Post on 06-Feb-2018
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
0
20
30
40
10
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
(%)
0
50
70
10
30
Appropriate initialantibiotic
Inappropriate initialantibiotic
p
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)
0
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20
30
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60
28-day mortality 60-day mortality
Mor
talit
y (%
)
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 (%)
0
10
20
30
40
50
60
70
Apr-09 Jun-09 Aug-09 Oct-09
Sepsis 6ResuscBoth
Ron Daniels 2008
Reproduction in part or whole not permitted
Compliance and mortality at Good Hope Hospital (%)
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50
60
70
Apr-09 Jun-09 Aug-09 Oct-09
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.