Surviving sepsis
Balraj APPADU M.D., FRCA, FFICM
Consultant in Anaesthesia & Intensive Care Medicine
Agenda
1
Understand the scope of the sepsis epidemic
2
Become familiar with the Surviving Sepsis
Campaign and the IHI defined sepsis
bundles
Recognize how time-critical therapies can save lives in
the emergency departments and ICUs
3
What's the problem?



Severe sepsis affects over 120,000
patients each year in the U.K.
(increasing at a rate of 1.5% per
annum)
Last year 78,000 of these patients
admitted to ITU
Mortality for these 30 – 80 %
Comparable Global
Epidemiology

95 cases per 100,000



95 cases per 100,000



2 week surveillance
206 French ICUs
3 month survey
23 Australian/New
Zealand ICUs
51 cases per 100,000

England, Wales and
Northern Ireland.
Severe Sepsis: Comparison With
Other Major Diseases
Incidence of Severe Sepsis
Mortality of Severe Sepsis
250,000
300
200,000
150,000
200
Deaths/Year
Cases/100,000
250
150
100
100,000
50,000
50
0
0
AIDS*
Colon
Breast
Cancer§
†National
CHF†
Severe
Sepsis‡
AIDS*
Breast
Cancer§
AMI†
Severe
Sepsis‡
Center for Health Statistics, 2001. §American Cancer Society, 2001. *American Heart Association. 2000. ‡Angus DC
et al. Crit Care Med. 2001
Sepsis Epidemiology: Effect of the Aging Population
45
Without Comorbidity
40
With Comorbidity
Overal
35
30
25
20
15
10
5
0
0
1
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85

Economics of Sepsis
Severe Sepsis



$22,000 per case
US annual cost $16.7 Billion
Nosocomial Sepsis


increased LOS - ICU 8 days, Hosp 24 days
$40,890 per case
Angus CCM, 2001
Pittet JAMA, 1994
Time Sensitive Interventions
“Door to PCI”
AMI
Focus on the timely return of blood flow to the affected
areas of the heart.
“Time is Brain”
Stroke
The sooner that treatment begins, the better are one’s
chances of survival without disability.
“The Golden Hour”
Trauma
Requires immediate response and medical care “on the scene.”
Patients typically transferred to a qualified trauma center for care.
Severe Sepsis vs. Current Care Priorities
Care Priorities
U.S.
Incidence
# of Deaths
Mortality Rate
AMI (1)
900,000
225,000
25%
Stroke (2)
700,000
163,500
23%
Trauma (3)
2.9 million
(Motor Vehicle)
(injuries)
42,643
1.5%
Severe Sepsis (4)
751,000
215,000
29%
Source: (1) Ryan TJ, et al. ACC/AHA Guidelines for management of patients with AMI. JACC. 1996; 28: 1328-1428. (2) American Heart
Association. Heart Disease and Stroke Statistics – 2005 Update. Available at: www.americanheart.org. (3) National Highway Traffic
Safety Administration. Traffic Safety Facts 2003: A Compilation of Motor Vehicle Crash Data from the Fatality Analysis Reporting
System and the General Estimates System. Available at http://www.nhtsa.dot.gov/. (4) Angus DC et al. Crit Care Med 2001;29(7): 13031310.
Surviving Sepsis Campaign



Launched in Autumn 2002 as a collaborative
effort of European Society of Intensive Care
Medicine, the International Sepsis Forum, and
the Society of Critical Care Medicine
Goal: reduce sepsis mortality by 25% in the next
5 years
Guidelines revealed at SCCM in Feb 2004,
REVISED 2008

Critical Care Medicine March 2004 32(3):858-87.

Website: survivingsepsis.org
What is sepsis?
Sepsis, Septic Shock,
SIRS (systemic inflammatory response
syndrome),
SSI (signs and symptoms of infection),
Septicaemia, Bacteraemia,
Toxic Shock Syndrome,
Bloodstream infection etc, etc….
ACCP/SCCM Consensus Definitions

Infection
– Inflammatory response to
microorganisms, or
– Invasion of normally sterile
tissues

Systemic Inflammatory
Response Syndrome (SIRS)
– Systemic response to a
variety of processes

Sepsis
– Infection plus
– 2 SIRS criteria

Severe Sepsis
– Sepsis
– Organ dysfunction

Septic shock
– Sepsis
– Hypotension despite fluid
resuscitation
Bone RC et al. Chest. 1992;101:1644-55.
What is SIRS?
A systemic response to a nonspecific insult
Infection, trauma, surgery, massive transfusion, etc
Defined as 2 of the following:
SIRS
Temperature
>38.3 or <36 0C
Heart rate
>90 min-1
Respiratory rate
>20 min-1
White cells
<4 or >12
Acutely altered mental state
Hyperglycaemia (BM>7.7) in absence of DM
SEVERE SEPSIS
What counts as an infection?
Pneumonia 50%
Urinary Tract infection
Meningitis
Endocarditis
Device related
Central line
Cannula
Abdominal 25%
Pain
Diarrhoea
Distension
Urgent laparotomy
Soft tissue/ musculoskeletal
Cellulitis
Septic arthritis
Fasciitis
Wound infection
what is Sepsis?
SIRS due to an infection
What is Severe Sepsis?
Sepsis with organ dysfunction, hypoperfusion or hypotension
CNS:
CVS:
Resp:
Renal:
Hepatic:
Bone marrow:
Hypoperfusion:
Coagulopathy:
Acutely altered mental status
Syst < 90 or mean < 65 mmHg
SpO2 >90% only with new/ more O2
Creatinine >177 μmol/l
or UO <0.5 ml/kg/hr for 2 hrs
Bilirubin >34 μmol/l
Platelets <100
Lactate >2 mmol/l
INR>1.5 or aPTT>60secs
What is shock?
Tissue perfusion is not adequate for the
tissues’ metabolic requirements
Types of Shock
Cardiogenic
Neurogenic
Hypovolaemic
Anaphylactic
and…
Septic Shock
Shock secondary to systemic
inflammatory response to a
new infection
What is shock?
Tissue perfusion is not adequate for the
tissues’ metabolic requirements
For sepsis, shock is one of:
SBP
MBP
< 90 mmHg
< 65 mmHg
fluids
Drop of <
Lactate >
40 mmHg
4 mmol/l
after IV
The Sepsis Continuum
SIRS

Sepsis
A clinical response
arising from a
nonspecific insult, with
2 of the following:
o
o
 T >38 C or <36 C
 HR >90 beats/min
 RR >20/min
3
 WBC >12,000/mm
or <4,000/mm3 or
>10% bands
SIRS with a
presumed
or confirmed
infectious
process
Severe
Sepsis
Septic
Shock
Sepsis with
organ failure
Refractory
hypotension
SIRS = systemic inflammatory
response syndrome
Chest 1992;101:1644.
Severe Sepsis Screening Tool
Are any 2 of the following SIRS criteria present and new to your patient?
Obs:
Temperature >38.3 or <36 0C
Respiratory rate >20 min-1
Heart rate >90 bpm
Acutely altered mental state
Bloods: White cells <4x109/l or >12x109/l
Glucose>7.7mmol/l
(if patient is not diabetic)
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 SEPSIS
Start SEPSIS BUNDLE
Check for SEVERE SEPSIS
BP
Syst < 90 / Mean < 65 mmHg
(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 μmol/l
O2
Needed to keep SpO2 > 90%
Platelets
< 100 x 109/l
Creatinine
> 177 μmol/l or UO < 0.5 ml/kg/hr
Severe Sepsis: Ensure Senior Doctor/ITU to
attend NOW!
What is a Bundle?

Specifically selected
care elements


From evidence based
guidelines
Implemented together
provide improved
outcomes compared to
individual elements
alone
6 Hour Resuscitation
Bundle



Early Identification
Early Antibiotics and
Cultures
Early Goal Directed
Therapy
6 - hour Severe Sepsis/
Septic Shock Bundle

Early Detection:
 Obtain serum lactate level.

Early Blood Cx/Antibiotics:
 within 3 hours of
presentation.


Early EGDT:
Hypotension (SBP < 90, MAP
< 65) or lactate > 4 mmol/L:

initial fluid bolus 20-40 ml of
crystalloid (or colloid equivalent)
per kg of body weight.
•
Vasopressors:
– Hypotension not responding to
fluid
– Titrate to MAP > 65 mmHg.
•
Septic shock or lactate > 4
mmol/L:
– CVP and ScvO2 measured.
– CVP maintained >8 mmHg.
– MAP maintain > 65 mmHg.
•
ScvO2<70%with CVP > 8 mmHg,
MAP > 65 mmHg:
– PRBCs if hematocrit < 30%.
– Inotropes.
Why does it matter?
Perspective
Severe Sepsis
127
No. cases per 100,000
per annum
NNT ‘basic’ care
Sepsis Six (our data)
First hour antibiotics
NNT invasive care
Acute coronary
syndrome
EGDT (Rivers)
Resusc Bundle (SSC)
200
6
Clopidogrel
48
5
β-blockade
42
Aspirin
26
6
18
Thrombolysis
15
PCI over thrombolysis
33
The Sepsis Six
1.
Give high-flow oxygen
via non-rebreath bag
2.
Take blood cultures
and consider source control
3.
Give IV antibiotics
according to local protocol
4.
Start IV fluid resuscitation Hartmann’s or equivalent
5.
Check lactate
6.
Monitor hourly urine output
consider catheterisation
within one hour
..plus Critical Care support to complete EGDT
Give Antibiotics
Start therapy as soon as possible and certainly in
the first hour...
...preferably after taking blood cultures!!
Choice should include one or more with activity
against likely pathogen
Penetration of presumed source
Guided by local pathogens
Give broad spectrum till defined
SSC- antibiotics

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)
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 sites
n = 2,154
median 6 h, 50% administered in 6h
Only 5% first 30 minutes- survival 87%
12% first hour- survival 84%
Cumulative Initiation of Effective Antimicrobial
Therapy and Survival in Septic Shock
1.0
survival fraction
fraction of total patients
cumulative antibiotic initiation
0.8
0.6
0.4
0.2
0.0
time from hypotension onset (hrs)
Kumar et al. CCM. 2006:34:1589-96.
Running
survival
in septic
shockShock
Runningaverage
Average
Survival
in Septic
based
on antibiotic
delayDelay
(n=4195)
Based
on Antibiotic
(n=4195)
1.0
fraction
0.8
0.6
running average survival
cumulative fraction of total survivors
0.4
Funk and Kumar
0.2
Critical Care Clinics 2012(in press)
0.0
0
20
40
60
AbRx Delay (hrs)
80
100
Running average survival in septic
shock based on antibiotic delay
(n=2154)
For each hour’s delay in
administering antibiotics in septic
shock, mortality increases by 7.6%
Funk and Kumar
Critical Care Clinics 2011 (in press)
Early antibiotics are good...
Author
n
Setting
Median time
(mins)
Odds Ratio for
death
Gaieski
261
ED, USA
(Shock)
119
0.30
Whole hospital,
UK
121
ED, Canada
(Shock)
360
Whole hospital,
UK
240
Crit Care Med 2010;
38:1045-53
Daniels
567
Emerg Med J 2010;
doi:10.1136
Kumar
2154
Crit Care Med 2006;
34(6):1589-1596
Appelboam
375
Critical Care 2010;
14(Suppl 1): 50
Levy
Crit Care Med 2010; 38
(2): 1-8
15022
Multi-centre
(first hour vs all times)
0.62
(first hour vs all times)
0.59
(first hour vs second hour)
0.74
(first 3 hours vs delayed)
0.86
(first 3 hours vs delayed)
Retrospective, 22 hospitals,
n= 4532
•64.4% septic shock patients
developed early AKI
•Median time shock to antibiotic =
5.5 h
•OR for AKI 1.14 (1.10-1.20) P <
0.001 per hour’s delay
Bagshaw SM et al Intensive Care Med. 2009;35(5):871-81
SSC Results: Critical Care Medicine 2010; 38(2): 1-8
SSC Results: Critical Care Medicine 2010;
38(2): 1-8
Appropriate antibiotics
Citation: Ibrahim et al. Chest 2000;118:146–155
BSI, n = 492
70
60
29.9% inadequate
8.3% fungal
VREs
Pseudomonas
Coag-neg Staph
50
Mortality (%)
59.1% HAI
p<0.001
40
30
20
10
0
Appropriate initial
antibiotic
Inappropriate initial
antibiotic
MONARCS trial OR 0.65 for death with adequate cover (n=2634)
MacArthur RD et al. Clin Infect Dis 2004; 38:284-288
Fluids
Why?
To reduce organ dysfunction and
multi-organ failure
By optimising tissue oxygen delivery
By increasing organ perfusion
Optimising oxygen delivery
DO2 = Oxygen delivery to the tissue
DO2 = CaO2 x CO
CaO2 = Amount of O2 in arterial blood
CaO2 = ([Hb] x SaO2 x 1.34) + (PaO2 x 0.0225)
Fluid therapy improves cardiac output by increasing
venous return to the heart
How to fluid resuscitate
Judicious fluid challenges
Up to 60ml/kg in divided boluses (min. 20ml/kg in shock)
Crystalloid
Colloid
(500ml boluses)
(250-300ml boluses)
Reassess for effect after each challenge
HR, BP, capillary refill, urine output, RR
In patients with cardiac disease
Use smaller volumes
More frequent assessment
Early CVC
Lactate
High lactate identifies tissue hypoperfusion in
patients at risk who are not hypotensive
‘Cryptic shock’
Gives an overview of current tissue oxygen delivery
The Goal
Lactate to improve
as resuscitation
progresses
Risk stratification by lactate
% in hospital Mortality
40
35
30
Low (0 - 2.0)
25
Intermediate ( 2.1 - 3.9)
20
15
Severe (>4.0)
10
5
0
Lactate threshold
Trzeciak, S et al , Acad Emerg Med; 13, 1150-1151. n-=1613
Urine Output
Accurate hourly urine output
monitoring
(for many, this will mean catheterisation)
The Goal
> 0.5 ml/kg/hr
> 40 ml/hour in the average adult
Urine Output
Urine output is a direct measure of GFR
GFR= Glomerular Filtration Rate
GFR is directly proportional to CO
Kidneys receive 1/5 cardiac output (1 L/min)
CO falls
UO falls
Therefore urine output in the early stages is a useful
assessment of cardiac output
Renal Blood Flow & Urine Output
In health, kidneys autoregulate, so
UO is independent of BP over a wide
range
In sepsis, this is lost and UO will fall
as BP falls
Early Goal Directed Therapy
EGDT
Call for specialist support
CVP line
< 8mmHg
Crystalloid
Colloid
>8
mmHg
< 65 or <90 mmHg
Vasoactive Drugs
MAP
>65 &
>90mmHg
ScvO2
< 70%
Transfuse red cells
until Hb > 10 g/dl
YES
>70%
ScvO2
>70%
NO
Goals
Achieved
Inotropic agents
Rivers et al 2001, NEJM; 345, 1368-1377
The Importance of Early Goal-Directed Therapy
for Sepsis Induced Hypoperfusion
Mortality (%)
60
50
40
Standard therapy
30
EGDT
20
10
0
NNT to prevent 1
event (death) = 6-8
In-hospital
mortality
(all patients)
28-day mortality
60-day mortality
ARR 16%
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
Mortality by Sepsis Six
Total
Cohort size
(%)
Mortality %
567 (100)
34.7
Sepsis Six

347 (61.2)
44.0
Sepsis Six

220 (38.8)
20.0
RRR %
(NNT)
-
46.6
(4.16)
Mortality by antibiotics
Cohort size
Mortality %
RRR %
(NNT)
Total
567 (100%)
34.7
-
Delayed
Antibiotics
217 (38.4%)
45.4
Antibiotics
within 1 h
350 (61.6%)
28.1
38.1
(5.77)
Mortality by fluid challenges
Cohort size
Mortality %
RRR %
(NNT)
Total
567 (100%)
34.7
-
No fluids in 1h
183 (32.3%)
44.8
Fluids in 1h
384 (67.7%)
30.0
33.0
(6.73)
For patients receiving the
Sepsis Six
2.0 fewer Critical Care bed days
3.4 fewer hospital bed days
Compared with other survivors
Equates to c. £5,000 cost ‘saving’
The clincher
Achieving 80% reliability
For each year, for every 500 beds..
62 lives saved
883 fewer bed days
520 fewer CC bed days
Direct costs for survivors reduced by £0.78M
Summary





Improve recognition/diagnosis
Alter attitude – treat sepsis like MI
Early aggressive treatment
Use EGDT
Collaborate with ITU early

Sepsis is a life-threatening condition that arises when the
body's response to an infection injures its own tissues and
organs.

Sepsis leads to shock, multiple organ failure and death
especially if not recognized early and treated promptly.

Sepsis remains the primary cause of death from infection
despite advances in modern medicine, including vaccines,
antibiotics and acute care.

Millions of people die of sepsis every year worldwide
Comments and Questions