Richard Beale FRCA, FFICMKing’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 Ramsay2.Assimilate the evidence in the most authoritative

manner possible – Professor R Phillip Dellinger3.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 BreastCancer§

CHF* Severe Sepsis‡

Cas

es/1

00,0

00

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 Hgb) MAP ≥ 65 mm Hgc) Urine output ≥ 0.5 mL/kg/hrd) Scvo2 ≥ 70%.

SSC 2012 Resuscitation Bundle

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

• 30 vs. 46%

Rivers Protocol

Potential for RBC and Inotropes

Therapy titrated to

CVP, MAP and ScvO2

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 MedVolume 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.

November 7th 201362 Countries from all continents1794 Patients

Top Countries1.USA 2.United Kingdom3.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

IMPRESS Study (1)

3 Hour Bundle Compliance % Compliance

Measurement of Lactate 56Obtain Blood Cultures Prior to Antibiotics 49Administer Broad Spectrum Antibiotics 64Administer 30 mL/kg crystalloid for hypotension

576 Hour Bundle Compliance %

ComplianceApply vasopressors 66Measure CVP 57Measure 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 mortalityodds 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.

1Adjusted 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 level2.Obtain blood cultures prior to administration of antibiotics3.Administer broad spectrum antibiotics4.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.

NQF BUNDLE: Sepsis 0500

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

NQF BUNDLE: Sepsis 0500

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

NICE Sepsis Guideline

• 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

NICE Sepsis Guideline

• 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

Where are we with these problems?

• 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

Where are we with these problems?

• 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

34% mortality

> 50% mortality

47% -> 27% 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

Thank You