surviving sepsis talk
TRANSCRIPT
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Surviving SepsisEloise Harman
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The SEPSIS CASCADE
Balk , adapted from R Bone
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The Sepsis Continuum
A clinical responsearising from anonspecific insult, with2 of the following:
T >38oC or 90 beats/min
RR >20/min
WBC >12,000/mm3or 10% bands
SIRS = systemic inflammatoryresponse syndrome
SIRS with apresumedor confirmed
infectiousprocess
Chest 1992;101:1644.
SepsisSIRSSevere
Sepsis
Septic
Shock
Sepsis withorgan failure
Refractoryhypotension
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Sepsis: A Major Cause of ICUDeath
More than 750,000 cases of severe sepsisin the US each year
Mortality about 20% (recent decline)
Economic cost of $17 billion each year
Incidence is projected to increase by 1.5%yearly
Although prognosis has improved,because of increased incidence, actualdeaths will increase
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Surviving Sepsis Campaign
Launched in Fall 2002 as a collaborative effort ofEuropean Society of Intensive Care Medicine,the International Sepsis Forum, and the Society
of Critical Care MedicineGoal: reduce sepsis mortality by 25% in the next5 years
Guidelines revealed at SCCM in Feb 2004
Critical Care Medicine March 2004 32(3):858-87.
Website: survivingsepsis.org
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Key Components
Fluid resuscitation
Appropriate cultures prior to antibiotic
administration
Early targeted antibiotics and sourcecontrol
Use of vasopressors/inotropes when fluidresuscitation optimized
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Key Components
Evaluation for adrenal insufficiency
Stress dose corticosteroid administration
Recombinant human activated protein C(xigris) for severe sepsis
Low tidal volume mechanical ventilationfor ARDS
Tight glucose control
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Key Components: PreventComplications of Critical Illness
Prophylaxis for DVT
Stress ulcer prophylaxis
Prevention of nosocomial pneumonia byelevation of head to 45 degrees
Facilitate extubation by daily interruption
of sedation and early SBTNarrowing of antibiotic spectrum whenappropriate
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Key Components: Infection Control
Appropriate cultures prior to antibiotic
administration
Early targeted antibiotics and sourcecontrol
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Early Appropriate Antibiotics andSource Control
Gram positive organisms have surpassedgram negatives as the most commonsource of sepsis
Therapy targeted to the suspected site(eg, CAP, intra-abdominal source)
Drainage, debridement and deviceremoval as indicated
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Therapy Across the Sepsis Continuum
Chest1992;101:1644.
SepsisSIRSSevere
Sepsis
Septic
Shock
Antibiotics and Source Control
Chest2000;118(1):146
62%
28%
Drainage
Debridement
Deviceremoval
Definitivecontrol
resection
amputation
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Therapy Across the Sepsis Continuum
Chest1992;101:1644.
SepsisSIRSSevere
Sepsis
Septic
Shock
Early Goal Directed Therapy
Antibiotics and Source Control
Early Goal-Directed Therapy (EGDT): involves adjustments of cardiacpreload, afterload, and contractility to balance O2 delivery with O2 demand
*
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Goal Directed Therapy
Administration of fluids, pressors andtransfusion based upon targets for CVP,blood pressure, urine output, mixed
venous oxygen saturation and hematocrit
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Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the
treatment of severe sepsis and septic shock. NEJM2001;345:1368.
Early Goal-Directed Therapy in the Treatment ofSevere Sepsis and Septic Shock
Study purpose: to evaluate the efficacy of earlygoal-directedtherapy in patients presenting to anemergency department with severe sepsis or
septic shock (prior to ICU admission)
Study design: prospective, randomizedcontrolled, partially blinded, single center trial
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Patientrandomized
N=263Early goaldirected therapyN=130
Standardtherapy N=133
CVP > 8-12 mm Hg
MAP > 65 mm HgUrine Output > 0.5 ml/kg/hr
CVP > 8-12 mm Hg
MAP > 65 mm HgUrine Output > 0.5 ml/kg/hrScvO2 > 70%SaO2 > 93%Hct> 30%
Antibiotics given atdiscretion of
treating clinicians
As soon aspossibleMean 6.2hrs
ICU MDs blinded to
study treatment NEJM2001;345:1368-77.
At least 6 hoursof EGDTMean 8hrs
Transfer to ICU
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CVP: central venouspressure
MAP: mean arterialpressure
ScvO2: central venousoxygen saturation
Early Goal-
Directed Therapy
NEJM2001;345:1368-77.
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49.2%
33.3%
0
10
20
30
40
50
60
Standard TherapyN=133
EGDTN=130
P = 0.01*
*Key difference was in sudden CV collapse, not MODS
Early Goal-Directed Therapy Results:28 Day Mortality
Sudden CV Collapse
MODS
21% vs 10%
p=0.02
22%vs16%
P=0.27
NEJM2001;345:1368-77.
Mortality
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Fluid Resuscitation
Crystalloids and colloids are equallyeffective in restoring intravascular volume
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SAFE Study
In a randomized, controlled trial conductedin 16 ICUs in Australia and New Zealand6997 patients were randomized to receive
either saline or 4% albumin for fluidresuscitation
The albumin group received less fluidvolume, but required more transfusion inthe first 48h
NEJM 2004; 350:2247
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The SAFE Study Investigators, N Engl J Med 2004;350:2247-2256
Kaplan-Meier Estimates of the Probability of Survival
Primary Endpoint was 28 day mortality
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SAFE STUDY
There were also no differences in durationof mechanical ventilation or ICU stay,development of single or multiple organ
failure or duration of hospitalization.
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The SAFE Study Investigators, N Engl J Med 2004;350:2247-2256
Relative Risk of Death from Any Cause among All the Patients and among the Patients in theSix Predefined Subgroups
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What Pressors for Septic Shock ?
Several non-randomized studies and onesmall prospective randomized study ofdopamine vs norepinephrine for septic
shock suggest that survival may beimproved with the use of norepinephrine
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Norepinephrine vs Dopamine+/_ Epinephrine in Septic Shock
Results of a prospective observational study
Claude, Critical Care Med 2000;28:2758
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If cardiac output is inadequate withnorepinephrine, as indicated by a reducedmixed venous oxygen saturation,
dobutamine may be added
Vasopressin is emerging as a valuableaddition to therapy for septic shock in
patients with catecholamine refractoryhypotension
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Why Vasopressin ?
There is vasopressin deficiency invasodiltory shock
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http://content.nejm.org/content/vol345/issue8/images/large/07f4.jpeg -
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A. Normal B. After one hour of hemorrhagic shock
VASOPRESSIN DEFICIENCY OCCURS IN SHOCK
http://content.nejm.org/content/vol345/issue8/images/large/07f3.jpeg -
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Why Vasopressin ?
Patients with septic shock have increasedsensitivity to its pressor effects
Vasopressin restores vascular tone in
catecholamine resistant shock by severalmechanisms including potentiation ofadrenergic agents
Low dose vasopressin increases urineoutput in septic patients, and increasescreatinine clearance
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Therapy Across the Sepsis Continuum
SepsisSIRSSevereSepsis
Septic
Shock
Insulin and tight glucose control
Early Goal Directed Therapy
Antibiotics and Source Control
Chest1992;101:1644.
*
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Glucose Control: Mechanisms
Stress hyperglycemia is common in sepsis
Glucose has pro-inflammatory effects
Insulin resistance is common in sepsisInsulin has an anti-inflammatory effect,possibly via NOS.
Benefit is likely related to both insulin itselfand lowering of blood glucose
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Tight Glucose Control
In a Belgian study, 1548 SICU patients onmechanical ventilation were prospectivelyrandomized to tight glucose control (80-
110) vs standard control (180-200)Tight glucose control had a dramatic effecton morbidity in mortality, especially for
patients in the ICU for>5 days
Van den Burghe, NEJM 2001; 345: 1359
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Randomization
Conventional Intensive
>215 mg/dL
180 to 200 mg/dL
(10.0 and 11.1mmol/L)
>110 mg/dL
80 to 110 mg/dL
(4.4 to 6.1mmol/L)
Blood glucose levelwhen insulin infusion
was started
Infusion adjusted to
maintain bloodglucose
van den Berghe G, et al. NEJM2001;345:1359-1367.
Intensive Insulin Therapy in Critically Ill Patients
39 % Received insulin 99% Received Insulin
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Tight Glucose Control ImprovedSurvival
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10.9%
7.2%
0%
5%
10%
15%
8.0%
4.6%
0%
5%
10%
15%
ICU Mortality was reducedby 42%
In-Hospital Mortality wasreduced by 34%
Mortality(%)
p = 0.01p < 0.04 (adjusted)
N=783 N=765
Conventional Intensive
N=783 N=765
NEJM
2001;345:1359-1367.
Intensive Insulin Therapy in Critically Ill Patients:Mortality
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Tight Glucose Control
Other dramatic effects: 46% decrease inbacteremias, 41% in acute renal failurerequiring dialysis, 50% reduction in
blood transfusion and a 44% decreasein critical illness polyneuropathy
Patients with bacteremia had a mortality
of 12.5% vs 29.5% and a decreasedrisk of MSOF
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Van den Berghe, G. et al. N Engl J Med 2006;354:449-461
Effect of Intensive Insulin Therapy on Morbidity In MICUPatients
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Van den Berghe, G. et al. N Engl J Med 2006;354:449-461
Tight Glucose Control in the MICU: Effect on Mortality
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SepsisSIRSSevereSepsis
SepticShock
Xigris (Drotrecogin)
Insulin and tight glucose control
Early Goal Directed Therapy
Antibiotics and Source Control
Chest1992;101:1644.
Therapy Across the Sepsis Continuum
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Activated Protein C in Sepsis
Protein C:
1. Inactivates
clotting factorslimiting
the generation
of thrombin
2. Inhibits prodnof inflammatory
cytokines
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PROWESS Study Design1690 Patients : Known or suspected infection > 3 of the SIRS criteria > 1 acute (< 24hr in duration) organ failures
Primary Endpoint: All-Cause Mortality at 28 days
Placebo96 hr infusion
+ standard treatment
Drotrecogin (xigris)24 mcg/kg/hr
96 hour infusion+ standard treatment
NEJM2001;344:699-709.
RANDOMIZED
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30.8%
24.7%
0.0%
10.0%
20.0%
30.0%
40.0%
Placebo Drotrecogin alfa (activated)
p=0.0054
PROWESS Results
6.1% inabsolute
mortality 19.4% inRR of death
Primary Stratified Intention-to-Treat Analysis
(n=850)(n=840)
NEJM2001;344:699-709.
Ad E t ith
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Adverse Events withDrotrecogin alfa
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Mortality as a Function of APACHE II at Study Entry
0.120.15
0.26
0.22
0.36
0.24
0.49
0.38
0%
10%
20%
30%
40%
50%
60%
1st 2nd 3rd 4th
Placebo Drotrecogin alfa (activated)
APACHE II Quartile28-Day
MortalityR
ate
Survival benefit was confined to patients with APACHE >25
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Xigris (Drotrecogin)
Mortality increased in patients with oneorgan failure who underwent surgerywithin the previous 30 days, and is
contraindicated in this group
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SepsisSIRSSevereSepsis
SepticShock
Drotrecogin
Insulin and tight glucose control
Early Goal Directed Therapy
Steroids
Antibiotics and Source Control
Chest1992;101:1644.
Therapy Across the Sepsis Continuum
*
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Adrenal Insufficiency in Septic
Shock
There is significant disagreement about how tobest evaluate adrenal function in critical illness
General agreement that a random cortisol of
less than 25 is abnormal in this populationSome screen with random cortisol and reserve
ACTH stim test for those with low levels
Use of total rather than free cortisol in those withhypoalbuminemia may overestimate theincidence of adrenal insufficiency
Stress Dose Corticosteroids in
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Stress Dose Corticosteroids inSepsis
In a double-blind, placebo controlledstudy in France, 300 patients wererandomized to receive stress dosesteroids (hydrocortisone 50 mg q6h)and fludrocortisone (50 mcg daily) orplacebo for 7 days
Patients first underwent a cortrosyn
stimulation test to determine relativeadrenal insufficiency
Annane, JAMA 2002;288:862
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Low Dose Steroid Treatment in Septic Shock:Study Design
Time 0Onset of shock
Randomization
Hydrocortisone IV 50mgevery 6 hours x 7 days
+Fludrocortisone 50mcg NG
daily x 7 days
PlaceboX 7 days
Cortrosyn stimulation
Primary Outcome:28-day survival
Annane D, et. al. JAMA 2002;288(7):862.
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Relative adrenal insufficiency was definedas a failure to increase serum cortisol bygreater than 9mcg/dl after a 250 mcg
ACTH stimulation test.Using this criteria, 77% of patients in thisstudy were adrenally insufficient
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Low Dose Steroid Treatment in Septic Shock:28 Day Mortality (Non-responders vs. Responders)
61%53%
0%
20%
40%
60%
80%
100%
53%63%
0%
20%
40%
60%
80%
100%
Low-dose Steroids Placebo
Patients with Relative AdrenalInsuffiency (ACTH Test Non-
responders) (77%)
Patients Without RelativeAdrenal Insufficiency (ACTH
Test Responders) (23%)
p = 0.04 p = 0.96
N=114 N=36 N=34N=11528-dayMort
ality
Annane D, et. al. JAMA 2002;288(7):862.
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Corticosteroids in Sepsis
Obtain a baseline cortisol or ACTHstimulation
Start stress dose steroids (hydrocortisone
200-300mg +/- fludrocortisone 50 mcg)
Discontinue if levels are adequate
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SURVIVING SEPSIS
Fluid resuscitation, goal-directed
Appropriate cultures prior to antibiotic
administrationEarly targeted antibiotics and sourcecontrol
Use of vasopressors/inotropes when fluidresuscitation optimized
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SURVIVING SEPSIS
Evaluation for adrenal insufficiency
Stress dose corticosteroid administration
Recombinant human activated protein C(xigris) for severe sepsis
Insulin drip for tight glucose control
Low tidal volumes (6cc/kg) for mechanicalventilation in ARDS
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PREVENT COMPLICATIONS
Stress ulcer and DVT prophylaxis
Narrow antibiotic spectrum
Prevent VAP: 45 degree elevationFacilitate early discontinuation ofmechanical ventilation: sedation
interruption, early SBT
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Acknowledgement
Michelle Allen Pharm D
Henry J. Mann, U of Minnesota