Severe Sepsis / Septic Shock Division of Critical Care Medicine University of Alberta.

Severe Sepsis / Severe Sepsis / Septic ShockSeptic Shock

Division of Critical Care MedicineDivision of Critical Care MedicineUniversity of AlbertaUniversity of Alberta

Case summaryCase summary43 y/o woman presented to E.R. with decreased LOC and 43 y/o woman presented to E.R. with decreased LOC and

hypotensionhypotension

Unwell at home for 5 days with cough, sputum, fever, Unwell at home for 5 days with cough, sputum, fever, chillschills

History of heavy smoking and ETOH abuseHistory of heavy smoking and ETOH abuse

Acutely ill, cyanosed, drowsy, resps 50/min, BP Acutely ill, cyanosed, drowsy, resps 50/min, BP 70/40mmHg, HR 140/min, temp 39.5°C, 70/40mmHg, HR 140/min, temp 39.5°C,

ABGsABGs 56/29/7.28, Lactate 656/29/7.28, Lactate 6

Hgb 150, Platelets 84, WBC 3.3 with 55% band formsHgb 150, Platelets 84, WBC 3.3 with 55% band forms

INR 1.9, PTT 63INR 1.9, PTT 63

Na 129, K 4.3, Cl 85, HCO3 16 BS 19.7Na 129, K 4.3, Cl 85, HCO3 16 BS 19.7

Urea 15 mmol/l, creatinine 137 Urea 15 mmol/l, creatinine 137 mol/lmol/l

CXR Dense LLL and patchy RLL consolidation, ECG sinus CXR Dense LLL and patchy RLL consolidation, ECG sinus tachycardiatachycardia

Intubated and ventilated FiOIntubated and ventilated FiO22 1.0, Vt 450 mls, PEEP 10, Paw 35 1.0, Vt 450 mls, PEEP 10, Paw 35

Sedated with fentanyl by IV infusion and intermittent Sedated with fentanyl by IV infusion and intermittent lorazepam IV prnlorazepam IV prn

IV fluid resuscitationIV fluid resuscitation

0.9% NaCl 3 litres over 3 hours0.9% NaCl 3 litres over 3 hours

IV ceftriaxone and azithromycinIV ceftriaxone and azithromycin

Central line inserted. Central line inserted.

Norepinephrine infusion at 10 mcg/kg/minNorepinephrine infusion at 10 mcg/kg/min

Vasopressin infusion 0.03 u/minVasopressin infusion 0.03 u/min

Hydrocortisone 50 mg IV q 6HHydrocortisone 50 mg IV q 6H

Insulin protocol startedInsulin protocol started

LP not performed because of coagulopathyLP not performed because of coagulopathy

Activated protein C commenced 24Activated protein C commenced 24g/kg/hrg/kg/hr

Hour 4Hour 4ABGs:ABGs: 86/39/7.2186/39/7.21CVP:CVP: 8 mmHg8 mmHgCentral venous gasesCentral venous gases PcvOPcvO22 29, ScvO2 56 29, ScvO2 56

Fluid loaded:Fluid loaded: RL 1 litre over 1 hourRL 1 litre over 1 hour

Hour 5Hour 5CVPCVP 12 mmHg12 mmHgCentral venous gases Central venous gases PcvOPcvO22 31 mmHg, SvO2 62% 31 mmHg, SvO2 62%

Inotropic supportInotropic support Dobutamine infusion Dobutamine infusion 55g/kg/ming/kg/min

More fluidMore fluid Pentaspan 1 l over 1 hour and Pentaspan 1 l over 1 hour and RL 250 RL 250 mls/hrmls/hr

Hour 6Hour 6CVPCVP 14 mmHg14 mmHgCentral venous gasesCentral venous gases PcvO2 36 mmHg, SvO2 67%PcvO2 36 mmHg, SvO2 67%

Vent change:Vent change: Vt 400, PEEP 15, Paw 34Vt 400, PEEP 15, Paw 34ABGs:ABGs: 153/56/7.14153/56/7.14IV NaHCOIV NaHCO33 pH maintained > 7.25pH maintained > 7.25

Day 2 - Day 2 - S. pneumoniaeS. pneumoniae isolated from blood, sputum isolated from blood, sputum

Day 3 Step sensitive to Penicillin. Pt switched to Day 3 Step sensitive to Penicillin. Pt switched to Pen GPen G

RL decreased to 125 cc/hrRL decreased to 125 cc/hr

Hemodynamically stabilized. Norepinephrine and Hemodynamically stabilized. Norepinephrine and vasopressin weaned off day 5. Hydrocortisone vasopressin weaned off day 5. Hydrocortisone weaned off by day 8.weaned off by day 8.

Slow improvement in oxygenation.Slow improvement in oxygenation.

Pt successfully weaned from ventilator over next 72 Pt successfully weaned from ventilator over next 72 hourshours

Transferred to medical unit after 2 weeks in ICUTransferred to medical unit after 2 weeks in ICU

Discussion pointsDiscussion points Sepsis/septic shock definitionsSepsis/septic shock definitions Antibiotic managementAntibiotic management ResuscitationResuscitation

Resuscitation goalsResuscitation goals Time Time CV parametersCV parameters

Fluid managementFluid management Crystalloid vs. colloidCrystalloid vs. colloid

Vasopressor managementVasopressor management

““Low-dose” corticosteroid therapyLow-dose” corticosteroid therapy Microvascular circulationMicrovascular circulation Control of sepsis cascadeControl of sepsis cascade Intensive glycemic controlIntensive glycemic control

Severe Sepsis: Comparative Severe Sepsis: Comparative Incidence and MortalityIncidence and Mortality

0

50

100

150

200

250

300

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Incidence

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150000

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ACCP/SCCM Consensus DefinitionsACCP/SCCM Consensus Definitions InfectionInfection

Inflammatory response to Inflammatory response to microorganisms, ormicroorganisms, or

Invasion of normally sterile Invasion of normally sterile tissuestissues

Systemic Systemic Inflammatory Inflammatory Response Response Syndrome (SIRS)Syndrome (SIRS) Systemic response to a Systemic response to a

variety of processesvariety of processes

SepsisSepsis Infection plusInfection plus 2 SIRS criteria2 SIRS criteria

Severe SepsisSevere Sepsis SepsisSepsis Organ dysfunctionOrgan dysfunction

Septic shockSeptic shock SepsisSepsis Hypotension despite fluid Hypotension despite fluid

resuscitationresuscitation

Multiple Organ Multiple Organ Dysfunction Dysfunction Syndrome (MODS)Syndrome (MODS) Altered organ function in an Altered organ function in an

acutely ill patientacutely ill patient Homeostasis cannot be Homeostasis cannot be

maintained without maintained without interventionintervention

Sepsis: Defining a disease Sepsis: Defining a disease continuumcontinuum

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

Temperature Temperature 3838ooC C or or 3636ooCC

HR HR 90 beats/min90 beats/min WBC count WBC count 12 12

000/mm000/mm33 or or 4000/mm4000/mm33, or >10% , or >10% immature neutrophilsimmature neutrophils

Respirations Respirations 20/min20/min

SepsisSepsisInfection/TraumaInfection/Trauma

SIRSSIRS Severe SepsisSevere Sepsis


SIRS with a presumed SIRS with a presumed or confirmed or confirmed

infectious processinfectious process






Sepsis with Sepsis with 1 sign of 1 sign of organ failureorgan failure Cardiovascular Cardiovascular RenalRenal RespiratoryRespiratory HepaticHepatic HematologicHematologic CNSCNS Unexplained Unexplained

metabolic acidosismetabolic acidosis

ShockShockRefractory

hypotension

Relationship of SIRS, Sepsis, Relationship of SIRS, Sepsis, and Infectionand Infection

Relationship of SIRS, Sepsis, Relationship of SIRS, Sepsis, and Infectionand Infection

The ACCP/SCCM consensus Conference Committee, Chest 1992;101:1644-55.

INFECTIONINFECTION

SEPSISSEPSIS

SIRSSIRS

BURNSBURNS

OTHEROTHER

TRAUMATRAUMA

BACTEREMIABACTEREMIA

FUNGEMIAFUNGEMIA

PARASITEMIAPARASITEMIA

VIREMIAVIREMIA

OTHEROTHER

PANCREATITISPANCREATITIS

POST-PUMP SYNDROMEPOST-PUMP SYNDROME

Endocarditis0.6%

Respiratory44.0%

Genitourinary

9.1%

Abdominal8.6%

Device-related

2.2%

Wound/soft tissue6.6%

CNS0.8%

Other10.8%

Bacteremia, site unspecified

17.3%

Sites of confirmed or Sites of confirmed or presumed infection in severe presumed infection in severe

sepsissepsis

Angus DC, et al. Crit Care Med 2001

Incidence of sepsis in USA Incidence of sepsis in USA 1979-20001979-2000

In-hospital mortality for sepsisIn-hospital mortality for sepsis

Incidence of sepsis by causative Incidence of sepsis by causative organismorganism

Older patientsOlder patients Higher proportion of patients with severe co-Higher proportion of patients with severe co-

morbidities, immune deficiency, and a higher morbidities, immune deficiency, and a higher proportion of surgical patients. proportion of surgical patients.

Lung is the primary source of infectionLung is the primary source of infection Decrease in urosepsisDecrease in urosepsis PseudomonasPseudomonas and and StaphylococcusStaphylococcus resistant to resistant to

methicillin-related septic shock have methicillin-related septic shock have dramatically increased with time, to reach a dramatically increased with time, to reach a worrying proportion of 20-25% of cases in worrying proportion of 20-25% of cases in 2000. 2000.

Likely from intensive antibiotic use in ICUs. Likely from intensive antibiotic use in ICUs.

Compared with the general ICU Compared with the general ICU population, the septic shock population, the septic shock subset has:subset has:

Pathophysiology of Shock in Pathophysiology of Shock in SepsisSepsis

Inflammation

Pro-coagulant state Inhibition of fibrinolysis

Pathogenesis of Shock

Infectious triggers

Cytokine and inflammatory mediator cascade

Cardiac dysfunction and microvascular injury

Hypotension and shock

Time

Antiinflammatory(endogenous)

Antiinflammatory(endogenous)

CARSCARS

SIRSSIRS

The Dynamic Nature of The Dynamic Nature of SepsisSepsis

RECOVERY

OrganInjuryOrganInjury

Insult

Risk factors for mortality in Risk factors for mortality in pneumoniapneumonia

FactorsFactors Odds ratioOdds ratio 95% 95% Confidence Confidence

IntervalIntervalPrevious Previous

hospitalizationhospitalization7.997.99 1.49-42.701.49-42.70

COPDCOPD 9.189.18 1.69-49.821.69-49.82

Multilobar Multilobar diseasedisease

14.2914.29 2.40-85.002.40-85.00

InappropriatInappropriatee

antibioticantibiotic

27.3527.35 1.82-410.161.82-410.16

NCCLS 2002

Bacterial PneumoniaDeath Rate in the United States

100

80

60

20

0Per

cen

t o

f P

ati

en

ts

Ad

jus

ted

Od

ds

of

30 D

ay M

ort

alit

y (

95%

CI)

Mortality increased for each hour delay

Mortality at 30 days was reduced significantly if antibiotics administered within 8 hrs

40

2 h 4 h 6 h 8 h 10 h

Time Until Antibiotic Therapy (h)

1.2

1.0

0.8

0.62 h 4 h 6 h 8 h 10 h

Hours Within Which Antibiotics WereAdministered

Medicare patients >65 yrs in US

Harbarth et al. Harbarth et al. Am J MedAm J Med 2003;115:5292003;115:529

Lenercept trial-904 patients with severe sepsisLenercept trial-904 patients with severe sepsis

468 documented bacteremia (52%)468 documented bacteremia (52%)

Appropriate Appropriate antibiotic antibiotic therapytherapy

Inappropriate Inappropriate antibiotic antibiotic therapytherapy

PatientsPatients 693 (77%)693 (77%) 211 (27%)211 (27%)

28 day mortality28 day mortality 24%24% 39%*39%*

*p<0.001

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

Appropriate Appropriate antibiotic antibiotic therapytherapy

Inappropriate Inappropriate antibiotic antibiotic therapytherapy

PatientsPatients 2396 (91%)2396 (91%) 237 (9%)237 (9%)

28 day 28 day mortalitymortality

33%33% 43%*43%*

MONARCS trial - Monoclonal Anti-TNF

Delay in Initiation of Effective Delay in Initiation of Effective AntibioticsAntibiotics

Septic Shock – Impact of time of Septic Shock – Impact of time of Antibiotic AdministrationAntibiotic Administration

An Injury Paradigm of Sepsis and An Injury Paradigm of Sepsis and Septic ShockSeptic Shock

Infectious load

Inflammatory response

Toxic burden

Cellular dysfunction/tissue injury

TIME

Antimicrobial therapy


Infectious load


Toxic burden


TIME

earlier antimicrobial

therapy


TIME

more intense antimicrobial

therapy

Infectious load

Toxic burden



Causes for DelaysCauses for Delays Failure to recognize that hypotension Failure to recognize that hypotension

represents septic shockrepresents septic shock Effect of inappropriate antibiotic initiationEffect of inappropriate antibiotic initiation Failure to appreciate risk of resistant Failure to appreciate risk of resistant

organisms in certain scenarios (e.g. organisms in certain scenarios (e.g. immunocompromised vs immunosuppressed; immunocompromised vs immunosuppressed; pre-shock antimicrobial use)pre-shock antimicrobial use)

Transfer from ER before antibiotics givenTransfer from ER before antibiotics given Failure to use “stat” ordersFailure to use “stat” orders No specified order with multiple drug regimensNo specified order with multiple drug regimens Administrative/logistic delays Administrative/logistic delays

(nursing/pharmacy/ ward clerk)(nursing/pharmacy/ ward clerk)

Time (hrs)

3-5.99

6-11.99

12-23.99

>24

Odd

s R

atio

of

Dea

th(9

5% C

onfid

ence

Int

erva

l)

0

2

4

6

8

10

12

14

Delays in Source Control in Delays in Source Control in Septic ShockSeptic Shock

Source Control DelaysSource Control Delays

Stabilization?Stabilization? Convenience?Convenience?

Eliminate InfectionEliminate Infection

1.1. Hit the organismHit the organism

2.2. Hit the organism earlyHit the organism early

3.3. Hit the organism hardHit the organism hard

* * Get in the ringGet in the ring

ResuscitationResuscitation

Rivers E et al. Rivers E et al. NEJM NEJM

2001;345:1368-2001;345:1368-7777..

Rivers E et al. Rivers E et al. NEJM NEJM

2001;345:1368-2001;345:1368-7777..

AnalysisAnalysis Major therapeutic difference Major therapeutic difference

between groupsbetween groups 3 litres more crystalloid in first 6 hours3 litres more crystalloid in first 6 hours No difference in fluid balance over 72 No difference in fluid balance over 72

hrshrs Other differencesOther differences

Use of packed rbcsUse of packed rbcs Use of dobutamineUse of dobutamine

EGDT OutcomesEGDT Outcomes

Rivers E et al. N Eng J Med 2001;345:1368-77.

NNT=16

Standard Standard therapy therapy (N=133)(N=133)

Early goal Early goal directed directed therapy therapy (N=130)(N=130)

P P valuvaluee

In-hospital In-hospital mortalitymortality

All patientsAll patients 59 (46.5%)59 (46.5%) 38 (30.5%)38 (30.5%) 0.000.0099

Severe sepsisSevere sepsis 19 (30.0%)19 (30.0%) 9 (14.9%)9 (14.9%) 0.060.06

Septic shockSeptic shock 40 (56.8%)40 (56.8%) 29 (42.3%)29 (42.3%) 0.040.04

Sepsis syndromeSepsis syndrome 44 (45.4%)44 (45.4%) 35 (35.1%)35 (35.1%) 0.070.07

28 Day mortality28 Day mortality 61 (49.2%)61 (49.2%) 40 (33.3%)40 (33.3%) 0.010.01

60 Day mortality60 Day mortality 70 (56.9%)70 (56.9%) 50 (44.3%)50 (44.3%) 0.030.03

Sudden CV Sudden CV collapsecollapse

25/119 (21%)25/119 (21%) 12/117 12/117 (10.3%)(10.3%)

0.020.02

Multiple organ Multiple organ failurefailure

26/119 26/119 (21.8%)(21.8%)

19/117 19/117 (16.2%)(16.2%)

0.270.27

ConclusionsConclusions Early goal directed therapy in management Early goal directed therapy in management

of severe sepsis/septic shock can result in of severe sepsis/septic shock can result in dramatically improved outcomedramatically improved outcome

Early aggressive resuscitation ameliorates Early aggressive resuscitation ameliorates later multiple organ dysfunctionlater multiple organ dysfunction

Outcome determined in first 6 hours for Outcome determined in first 6 hours for many patientsmany patients

Fluid resuscitation criticalFluid resuscitation critical NNT 16NNT 16

Resuscitation goalsResuscitation goals

BPBP CVPCVP Urine outputUrine output ScvO2ScvO2 HgbHgb pHpH LactateLactate

Resuscitation goalsResuscitation goals BPBP MAP>65 mmHg/SBP>90 MAP>65 mmHg/SBP>90

mmHgmmHg CVPCVP 8-12 mmHg8-12 mmHg Urine outputUrine output 0.5-1 ml/kg/hr0.5-1 ml/kg/hr ScvO2ScvO2 >70%>70% HgbHgb >70-100 g/L>70-100 g/L pHpH >7.30>7.30 LactateLactate <4<4

However time frame is likely as important as absolute goals!!

Impact of medical emergency Impact of medical emergency team on unexpected cardiac team on unexpected cardiac

arrestsarrests

0

5

10

15

20

25

30

35

Cardiac arrests

ControlMET

P=0.0003

Percentage reduction: 66.6%

Bellomo R et al. Crit Care Med 2004;32:916-921.

Impact of Medical Emergency Team on ARF Impact of Medical Emergency Team on ARF requiring Renal Replacement Therapyrequiring Renal Replacement Therapy

27

2

0

5

10

15

20

25

30

Events

Control

MET

p<0.001

Pat

ient

s

Bellomo R et al. Crit Care Med 2004;32:916-921.

They’re baaack!!They’re baaack!!

Corticosteroids for Corticosteroids for septic shockseptic shock

Outcomes with corticosteroids Outcomes with corticosteroids in septic shockin septic shock

NNT=8NNT=8

Adrenal insufficiency during Adrenal insufficiency during septic shockseptic shock

Adrenal insufficiency common in patients with Adrenal insufficiency common in patients with

septic shockseptic shock

ACTH stimulation test idealACTH stimulation test ideal

No absolute diagnostic random serum cortisol level No absolute diagnostic random serum cortisol level

Random serum cortisol level < 690 nmol/l in a Random serum cortisol level < 690 nmol/l in a

highly stressed patient is useful diagnostic highly stressed patient is useful diagnostic

threshold for diagnosis of adrenal insufficiencythreshold for diagnosis of adrenal insufficiency

Hydrocortisone in septic Hydrocortisone in septic shockshock

““Low dose” hydrocortisone (HC 50 mg q Low dose” hydrocortisone (HC 50 mg q

6H) :6H) :

Inhibited NOx formationInhibited NOx formation

Reduced vasopressor requirementsReduced vasopressor requirements

Improved hemodynamic stabilityImproved hemodynamic stability

Differentially reduced inflammation without Differentially reduced inflammation without

significant immunosuppression significant immunosuppression

Vasopressor therapy in Vasopressor therapy in septic shockseptic shock

To restore systemic vascular To restore systemic vascular resistance towards normal and resistance towards normal and allow tissue and organ perfusionallow tissue and organ perfusion DopamineDopamine NorepinephrineNorepinephrine VasopressinVasopressin

How should we use How should we use vasoactive agents?vasoactive agents?

Forget about low-dose dopamineForget about low-dose dopamine

Perhaps forget about dopamine entirely!!!Perhaps forget about dopamine entirely!!!

Should we titrate to SBP or MAPShould we titrate to SBP or MAP

What target BP?What target BP?

Other?Other?

Effects of Dopamine, Effects of Dopamine, Norepinephrine,Norepinephrine,

and Epinephrine on the Splanchnicand Epinephrine on the SplanchnicCirculation in Septic ShockCirculation in Septic Shock

NE improves survival in NE improves survival in patients with severe sepsispatients with severe sepsis

Days

Su

rviv

al

MAP (mm Hg)MAP (mm Hg)

00 100100 200200

1.0 1.0

0.1 0.1 Flo

w r

ate

(L /

min

)F

low

rat

e (L

/ m

in)

Normal renal vascular Normal renal vascular autoregulationautoregulation

Renal Blood FlowRenal Blood Flow

GFRGFR

5050 15015075

VasopressinVasopressin

Secreted under osmotic control to modify Secreted under osmotic control to modify

permeability of renal collecting ducts to water (0.9-permeability of renal collecting ducts to water (0.9-

6.5 pmol/L) - V6.5 pmol/L) - V22 receptors receptors

Secreted under baroreceptor control to modify BP Secreted under baroreceptor control to modify BP

(9-187 pmol/L) - V(9-187 pmol/L) - V11 receptors receptors

Rapid increase in vasopressin levels in early phase Rapid increase in vasopressin levels in early phase

of hemorrhagic shock (>280 pmol/L)of hemorrhagic shock (>280 pmol/L)

Subsequent decrease in levels (30 pmol/L) due to Subsequent decrease in levels (30 pmol/L) due to

depletion of posterior pituitary storesdepletion of posterior pituitary stores

Posterior Pituitary Vasopressin Posterior Pituitary Vasopressin Depletion in ShockDepletion in Shock

NormalNormal Post shockPost shock

Vasopressin Deficiency Contributes to the Vasodilation of Septic Vasopressin Deficiency Contributes to the Vasodilation of Septic

Shock Landry DW et al. Shock Landry DW et al. Circulation.Circulation. 1997;95:1122-1125. 1997;95:1122-1125.

SepticSepticShockShock(n=19)(n=19)

Cardiogenic Cardiogenic ShockShock(n=12)(n=12)

AVPAVP(pg/ml)(pg/ml)

22.722.7±2.2±2.2

3.1±0.43.1±0.4

Rationale for use of Rationale for use of Vasopressin in septic shockVasopressin in septic shock

Low levels of vasopressin in patients with Low levels of vasopressin in patients with

septic shockseptic shock

Infusion of vasopressin to provide serum Infusion of vasopressin to provide serum

levels normally seen in shock provides levels normally seen in shock provides

significant improvement in BP even in significant improvement in BP even in

patients refractory to NE and Epipatients refractory to NE and Epi

Vasopressin

• Not a replacement for norepinephrine or dopamine as a first-line agent

• Consider in refractory shock despite high-dose conventional vasopressors

• If used, administer at 0.01-0.04 units/min in adults

Cardiac Dysfunction during Septic Shock

10 Days Post Shock

Diastole Systole

Diastole Systole

Images used with permission from Joseph E. Parrillo, MD

Microcirculation Microcirculation in severe sepsisin severe sepsis

Time course of small vessel Time course of small vessel perfusionperfusion

Sakr Y et al. Crit Care Med 2004; 32:1825-1831

Evolution of small vessel perfusion Evolution of small vessel perfusion between first (between first (hatchedhatched) and last ) and last

((whitewhite) measurement) measurement

Sakr Y et al. Crit Care Med 2004; 32:1825-1831

(*p < .01 last vs. first

Videomicroscopy of capillaries in a normal and septic patient with vasodilation. (approx 1 min)

Why?Why?

Low perfusion pressureLow perfusion pressure

Low cardiac outputLow cardiac output

MicrothrombosisMicrothrombosis

Microvascular events in severe Microvascular events in severe sepsissepsis

SepsisSepsis

CoagulationCoagulation Fibrinolysis Fibrinolysis InflammationInflammationEndothelial Endothelial

injuryinjury

Organ failureOrgan failure

DeathDeath

Digital ischemiaDigital ischemia

GangreneGangrene

MicrothrombosisMicrothrombosis

Clinical impact of Clinical impact of microthrombosismicrothrombosis

The sepsis cascadeThe sepsis cascade

Activated Protein C interrupts Activated Protein C interrupts the sepsis cascade the sepsis cascade

rAPC reduces microvascular thrombosis through rAPC reduces microvascular thrombosis through multiple mechanisms of action.multiple mechanisms of action.

rAPC

N Eng J Med 2001;344:699-709.

Absolute mortality reduction NNT •All patients 6% 16 •APACHE II score ≥ 25 13% 8

ENHANCE TrialENHANCE Trial Large open label trial of rAPC in severe Large open label trial of rAPC in severe

sepsissepsis Showed mortality improvement when Showed mortality improvement when

rAPC given within 24 hours of admissionrAPC given within 24 hours of admission

ADDRESS Trial• rAPC in septic patients with APACHE II score <25• Trial discontinued at interim analysis because of lack of efficacy

APC Complication-APC Complication-HemorrhageHemorrhage Absolute contraindications:Absolute contraindications:

Active internal bleedingActive internal bleeding Recent (within 3 months) hemorrhagic strokeRecent (within 3 months) hemorrhagic stroke Recent (within 2 months) intracranial or intraspinal Recent (within 2 months) intracranial or intraspinal

surgery, or severe head traumasurgery, or severe head trauma Trauma with an increased risk of life-threatening bleedingTrauma with an increased risk of life-threatening bleeding Presence of an epidural catheterPresence of an epidural catheter Intracranial neoplasm or mass lesion or evidence of Intracranial neoplasm or mass lesion or evidence of

cerebral herniationcerebral herniation Relative contraindicationsRelative contraindications

Platelet count < 30Platelet count < 30 PTT PTT ≥≥ 100 100 INR INR ≥≥ 3 3

Intensive Insulin TherapyIntensive Insulin Therapy

Intensive insulin therapyIntensive insulin therapy

Standard therapy Intensive

(N=783) (N=785) P Value

Insulin required 307 (39.2%) 755 (98.7%) <0.001

Median insulin dose IU/day 33 71 <0.001

Inotropic/Vasopressor Tx 586 (74.8%) 574 (75%) 0.9

Morning blood glucose (mg/dl) 153+33 103+19 <0.001

Van den Berghe G et al. N Eng J Med 2001;345:1359-1367

MorbidityMorbidity

Standard therapy Intensive

Variable (N=783) (N=785) P Value

Death in ICU 63/783 (8.0%) 35/765 (4.6%) <0.04

During first 5 days 14/783 (1.8%) 13/765 (1.7%) 0.9

After day 5 49/243 (20.2%) 22/208 (10.6%) 0.005

Cause of death

MOF with septic focus 33 8

MOF without septic focus 18 14



SummarySummary Early diagnosisEarly diagnosis Early appropriate antibiotic therapy Early appropriate antibiotic therapy

and source controland source control Early aggressive goal directed Early aggressive goal directed

resuscitation resuscitation Low dose corticosteroid therapyLow dose corticosteroid therapy Vasopressor therapyVasopressor therapy Intensive glycemic controlIntensive glycemic control Activated protein CActivated protein C

Severe Sepsis / Septic Shock Division of Critical Care Medicine University of Alberta.

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