ATS Clinical Year in Review Sepsis Charles L. Sprung, M.D

Department of Anesthesiology and Critical Care Medicine

Hadassah Medical Center

ATS Clinical Year in Review

Sepsis

Charles L. Sprung, M.D.

Presenter DisclosuresPart 1: Personal financial relationships with commercial

interests relevant to this presentation during the past 12 months:

1. Eli Lilly & Co – Consultancies2. Novartis Corp- Other- Data Monitoring Committee 3. Takeda- Industry-sponsored grants4. Eisai, Corp- Other- Steering Committee + Industry-

sponsored grants5. Artisan Pharma, Inc- Other- Data Monitoring Committee 6. Hutchinson Technology Incorporated- Other- Data

Monitoring Committee

Presenter Disclosures

Part 2: Personal financial relationships with non-commercial interests (e.g., government or other nonprofit funding) relevant to this presentation, within past 12 months:

No relationships to disclose

Part 3: Relevant institutional financial interests: No relationships to disclose

Part 4: Personal financial relationships with tobacco industry entities within the past 3 years:

No relationships to disclose

• Russell JA, et al and the VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-87.

• Ferrer R, et al and Edusepsis Study Group. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA. 2008;299:2294-2303.

• Moreno RP, et al and SAPS 3 Investigators. Sepsis mortality prediction based on predisposition, infection and response. Intensive Care Med 2008; 34:496–504.

• Dulhunty JM, et al and for the ANZICS Clinical Trials Group. Does severe non-infectious SIRS differ from severe sepsis? Results from a multi-centre Australian and New Zealand intensive care unit study. Intensive Care Med. 2008;34:1654-61.

Clinical Year in Review- Sepsis

Surviving Sepsis Campaign Guidelines Vasopressors

• Either norepinephrine or dopamine as the first choice vasopressor agent to correct hypotension in septic shock.

Grade 1C

• Epinephrine, phenylephrine, or vasopressin should not be administered as the initial vasopressor in septic shock.

Grade 2C

• Vasopressin 0.03 units/min may be subsequently added to norepinephrine with anticipation of an effect equivalent to norepinephrine alone.

• Epinephrine be the first chosen alternative agent in septic shock that is poorly responsive to norepinephrine or dopamine. Grade 2B

Dellinger P. Crit Care Med 2008;36:296-327

• In this multicenter, randomized, double-blind placebo-controlled study, patients in septic shock receiving a minimum of 5 μg of norepinephrine per minute were randomized to receive either low-dose vasopressin (0.01-0.03 U per minute) or norepinephrine (5 to 15 μg per minute) in addition to open-label vasopressors.


Russell JA. N Engl J Med 2008;358:877

VASST PRIMARY HYPOTHESIS

• Low dose vasopressin (0.03 U/min) infusion compared to norepinephrine infusion decreases 28 day mortality from 60% to 50% in severe septic shock.

• N= 776 (power = 80%, α= 0.05)


VASST SECONDARY HYPOTHESES• The beneficial effects of vasopressin are more

pronounced in the subgroup of patients with more severe septic shock.

More Severe septic shock: ≥ 15 μg/min norepinephrine Less Severe septic shock: 5 - 14 μg/min norepinephrine

• 90-day mortality, days alive & free of organ dysfunction, length of stay (ICU & hospital)


CENTRES

• 27 centres in Canada, Australia and US

Plasma Vasopressin Norepinephrine vs. Vasopressin

Off AVP

NE

AVP


0

20

40

60

80

100

120

140

Baseline 6 hours 24 hours 72hours 7days

Timepoint

Pla

sma

vaso

pre

ssin

leve

l (

pmol

/L, m

edia

n +

IQR

)

Mean Arterial PressureVasopressin vs Norepinephrine

NE

AVP


0

20

40

60

80

100

120

0 5 10 15 20 25 30

Time from study drug infusion (days)

MA

P (

mm

Hg

, m

ea

n +

/-S

D)

Heart rate Vasopressin vs Norepinephrine (p < 0.001)

NE

AVP


50

60

70

80

90

100

110

120

130

0 5 10 15 20 25 30


He

rat

rate

(b

ea

ts /

min

, m

ea

n +

/-S

D)

Heart rate AVP vs. NE (Days 1 - 4, p < 0.001)

NE

AVP


50

60

70

80

90

100

110

120

130

0 5 10 15 20 25 30


He

rat

rate

(b

ea

ts /

min

, m

ea

n +

/-S

D)

Survival - All Patients

Log-rank statistic

p = 0.27 day 28

p = 0.10 day 90

VasopressinNorepinephrine

0 10 30 50 70 90

00.2

0.4

0.6

0.8

1

Days since initiation of study drug

Pro

babili

ty o

f surv

ival


Serious Adverse Events

Norepinephrine

(N=382)

Vasopressin

(N=397)

p

Myocardial infarction / ischemia 7 (1.8) 8 (2.0) 1.0

Cardiac arrest 8 (2.1) 3 (0.8) 0.14

Tachyarrythmia 3 (0.8) 4 (1.0) 1.0

Bradyarrythmia 3 (0.8) 4 (1.0) 1.0

Mesenteric ischemia 13 (3.4) 9 (2.3) 0.39

Hyponatremia 1 (0.3) 1 (0.3) 1.0

Digital ischemia 2 (0.5) 8 (2.0) 0.11

Cerebrovascular accident 1 (0.3) 1 (0.3) 1.0

Other 2 (0.5) 5 (1.3) 0.45

Total 40 (10.5) 41 (10.3) 1.0


Survival - Less Severe Shock

Log-rank statistic

p = 0.05 day 28

p = 0.03 day 90


0 10 30 50 70 90

00.2

0.4

0.6

0.8

1


Pro

babili

ty o

f surv

ival


Survival - More Severe Shock

Log-rank statistic

p = 0.77 day 28

p = 0.92 day 90


0 10 30 50 70 90

00.2

0.4

0.6

0.8

1


Pro

babili

ty o

f surv

ival


• This study demonstrates the comparable effectiveness of vasopressin to norepinephrine therapy for vasopressor treatment of septic shock.

• Vasopressin was used as an addition to norepinephrine and/or other vasopressor therapy for patients with relatively stable blood pressures on vasopressors, not rescue therapy for shock unresponsive to vasopressors.

• Similar adverse events in the two groups may have been due to the exclusion of patients with acute heart disease in the study.

• Vasopressin plus norepinephrine may decrease mortality compared to norepinephrine alone in less severe septic shock.

• Treatment started 12 hours after septic shock may be too late for a vasopressor or any other therapeutic agent to affect mortality.

Clinical Year in Review- Comments

• Recent septic shock studies demonstrate lower mortalities- this study - 37%, Sprung (N Engl J Med. 2008;358:111-124 )- 33% and Annane (Lancet 2007; 360: 767−84)- 37% than those previously reported- Annane (JAMA 2002;288:862-870 )- 58% and Annane (Am J Respir Crit Care Med 2003;168:165-72)- 60%.

• Physicians should be aware of the less recognized detrimental effects of catecholamines including stimulation of bacterial growth, increasing factors related to bacterial virulence and biofilm formation, affects on immune-cell populations and metabolic derangements which may not be present with alternatives such as vasopressin (Singer M. Lancet 2007;370:636-637).


Survival - All Patients

Log-rank statistic

p = 0.27 day 28

p = 0.10 day 90


0 10 30 50 70 90

00.2

0.4

0.6

0.8

1


Pro

babili

ty o

f surv

ival


Outcomes: Mortality NICE SUGAR Study

Intensive Glucose Control

Conventional Glucose Control

Odds ratio

(95% CI)

Dead at 28 days670/3010

22.3%

627/3012

20.8%

1.09

(0.96 - 1.23)P = 0.17

Dead at 90 days829/3010

27.5%

751/3012

24.9%

1.14

(1.02 - 1.28)P = 0.02

Adjusted mortality at 90 days

Adjusted for operative admission, geographic region, age, admission

source, APACHE II score, mechanical ventilation

1.14

(1.01 - 1.29)P = 0.04

Finfer S. N Engl J Med 2009;360:1283

Interaction of Vasopressin Infusion, Corticosteroid Treatment and Mortality of

Septic Shock

Russell et al. Crit Care Med 2009;37:811 - 818

Vasopressin /Corticosteroid Mortality Interaction

Steroids Steroids P No

Steroids

No Steroids P

NE AVP NE AVP

131 (44.7) 106 (35.9) 0.03 19 (21.3) 34 (33.7) 0.06

0.008 (1)

0.001 (2)

1. Interaction statistic by logistic regression.2. Age-adjusted interaction statistic by logistic regression Russell et al. Crit Care Med 2009;37:811 - 818






• Most studies of new therapeutic agents to decrease the high mortality of patients with severe sepsis have been negative.

• Clinical study results and evidence-based guidelines are often not translated into clinical practice.


EDUCATIONALPROGRAMME

POST-EDUCATIONDATA COLLECTION

NOV-DEC854 patients JAN-FEB MAR-JUN

1465 patients

2005 2006

BASELINE DATA COLLECTION

a before-and-after intervention study

2007

LONG-TERMFOLLOW-UP

MAR-JUN247 patients

JAMA 2008;299(19):2294-2303

Study Timeline

PE

RC

EP

TIO

N

THE SPANISH NETWORK

59 ICUs (21% of all Spanish ICUs)3 1

2

2

1

13

8

9

9

24

6

3

4

3

J. Ibañez

(Palma de Mallorca)

R. Ferrer

(Sabadell)

G. González-Díaz

(Murcia)Manuel Quintana (Talavera)

J. Blanco

(Valladolid)Mª Victoria de la Torre (Málaga)

E. Palencia

(Madrid)

J. Garnacho

(Sevilla)

Area Coordinators:

General Coordination:Antonio ArtigasRicard Ferrer(Sabadell, Barcelona)

SSC CoordinationM. Levy

Educational Program

Sepsis DefinitionsSepsis early recognitionSepsis treatments

Design EP

GeneralCoordination

AreaCoordinators

Area Coordinators + PI

Homogenize the EP

Educational Material

Educational Program: Homogeneity

PI

HospitalManager

Interview

Physicians

Nurses

ICU

ED

Medical Ward

Surgical Ward

Graphic material: distribution and display

Clinical training

Inclusion Criteria

• All ICU admissions from the emergency department or from wards because of severe sepsis or septic shock.

• All ICU patients who develop severe sepsis or septic shock.

Process-of-care variables

SEPSIS RESUSCITATION BUNDLE

SEPSIS MANAGEMENT BUNDLE

6H

24H

Resuscitation Bundle (6H)

* p<0.05

*

*

*

*

* *0

10

20

30

40

50

60

70

80

90

% C

om

pli

an

ce

Lactate Blood Cultures Antibiotics Fluids +Vasopresors

CVP>8 SvcO2>70 All

Preintervention Intervention

39.0

50.1 54.4

62.4 66.5

68.9

40.9

46.7

21.4

26.7

6.3

11.4

5.3

10.0

Management Bundle (24h)

* p<0.05

* * *

*

0

10

20

30

40

50

60

70

80

90

% C

om

pli

an

ce

Steroids APC Glucose IPP All


45.4

54.7

44.3

51.9

44.6

49.6

85.782.7

10.9

15.7

Educational Program and Mortality

4439.7

36.4

31.1

0

10

20

30

40

50

%

Hospital Mortality ICU Mortality


p= .036 p= .01

Absolute reduction: 4.3%Relative reduction 10%

28d Mortality: Kaplan-Meier curve

Absolute reduction: 4.3%Relative reduction 10%SSC objective was 25%!

Impact of Baseline Compliance

0

5

10

15

20

25

30

Pre-Intervention Post-Intervention

%

Cat 1 Cat 2 Cat 3

0

5

10

15

20

25

30


%

Cat 1 Cat 2 Cat 3

20

25

30

35

40

45

50


%

Cat 1 Cat 2 Cat 3

Resuscitation Bundle Management Bundle

Mortality

* p<0.05

***

*

*

Cat 1: < 4 tasks (n= 20)Cat 2: 4-5 tasks (n= 19)Cat 3: > 5 tasks (n= 20)

Resuscitation Bundle (6H)

0

10

20

30

40

50

60

70

80

90

% C

om

pli

an

ce

Lactate Blood Cultures Antibiotics Fluids + Vasopresors CVP>8 SvcO2>70 All

Preintervention Intervention Long-term

Long-term follow up (23 centers) * p<0.05

* **

*

*

42.8

61.1

69.6

53.5

60.5 59.165.4

71.0

56.7

44.7

53.0

65.2

25.2

30.0

39.3

10.0 13.7 14.6

6.3

12.97.3

Management Bundle (24h)

0

10

20

30

40

50

60

70

80

90

100

% C

om

pli

an

ce

Steroids APC Glucose IPP All


Long-term follow up (23 centers) * p<0.05

*

* *

*

44.3

59.1

69.7

38.4

49.0

59.1

44.7

51.056.3

87.889.6 94.8

9.4

19.6

26.7

Educational Program and Mortality

42.538.7

0

10

20

30

40

50

%

Hospital Mortality


38,5

Long-term follow up (23 centers)

• At baseline, process of care compliance rates were extremely low.

• After the intervention, compliance improved in the sepsis resuscitation and management bundles and hospital mortality decreased from 44% to 40%.

• Long-term follow-up revealed that compliance with sepsis resuscitation bundles returned to baseline but compliance with sepsis management and mortality remained stable in relation to the post-intervention period.


• This study demonstrated that a national educational program decreased hospital mortality in patients with severe sepsis.

• The study suggests that quality improvement programs using bundles of care may be more effective in decreasing mortality in sepsis than new treatments.

• Despite the fact that the interventions were rather simple, not institution specific and did not include more sophisticated, effective methods, mortality still decreased.


• Baseline compliance was rather poor and although compliance improved, the improvement rates were not dramatic nor sustained, especially for some bundles which would seem important in decreasing mortality such as antibiotic administration.

• Recent studies of steroid therapy (Sprung CL. N Engl J Med. 2008;358:111-124) and glucose control (Brunkhorst FM. N Engl J Med 2008;358:125-39; Finfer S. N Engl J Med 2009;360:1283-97) showing a lack of benefit in decreasing mortality raise questions as to the benefit of these bundles used in this study in decreasing mortality.

• The design without a control group makes it difficult to establish a causal connection between the intervention, improvement in process of care variables and outcome.







The PIRO ConceptThe PIRO Concept• Predisposition: Premorbid illness with reduced

probability of short term survival. Cultural or religious beliefs, age, gender.

• Insult: Culture and sensitivity (infection) of infecting pathogens; detection of disease amenable to source control.

Levy MM, Fink MP, Marshall JC, et al. (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.

Intensive Care Med 29:530-538.

• Organ: Organ dysfunction as number dysfunction of failing organs or composite score (e.g., MODS; SOFA; LOD).

• Response: SIRS, other signs of sepsis, shock, C-reactive protein.

• PIRO (predisposition, infection, response, organ dysfunction/failure), a system for risk stratification, remains a concept that has not been tested clinically.

• Using the SAPS 3 database, 2628 patients in the ICU for > 48 hours were evaluated to determine the usefulness of PIRO for predicting mortality in patients with infection and sepsis.


SAPS 3 PIRO ScoreSAPS 3 PIRO Score

Predisposition

• Age• Intra-hospital location• Co-Morbidities• Length of stay in the

hospital• Reasons for ICU

admission

Injury

• Acquisition of infection• Extension of infection• Site of infection• Agent

Response/Organdysfunction/failure

• Renal dysfunction• Coagulation dysfunction• Cardiovascular failure• Respiratory failure• Renal failure• Coagulation failure• CNS failure

Moreno R. Intensive Care Med 2008;34:496-504

• Hospital mortality was 41%.

• The SAPS 3 PIRO score had excellent predictive value for mortality and the PIRO components independently contributed to outcome prediction.


SAPS 3 INFECTION MODEL SCORE SHEETSAPS 3 INFECTION MODEL SCORE SHEET

Moreno R. Intensive Care Med 2008;34:496-504

PROGNOSTIC PERFORMANCE: PROGNOSTIC PERFORMANCE: DiscriminationDiscrimination

SAPS 3 model:

aROC: 0.735

(95% CI: 0.716-0.754)

PIRO model:

aROC: 0.772

(95% CI: 0.754-0.790)1,00,80,60,40,20,0

1 - Specificity

1,0

0,8

0,6

0,4

0,2

0,0

Se

ns

itiv

ity

PIROmodel

SAPS 3model

Diagonale Segmente ergeben sich aus Bindungen.

ROC-Kurve

• This is the first study addressing the question as to which factors affect the outcome of patients with sepsis in which the three levels of predisposition, injury and response were addressed together.

• This study demonstrates the clinical validity of the PIRO concept whose components independently contributed to mortality prediction.

• This PIRO system modeling the risk of mortality from sepsis attributes different weights to specific organ failures which is different than other scores which give all organ failures the same weight.

• Although provocative, the proposed system should be prospectively validated in an independent cohort to demonstrate its specific usefulness and clinical utility.


Does severe non-infectious SIRS differ Does severe non-infectious SIRS differ from severe sepsis?from severe sepsis?

Results from a multi-centre Australian and New Zealand intensive care unit study

Dulhunty JM1,2, Lipman J1,2, Finfer S3-5, and the Sepsis Study Investigators for the ANZICS Clinical Trials Group

Intensive Care Med. 2008;34:1654-1661

Background• Systemic inflammatory response syndrome (SIRS) -

physiological & laboratory abnormalities that accompany

inflammation

• Severe sepsis (SS) – well-described (high mortality & treatment

costs)

• Severe non-infectious SIRS (SNISIRS) – poorly described

SS = infection + SIRS + organ dysfunction

SNISIRS = non-infectious insult + SIRS + organ dysfunction

What is the mortality rate and cause of death in SNISIRS?

Is there a difference in the time-course of organ failure between SS and SNISIRS?

Methods• Prospective inception cohort study involving 23 ICUs

• Inclusion criteria: all elective & unscheduled ICU admissions ≥ 48 hours or < 48 hours with SIRS/organ dysfunction

• Patients screened daily for SIRS, an infectious focus & organ dysfunction from day 1 to ICU discharge or day 28

• SOFA scores used to monitor organ dysfunction

• The ICU prevalence of SS and SNISIRS was 20% and 28%, respectively.

• ICU (27% vs. 25%) and 28-day (33% vs. 32%) mortalities were similar in both groups.

• Multi-organ failure was the most common cause of death in SS and neurological failure in SNISIRS.

• The time to peak organ dysfunction, overall duration of organ dysfunction and ICU stay were shorter in SNISIRS patients.


Mortality was similar in patients with SS and SNISIRS

Days post ICU admission

2824201612840

Su

rviv

al %

100

80

60

40

20

0

SNISIRSSS

P = 0.50

Dulhunty JM. Intensive Care Med. 2008;34:1654-61

Organ dysfunction due to infectious & non-infectious insults is common & frequently present

on admission to the ICU

ICU prevalence:

SS – 20% (707/3543)

SNISIRS – 28% (980/3543)

2119

1570

1152

891

728627

514

202106

271203

17 124539

160

486

822

668

352

70221

16

364307 253

31

602 560453

0

500

1000

1500

2000

2500

1 2 3 4 5 6 7 14 21 28

Day of admission

Nu

mb

er

of

pa

tie

nts

No organ dysfunction SNISIRS SS

Prevalence of organ failure differed

Resp.Haem. Liver

Card.CNS

Renal

0

10

20

30

40

50

60

70

80

%

SS SNISIRS

Causes of death differed

Multi-organfailure

Neuro-logical

Cardiacarrest

Isolatedresp.

failure

Haem.shock

Pulmonaryembolism

Other Unknown

0

20

40

60

80

100

120

140

160

180

N

SS SNISIRS

• This study demonstrates that organ dysfunction from both SS and SNISIRS are common in ICU patients.

• The fact that SNISIRS is common in ICU patients should alert intensivists to the fact that many of these patients do not require antibiotics. Continued antibiotic use in these patients could lead to unnecessary increased antibiotic resistance.

• This is the first study to evaluate the type and time course of organ dysfunction comparing SS to SNISIRS.


• The similar mortalities of SNISIRS compared to SS require further investigation.

• Although the study prospectively evaluated a large number of patients, the findings in SNISIRS patients may relate to the specific case mix and geographic location of the patients.

• The study is limited by the lack of data on the time course of organ dysfunction prior to ICU admission.


Documents

ATS Clinical Year in Review Sepsis Charles L. Sprung, M.D