Sepsis management bundle:is it time to forget it?

Djillali Annane,Hôpital Raymond Poincaré (AP-HP)Université de Versailles SQY

Severe sepsis and septic shock

Comparison With Other Major Diseases

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00

250

300

Incidence of Severe Sepsis Mortality of Severe Sepsis

200 000

250 000

†National Center for Health Statistics, 2001. §American Cancer Society, 2001. *American Heart Association. 2000. ‡Angus DC et al. Crit Care Med. 2001;29(7):1303;29(7):1303--13101310.

AIDS* Colon BreastCancer§

CHF† Severe Sepsis‡

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100

150

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50 000

100 000

150 000

200 000

Dea

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AIDS* SevereSepsis‡

AMI†Breast Cancer§

Comparable Global Epidemiology

� 95 cases per 100,000 � 2 week surveillance � 206 French ICUs

� 95 cases per 100,000 � 95 cases per 100,000 � 3 month survey � 23 Australian/New

Zealand ICUs

� 51 cases per 100,000� England, Wales and

Northern Ireland.

Clinical Inertia: Tales from the Past

� National Registry MI 2� 84,663 MI patients

eligible for reperfusion� 24% got NO form of

reperfusionreperfusion

� 10 years after therapy shown to save lives� 1 of 4 not treated� 10,000 lives lost/year � Estimated 100,000

lives lost due to failure to treat Barron, HV. Circulation. 1998;97:1150-1156.

What is a Bundle?

� Specifically selected care elements � From evidence based

guidelines guidelines � Implemented together

provide improved outcomes compared to individual elements alone

� 2004: International group of experts, representing 11 organisations, published 46 guidelines to improve outcome

� 2008: Revision of these guidelines� Use of GRADE system to classify

strength of recommendations -> large improvement guidelines

6 - hour Severe Sepsis/

Septic Shock Bundle

� Early Detection:� Obtain serum lactate

level.

� Early Blood Cx/Antibiotics:within 3 hours of

� Vasopressors:� Hypotension not

responding to fluid� Titrate to MAP > 65

mmHg.

Septic shock or lactate > 4 � within 3 hours of presentation.

� Early EGDT: � Hypotension (SBP < 90, MAP <

65) or lactate > 4 mmol/L:� initial fluid bolus 20-40 ml of

crystalloid (or colloid equivalent) per kg of body weight.

� Septic shock or lactate > 4 mmol/L:� CVP and ScvO2 measured.� CVP maintained >8 mmHg.� MAP maintain > 65 mmHg.

� ScvO2<70%with CVP > 8 mmHg, MAP > 65 mmHg:� PRBCs if hematocrit < 30%. � Inotropes.

185

180

200

300

350

450

500

Time from Entering ED to Transfer to MICUReduced by 51%

Time from Entering ED to Catheter Insertion

Reduced by 60%

Time from Entering EDto Receiving Antibiotics

Reduced by 42%

Rhode Island Hospital EGDT Data

148

9095

10611

0

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100

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0

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100

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24 - hour Severe Sepsis and Septic Shock Bundle

� Glucose control:

� maintained on average <150 mg/dL (8.3 mmol/L)� Drotrecogin alfa (activated):

� administered in accordance with hospital � administered in accordance with hospital guidelines

� Steroids:

� for septic shock poorly responsive to fluid and vasopressor.

� Lung protective strategy:

� Maintain plateau pressures < 30 cm H2O for mechanically ventilated patients

Between January 2005 to March 2008, 15 775 patients in 252 sites

31.1%58.9%

10%

Let’s have a close look at what would you forget….

6 Hour Resuscitation Bundle

� Early Identification� Early Antibiotics

and Cultures� Early Goal Directed � Early Goal Directed

Therapy

Septic Shock: Timing of Antibiotics

.60.60.60.60.60.60.60.60

.80.80.80.80.80.80.80.80

1.001.001.001.001.001.001.001.00

% Survival

% Total receiving antibioticsPercentPercentPercentPercentPercentPercentPercentPercent

14 ICUs; n = 2,731

Kumar Crit Care Med 2006

0.00.0

.20.20.20.20.20.20.20.20

.40.40.40.40.40.40.40.40

.60.60.60.60.60.60.60.60

Time, hrsTime, hrs

Only 50% of patients in Septic Shock

received antibiotics w/in 6 hrs.

Dunser et al, Crit Care 2009

24 - hour Severe Sepsis and Septic Shock Bundle

� Glucose control:

� maintained on average <150 mg/dL (8.3 mmol/L)

Takahashi et al, Intensive Care Med 2003

Blood Glucose Levels and Mortality

Finney, JAMA 2003

The Danger of Misinterpretating the

Clinical EvidenceClinical Evidence

Studies similarities and differences

VDB 2001 VDB 2006 VISEP 2008 NICE Sugar 2009

Glucontrol 2009

Population All consecutive patients except 14 in a SICU

1200/2110 consecutive patients in a MICU

537 patients with sepsis in 18 sites over 26 months

6104/40171ICU patients

1091 mixed ICU patients in 21 sites over 24 monthsSICU months

Exp arm 4.4 to 6.1 mmol/l and control after ICU discharge

4.4 to 6.1 mmol/l and control after ICU discharge

4.4 to 6.1 mmol/l and NO control after ICU discharge

4.5 to 6.0 mmol/l and NO control after ICU discharge

4.4 to 6.1 mmol/l and NO control after ICU discharge or oral feeding

Control arm Insulin started if BG>11.9Target: 10 to 11.1

Insulin started if BG>11.9Target: 10 to 11.1

Insulin started if BG>11.1Target: 10 to 11.1

Insulin started if BG>10?Target: less than 10 Target: 7.8 to

10

Studies similarities and differences

VDB 2001 VDB 2006 VISEP 2008 NICE Sugar 2009

Glucontrol 2009

Samples Whole BG in undiluted arterial blood

Whole BG in undiluted arterial bloodOr capillary

Whole BG in undiluted arterial bloodOr capillary

Whole BG in undiluted arterial bloodOr capillary

Whole BG in undiluted arterial bloodOr capillary Or capillary

bloodOr capillary blood

Or capillary blood

Or capillary blood

Team training

1 year prior to study

3 months prior to study

unclear unclear 1 month prior to study

Main endpoint

ICU mortality in long stayers >5days

In-hospital mortality in long stayers >3 days

28-day mortality and mean SOFA

90-day mortality

ICU mortality

Studies similarities and differences

6,57

7,58

8,59

Blo

od G

luco

se le

vels

, mm

ol/L

44,5

55,5

66,5

VDB2001

VDB2006

VISEP20

08

NICE S

UGAR 200

9

GLUCONTROL2

009

Exp armControl arm

Blo

od G

luco

se le

vels

, mm

ol/L

250

200

Blood

gluco

se, mg/

dl p < 0.001

For eachcomparison

Target range (CIT)

Studies similarities and differences

150

100

50

Blood

gluco

se, mg/

dl

Difficulties in Achieving Target Ranges

112

151

VISEP2008 VDB2001 VDB2006 Glucontrol2009 NICESUGAR2009

153

103

153

111

139

110 118

145

Effects of Baseline Glucose Levels on Response to IIT

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Odd

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atio

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urvi

val

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17,6 7,8 8 8,2 8,4 8,6 8,8 9

Blood glucose levels mmol/L

Odd

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atio

of s

urvi

val

Effects of Nutritional Support

24 - hour Severe Sepsis and Septic Shock Bundle

� Steroids:

� for septic shock poorly responsive to fluid and vasopressor.

Current Use of Corticosteroids in Practice

50607080

01020304050

CATS

VASSTH1N

1 AN

ZIC

H1N1

USH1N

1 Can

ada

NICE S

UGARSSC s

urvey

ANZICS Survey on Steroids Use

� between July-Oct 2009 � 93 respondents� 93 respondents� 72% routinely use steroids in sepsis !

Venkatesh, personal communication

Secular Trends in Mortality with Introduction of Corticosteroids

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2000

2001

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2009

Ger-Inf-05, CATS and COIITTS trials network

ICU Length of Stay

Annane, JAMA 2009

CORTICUS- sub group mimicking Jama 2002 studyITT-Analysis-Ger-Inf-05 Corticus- subgroup

Steroids 82/150 (55%) 31/69 (45 %) Placebo 91/149 (61%) 32/57 (56%)

Total 173/299 (58%) 63/126 (50%)

Hazard ratio 0.45 95% CI 0.21 to 0.93 P = 0,0323

Steroids

Placebo

non responders

Hazard ratio 0.90 95% CI 0.45 to 1.78 P = 0.75

responders

1

10

-100 -50 0 50 100 150 200 250 300 350 400

Rel

ativ

e R

isk

of

dea

th a

t 28

-day

y=-0.002x + 1.18p=0.015

The Influence of Duration of Treatment at Full Dose

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0,1

-100 -50 0 50 100 150 200 250 300 350 400

Time at full dose of glucocorticoids (hours)

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Annane JAMA 2009

24 - hour Severe Sepsis and Septic Shock Bundle

� Drotrecogin alfa (activated):

� administered in accordance with hospital guidelines

Toussaint, NEJM 2009

Toussaint, NEJM 2009

30

35

PROWESS: 28-Day All Cause Mortality

30.8%30.8%

24.7%24.7%

Primary Analysis Results2-sided p-value 0.005Relative Risk Reduction 19.4%Increase in Odds of Survival 38.1%

0

5

10

15

20

2524.7%24.7%

PlaceboPlacebo(N=840(N=840))

DrotrecoginDrotrecoginAlfaAlfa

(activated)(activated)(N=850)(N=850)

G. Bernard, et al. N Engl J Med 2001;344:699-709

Ongoing Confirmatory Trials

� APROCCHS� PROWESS SHOCK

In conclusion

1. SSC guidelines are still up to date2. Implementation of SSC guidelines has

proven survival benefit3. Earlier trials (APC, EGDT, IIT, LDS)

supporting part of SSC bundles have NOT been replicated. Trials conducted after 2002 have used different design, different populations and could NOT be used to argue against the earlier trials