Sepsis Surgery Residents 2012

8/12/2019 Sepsis Surgery Residents 2012

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Sepsis:Evolving Concepts

John C. Marshall, MD FRCSC

St. Michaels Hospital University of Toronto


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Hippocrates

460370 BC

Sepsis

Pepsis


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Louis Pasteur

1822 - 1895

Fermentation

caused by living

organisms

Germ theoryof disease


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Consequences

Public health

Immunization

Sterilization

Antibiotics


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Susceptibility to LPS is

Transferred with Bone Marrow Cells

C3H HeJ

(Resistant) C3H HeN(Sensitive)

- Michalek, J.Infect.Dis.141:55, 1980


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C3H HeJ

(Resistant) C3H HeN(Sensitive)IRRADIATION

CROSSOVER BONE MARROW TRANSPLANT

+ LPS- Michalek, J.Infect.Dis.141:55, 1980


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C3H HeJ

(Resistant) C3H HeN(Sensitive)

HeN Marrow Die

HeJ Marrow Live

IRRADIATION

CROSSOVER BONE MARROW TRANSPLANT

+ LPS- Michalek, J.Infect.Dis.141:55, 1980


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Bruce Beutler

Passive immunization

against tumor necrosis

factor/cachectin protects

mice from the lethal effects

of endotoxin.

Beutler, Milsark, & Cerami

Science229:869, 1985


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Consequences

New diseases

New therapeutic targets

Response is the disease

Not unique to infection


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InfectionSepsis

Systemic Inflammatory

Response Syndrome

SIRSTrauma

Pancreatitis

Burns

ACCP/SCCM Consensus Conference 1991


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Rates of Sepsis, U.S. 1979 - 2001

- Martin, N Engl J Med348:1546, 2003


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Most Common Causes

of Death (WHO 2008)

1. Heart disease

2. Stroke

3. Lower respiratory infections4. COPD

5. Diarrheal diseases

6. HIV/AIDS

7. Tuberculosis8. Lung cancer

9. Vehicular trauma

10. Prematurity


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- Crit Care Med 36:296, 2008


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CVP

Mean Arterial Pressure

> 8

65 70Transfusion,

Inotropes


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The Impact of Goal-DirectedTherapy

Rivers E, et al. N Eng l J Med 2001;345:1368

0102030405060 Standard TherapyGoal directed

HospitalMortality 28 DayMortality 60 DayMortality

NNT to prevent 1 death = 6 8

Mortality(%

)


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OddsRatiof

orDeath

(95%C

I)

1

10

100

Time from Onset of Hypotension

(Hours)

-Kumar, Crit Care Med 34:1589, 2006

Impact of Delayed Antibiotic

Therapy on Clinical Outcome


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Impact of Source Control in

1170 Patients with Sepsis

28 Day Mortality

Adequate Inadequate p.

31.4% (303/964) 42.7% (88/206) 0.003

Odds Ratio 0.61 (0.45-0.83)


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Despite conventional

treatment, 25 - 30% of septic

patients die of a process

characterized by persistent

inflammation and non-resolving

organ dysfunction.


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Lipopolysaccharide (LPS)


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TLR4CD14

Endotoxin

IRAKMyD88

TRAF2

NFkB

MAP Kinases: Erk, p38, Jnk

PI3 Kinase

Pro-inflammatory genes:

IL-1, TNF

PAF, Nitric oxide,

CoagulationTissue ischemia,

Cell necrosis,

Apoptosis


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TLR4CD14

Endotoxin

IRAKMyD88

TRAF2

NFkB


PI3 Kinase


IL-1, TNF

PAF, Nitric oxide,


Cell necrosis,

Apoptosis


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TLR2 Lipoteichoic acid, bacterial

lipoprotein, Injured tissue

TLR3 Double-stranded RNA

TLR4 Endotoxin, elastase, heparan,

HSP60, oxidized phospholipids

TLR5 Flagellin

TLR6 Mycoplasmalipopeptide

TLR7 Imiquod, viral DNA

TLR8 Viral DNA, single-strand RNA

TLR9 Bacterial DNA

Toll-like Receptors


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Baseline 4 Hours

PMN/Mouse(X106)

0

2

4

6

8

10

C3H/HeN

C3H HeJDay 1 Day 7

Logcfu/Gmk

idney

0

2

4

6

8C3H HeN

C3H/HeJ

*

**

Clearance of Candidais Impaired

in TLR4 Mutant C3H/HeJ Mice

- Netea, J Infect Dis185:1483, 2002


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Mediators of

Lethality in Murine Endotoxemia

Cytokines IL-1, IL-12, IL-18, IL-27, TNF, IFN, TGF, LIF,MIF, G-CSF, HMGB-1, MIP-1, MFP-14, LBP, PTH-RP

IL-1ra, IL-4, IL-10, IL-13, IFN, HGF, LIF, CRP, MCP-1,

BPI, CAP18, TSG-14, VLDL, VIP, C3, C4, melatonin

Receptors TNFr p55, IL-1r, PAFr, LECAM-1, TREM-1, LDLr,CD11a, CD14VIPr, Adenosine A3r

Non-proteins PAF, PLA2Vitamin B12, Vitamin D3

Signal hck, COX-2, p38, jnk, NFB, iNOS, caspase-3transduction Stat4, Stat6, IB, HSP70, hemoxygenase

Coagulation PAI 1, Tissue Factor

Factors TFPI, APC

- Marshall Nature Rev Drug Disc 2:391, 2003


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LPS challenge inhuman volunteers

causes altered

expression of 3714

distinct genes.

- Calvano, Nature437:1032, 2005


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TLR4 Antagonists E5564 (Eisai)Others

CD14 Antagonists IC14

Anti-LPS Strategies Antibodies:J5, HA-1A, E5

rBPI21

Polymyxin B dextran

HDL, taurolidineAlkaline phosphatase

Lipid emulsion

Extracorporeal removal

Therapies Targeting Endotoxin


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TLR4CD14

Endotoxin

IRAKMyD88

TRAF2

NFkB


PI3 Kinase


IL-1, TNF

PAF, Nitric oxide,


Cell necrosis,

Apoptosis


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TLR4CD14

Endotoxin

IRAKMyD88

TRAF2

NFkB


PI3 Kinase


IL-1, TNF

PAF, Nitric oxide,


Cell necrosis,

Apoptosis


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Neutralization of Pro-Inflammatory

Cytokines in Sepsis

Interleukin-1 Receptor Antagonist

3 Studies; 1688 patients

28 Day Mortality

Odds Ratio: 0.80 (0.65-0.99)p=0.04


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Anti-TNF Antibodies

8 Studies; 6500 patients

28 Day Mortality

Odds Ratio: 0.93 (0.87-0.99)p=0.02

Neutralization of Pro-Inflammatory

Cytokines in Sepsis


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TLR4CD14

Endotoxin

IRAKMyD88

TRAF2

NFkB


PI3 Kinase


IL-1, TNF

PAF, Nitric oxide,


Cell necrosis,

Apoptosis


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Recombinant PAF Acetylhydrolase

Phase II Trial (N = 240)

28 Day Mortality (%)

Placebo Treated p.

Overall 28.4 14.5 0.03

Severe Sepsis 44.2 21.4 0.03

Trauma 10.5 5.9 NS

- Shuster, Crit Care Med31:1612, 2003


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Day of Study

P

ercentSurviving

0

20

40

60

80

100

0 7 14 21 28

Placebo

L-NMMAp


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rhAPC Reduces Mortality in Sepsis

-Bernard et al; NEJM 344:649, 2001


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TLR4CD14

Endotoxin

IRAKMyD88

TRAF2

NFkB


PI3 Kinase


IL-1, TNF

PAF, Nitric oxide,


Cell necrosis,

Apoptosis


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Annane D BMJ2004;329:480

Corticosteroids in Septic Shock:

A Meta-analysis


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0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3

Experimental Agent Better Placebo Better

Anti-TNF Antibodies

10 Trials; 6821 Patients

Anti-endotoxin Therapy

9 trials; 3057 Patients

IL-1ra


Intravenous immune globulin


Activated Protein C; All Patients

2 Trials 4303 Patients

Activated Protein C; Patients with MOF2 Trials; 2133 Patients

Adjuvant Therapy in Sepsis

- Marshall, J Leukoc Bio l83:471, 2008


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Ranieri et al. N Engl J Med 2012;366(22):2055-64.

Probability of Survival at 90Days

1.00.90.80.70.60.5

0.40.30.20.10.0

0 10 20 30 40 50 60 70 80 90Days Since Randomization

Placebo

DrotAA

Probabilityof

Survival

Number at risk

Placebo 845 703 656 622 593 579 569 563 557 553

DrotAA 851 701 645 616 596 584 576 567 561 555


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But Impact is modest

Indications for use poorly

defined


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0 1 2 3 4 5 6

Study Drug Better

All doses

5mg/kg/hr

Dose-dependent Effects of L-NMMA

on Survival

- Lopez, Crit Care Med32:21, 2004


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TNF Levels Following Infusion

Hours Post-Infusion

Pre 2 24 72

TNF(ng

/ml)

0

1

2

3

4

5

6

7

8

TNF MAb

Placebo


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Sepsis Syndrome

(Bone et al; 1987)

Suspected or proven infection, in

association with:

Tachycardia Tachypnea Hyper- or hypothermia Dysfunction of one or more organs


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Sepsis Syndrome

24 year old man with penetrating

injury to colon

86 year old woman with CHF and

Enterococcal UTI

51 year old man with COPD

exacerbation; Candidain sputum


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Median (pg/ml) Range

TNF 83 7 57,151

IL-6 965 81,553,435

IL-8 2130 16651,338

Cytokine Levels in Human Sepsis

- MONARCS, Unpublished


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The PIRO Concept

Predisposition

Insult Response

Organ dysfunction

- Crit Care Med 31:1250, 2003


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Cancer stagingstratifies by:

Prognosis

Potential torespond to

treatment


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Inflammatory Organ

Insult Response Dysfunction

Infection Adaptive Injurious Inflammation

Injury, Ischemia Iatrogenic

Ri k f D th


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Risk of Death:

Cause of Death of Biologic Parent

RR 95% CI

All causes 1.71 1.142.57Natural causes 1.98 1.253.12

Infection 5.81 2.4713.7

Cardiovascular 4.52 1.3215.4

Cancer 1.19 0.168.99

- Sorensen et al N Engl J Med318:727, 1988


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Tumor Necrosis Factor

G A; -308 (Promoter)

Author Disease Cases Controls p.

Nadel Meningococcemia 0.56 0.29 0.03

(deaths)

Mira Septic shock 0.52 0.24 0.008

(deaths)

Tang Septic shock 0.40 0.08


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M

eanChangeinDAS28

-4

-3

-2

-1

0

1 GGGA

AA

Etanercept (N=455) Infliximab (N=453)

*p=0.001

*

The TNF -308A/G Polymorphism Modifies

the Response to Anti-TNF Therapy

- Maxwell, Hum Mol Genet17:3532, 2008

Influence of Infectious Challenge on


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Absolute Risk Reduction (%)-40 -20 0 20 40 60S. pneumoniae

Grp. B Strep.S. aureus

CLPE. col i

LPS N=256

N=56N=23

N=14N=10

N=21

Influence of Infectious Challenge on

Response to Neutralization of TNF

- Lorente & Marshall, Shock 24 (Suppl):107, 2005


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Absolute Risk Reduction (%)-40 -30 -20 -10 0 10 20 30

M. tuberculos isListeria

Candida

Salmonel la N=11

N=14

N=10

N=11

- Lorente & Marshall, Shock24 (Suppl):107, 2005


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OR for 95%

Infectious Focus N Mortality CI

Intra-abdominal 31 1.38 0.56-3.40

Pneumonia 30 1.82 0.74-4.47

Bacteremia 57 1.83 0.79-4.26

Urinary Tract 23 0.49 0.15-1.60

Impact of Infection-Related Variables

on ICU Outcome


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Source Control Mortality

Adequate 126 (23.1%)

(N=545)

Inadequate 48 (39.7%)*(N=121)

* p


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Source Control Mortality

Adequate 177 (42.3%)

(N=419)

Inadequate 40 (47.1%)*(N=85)

* p=0.49

Impact of Source Control in

Patients with High IL-6 Levels


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Impact of Organ Dysfunction

on Response to Antibiotics

ICU Mortality

Adequate Inadequate p.

LOD > 4

(N=72) 21/36 (59%) 20/36 (56%) 0.81

LOD < 4(N=70) 2/27 (7%) 16/43 (37%) 0.006

- Clech, Intens ive Care Med 30:1327, 2004

Anti TNF is Most Efficacio s in


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* p=0.003;

OR 0.51 (0.32-0.80)

Baseline MOD Score

0-4 5-8 9-12 13-16 17-20 21-2428Da

yMortality

(Percent)

0

20

40

60

80

100

Placebo

Afelimomab

*

Anti-TNF is Most Efficacious in

Patients without Organ Dysfunction


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Sepsisis an

iatrogenic disorder:

It develops in the survivors

of acute life-threatening

infection

ICU care shapes its evolution


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Ventilation with lower tidal volumes as compared

with traditional tidal volumes for acute lung injury

and the acute respiratory distress syndrome

Mortality (%)

Controls 39.8

Volume-limited 31.0*

ARDSNet; NEJM342:1301, 2000

*P=0.007


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Fluid

resuscitation


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Impact of Fluid Strategy in ARDS

Conservative Liberal p.

(N=503) (N=497)

60 day mortality 25.5% 28.4% 0.30

Ventilator-free days 14.60.5 12.10.5


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Randomized Trials of

Antibiotic Minimization

Control Restrictive p.

Singh 2000 35% 15% 0.02

(Resistance)

Fagon 2000 25.8% 16.2% 0.02

(Mortality)

Chastre 2003 62.0% 42.1% 0.04

(Resistance)

S i i S i


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Global process change initiativebased on sepsis bundles

15,022 patients enrolled

7% absolute, 5.4% relative mortalityreduction (p


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Impact of Bundle Elements on

Hospital Mortality

O.R. 95% CI p.

Start antibiotics 0.86 0.790.93


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Conclusions

Improved understanding of biology

of response to injury

Can be translated into effective new

therapies

The obstacle is our intrinsic

conceptual conservatism


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Documents

Sepsis Surgery Residents 2012