Surviving sepsis

Balraj APPADU M.D., FRCA, FFICM

Consultant in Anaesthesia & Intensive Care Medicine

AgendaUnderstand the scope of the sepsis epidemic1

Become familiar with the Surviving Sepsis Campaign and the IHI defined sepsis bundles2

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 2 week surveillance 206 French ICUs

95 cases per 100,000 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

AIDS* Colon Breast

Cancer§

CHF† Severe Sepsis‡

Cas

es/1

00,0

00

Incidence of Severe Sepsis Mortality of Severe Sepsis

AIDS* SevereSepsis‡

AMI†Breast Cancer§

Dea

ths/

Ye

ar

†National 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

Economics of Sepsis Severe SepsisSevere Sepsis

$22,000 per case$22,000 per case US annual cost US annual cost $16.7$16.7 BillionBillion

Nosocomial SepsisNosocomial Sepsis increased LOS - ICU 8 days, Hosp 24

days $40,890 per case

Angus CCM, 2001Pittet JAMA, 1994

Time Sensitive Interventions

AMI

Stroke“Time is Brain” The sooner that treatment begins, the better are one’s chances of survival without disability.

Trauma“The Golden Hour” Requires immediate response and medical care “on the scene.” Patients typically transferred to a qualified trauma center for care.

“Door to PCI” Focus on the timely return of blood flow to the affected areas of the heart.

Severe Sepsis vs. Current Care Priorities

Care PrioritiesU.S.

Incidence# of Deaths Mortality Rate

AMI (1) 900,000 225,000 25%

Stroke (2) 700,000 163,500 23%

Trauma (3)

(Motor Vehicle)

2.9 million (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): 1303-1310.

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….

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.

ACCP/SCCM Consensus Definitions

A systemic response to a nonspecific insultInfection, trauma, surgery, massive transfusion, etc

Defined as 2 of the following:

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

SIRSSEVERE SEPSIS

What is SIRS?

Pneumonia 50%

Urinary Tract infection

Meningitis

Endocarditis

Device relatedCentral lineCannula

Abdominal 25%PainDiarrhoeaDistensionUrgent laparotomy

Soft tissue/ musculoskeletal

CellulitisSeptic arthritisFasciitisWound infection

What counts as an infection?

SIRS due to an infection

what is Sepsis?

Sepsis with organ dysfunction, hypoperfusion or hypotension

CNS: Acutely altered mental statusCVS: Syst < 90 or mean < 65 mmHgResp: SpO2 >90% only with new/ more O2 Renal: Creatinine >177 μmol/l

or UO <0.5 ml/kg/hr for 2 hrsHepatic: Bilirubin >34 μmol/lBone marrow: Platelets <100Hypoperfusion: Lactate >2 mmol/lCoagulopathy: INR>1.5 or aPTT>60secs

What is Severe Sepsis?

Tissue perfusion is not adequate for the tissues’ metabolic requirements

What is shock?

Septic ShockShock secondary to systemic inflammatory response to a

new infection

Types of Shock

Cardiogenic

Neurogenic

Hypovolaemic

Anaphylactic

and…

Tissue perfusion is not adequate for the tissues’ metabolic requirements

For sepsis, shock is one of:

SBP < 90 mmHgMBP < 65 mmHg after IV

fluidsDrop of < 40 mmHgLactate > 4 mmol/l

What is shock?

The Sepsis Continuum

A clinical response arising from a nonspecific insult, with 2 of the following:

T >38oC or <36oC HR >90 beats/min RR >20/min WBC >12,000/mm3 or

<4,000/mm3 or >10% bands

SIRS = systemic inflammatory response syndrome

SIRS with a presumed or confirmed infectious process

Chest 1992;101:1644.

SepsisSIRSSevere Sepsis

SepticShock

Sepsis with organ failure

Refractoryhypotension

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

Severe Sepsis Screening Tool

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

Severe Sepsis: Ensure Senior Doctor/ITU to attend NOW!

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

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

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

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 pathogensGive broad spectrum till

defined

Give Antibiotics

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

Kumar et al. CCM. 2006:34:1589-96.

time from hypotension onset (hrs)

0-0.

50.

5-11-

22-

33-

44-

55-

66-

99-

1212

-24

24-3

6

36+

frac

tion

of t

otal

pat

ient

s

0.0

0.2

0.4

0.6

0.8

1.0 survival fraction

cumulative antibiotic initiation

Cumulative Initiation of Effective Antimicrobial Therapy and Survival in Septic Shock

Running Average Survival in Septic ShockBased on Antibiotic Delay (n=4195)

AbRx Delay (hrs)0 20 40 60 80 100

fra

ctio

n

0.0

0.2

0.4

0.6

0.8

1.0

running average survivalcumulative fraction of total survivors

Funk and Kumar

Critical Care Clinics 2012(in press)

Running average survival in septic shock based on antibiotic delay (n=4195)

Funk and Kumar

Critical Care Clinics 2011 (in press)

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%

Author n Setting Median time (mins)

Odds Ratio for death

GaieskiCrit Care Med 2010; 38:1045-53

261 ED, USA(Shock)

119 0.30(first hour vs all times)

DanielsEmerg Med J 2010; doi:10.1136

567 Whole hospital, UK

121 0.62(first hour vs all times)

KumarCrit Care Med 2006; 34(6):1589-1596

2154 ED, Canada(Shock)

360 0.59(first hour vs second hour)

AppelboamCritical Care 2010; 14(Suppl 1): 50

375 Whole hospital, UK

240 0.74(first 3 hours vs delayed)

LevyCrit Care Med 2010; 38 (2): 1-8

15022 Multi-centre 0.86(first 3 hours vs delayed)

Early antibiotics are good...

Retrospective, 22 hospitals, Retrospective, 22 hospitals, n= 4532n= 4532•64.4% septic shock patients 64.4% septic shock patients developed early AKIdeveloped early AKI•Median time shock to antibiotic = Median time shock to antibiotic = 5.5 h5.5 h•OR for AKI OR for AKI 1.14 (1.10-1.20) P < 1.14 (1.10-1.20) P < 0.001 0.001 per hour’s delayper hour’s delay

Bagshaw SM et al Intensive Care Med. 2009;35(5):871-81 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

Citation: Ibrahim et al. Chest 2000;118:146–155

BSI, n = 492

59.1% HAI

29.9% inadequate 8.3% fungalVREsPseudomonasCoag-neg Staph

MONARCS trial OR 0.65 for death with adequate cover (n=2634)

Mor

tality

(%)

0

50

70

10

30

Appropriate initialantibiotic

Inappropriate initialantibiotic

p<0.001

40

60

20

MacArthur RD et al. Clin Infect Dis 2004; 38:284-288

Appropriate antibiotics

Fluids

Why?

To reduce organ dysfunction and

multi-organ failure

By optimising tissue oxygen delivery

By increasing organ perfusion

DO2 = Oxygen delivery to the tissue

CaO2 = Amount of O2 in arterial blood

Fluid therapy improves cardiac output by increasing venous return to the heart

CaOCaO22 = ([Hb] x SaO = ([Hb] x SaO22 x 1.34) + (PaO x 1.34) + (PaO22 x 0.0225) x 0.0225)

DODO22 = CaO = CaO22 x CO x CO

Optimising oxygen delivery

Judicious fluid challengesUp to 60ml/kg in divided boluses (min. 20ml/kg in shock)

Crystalloid (500ml boluses)Colloid (250-300ml boluses)

Reassess for effect after each challengeHR, BP, capillary refill, urine output, RR

In patients with cardiac diseaseUse smaller volumesMore frequent assessmentEarly CVC

How to fluid resuscitate

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 GoalLactate to improve

as resuscitation progresses

Trzeciak, S et al , Acad Emerg Med; 13, 1150-1151. n-=1613

Risk stratification by lactate

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 GFRGFR= Glomerular Filtration Rate

GFR is directly proportional to COKidneys 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

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

Renal Blood Flow & Urine Output

Early Goal Directed Therapy

Rivers et al 2001, NEJM; 345, 1368-1377

EGDT Call for specialist support

CrystalloidColloidCVP line

< 8mmHg

< 65 or <90 mmHgMAP Vasoactive Drugs

>8 mmHg

ScvO2Transfuse red cells

until Hb > 10 g/dl

YES

Goals Achieved

ScvO2

>70%

< 70%

Inotropic agents

NO

>65 & >90mmHg

>70%

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

10

20

30

40

50

60

28-day mortality

60-day mortality

Mor

talit

y (%

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

Mortality by Sepsis Six

Cohort size (%)

Mortality % RRR %

(NNT)

Total 567 (100) 34.7 -

Sepsis Six 347 (61.2) 44.0

Sepsis Six 220 (38.8) 20.0 46.6

(4.16)

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 antibiotics

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)

Mortality by fluid challenges

2.0 fewer Critical Care bed days3.4 fewer hospital bed days

Compared with other survivors

Equates to c. £5,000 cost ‘saving’

For patients receiving the Sepsis Six

The clincher

For each year, for every 500 beds..

62 lives saved883 fewer bed days520 fewer CC bed days

Direct costs for survivors reduced by £0.78M

Achieving 80% reliability

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

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