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Update in Sepsis Management

National Taiwan University Hospital

Department of Internal Medicine

Outline
Definition and pathophysiology of sepsis syndrome Guidelines for management of severe sepsis/septic shock
Sepsis resuscitation bundle Sepsis management bundle

National Taiwan University Hospital

Department of Internal Medicine

Definition and Pathophysiology of Sepsis Syndrome

National Taiwan University Hospital

Department of Internal Medicine

Incidence and Cost Regarding Sepsis


250,000 death in non-CCU in USA annually 18 millions cases of sepsis worldwide yearly The mortality rates :
30% to 50% for severe sepsis 50% to 60% for septic shock

40% total ICU expenditure in Europe Average cost per individual case is approximately $22,000
National Taiwan University Hospital

Department of Internal Medicine

Category of Sepsis Syndrome


SEPSIS is defined as a documented or suspected infection with one or more of the following:
Systemic inflammatory response syndrome (SIRS) Fever or hypothermia Heart rate >90 /min Tachypnea Altered mental status Edema Hyperglycemia Leukocytosis, leukopenia or immature form 10% Elevation of CRP or procalcitonin
National Taiwan University Hospital

Department of Internal Medicine

Category of Sepsis Syndrome (cont.)


Severe sepsis
Severe sepsis is defined as sepsis associated with organ dysfunction, hypoperfusion, hypotension

Septic shock
Acute circulatory failure as persistent arterial hypotension (SBP <90 mmHg, MAP <60, or a reduction in SBP >40 mm Hg from baseline) despite fluid resuscitation
National Taiwan University Hospital

Department of Internal Medicine

Identifying Acute Organ Dysfunction as a Marker of Severe Sepsis


Altered Consciousness Confusion Psychosis Tachycardia PaO2<70 mmHg SaO2 <90% PaO2/FiO2<300 Tachycardia Hypotension Altered CVP Altered PAOP

Oliguria Anuria Creatinine

Jaundice Enzymes Albumin PT


National Taiwan University Hospital

Platelets PT/APTT Protein C D-dimer

Balk RA Cnt Care Clin 2000;Internal Medicine 16:337-52 Department of

Infection

Severe Sepsis

Increasing inflammation
High risk of infection Infection SIRS plus infection Septic shock

Prophylactic Antibiotics, Immune stimulants

Antibiotics, antitoxins

Coagulation Inhibitors antioxidants

Anti-inflammatory Cytokines, Inflammatory Cytokine antagonists

National Taiwan University Hospital

Department of Internal Medicine

Endotoxin (LPS)

Trigger

Cytokine Storm
Hyperreactive immune response Hyporeactive immune response, immnoparalysis
Edema Tissue damage Organ failure Phagocytic cell function Susceptibility to infection

Causative agents
Pro-inflammatory cytokines + chemokines ROS production Enzyme release
National Taiwan University Hospital

Vascular permeability Bacterial killing DIC Leukocytosis Peripheral resistance

Department of Internal Medicine

Homeostasis is Lost in Sepsis


Proinflammatory mediators Endothelial injury Tissue factor expression Thrombin production

Fi

s lysi o brin

n atio n gul atio Coa mm la Inf

Homeostasis
National Taiwan University Hospital

Increased PAI-1 Increased TAFI Reduced Protein C (endogenous activated Protein C inhibits PAI-1)

Department of Internal Medicine

Physiologic changes during sepsis

National Taiwan University Hospital

Department of Internal Medicine

Guideline for Management of Severe Sepsis & Septic Shock


Surviving Sepsis Campaign Management Guidelines Committee

National Taiwan University Hospital

Department of Internal Medicine

Surviving Sepsis Campaign


To improve the management, diagnosis, and treatment of sepsis Aim to: Reduce sepsis mortality

National Taiwan University Hospital

Department of Internal Medicine

Surviving Sepsis Campaign


2002, Phase I: public awareness 2004, Phase II: forming guidelines Phase III: implementation of guidelines Till 2009, Goal: To reduce the mortality of severe sepsis/septic shock by 25% within 5 years
http://www.survivingsepsis.org/
National Taiwan University Hospital

Department of Internal Medicine

2004
Dellinger RP, Carlet JM, et al. Crit Care Med 2004; 32:858

2008
Dellinger RP, Levy MM, et al. Intensive Care Med 2008; 34:17
National Taiwan University Hospital

Department of Internal Medicine

Management of Sepsis
Infection control
Antibiotics, source control

Hemodynamic support
Ventilation, vasopressor, infusion, pump

Metabolic / endocrine support


Steroids, glucose control

New drug
Activated protein C
National Taiwan University Hospital

Department of Internal Medicine

Surviving Sepsis Campaign


Sepsis resuscitation bundle Sepsis management bundle

http://www.survivingsepsis.org/
National Taiwan University Hospital

Department of Internal Medicine

Sepsis Resuscitation Bundle - within 6 hrs of sepsis onset


Serum lactate measured 1C Blood culture prior to antibiotic 1C Empirical antibiotic within first hour of recognition of severe sepsis (1D) and septic shock 1B Fluid challenge 20ml/kg crystalloid and vasopressor keep MAP > 65 mmHg 1C CVP > 8 mmHg, ScvO2 >70 % 1C
National Taiwan University Hospital

Department of Internal Medicine

Sepsis Management Bundle - within 24 hrs of sepsis onset


Low dose steroid for septic shock Activated protein C in selected cases Glucose control maintained <150 mg/dl Lung protective strategy for mechanical ventilation 2C 2B 2C 1B

National Taiwan University Hospital

Department of Internal Medicine

Sepsis Resuscitation Bundle

National Taiwan University Hospital

Department of Internal Medicine

Sepsis guideline - Antibiotics


IV antibiotic therapy should be started within the first hour of recognition of sepsis, after appropriate culture Choice should be empirical, reviewed after 4872 hours of use
Coverage of pseudomonas Combination therapy for neutropenic patients

Stop once identified non-infective cause of SIRS


National Taiwan University Hospital

Department of Internal Medicine

Source control
Drainage Debridement Device removal Definitive control

National Taiwan University Hospital

Department of Internal Medicine

Pneumonia: Effect of Early Administration of Antibiotics on Outcomes


Variable 30-day mortality In-hospital mortality % of patients with LOS>5 days 30-day readmission rate All patients 12.0 7.0 43.3 Antibiotics Antibiotics within 4 hours after 4 hours 11.6 6.8 42.1 12.7 7.4 45.1 Adjusted Odds Ratio 0.85 0.85 0.90 p Value .005 .03 .003

13.4

13.1

13.9

0.95

.34

Retrospective study of a national random sample of 18,209 Medicare patients older than 65 years of age with pneumonia
National Taiwan University Hospital

Houck et al. Arch Intern Med 2004; 164:637-44 Department of Internal Medicine

Mortality Rates Related to Appropriateness of Initial Empiric Therapy


Inadequate
100 90 80 70 60 50 40 30 20 *=p<.001 10 #=p=.06 0
+=p=.001
National Taiwan University Hospital

Adequate

Luna

AlvarezLerma

Rello

Kollef

SanchezNieto

Ruiz

Dupont

Fagon JY, Chastre J. Clin Chest Med 2005; 26:97-104 Department of Internal Medicine

Fluid Therapy: Fluid Challenge


Fluid challenge in patients with suspected hypovolemia may be given
500 - 1000 mL of crystalloids over 30 mins 300 - 500 mL of colloids over 30 mins Repeat based on response and tolerance Usually, up to 6-10 L of crystalloids or 2-4 L of colloids may be required in the first 24 hours of management No evidence-based support for one type of fluid over another
National Taiwan University Hospital

Department of Internal Medicine

Therapeutic goals of volume support in critically ill patients


PCWP CVP Hemoglobin Albumin DO2 12-15 mmHg 8-12 mmHg 8-10 g/dl 2.5 g/dl 450-600 ml/min/m2

National Taiwan University Hospital

Department of Internal Medicine

Crystalloid vs Colloid
Crystalloid
Intravascular persistence Poor Hemodynamic stabilization Transient Required infusion volume Risk of tissue edema Enhancement of capillary perfusion Risk of anaphylaxis Plasma colloid osmotic pressure Cost
National Taiwan University Hospital

Colloid
Good Prolonged Moderate Insignificant Good Low to moderate Maintained Expensive

Large Obvious Poor Nil Reduced Inexpensive

Department of Internal Medicine

Vasopressors
Initiate vasopressor if appropriate fluid challenge fails to restore adequate BP and perfusion Either NE or dopamine are first line agents to correct hypotension in septic shock
NE is more potent than DA and may be more effective at reversing hypotension in septic shock Dopamine may cause more tachycardia and more arrhythmogenic
National Taiwan University Hospital

Department of Internal Medicine

Vasopressors
Low dose DA should NOT be used for renal protection in severe sepsis An arterial catheter should be placed as soon as possible Vasopressin may be considered in shock patients that are refractory to fluid resuscitation and high dose vasopressors
Infusion rate of 0.01-0.04 units/min in adults May decrease stroke volume
National Taiwan University Hospital

Department of Internal Medicine

Inotropic Therapy
In patients with low cardiac output despite adequate fluid resuscitation, dobutamine may be used to increase cardiac output Epinephrine, phenylephrine, vasopressin should Not be the initial vasopressor It is NOT recommended to increase cardiac index to target an arbitrarily predefined elevated level
No benefit from increasing oxygen delivery to supranormal levels by use of dobutamine
National Taiwan University Hospital

Department of Internal Medicine

Early-Goal Directed Therapy (EGDT)


Goals of therapy within first 6 hours are
Central Venous Pressure 8-12 mm Hg (12-15 in ventilator pts) Mean arterial pressure > 65 mm Hg Urine output > 0.5 mL/kg/hr ScvO2 or SvO2 70%; if not achieved with fluid resuscitation during first 6 hours:
-

Transfuse PRBC to Hct > 30% and/or Administer dobutamine (max 20 g/kg/min) to goal
River E. N Engl J Med 2001;345:1368.

National Taiwan University Hospital

Department of Internal Medicine

National Taiwan University Hospital

Department of Internal Medicine

Early Goal-Directed Therapy (EGDT)


28-day Mortality
60 50 40 30 20 10 0 49.2%

P = 0.01*
33.3%

Standard Therapy EGDT n=133 n=130 *Key difference was in sudden CV collapse, not MODS
National Taiwan University Hospital

River E. N Engl J Med 2001;345:1368.

Department of Internal Medicine

Sepsis Management Bundle

National Taiwan University Hospital

Department of Internal Medicine

Stress, Cytokines

HPA axis during stress response

National Taiwan University Hospital

globulin Local CS activation

CS-binding

(Lamberts et al. NEJMDepartment of Internal Medicine 2004;337:1285)

Intact HPA axis is Crucial for the survival of critical ill patients
Mortality rate of patients with multiple injuries, University hospital of Glasgow, Scotland
1969-1980 22-29% vs. 1981,1982 44% Coincides with the use of Etomidate, a shortacting hypnotic drug (a selective inhibitor of adrenal 11-hydroxylase)
(Ledingham & Watt. Lancet 1983;1:1270)
National Taiwan University Hospital

Department of Internal Medicine

Cortisol Level and Sepsis Mortality


Morning cortisol level
Group 1: 345 nmol/L Group 2: 345~552 nmol/L Group 3: 552~1242 nmol/L Group 4: 1242 nmol/L

National Taiwan University Hospital

(Sam S et al. Clin Endocrinol 2004:60:29)

Department of Internal Medicine

Prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin
Baseline cortisol level (g/dL) Good Intermediate Poor 34 34 > 34 > 34 max (g/dL) >9 9 >9 9 28 d mortality (%) 26 67 82

(Annane et al. JAMA 2000;283:1038)


National Taiwan University Hospital

Department of Internal Medicine

Low Dose Steroids and Septic Shock


Relative adrenal insufficiency: max < 9 g/dL, 30-60 min after test
Patients with Relative Adrenal Insufficiency (ACTH Test Nonresponders) (77%) Patients Without Relative Adrenal Insufficiency (ACTH Test Responders) (23%)

100%

100%

P=0.04 28-day Mortality


80% 63% 60% 40% 20% 0% 53%
N=114 N=115

P=0.96
80% 61% 60% 40% 20% 0%
N=36

53%
N=34

Low-dose Steroids
National Taiwan University Hospital

Placebo
(Annane et al. JAMA 2002;288:862)

Department of Internal Medicine

Steroids
Intravenous corticosteroids are recommended in patients with septic shock who require vasopressor therapy to maintain blood pressure
Administer intravenous hydrocortisone 200-300 mg/day for 7 days in three or four divided doses or by continuous infusion with gradual tapering ACTH stimulation is not recommended routinely done Shown to reduce mortality rate in patients with relative adrenal insufficiency
National Taiwan University Hospital

Department of Internal Medicine

Mechanical Ventilation of Sepsis-Induced ALI/ARDS

National Taiwan University Hospital

Department of Internal Medicine

Tidal volume and ARDS Mortality


16 14 12

VT (mL/kg)

10 8 6 4 2 0

Mortality rate 64%

Mortality rate 50%

Mortality rate 40%

1978-1981

1986-1989

1993-1996

2000-2004

Years
National Taiwan University Hospital

Mortality rate 30%

Department of Internal Medicine

Mechanical Ventilation of SepsisInduced ALI/ARDS


Reduce tidal volume over 12 hrs to 6 ml/kg predicted body weight Maintain inspiratory plateau pressure < 30 cm H20 Optimal PEEP
Prevent end expiratory lung collapse

Setting PEEP based on FIO2 requirement and thoracopulmonary compliance Consider prone positioning in ARDS when:
Potentially injurious levels of F1O2 or plateau pressure exist and not at high risk from positional changes
National Taiwan University Hospital

Department of Internal Medicine

ARDS: Ventilator setup & adjustment

ARDS: oxygenation goal & protocol

National Taiwan University Hospital

(downloaded fromDepartment of Internal Medicine www.ardsnet.org)

ARDSnet - Lung Protective Ventilatory Strategy


40 35

% Mortality

30 25 20 15 10 5 0 6 ml/kg 12 ml/kg

National Taiwan University Hospital

(The ARDS Network, NEJM 2000;342:1301) Department of Internal Medicine

Intensive Glucose Control


Initial Infusion Rate
Blood Glucose Level (mg/dl) 110-220 > 220 Insulin Infusion Rate(U/hr) 2 4

Blood Glucose Monitoring Guidelines


Accuchecks every hour during insulin infusion until four consecutive values are within 80-110 mg/dl, then every 4 hours. If tube feedings or total parenteral nutrition is held or discontinued, hold infusion and monitor blood glucose levels every 2 hours.

Insulin Infusion Titration Guidelines


Blood Glucose Level (mg/dl) 41-60 61-80 81-111 111-120 121-139 > 140
National Taiwan University Hospital

Insulin Bolus and Infusion Rate Stop infusion Reduce rate by 0.1-0.5 U/hr No change unless decreased > 20% from previous result; if > 20%, decrease rate 20% Increase rate by 0.1-0.5 U/hr Increase rate by 0.5-1 U/hr Increase rate by 2 U/hr

Department of Internal Medicine

Tight Glycemic Intensive Insulin Control in SICU


Mortality During Intensive Care
15%

In-Hospital Mortality
15%

p < 0.04 (adjusted)

p = 0.01
10.9%

Mortality (%)

10%

8.0% 4.6%

10% 7.2% 5%
n=783 n=765

5%
n=783

n=765

0%

0%

Conventional

Intensive Insulin

Berghe G, et al. N Engl J Med 2001;345:1359-67


National Taiwan University Hospital

Department of Internal Medicine

Intensive Insulin Therapy in MICU


In-hospital survival (%)
100 80 60 40 20 0

ITT group
In-hospital survival (%) Intensive treatment
P=0.40

100 80 60

ICU3 days
Intensive treatment
P=0.02

Conventional treatment

40

Conventional treatment
20 0

100

200

300

400

500

100

200

300

400

500

Days after admission

Days after admission

Berghe G, et al. N Engl J Med 2006;354:449-61


National Taiwan University Hospital

Department of Internal Medicine

Dysfunctional Protein C Pathway in Severe Sepsis

National Taiwan University Hospital

Department of Internal Medicine

PROWESS Trial Description


Randomized, double-blind, placebo-controlled trial 1690 patients, 164 centers, 11 countries. Enrollment criteria included:
Presence of suspected or proven infection, Evidence of systemic inflammatory response (SIRS3 or SIRS4) 1 sepsis-induced organ dysfunction(s)

Hypotension <90 mmHg or MAP<70 mmHg Hypoxia pO2 /FiO2 < 250 Oliguria < 0.5cc/kg for 1h Platelets <80k /D.I.C. or 50% drop Lactic acidosis (level >1.5 X normal) with pH<7.35
Bernard GR. N Engl J Med. 2001;344(10):699-709.

National Taiwan University Hospital

Department of Internal Medicine

Recombinant human Activated Protein C*


PROWESS 28-day Mortality High Risk of Death Patients*
60% 50% 44% 31% 30% 20% 10% 0%

Absolute Risk = 13% Reduction

Mortality Rate

40%

Placebo

Drotrecogin alfa (activated)

* as defined by APACHE II 25

*rhAPC is drotrecogin alfa (activated)


National Taiwan University Hospital

Department of Internal Medicine

Recombinant human Activated Protein C


High risk of death
APACHE II score 25, or Sepsis-induced multiple organ failure, or Septic shock, or Sepsis induced acute respiratory distress syndrome

Treatment should begin as soon as possible once been identified No absolute contraindication
Dellinger, et. al. Crit Care Med 2004, 32: 858-873.
National Taiwan University Hospital

Department of Internal Medicine

Risk v.s. Benefits in the real world

National Taiwan University Hospital

Department of Internal (Eichacker & Natanson. Intensive Care Med 2007;33:396) Medicine

Importance of establishing therapeutic goals in managing sepsis


Therapeutic goals
Low VT MV, Pplat 30 cmH2O Appropriate antibiotic within 4 hrs EGDT Decreasing lactate to 2 mmol/L in 24hrs Steroid when indicated Insulin for glucose 80-110 mg/dL DrotAA for APACHE II 25
National Taiwan University Hospital

Absolute Mortality Rate


9% 24% 16% 25% 10% 3% 13%

Department of Internal Medicine

Sepsis Bundles: Compliance vs. non-compliance

National Taiwan University Hospital

(Gao F et al. Crit Care 2005;9:R764) Medicine Department of Internal

Compliance to 24 h sepsis bundle


Compliance (%) Glucose control < 8.3mmol/L Low dose steroid Activated protein C Plateau pressure < 30cmH2O Total 64% 43% 30% 85% 30%
(Gao F et al. Crit Care 2005;9:R764)
National Taiwan University Hospital

Department of Internal Medicine

Improvement in Process of Care after Severe Sepsis Educational Program


In Spain, 59 ICUs with educational program for severe sepsis/shock definition, recognition and treatment by guidelines 854 pt in Pre- (11- 12/ 2005) and 1465 pt Postintervention (3-6/2006) Compliance with bundle improved after intervetnion A lower risk of hospital mortality (44.0 vs 39.7%, p=0.04) Hospital LOS did not change Compliance with resuscitation bundle return to baseline in long-term follow-up
(Ferrer R et al. JAMA 2008;299:2294)
National Taiwan University Hospital

Department of Internal Medicine

Closing Remarks
Goal of Surviving Sepsis Campaign Managing sepsis based on evidence Managing sepsis with protocol Sepsis resuscitation & management bundle

National Taiwan University Hospital

Department of Internal Medicine

Thanks for your attention!

National Taiwan University Hospital

Department of Internal Medicine

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