

0%

Low-dose Steroids

N=36

Placebo

N=34

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Annane, D. JAMA, 2002; 288 (7): 868

250 mcg ACTH stimulation test


ACTH

: CortisolACTH30-60min
>9 mcg/dL
ACTH

(tapering)
fludrocortisone

ACTH stimulation test


Annane, D. JAMA, 2002; 288 (7): 868

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IV hydrocortisone 200-300mg/day * 7days in 3


or 4 divided doses

Annane, D. JAMA, 2002; 288 (7): 868

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Hydrocortisone >300 mg

Bone RC. N Engl J Med 1987;653-658.


VA Systemic Sepsis Cooperative Study Group. N Engl J Med 1987;317:659-665.

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Proposed actions of Activated Protein C


(PROWESS study)

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Bernard GR, et al. NEJM 2001;344:699-709

PROWESS study

ARR: 6.1%

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Bernard GR, et al. NEJM 2001;344:699-709

APC should not be used in low risk patients


(Severe sepsis + APACHE II < 25 or 1 organ failure)

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Abraham E, et al. (ADDRESS study). NEJM 2005:353:1332-41

rh Activated Protein C (Xigris)


Dose: 24 g/kg/hr IV for 96 hours
Indications:
Contraindications:
>18y & infection
Active internal bleeding
3 items in SIRS
Intracranial lesions
exp. Survival > 6m
Using heparin & >15IU/kg/hr
2 organ dysfunction
Bleeding tendency (w/o DIC)
Hypotension
Chr. & Severe liver disease
Renal
Platelete <30k
Respiratory
High risk bleeding groups
Platelet
Exaggerating coagulation
Metabolic acidosis
APACHE II 25 & <53
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within 12-48h ICU

Activated Protein C (rhAPC)

Drotrecogin alfa (activated):


APACHE II score 25, or
, or
, or
acute respiratory distress syndrome

Drotrecogin alfa (activated):

rhAPC

Bernard GR. N Eng J Med 2001;344:699-709.

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rhAPC
rhAPC (drotrecogin alfa [activated])rhAPC
:
Active internal bleeding
- Recent (within 3 months) hemorrhagic stroke
- Recent (within 2 months) intracranial or intraspinal surgery, or
severe head trauma
- Trauma with increased risk of life-threatening bleeding
- Presence of an epidural catheter
- Intracranial neoplasm or mass lesion or evidence of cerebral
herniation
See labeling instructions for relative contraindications (i.e. warnings)
rhAPC30,000
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< 7 g/dL
:

:
Hb 7 9 g/dL

Erythropoietin(EPO)

EPO

(FFP)
Corwin HL. JAMA 2002;288:2827-2835.

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Antithrombin

High dose antithrombin in a phase III trial did


not demonstrate a beneficial effect on 28-day
mortality and was associated with increased
risk of bleeding when administered with
heparin

5000/mm3
5000 - 30,000/mm3
/ 50,000/ mm3

Warren BL. JAMA 2001;286:1869-1878.

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Lung protective ventilation


Traditional: 12mL/kg; Pplateau <50 cmH20
Protective: 6mL/kg; Pplateau <30 cmH20
ARR: 8.8%

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ARDS Network. NEJM 2000;342:1301-8

ALI/ARDS

Mortality* - Low vs Traditional Tidal Volume


P=0.007
50

39.8
Mortality (%)

40

31
30

20

Low Tidal
Volume

* death before
discharge home
and breathing without
assistance

Traditional
Tidal
Volume

10

ARDSNet. N Eng J Med 2000;342:1301-1308.

57
Traditional: 12mL/kg; Pplateau <50 cmH20
Protective: 6mL/kg; Pplateau <30 cmH20

ALI/ARDS

:
High tidal volumes, > 6 ml/kg
High plateau pressures, > 30 cm H2O

plateau pressure and tidal volume


Hypercapnia

positive end expiratory pressure

ARDSNet. N Eng J Med 2000;342:1301-1308.

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ALI/ARDS

FiO2plateau
pressure
(prone position)

(mechanical ventilation)
45%,
(ventilator associated
pneumonia)
Drakulovic M. Lancet 1999;354:1851-1858.

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ALI/ARDS

ALI/ARDS

ALI/ARDS

ALI
60

ALI/ARDS

:




FiO2

Esteban A. Am J Respir Crit Care Med 1999;159:512-518.


Ely EW. N Engl J Med 1996;335:1864-1869.
Esteban A. Am J Respir Crit Care Med 1997;156:459-465.

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//

(Protocols)

Brook AD. Crit Care Med 1999;27:2609-2615.

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IIT in SICU: the Leuven Study


25.0%
Conventional (180-200mg/dL)

Mortality (%)

20.0%

20. 20%

IIT (80-110 mg/dL)

15.0%
10. 60%

10.0%
5.0%

8. 00%

10. 90%

7. 20%
4. 60%

0.0%
ICU

ICU >5 day

In-hospital

63

Van den Berghe G, et al. NEJM 2001;345:1359-67

NICE-SUGAR trial:
Goal 150mg/dl

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N Engl J Med 2009;360:1283-97


check
q1~2 hours

< 150 mg/dL
()

5% or 10% dextrose
van den Berghe G. N Engl J Med 2001;345:1359-1367.

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CVVHHD
CVVH

Mehta RL. Kidney Int 2001;60:1154-1163


Kellum J. Intensive Care Med 2002;28:29-37.

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Bicarbonate

(lactic acidosis) pH 7.15
bicarbonate

Bicarbonate NS
pH 7.13

Cooper DJ. Ann Intern Med 1990;112:492-498.


Mathieu D. Crit Care Med 1991;19:1352-1356.

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Better compliance Better


outcome
Resus. bundle: 10.9% to 31.3% (P<0.0001)
Manag. bundle: 18.4% to 36.1% (P = 0.008)

37% to 30.8%, P=0.001

The Surviving Sepsis Campaign: results of an international guideline69 performance improvement program targeting severe sepsis
based
Intensive Care Med (2010) 36:222231

Strategies to Timely
Obviate the Progression
of Sepsis

STOP Sepsis
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The Golden 6 hours

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The Golden 6 hours

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Goal

The Sepsis Bundles


The SSC/ICI Template: Phase III

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http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Tools/SepsisBundleIHITool.htm

The Sepsis Bundles


The SSC/ICI Template: Phase III

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http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Tools/SepsisBundleIHITool.htm

Heads of Sepsis
hypotension, hypoperfusion, and organ dysfunction

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Criti Care Med. 2004;32(Suppl):S595-S597


1-2-3-4-5-6-7-8-9-10-11-12-15-30
The End
Juice119@gmail.com

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