Surviving Sepsis

Dr Ron Daniels

NHS Institute Safer Care Faculty

Chair: United Kingdom Sepsis Trust & Pre-hospital Working Group

ICC Birmingham, March 2010

A U.K. PerspectiveICNARC data 6 months to

01/06Severe Sepsis or Septic shock

Admissions Total 21,025

ICU mortality n (%) Total 6,534 (31.1%)

Hospital mortality n (%) Total 8,372 (39.8%)

Ron Daniels 2010

Lung1 Colon2 Breast3 Sepsis4

cancers

Annual

UK mortality

(2003),

thousands

1,2,3 www.statistics.gov.uk, 4 Intensive Care National Audit Research Centre (2006)

A U.K. Perspective

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Ron Daniels 2010

Sepsis Resuscitation Bundle (To be started immediately and completed within 6 hours)

Serum lactate measured

Blood cultures obtained prior to antibiotic administration

From the time of presentation, broad-spectrum antibiotics to be given within 1 hour

Control infective source

In the event of hypotension and/or lactate >4mmol/L (36mg/dl):

Deliver an initial minimum of 20 ml/kg of crystalloid (or colloid equivalent)

Give vasopressors for hypotension not responding to initial fluid resuscitation to maintain mean arterial pressure (MAP) > 65 mm Hg.

In the event of persistent arterial hypotension despite volume resuscitation (septic shock) and/or initial lactate >4 mmol/l (36 mg/dl):

Achieve central venous pressure (CVP) of >8 mm Hg

Achieve central venous oxygen saturation (ScvO2) >70%

Ron Daniels 2010

Sepsis Resuscitation Bundle (To be started immediately and completed within 6 hours)

Serum lactate measured

Blood cultures obtained prior to antibiotic administration

From the time of presentation, broad-spectrum antibiotics to be given within 1 hour

Control infective source

In the event of hypotension and/or lactate >4mmol/L (36mg/dl):

Deliver an initial minimum of 20 ml/kg of crystalloid (or colloid equivalent)

Give vasopressors for hypotension not responding to initial fluid resuscitation to maintain mean arterial pressure (MAP) > 65 mm Hg.

In the event of persistent arterial hypotension despite volume resuscitation (septic shock) and/or initial lactate >4 mmol/l (36 mg/dl):

Achieve central venous pressure (CVP) of >8 mm Hg

Achieve central venous oxygen saturation (ScvO2) >70%

Ron Daniels 2010

The Sepsis Six

1. Give high-flow oxygen via non-rebreathe bag

2. Take blood cultures and consider source control

3. Give IV antibiotics according to local protocol

4. Start IV fluid resuscitation Hartmanns or equivalent

5. Check lactate

6. Monitor hourly urine output consider catheterisation

within one hour

..plus Critical Care support to complete EGDT Ron Daniels 2010

SSC guidelines:Diagnosis, antimicrobials, control

Its not all about the infection!

CARS

SIRS

Organ dysfunction

Time

Infective insult

Antimicrobials

Septic shock: the golden hours

Organ i

njury

Inflamm

atory re

sponse

Toxic lo

ad

Microb

ial load

Shock threshold

Acknowledgement to Anand Kumar

SSC- diagnosis Obtain appropriate cultures before starting antibiotics

provided this does not significantly delay antimicrobial administration (1C)

Obtain two or more BCsOne or more percutaneouslyOne from each vascular access device in place > 48 hrsOther sites as clinically indicated

Perform imaging studies promptly to confirm and sample any source of infection, if safe to do so (1C)

SSC- diagnosisObtain two or more BCs

One or more percutaneously

Citation: Weinstein MP et al. Rev Infect Dis 1983

n = 500Retrospective99% sensitivity if 2 samples cultured

More recent work not cited, e.g:

Mayo Clinic 2005n = 37,5682 cultures 80%, 3 cultures 96%, 4 cultures 100%

One from each vascular access device in place > 48 hrs

Citation: Blot F et al J Clin Microbiol 1998

No mention of DTP91% specific, 94% sensitive for CRBSI (long-term)

No mention of gram stain AOLC test

SSC- diagnosis

SSC- antibiotics (1) Begin IV antibiotics as early as possible, and always

within the first hour of recognising severe sepsis (1D) and septic shock. (1B)

Broad-spectrum: one or more agents active against likely bacterial/ fungal pathogens and with good penetration into presumed source. (1B)

Reassess antimicrobial regimen daily to optimise efficacy, prevent resistance, avoid toxicity & minimise costs. (1C)

Consider combination therapy in Pseudomonas infections. (2D)

SSC- antibiotics (1)Begin IV antibiotics as early as possible, and always within the first hour of recognising severe sepsis (1D) and septic shock. (1B)

Citation: Kumar A et al. Crit Care Med 2006: 34(6)

Retrospective, 15 years, 14 sitesn = 2,154median 6 h, 50% administered in 6hOnly 5% first 30 minutes- survival 87%12% first hour- survival 84%

SSC- antibiotics (1)Broad-spectrum: one or more agents active against likely bacterial/ fungal pathogens and with good penetration into presumed source (1B)

Citation: Ibrahim et al. Chest 2000;118:146155

BSI, n = 492

59.1% HAI

29.9% inadequate, 8.3% fungal Mor

tality

(%)

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SSC- antibiotics (1)Consider combination therapy in Pseudomonas infections (2D)

Citation: Garnacho-Montero et al. Crit Care Med 2007; 25

n=183Initial combination Rx reduced risk inadequate coverNo outcome difference combination vs. mono

NNIS (US) 25% fluoroquinolone resistant

Safdar N et al. Lancet Infect Dis 2004; 4

Meta-analysis of 6 RCTs

Summary Risk Ratio 0.50 (0.32-0.79) in favour of combination

Strong trend in support in retrospective SGA of Paul meta-analysis

SSC- antibiotics (2) Consider combination empiric therapy in neutropenic

patients.(2D)

Combination therapy no more than 3-5 days and de-escalation following susceptibilities. (2D)

Duration of therapy typically limited to 710 days; longer if response slow, undrainable foci of infection, or immunologic deficiencies. (1D)

Stop antimicrobial therapy if cause is found to be non-infectious (1D)

SSC- antibiotics (2)Consider combination empiric therapy in neutropenicpatients.(2D)

Combination therapy no more than 3-5 days and de-escalation following susceptibilities. (2D)

Citations incl: Cochrane Syst Rev 2006 Jan 25;(1)

n = 7586 (68 RCT)-lactam alone or -lactam + aminoglycoside No all-cause mortality difference: RR 0.87(0.75-1.02)Similar results with vancomycin Paul et al JAC 2005

Combination or mono- HAP?Author Drugs Outcome CommentMangi Cefoloperazone

vs Ceftaz/ Gent87 vs 72 Monotherapy

cheaperCometta Imipenem vs

Imipen/ Netil80 vs 86 6 nephrotoxicitiy

with comboRubinstein Ceftazidine vs

Ceftriax/ Tobra85 vs 77 9 nephrotoxicity

with comboSeiger Meropenem vs

Ceftriax/ Tobra80 vs 72 Monotherapy

superiorAlvarez-Lerma Meropenem vs

Ceftaz/ Amikacin88 vs 85 Monotherapy

superior for VAPHeyland Meropenem vs.

Mero/ Cipro80 vs 82 No difference

Antibiotics- summary

Adequacy of initial spectrum the keyReduce microbial and toxic load

Possible role for combination therapy Pseudomonas, neutropenia, septic shock

Hit hard and hit fast

.... BUT....

Whos gonna develop shock?

We often dont know the source, let alone the bug....

AND the biggest but of all:

Are any 2 of the following SIRS criteria present and new to your patient?

Obs: Temperature >38.3 or 20 min-1

Heart rate >90 bpm Acutely altered mental state

Bloods: White cells 12x109/l Glucose>7.7mmol/l (if patient is not diabetic)

Severe Sepsis Screening Tool

If yes, patient has SIRS

Is this likely to be due to an infection?For example

Cough/ sputum/ chest pain Dysuria

Abdo pain/ diarrhoea/ distension Headache with neck stiffness

Line infection Cellulitis/wound infection/septic arthritis

Endocarditis

If yes, patient has SEPSISStart SEPSIS SIX

Screening Tool

Senior staff: check for SEVERE SEPSIS

Severe Sepsis: Ensure Outreach and Senior Doctor attend NOW!

BP Syst < 90 / Mean < 65(after initial fluid challenge)

Lactate > 4 mmol/l

Urine output < 0.5 ml/kg/hr for 2 hrs

INR > 1.5

aPTT > 60 s

Bilirubin > 34 mol/l

O2 Needed to keep SpO2 > 90%

Platelets < 100 x 109/l

Creatinine > 177 mol/l or UO < 0.5 ml/kg/hr

SSC- source control A specific anatomical source of infection amenable to

urgent drainage be sought and diagnosed or excluded as soon as possible (1C) and within 6 hours following presentation (1D)

If infected peripancreatic necrosis is identified, source control is best delayed until adequate demarcation has occurred (2B)

The intervention associated with the least insult should be employed (1D)

When VADs are a potential source, they should be promptly removed (1C)

The remainder of the Bundle:

EGDT

The Importance of Early Goal-Directed Therapy for Sepsis Induced Hypoperfusion

Adapted from Table 3, page 1374, with permission from Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-1377

Standard therapy

EGDT

NNT to prevent 1 event (death) = 6-8

ARR 16%In-hospital mortality

(all patients)

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28-day mortality 60-day mortality

Mor

talit

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Huang DT, Clermont G, Dremsizov TT, Angus DC. Implementation of early goal-directed therapy for severe sepsis and septic shock: A decision analysis. Crit Care Med 2007; 35(9): 2090-2100Early delivery of EGDT could be associated with favourable lifetime cost effectiveness projections

Jones AE, Focht A, Horton JM, Kline JA. Prospective external validation of the clinical ED-based EGDT protocol for severe sepsis and septic shock. Chest 2007;132 (2):425-32Prospective interventional evaluation of continuous EGDT ED to ICU. 9% ARR, 33% RRR

Ron Daniels 2008

3 arms, n=650 each Rivers Simple protocol- no transfusion, OGD Standard care

Subprojects Efficacy Mechanisms Cost

Open label RCT

Rivers vs standard care

118 of 1800 recruited across 21 sites

90 day mortality

ProMISe

UK

Protocolised management in septic shock

Design/ prospective centre recruitment

Evidence emerging

Sepsis Nurse Practitioners

NIHR grant1.0 WTE for 1 yearDuties:

Prospective observational studyEducationClinical leadData capture and reporting

Compliance at Good Hope Hospital (%)

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Sepsis 6ResuscBoth

Ron Daniels 2008

Reproduction in part or whole not permitted

Compliance and mortality at Good Hope Hospital (%)

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Sepsis 6ResuscBothMortality

Ron Daniels 2008

Reproduction in part or whole not permitted

Mortality by Sepsis Six

Cohort size Mortality % RRR

Total 567 34.7

Sepsis Six : Oxygen therapyBlood cultureAntibiotic administrationFluid challengesLactate and haemoglobin measurementUrine output monitoring. within one hour

Resuscitation Bundle: SSC, within 6 hours following recognition

Ron Daniels 2010

Reproduction in part or whole not permitted

Mortality by Sepsis Six

Cohort size (%)

Mortality % RRR %(NNT)

Pending publication: data withheld

Risk reduction > 40%Sepsis Six

Sepsis Six

Ron Daniels 2010

Reproduction in part or whole not permitted

Mortality by SSC Resuscitation Bundle

Cohort size Mortality % RRR %(NNT)

TotalPending publication: data withheld

Risk reduction > 70%Resusc.bundle

Resusc.bundle

Ron Daniels 2010

Reproduction in part or whole not permitted

Mortality by antibiotics

Cohort size Mortality % RRR %(NNT)

TotalPending publication: data withheld

Risk reduction > 35%Delayed AntibioticsAntibiotics within 1 h

Ron Daniels 2010

Reproduction in part or whole not permitted

Mortality by fluid challenges

Cohort size Mortality % RRR %(NNT)

TotalPending publication: data withheld

Risk reduction > 40%No fluids in 1h

Fluids in 1h

Ron Daniels 2010

Reproduction in part or whole not permitted

Mortality by fluids and antibiotics

Cohort size Mortality % RRR %(NNT)

TotalPending publication: data withheld

Risk reduction > 40%Neither fluids nor antibiotics in 1hrAntibiotics after BC andfluids

Ron Daniels 2010

Reproduction in part or whole not permitted

PerspectiveSevere Sepsis Acute coronary

syndrome

No. cases per 100,000 per annum 127 200

NNT basic care Sepsis Six (our data) 6.4 Clopidogrel 48

-blockade 42

Aspirin 26

NNT invasive care EGDT (Rivers) 6.3

Resusc Bundle (SSC) 18.5

Thrombolysis 15

PCI over thrombolysis 33

SSC Results: Critical Care Medicine 2010; 38(2): 1-8

15,022 patients, 165 sites

Compliance up from 11 to 31% (in 2 years)

ARR 6.2%

RRR 16.8%

P< 0.001

Ron Daniels 2010Not for reproduction in any form

SSC Results: Critical Care Medicine 2010; 38(2): 1-8

Ron Daniels 2010

Bundle target OR (95% CI)for mortality

p

Antibiotics 0.86 (0.79-0.93) 0.0001

Blood cultures 0.76 (0.70-0.83) 0.0001

Glycaemic control 0.67 (0.63-0.71) 0.0001

What next?

www.clinicaltrials.gov

As at 1st March:

491 trials registered

51 phase II actively recruiting

52 phase III actively recruiting

Global Sepsis Alliance

U.K Pre-hospital Sepsis Working Group

U.K Sepsis Trust

NPSA

Recognition

Biomarker blueprintProcalcitonin, CRP, IL-6, Adrenomedullin, Soluble adhesion molecules, lipoprotein binding molecule

Genetic predisposition/ risk stratificationGenOSept in progress (ESICM)Standardised genotyping- TNF receptor, TLR 4

Pathway Target Treatment

Hostpathogen interaction LPS Antiendotoxin

Toll receptors TLR antagonists TAK242

Neutrophil GCSF

Cell adhesionLeukocyteendothelial interactions

Inflammatory cascade TNF alpha Anti TNF

IL1 beta IL1ra

IL6 IL6 antagonist

Prostagrlandins, leukotrienesIbuprofenHigh dose steroids

Platelet activating factor PAF acetyl hydrolase

Isoprenoid intermediates Statins

HighMobility Group B1 Protein

Ethyl pyruvate

Oxidants Nacetylcysteine

Microcirculation Microcirculatory dysfunction Prostacyclin

Nitrates

Dobutamine

Coagulation Protein C Activated protein C

Protein S Protein S

Antithrombin III Antithrombin III

Tissue factor Tissue factor antagonist

Apoptosis White cell apoptosis Anticaspases

Epithelial cells Anticaspases

With permission from Daniels R, Perkins G. NHS Evidence Library, October 2009

Potential sites for targeted therapies

Sepsis is the worlds second biggest killer

The SSC has generated guidelines, discussion and multi centre trials

Guidelines and evidence are incomplete

Data suggests improved outcomes

SCCM/ACCP consensus definitions are imperfect and will be improved upon

Well have more robust bundles soon...

Summary

To Survive Sepsis...Organisational awarenessIndividual awarenessEmpowered personnelImmediate

SamplingAntibioticsFluidsSepsis Six?

In non-respondersCVC and vasopressorsEGDT?

The choicesInaction SSC evangelist Well do our own

thing

Rationale Ill wait for evidence International guidance

Local excellence

Benefits Robust medicine, lack of harm

Supported by many and by much

evidence, doing something

More likely to lead to innovation

Concerns Patients denied treatment

Patients treated inappropriately and ?

harmed

Good practice may not be disseminated

ReproducibilityMortality 39.8%. Thats ok. Strive toward 30% May be lower than

30%, may not be

Statement of interests

Within the last 24 months, I have received travel expenses to deliver one European lecture and have

been sponsored to attend one European international meeting by Eli Lilly and Co. I have received no honoraria

or other personal remuneration.