Sepsis overviewSepsis overviewDr. Tsang Dr. Tsang HinHin HungHungMBBS FHKCP FRCPMBBS FHKCP FRCP

EpidemiologyEpidemiologySepsis, severe sepsis, septic shockSepsis, severe sepsis, septic shockPathophysiologyPathophysiology of sepsisof sepsisRecent researches and advancesRecent researches and advancesFrom bench to bedsideFrom bench to bedsideSepsis bundleSepsis bundle

Angus DC. Angus DC. CritCrit Care Med.Care Med. 2001;29(7):13032001;29(7):1303--1310.1310.

TodayToday

>750,000 cases of severe

sepsis/year in the US*

FutureFuture

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1,400,000

1,600,000

1,800,000

2001 2025 2050

Year

100,000

200,000

300,000

400,000

500,000

600,000Severe Sepsis CasesUS Population

Seps

is C

ases

Tota

l US

Popu

latio

n/1,

000

Incidence projected to increase by 1.5% per year

Severe sepsis in USSevere sepsis in US

Angus DC. Angus DC. CritCrit Care Med.Care Med. 2001;29(7):13032001;29(7):1303--1310.1310.

Comparable Global Comparable Global EpidemiologyEpidemiology

95 cases per 100,000 95 cases per 100,000 •• 2 week surveillance 2 week surveillance •• 206 French ICUs 206 French ICUs

95 cases per 100,000 95 cases per 100,000 •• 3 month survey 3 month survey •• 23 Australian/New 23 Australian/New

Zealand ICUs Zealand ICUs 51 cases per 100,00051 cases per 100,000•• England, Wales and England, Wales and

Northern Ireland. Northern Ireland.

Comparison With Comparison With Other Major DiseasesOther Major Diseases

†National Center for Health Statistics, 2001. §American Cancer Society, 2001. *American Heart Association. 2000. ‡Angus DC et al. Crit Care Med. 2001;29(7):1303;29(7):1303--13101310.

AIDS* Colon BreastCancer§

CHF† Severe Sepsis‡

Cas

es/1

00,0

00

0

50

100

150

200

250

300

Incidence of Severe Sepsis Mortality of Severe Sepsis

0

50,000

100,000

150,000

200,000

250,000

Dea

ths/

Year

AIDS* SevereSepsis‡

AMI†Breast Cancer§

What is Sepsis?What is Sepsis?

Systemic inflammatory response Systemic inflammatory response syndrome syndrome InfectionInfection

Definition of sepsisDefinition of sepsisSepsis is considered present if infection is highly suspected Sepsis is considered present if infection is highly suspected or proven and two or more of the following or proven and two or more of the following systemic systemic inflammatory response syndromeinflammatory response syndrome (SIRS) criteria are met(SIRS) criteria are met

Heart rateHeart rate > 90 beats per minute (tachycardia)> 90 beats per minute (tachycardia)

Body temperatureBody temperature < 36 < 36 °°C (96.8 C (96.8 °°F) or > 38 F) or > 38 °°C (100.4 C (100.4 °°F) F) (hypothermia or fever) (hypothermia or fever)

Respiratory rateRespiratory rate > 20 breaths per minute or, on blood gas, > 20 breaths per minute or, on blood gas, a PaCO2 less than 32 mm Hg (4.3 a PaCO2 less than 32 mm Hg (4.3 kPakPa) () (tachypnoeatachypnoea or or hypocapnoeahypocapnoea due to hyperventilation) due to hyperventilation)

White blood cell countWhite blood cell count < 4000 cells/mm< 4000 cells/mm³³ or > 12000 or > 12000 cells/mmcells/mm³³ or greater than 10% band forms (immature or greater than 10% band forms (immature white blood cells). white blood cells).

Definition of sepsisDefinition of sepsisSepsisSepsis is a serious medical condition characterized by a is a serious medical condition characterized by a wholewhole--body inflammatory statebody inflammatory state (called a systemic (called a systemic inflammatory response syndrome or SIRS) caused by inflammatory response syndrome or SIRS) caused by infection.infection.

Severe sepsis: sepsis + acute organ Severe sepsis: sepsis + acute organ dysfunction(organdysfunction(organhypoperfusionhypoperfusion))

Septic shock: sepsis + refractory arterial hypotension (SBP Septic shock: sepsis + refractory arterial hypotension (SBP <90mmHg)<90mmHg)

Septic shock

Severe sepsis

Sepsis

Mortality

Sepsis Sepsis –– a systemic disease!!a systemic disease!!

Infective agents

CytokinesCytokinessoluble (soluble (glyco)proteinsglyco)proteinsnonimmunoglobulinnonimmunoglobulin in in nature nature released by living cells of released by living cells of the hostthe hostact act nonenzymaticallynonenzymatically in in picomolarpicomolar to to nanomolarnanomolarconcentrations concentrations through specific receptors through specific receptors to regulate host cell to regulate host cell function.function.

Cytokine storm

Cardiovascular changes in septic shock.

Fluid TherapyFluid Therapy

Fluid resuscitation Fluid resuscitation

Colloids or crystalloids?Colloids or crystalloids?

Crystalloids vs. colloids in fluid resuscitation: A systematic review. Crit Care Med 1999; 27:200–210

The Saline versus Albumin Fluid Evaluation (SAFE) The Saline versus Albumin Fluid Evaluation (SAFE) Study investigators Study investigators

3497 patients were assigned to receive albumin 3497 patients were assigned to receive albumin

and 3500 to receive salineand 3500 to receive saline

Primary outcome: 28Primary outcome: 28--day mortalityday mortality

NEJM 2004

Kaplan-Meier Estimates of the Probability of Survival. P=0.96 for the comparison between patients assigned to receive albumin and those assigned to receive saline. NEJM 2004

Which Which vasopressorsvasopressors??

NoradrenalineNoradrenaline is better than is better than dopamine or adrenaline?dopamine or adrenaline?

Vasopressin is better?Vasopressin is better?

Effects of Dopamine, Norepinephrine,Effects of Dopamine, Norepinephrine,and Epinephrine on the and Epinephrine on the SplanchnicSplanchnic

CirculationCirculation in Septic Shockin Septic Shock

Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: Which is best? Crit Care Med 2003; 31:1659-1667

Low dose dopamine for Low dose dopamine for renal protection?renal protection?

Surviving sepsis campaign 2008Surviving sepsis campaign 2008

Use of steroid in sepsisUse of steroid in sepsis

Effect of treatment with low doses hydrocortisone and Effect of treatment with low doses hydrocortisone and fludrocortisonefludrocortisone on mortality in patients with septic shockon mortality in patients with septic shock

Annane et al, JAMA 2002

Hydrocortisone Therapy for Patients with Hydrocortisone Therapy for Patients with Septic Shock Septic Shock CORTICUS CORTICUS NEJM 2008NEJM 2008

Activated protein CActivated protein C

35

30

25

20

15

10

5

0

30.8%

24.7%

Placebo

(n-840)

Drotrecoginalfa

(activated) (n=850)

Mor

talit

y (%

)

6.1% absolute reduction in

mortality

Results: 28-Day All-Cause MortalityPrimary analysis results

2-sided p-value 0.005Adjusted relative risk reduction 19.4%Increase in odds of survival 38.1%

Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344:699-709

Mortality and APACHE II QuartileMortality and APACHE II Quartile

APACHE II Quartile*Numbers above bars indicate total deaths

05

101520253035404550

1st (3-19) 2nd (20-24) 3rd (25-29) 4th (30-53)

PlaceboDrotrecogin

Mor

talit

y (p

erce

nt)

26:33

57:49

58:48

118:80

Adapted from Figure 2, page S90, with permission from Bernard GR. Drotrecogin alfa (activated) (recombinant human activated protein C) for the treatment of severe sepsis. Crit Care Med 2003; 31[Suppl.]:S85-S90

Mortality and Numbers of Organs FailingMortality and Numbers of Organs Failing

PercentMortality

0

10

20

30

40

50

60

1 2 3 4 5

PlaceboDrotrecogin

Number of Organs Failing at Entry

Adapted from Figure 4, page S91, with permission from Bernard GR. Drotrecogin alfa (activated) (recombinant human activated protein C) for the treatment of severe sepsis. Crit Care Med 2003; 31[Suppl.]:S85-S90

Recombinant Human Activated Recombinant Human Activated Protein C (Protein C (rhAPCrhAPC))

High risk of deathHigh risk of death•• APACHE II APACHE II ≥≥ 2525•• SepsisSepsis--induced multiple organ induced multiple organ

failurefailure•• Septic shockSeptic shock•• Sepsis induced ARDSSepsis induced ARDS

No absolute contraindicationsNo absolute contraindicationsWeigh relative contraindicationsWeigh relative contraindications

6 Hour Resuscitation 6 Hour Resuscitation Golden hours for sepsis resuscitationGolden hours for sepsis resuscitation

Early IdentificationEarly IdentificationEarly Antibiotics Early Antibiotics and Culturesand CulturesEarly Goal Directed Early Goal Directed TherapyTherapy

Early Goal Directed TherapyEarly Goal Directed Therapy

The Importance of Early GoalThe Importance of Early Goal--DirectedDirectedTherapy for Sepsis Induced HypoperfusionTherapy for Sepsis Induced Hypoperfusion

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

In-hospital mortality

(all patients)

0102030405060 Standard therapy

EGDT

28-day mortality

60-day mortality

NNT to prevent 1 event (death) = 6-8

Mor

talit

y (%

)

Do not delay resuscitation Do not delay resuscitation pending ICU admissionpending ICU admission

Intensive insulin therapyIntensive insulin therapy

The Role of IntensiveThe Role of IntensiveInsulin Therapy in the Critically IllInsulin Therapy in the Critically Ill

At 12 months, intensive At 12 months, intensive insulin therapy reduced insulin therapy reduced mortality by 3.4% mortality by 3.4% (P<0.04)(P<0.04)

van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients.N Engl J Med 2001;345:1359-67

In-h

ospi

tal s

urvi

val (

%)

100

00

Intensive treatment

Conventional treatment

Days after admission

80

84

88

92

96

50 100 150 200 250

P=0.01

Intensive insulin therapy in medical ICUIntensive insulin therapy in medical ICUvan den Berghe G, NEJM 2006

Multiple organ failure in sepsisMultiple organ failure in sepsis

Acute respiratory distress Acute respiratory distress syndrome syndrome –– ARDSARDSCirculatory failureCirculatory failureAcute renal failure Acute renal failure –– ARFARFLiver Liver derrangementderrangementCoagulopathyCoagulopathyEncephalopathyEncephalopathy

ARDS – Acute respiratory distress syndrome

Mechanical Ventilation of Mechanical Ventilation of SepsisSepsis--Induced ALI/ARDSInduced ALI/ARDS

0

5

10

15

20

25

30

35

40

6 ml/kg12 ml/kg

% M

orta

lity

ARDSnet Mechanical Ventilation ProtocolResults: Mortality

The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301-1378

Renal failure in sepsisRenal failure in sepsis

Renal replacement Renal replacement therapytherapy

Blood purificationBlood purification

Transfusion Strategyin the Critically Ill

Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999; 340:409-417

Other supportive therapies in Other supportive therapies in sepsissepsis

DVT prophylaxisDVT prophylaxis

Stress ulcer prophylaxisStress ulcer prophylaxis

Sedation and weaning from Sedation and weaning from ventilatorventilator

…………………………………………....

From Bench to BedsideFrom Bench to Bedside

Surviving Sepsis CampaignSurviving Sepsis Campaign

A global program to:A global program to:Evidence based guidelineEvidence based guideline

Implementation and educationImplementation and educationReduce mortality ratesReduce mortality ratesImprove standards of careImprove standards of care

Sepsis Bundle Approach

6 6 -- hour Severe Sepsis/hour Severe Sepsis/Septic Shock BundleSeptic Shock Bundle

Early Detection:Early Detection:•• Obtain serum lactate Obtain serum lactate

level.level.

Early Blood Early Blood CxCx/Antibiotics:/Antibiotics:•• within 3 hours of within 3 hours of

presentation. presentation.

Early EGDT: Early EGDT: Hypotension (SBP < 90, Hypotension (SBP < 90, MAP < 65) or lactate > 4 MAP < 65) or lactate > 4 mmol/L:mmol/L:•• initial fluid bolus 20initial fluid bolus 20--40 ml 40 ml

of crystalloid (or colloid of crystalloid (or colloid equivalent) per kg of body equivalent) per kg of body weight.weight.

Vasopressors:Vasopressors:•• Hypotension not Hypotension not

responding to fluidresponding to fluid•• Titrate to MAP > 65 Titrate to MAP > 65

mmHg.mmHg.

Septic shock or lactate > Septic shock or lactate > 4 mmol/L:4 mmol/L:•• CVP and ScvOCVP and ScvO22 measured.measured.•• CVP maintained >8 CVP maintained >8

mmHg.mmHg.•• MAP maintain > 65 MAP maintain > 65

mmHg.mmHg.

ScvO2<70%with CVP > 8 ScvO2<70%with CVP > 8 mmHg, MAP > 65 mmHg:mmHg, MAP > 65 mmHg:•• PRBCs if hematocrit < PRBCs if hematocrit <

30%. 30%. •• InotropesInotropes..

24 24 -- hour Severe Sepsis hour Severe Sepsis and Septic Shock Bundleand Septic Shock Bundle

Glucose control:Glucose control:•• maintained on average <150 mg/dL (8.3 maintained on average <150 mg/dL (8.3 mmolmmol/L)/L)

Drotrecogin alfa (activated):Drotrecogin alfa (activated):•• administered in high risk patients and without administered in high risk patients and without

contraindicationcontraindication

Steroids:Steroids:•• for septic shock requiring continued use of vasopressors for septic shock requiring continued use of vasopressors

for equal to or greater than 6 hours.for equal to or greater than 6 hours.

Lung protective strategy:Lung protective strategy:•• Maintain plateau pressures Maintain plateau pressures << 30 cm H30 cm H22O, tidal volume 6O, tidal volume 6--

8ml/kg and optimal PEEP8ml/kg and optimal PEEP

ConclusionConclusionSevere sepsis is a common, expensive and Severe sepsis is a common, expensive and frequently fatal conditionfrequently fatal condition

Growing problem and leading cause of Growing problem and leading cause of deathdeath

A systemic diseaseA systemic disease

Sepsis bundle Sepsis bundle –– improve standards of care improve standards of care and reduce mortality rateand reduce mortality rate

Thank you

Mechanical Ventilation ofMechanical Ventilation ofSepsisSepsis--Induced ALI/ARDSInduced ALI/ARDSReduce tidal volume over 1Reduce tidal volume over 1––2 hrs to 6 ml/kg predicted 2 hrs to 6 ml/kg predicted body weightbody weightMaintain inspiratory plateau Maintain inspiratory plateau pressure < 30 cm Hpressure < 30 cm H2200

Mechanical Ventilation ofMechanical Ventilation ofSepsisSepsis--Induced ALI/ARDSInduced ALI/ARDSMinimum PEEPMinimum PEEP•• Prevent end expiratory lung Prevent end expiratory lung

collapsecollapseSetting PEEPSetting PEEP•• FIO2 requirementFIO2 requirement•• Thoracopulmonary Thoracopulmonary

compliancecompliance