Severe Sepsis / Septic Shock Division of Critical Care Medicine University of Alberta.
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Transcript of 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
AIDS BreastCancer
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Incidence
Cas
es/1
00,0
00
0
50000
100000
150000
200000
250000
AIDS BreastCancer
AMI SevereSepsis
Mortality
Dea
ths/
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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
Sepsis: Defining a disease Sepsis: Defining a disease continuumcontinuum
SIRS with a presumed SIRS with a presumed or confirmed or confirmed
infectious processinfectious process
SepsisSepsisInfection/TraumaInfection/Trauma
SIRSSIRS Severe SepsisSevere Sepsis
Sepsis: Defining a disease Sepsis: Defining a disease continuumcontinuum
SepsisSepsisInfection/TraumaInfection/Trauma
SIRSSIRS Severe SepsisSevere Sepsis
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
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
earlier antimicrobial
therapy
An Injury Paradigm of Sepsis and An Injury Paradigm of Sepsis and Septic ShockSeptic Shock
TIME
more intense antimicrobial
therapy
Infectious load
Toxic burden
Inflammatory response
Cellular dysfunction/tissue injury
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
Van den Berghe G et al. N Eng J Med 2001;345:1359-1367
Van den Berghe G et al. N Eng J Med 2001;345:1359-1367
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