Professor Richard Beale @ MRF's Meningitis & Septicaemia in Children & Adults 2015

Richard Beale FRCA, FFICM
King’s Health Partners
London, UK
On behalf of the SCCM/ESICM Surviving Sepsis Campaign
Surviving Sepsis 2015

Disclosures
• Personal:
– Financial:
• None
• SSC
– Financial:
• None
• No industry support since 2006
• Initial industry support from Eli Lilly & Co, Baxter
Lifesciences and Philips Medical Systems
• Robust COI policy in place

Let me remind you…
• In the 1990s – common presentation of severe
sepsis was “sudden” respiratory arrest (or peri-
arrest)
• Recognition, and presentation to ICU, was
frequently physiological decompensation, and final
collapse, with established multi-organ failure
• Mortality was high
• Severe sepsis was an ICU “disease”

Let me remind you…
• Attitudes to treatment were nihilistic – all trials were
negative, clinician opinion was the dominant driver
of practice, with much inconsistency
Then, from 2000 onwards, seminal studies
appeared:
• 2000 - Tidal volume control in ARDS
• 2001 - Tight glycaemic control
• 2001 - Early Goal Directed Therapy

Origins of the Surviving Sepsis Campaign
• It was against this context that the SSC was
established:
– A desire to address the ongoing and potentially
preventable mortality from sepsis
– The emergence of new therapeutic approaches
that finally held out hope of reducing mortality
– The realisation that processes of care were too
fragmented to deliver these new approaches
reliably

Campaign Structure
• And so the Campaign had an unique approach:
1.Build awareness and establish the need for
change – Professor Graham Ramsay
2.Assimilate the evidence in the most authoritative
manner possible – Professor R Phillip Dellinger
3.Design an implementation approach that would
ensure the process change necessary actually to
deliver the new evidence-based practices, and so
improve outcome - Professor Mitchell Levy

The sepsis landscape is changing…
• Definitions
• Incidence and outcome
• Recent large studies
• New SSC guidelines
• Health system interest
• But – also still considerable disparities in
performance
• This is therefore a crucial time to build upon what
we have achieved

Sepsis Definitions
• New Sepsis Task Force established by SCCM and
ESICM – working currently
• Chairmanship of Professor Cliff Deutschman and
Professor Mervyn Singer
• Definitions will be released soon, but we already
know:
– More data based, i.e tested against large
databases
– Will be simpler
– Term severe sepsis will disappear

Comparative Incidence
• The incidence of severe
sepsis is greater than
that of AIDS, colon &
breast cancer, and
Chronic Heart Failure
(CHF) 0
50
100
150
200
250
300
†
National Center for Health Statistics, 2001.
§
American Cancer Society, 2001.
*American Heart Association. 2000.
‡
Angus DC et al. Crit Care Med. 2001.
AIDS†
Colon Breast
Cancer§
CHF* Severe
Sepsis‡
Cases/100,000

0%
10%
20%
30%
40%
50%
60%
Italy Spain Germany UK France USA
8%
13%
53%
14%
4%
19%
yes
yes
Surviving Sepsis Campaign:
Public Awareness Survey

The Epidemiology of Sepsis: USA 1979-
2000 Martin GS et al. NEJM 2003;
• ICD-9 sepsis codes
• Sample of 500 acute hospitals
• 750 million hospitalisations
• 10,319,418 cases of sepsis / 22 yrs
Incidence Mortality

What is the true impact of sepsis?
• What do we need to know to judge the
epidemiological landscape?
– The true incidence
• requires comprehensive data capture and
standard definitions
– Unconfounded outcomes
• Equity of treatment
• We have neither of these things…

Message
• There are major methodological issues with
documenting the true incidence and outcomes for
severe sepsis
• Nevertheless, there seems little doubt that the
recognition and incidence are both genuinely going up
• Outcomes also seem to be improving
• Even if the denominator is changing, and access is
improving, these are good rather than bad things
• The Campaign, and the efforts of dedicated clinicians,
have resulted in this dramatic change

Change in Compliance Over Time
Levy MM et al. CCM 38(2):367-374, February 2010.

Mortality of Sites During Campaign
Mortality over 4 year study period
• 36.7% to 27.5%
• ARR: 9.2% and RRR: 25.0%
• p=0.005

• We recommend the protocolized, quantitative resuscitation of
patients with sepsis- induced tissue hypoperfusion. During the
first 6 hours of resuscitation, the goals of initial resuscitation
should include all of the following as a part of a treatment
protocol (grade 1C):
a) CVP 8–12 mm Hg
b) MAP ≥ 65 mm Hg
c) Urine output ≥ 0.5 mL/kg/hr
d) Scvo2 ≥ 70%.

Background of Resuscitation Bundle
• Landmark trial by Rivers in
2001
• Single-centre design RCT
• N=263
• Randomized EGDT vs. usual
care
• 16% Absolute Mortality
reduction

Rivers Protocol
Potential for RBC
and Inotropes
Potential for RBC
and Inotropes
Therapy
titrated to
CVP, MAP
and ScvO2
Therapy
titrated to
CVP, MAP
and ScvO2
Early insertion of
ScvO2 catheter
Early insertion of
ScvO2 catheter

Questions still to be answered from Rivers..
• Is the difference due to protocolized care?
• Is it necessary to use all elements of the protocol?
– Controversial aspects include:
• Early CVP line insertion
• ScvO2 monitoring, which drives RBC and inotropes
• Are the results generalizable?
– In 2015 where we have SSC +
• With current practices
• In a multi-centric design

Why continue with CVP and ScvO2?
• Evidence base
– Including (crucially) the success of the first
phase of the Campaign itself
• Belief that patients with severe sepsis and septic
shock should have a central line
• Limitations of all postulated alternative approaches
• Inability to generalise other technologies
– Only a CVC/blood gas analyser combination is
available (nearly) everywhere

In the last 12 months there have been 3
RCTs published in the NEJM repeating this
work.
• ProCESS / ARISE / PROMISE
• Each of these essentially repeats the Rivers work,
but
– In a multi-centric design
– In a group of patients with a better outcome
• None of them have been able to repeat the
findings of improved outcomes with this
protocolised methodology

Caveats / Limitations of ProCESS, ARISE
& PROMISE
• Usual care was usual care when shock was recognized
– It did not test:
• Early versus late recognition
• Prompt versus late treatment
• Therefore these studies do not undermine efforts to
– Promote sepsis awareness, early diagnosis and prompt
treatment.
• These studies were not a repeat of the Rivers study
– Single versus multi-centered
– Late 1990s versus 2008-13

Original Article
A Randomized Trial of Protocol-Based Care for
Early Septic Shock
The ProCESS Investigators
N Engl J Med
Volume 370(18):1683-1693
May 1, 2014

Study Overview
• In septic shock, the first few hours of care are critical for survival.
• In this study, two protocols for the care of patients with septic shock were
compared with usual care with respect to 60-day mortality and other
outcomes.
• There were no significant differences in outcome.

Cumulative Mortality.
The ProCESS Investigators. N Engl J Med
2014;370:1683-1693

Characteristics of the Patients
at Baseline.
The ProCESS Investigators. N Engl J Med
2014;370:1683-1693

Outcomes
The ProCESS Investigators. N Engl J Med 2014;370:1683-1693

Conclusions
• In a multicenter trial conducted in the tertiary care setting, protocol-based
resuscitation of patients in whom septic shock was diagnosed in the
emergency department did not improve outcomes.

ProCESS$RCT$
Supplementary,Figures,
Figure,S1.,–,Protocol,for,early,goal9directed,therapy,(EGDT).,
,

ProCESS$RCT$
Figure,S6.,Processes,of,care,during,the,6h,resuscitation,intervention.,
$
Panel$A$–$time$(minutes)$until$a$central$venous$catheter$is$placed.$Panel$B$–$time$(minutes)$until$a$central$venous$catheter$for$oximetric$
monitoring$is$placed.$Central$venous$catheterization$defined$as$use$of$oximetric$catheter$or$multiple$serial$ScvO2$measures.$Panel$C$–$$
Intravenous$fluid$volume$by$hour$(mean$+$SD).$Panel$D$–$use$of$resuscitation$interventions.$ScvO2$–$central$venous$oxygen$saturation;$PRBC$–$
packed$red$blood$cell;$EGDT$–$early$goalHdirected$therapy..$
PPvalues$represent$comparisons$across$the$3$arms.$
&

ProCESS$RCT$
Table&S4.&–&Resuscitation&and&processes&of&care&from&baseline&to&72h.a
&
Intervention&
ProtocolAbased&EGDT&
(N=439)&
ProtocolAbased&Standard&
Therapy&(N=446)&
Usual&care&(N=456)& pAvalue
g
&
PreArandomization& $ $ $ $
Intravenous$fluids
b
$–$mL$ 2254$+$1472$ 2226$+$1363$ 2083$+$1405$ 0.15$
Fluids$per$body$weight$(mL/kg)$ 30.5$±$22.3$ 29.2$±$19.1$ 28$±$21$ $
Vasopressor$use
c
$$ 84$(19.1)$ 75$(16.8)$ 69$(15.1)$ 0.28$
Dobutamine$use$$ 0$(0)$ 0$(0)$ $0$(0)$ $
Blood$transfusion$$ 5$(1.1)$ 7$(1.6)$ 9$(2.0)$ 0.63$
Mechanical$ventilation$$ 60$(13.7)$ 65$(14.6)$ 63$(13.8)$ 0.93$
Intravenous$antibiotics$$ 332$(75.6)$ 343$(76.9)$ 347$(76.1)$ 0.91$
Corticosteroids$$ 41$(9.3)$ 42$(9.4)$ 38$(8.3)$ 0.82$
Activated$protein$C$$ 0$(0)$ 0$(0)$ 0$(0)$ $
$ $ $ $ $
Randomization&to&hour&6
d
& $ $ $ $
Resuscitation$elements$ $ $ $ $
Central$venous$catheterization$ 411$(93.6)$ 252$(56.5)$ 264$(57.9)$ <0.0001$
Central$venous$oximeter$catheterization
e
$ 409$(93.2)$ 18$(4.0)$ 16$(3.5)$ <0.0001$
Intravenous$fluids$–$mL$ 2805$±$1957$ 3285$±$1743$ 2279$±$1881$ <0.0001$
Vasopressor$use$$ 241$(54.9)$ 233$(52.2)$ 201$(44.1)$ 0.003$
Dobutamine$use$$ 35$(8)$ 5$(1.1)$ 4$(0.9)$ <0.0001$
$ $ $ $ $
Ancillary$care$ $ $ $ $
Mechanical$ventilation$$ 116$(26.4)$ 110$(24.7)$ 99$(21.7)$ 0.25$
Tidal$volume,$mL/kg$predicted$body$weight
f
$ 8.5$±$2.4$ 8.1$±$1.6$ 8.0$±$1.8$ 0.11$
Tidal$volume,$mL/kg$body$weight$ 6.7$±$2.1$ 6.5$±$1.9$ 6.8$±$2.1$ 0.32$
Intravenous$antibiotics$$ 428$(97.5)$ 433$(97.1)$ 442$(96.9)$ 0.90$
Corticosteroids$$ 54$(12.3)$ 48$(10.8)$ 37$(8.1)$ 0.16$
Activated$protein$C$$ 1$(0.2)$ 1$(0.2)$ 0$(0)$ 0.55$
$ $ $ $ $
Processes&of&care&from&6A72&h$ $ $ $ $
Intravenous$fluids$–$mL$ 4458$±$3878$ 4918$±$4308$ 4354$±$3882$ 0.08$
Vasopressor$use$$ 209$(47.6)$ 208$(46.6)$ 197$(43.2)$ 0.38$
Dobutamine$use$$ 19$(4.3)$ 9$(2.0)$ 10$(2.2)$ 0.08$
Mechanical$ventilation& 148$(33.7)$ 140$(31.4)$ 127$(27.9)$ 0.16$
Tidal$volume,$mL/kg$predicted$body$weight$ 8.5$±$2.5$ 8.6$±$2.6$ 8.1$±$1.8$ 0.05$
$ $ $ $ $
Processes&of&care&from&0A72&h$ $ $ $ $
Intravenous$fluids$–$mL$ 7253$±$4605$ 8193$±$4989$ 6633$±$4560$ <0.0001$
Vasopressor$use$$ 265$(60.4)$ 273$(61.2)$ 245$(53.7)$ 0.05$
Dobutamine$use$$ 41$(9.3)$ 11$(2.5)$ 13$(2.9)$ <0.0001$
Mechanical$ventilation$ 159$(36.2)$ 152$(34.1)$ 135$(29.6)$ 0.10$
Tidal$volume,$mL/kg$predicted$body$weight$ 8.5$±$2.5$ 8.4$±$2.4$ 8.1$±$1.8$ 0.03$
EGDT$–$early$goalHdirected$therapy.$
a
$Values$indicated$with$±$are$means$±$SD.$$Values$indicated$with$N$(n)$are$number$of$subjects$(%).$Denominators$are$all$individuals$for$whom$
data$are$available.$
b
$Includes$all$intravenous$crystalloid,$colloid$and$blood$product$administration.$$
c
$Vasopressor$use$defined$as$dopamine$infusion$at$>5$mcg/kg/min$or$any$infusion$of$epinephrine,$norepinephrine,$vasopressin$or$
phenylephrine.$$
d
$Mechanical$ventilation,$central$venous$catheterization,$and$ancillary$care$(antibiotics,$corticosteroids,$and$activated$protein$C)$are$counted$
from$emergency$department$arrival$to$6h.$Resuscitation$therapies$(intravenous$fluids,$vasopressor$and$dobutamine$infusions,$and$blood$
product$administration)$are$counted$from$randomization$to$6h.$
e
$Central$venous$catheterization$defined$as$use$of$oximetric$catheter$or$multiple$serial$ScvO2$measures.$
f
$Predicted$body$weight$(PBW)$as$per$http://www.ardsnet.org/system/files/pbwtables_2005H02H02_0.pdf.$
g$
PHvalues$are$for$overall$tests$across$the$three$arms.$
%

November 7th
2013
62 Countries from all continents
1794 Patients
Top Countries
1.USA
2.United Kingdom
3.Malaysia
4.Spain
5.India
6.Italy
7.China
8.Brazil
9.Greece
10.Belgium
The IMPRESS-SSC Study
An International Multi-Centre Prevalence Study of Sepsis

IMPRESS Study
• SSC point prevalence study
• November 7th
2013
• Aim was to inform current performance in real life
setting compared with study populations

3 Hour Bundle Compliance %
Compliance
Measurement of Lactate 56
Obtain Blood Cultures Prior to Antibiotics 49
Administer Broad Spectrum Antibiotics 64
Administer 30 mL/kg crystalloid for
hypotension
57
6 Hour Bundle Compliance %
Compliance
Apply vasopressors 66
Measure CVP 57
Measure ScvO2 47
19% Overall Compliance
36% Overall Compliance
The IMPRESS-SSC Study
An International Multi-Centre Prevalence Study of Sepsis

Hospital Mortality (%) by Bundle
Compliance
P<0.001 P<0.001

Variable
Hospital mortality
odds ratio1
95% CI p-value
Full 3 hour bundle 0.70 0.51 – 0.96 0.026
Full 6 hour bundle 0.75 0.58 – 0.96 0.020
Relationship Between Bundle
Compliance and Outcome.
1
Adjusted for ICU admission, sepsis status (severe vs. shock), location
(ED, ward, ICU, OR, unknown), and APACHE II
GEE population-averaged logistic regression model adjusted
hospital mortality odds ratios

Lessons from SSC Database (s)
Participation alone is
associated with improvement.
Continued participation is
associated with further
benefits.
• For every quarter, mortality
reduced by 1%
Higher compliance was
associated with:
• Even greater mortality reductions
• Reduced use of resources

Summary
• Resuscitation of patients with sepsis should be initiated as soon as
hypoperfusion is recognized and should not be delayed pending ICU
admission.
• The goal of resuscitation is to restore tissue perfusion within the first 6
hours (Best Practice Statement), reasonable goals may include:
– CVP 8–12 mm Hg (if available),
– MAP ≥ 65 mm Hg,
– urine output ≥ 0.5 mL/kg/hr,
– and resolution of clinical signs of hypoperfusion (including altered
mental status, mottled skin, and oliguria).

Summary
• Frequent assessment of the patients’ volume status is crucial
throughout the resuscitation period.
• We suggest targeting resuscitation to normalize lactate in patients with
elevated lactate levels as a marker of tissue hypoperfusion (grade 2C).
• We do not suggest routine measurement of ScvO2 or SvO2 to guide
therapy during resuscitation of patients with sepsis and hypoperfusion
(grade 2B).

What are the consequences of this?
• Mandated sepsis protocols in New York State
• Sepsis bundle approach being incorporated into
the US National Quality Framework
• Increasingly, a “must-do” mentality
• Often beneficial, but always risk on unintended
consequence
• Considerable concerns about medico-legal
implications, and issues of physician autonomy

New Bundles &
CMS “Core Measures” to Begin
October 2015

NQF BUNDLE: Sepsis 0500
TO BE COMPLETED WITHIN 3 HOURS OF TIME OF
PRESENTATION† :
1.Measure lactate level
2.Obtain blood cultures prior to administration of antibiotics
3.Administer broad spectrum antibiotics
4.Administer 30ml/kg crystalloid for hypotension or lactate
≥4mmol/L
† “time of presentation” is defined as the time of triage in the
Emergency Department or, if presenting from another care
venue, from the earliest chart annotation consistent with all
elements severe sepsis or septic shock ascertained through
chart review.

TO BE COMPLETED WITHIN 6 HOURS OF TIME OF
PRESENTATION:
5. Apply vasopressors (for hypotension that does not respond
to initial fluid resuscitation) to maintain a mean arterial
pressure (MAP) ≥65mmHg
6. In the event of persistent hypotension after initial fluid
administration (MAP < 65 mm Hg) or if initial lactate was ≥4
mmol/L, re-assess volume status and tissue perfusion and
document findings according to table 1.
7. Re-measure lactate if initial lactate elevated.

DOCUMENT REASSESSMENT OF VOLUME STATUS AND TISSUE
PERFUSION WITH:EITHER• Repeat focused exam (after initial fluid
resuscitation) including vital signs, cardiopulmonary, capillary refill, pulse, and
skin findings.OR TWO OF THE FOLLOWING:• Measure CVP• Measure
ScvO2 • Bedside cardiovascular ultrasound• Dynamic assessment of fluid
responsiveness with passive leg raise or fluid challenge

What are the next challenges?
• Allow me to use the current process in the UK as
an illustration:
• NICE
– National Institute for Health and Care
Excellence
– Responsible for clinical guidance in the NHS
– Now considering sepsis

NICE Sepsis Guideline
• Scope:
– All populations
– All healthcare settings
– Recognition and early assessment
– Diagnosis and prognosis
– Initial treatment
– Escalating treatment
– Identifying the source of infection
– Early monitoring
– Information for patients and carers
– Training and education

• Outcomes:
– Mortality
– Progression to sepsis
– Duration of hospital stay
– Duration of ICU stay
– Number of organs supported
– Change in physical signs and symptoms
– Adverse events
– Health-related quality of life
– Psychological outcomes
– Outcomes indicating long-term disability/rehabilitation
needs

• Economic analysis:
– Recommendations have to be cost-effective
– Maximum cost per QALY of £30,000
• Exclusions:
– Managing sepsis in neonates, children and adults in the
ICU
– Procalcitonin
– Treatment and care of secondary effects on other
organs
– Preventing sepsis
– Premature neonates and infants

What does this approach reveal?
• Breadth of problems
• Wide number of stakeholders
• Sepsis is no longer just, or even primarily, an ICU
“disease”
• Education and recognition requires meaningful
definition
• Community and pre-hospital care highly relevant
• Both emphasise need for better diagnostics with
point-of-care utility

Where are we with these problems?
• First, require political engagement
– Access to the levers of the health system,
including mandating elements of care
– Needs patient and public involvement
– Requires responsible professional engagement

• Second, require better definitions
• For research and for clinical use
• Recent exemplar of Belin definition for ARDS
• Joint ESICM/SCCM working group currently
producing new sepsis definition

• Third, need for education and intervention in/from
healthcare professional not previously engaged
– Many challenges here
– Most practitioners will see very few individual
patients
– But, increasing work as a result of SSC
– Many generic examples from other fields
– Developing pre-hospital care intervention,
building on experience with trauma, AMI and
stroke

8hrs to
antibiotics
47%
mortality

> 50%
mortality
47% -> 2 7%
mortality

Conclusion
• Much progress has been made
• Indeed – sepsis management is already a major
success story, in advanced health systems
• But, still much more to do
• Treatment standards are now becoming a
mainstream health system activity
• In less advanced environments, though, we have
barely started, and will need quite different
solutions

Professor Richard Beale @ MRF's Meningitis & Septicaemia in Children & Adults 2015

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