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1
Joshua Solomon, M.D.
Associate Professor of Medicine
National Jewish Health
University of Colorado Denver
Updates in Sepsis
2017
Outline• Background
• New Definition of Sepsis
• New Trials of EGDT
• Transfusions
• New sepsis bundle
• Survivors of sepsis
A 62 year-old female presents to the ED with fever, cough,
dyspnea. She has a history of diabetes and CHF.
T 102, HR 130, RR 24, BP 100/50, SaO2 = 94% on 6L.
CXR shows right lower lobe consolidation.
Wbc 14, Creatinine 2.1, Lactate 2.1
Epidemiology of sepsis
• Sepsis is a devastating medical condition
• Incidence has risen dramatically over the past 20 years
(3/1000 population)
• While in–hospital mortality is improving, 10th leading cause
of death in the United States
– mortality ranges from 30-50%
– >210,000 deaths/year
• Considerable impact on quality of life among survivors –
post critical illness syndrome
Angus DC, et al. Crit Care Med. 2001.
•0%
•5%
•10%
•15%
•20%
•25%
•30%
•35%
•40%
•45%
•0 •1 •5 •10 •15 •20 •25 •30 •35 •40 •45 •50 •55 •60 •65 •70 •75 •80 •85
Age
Mo
rta
lity
•Without Co-morbidity
•With Co-morbidity
•Overall
Mortality of Severe Sepsis by Age in the US
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
600,000
Severe Sepsis CasesUS Population
Se
ps
is C
as
es
To
tal U
.S. P
op
ula
tio
n/1
,00
0
Angus DC, et al. Crit Care Med. 2001.
Projected Incidence of Severe Sepsis in US 2001-2050
2
Bone et al. Chest 1992
Nidus of InfectionAbscessPneumoniaPeritonitisPyelonephritisCellulitis
Organism
Exotoxin
TSST-1Toxin-A
Structural ComponentTeichoic Acid AntigenPeptidoglycan, Endotoxin (LPS)Bacterial nucleic acids
Gut release ofendotoxin
Plasma
- Extrinsic / intrinsic pathways
- Protein C; S- TFPI
Complement Kinins
Coagulation
Monocyte-Macrophage
- TNF- Interleukins- Interferons- MIF- HMGB1
Cytokines
Endothelial Cells
Selectins, IcamsRenin-angiotensin systemProstaglandinsLeukotrienesProstacyclinThromboxaneEndothelin
Neutrophils
LysosomesOxygen free radicals
(superoxides)Granulocyte Colony
Stimulating Factor(G-CSF)
Cellular Dysfunction
Platelet Activating Factor
Nitric Oxide
Tissue Factor
Vasculature- Vasodilation- Vasoconstriction- Leukocyte aggregation- Endothelial cell dysfunction
Cellular Dysfunction
Organs- Dysfunction- Metabolic abnormalities
Myocardium- Depression- Dilatation
Shock
Refractory Hypotension Multiple Organ Dysfunction Recovery
Death
Pathogenesis of Septic Shock A 62 year-old female presents to the ED with fever, cough,
dyspnea. She has a history of diabetes and CHF.
T 102, HR 130, RR 24, BP 100/50, SaO2 = 94% on 6L.
CXR shows right lower lobe consolidation.
Wbc 14, Creatinine 2.1, Lactate 2.1
What is the patient’s diagnosis?
A. SIRS
B. Sepsis
C. Severe sepsis
D. Septic shock
SIRS
Sepsis
Severe Sepsis
Old Sepsis Definitions
Septic Shock
SIRS
Sepsis
Severe Sepsis
Old Sepsis Definitions
Septic Shock
Systemic Inflammatory Response Syndrome
2 or more of:
Temperature >380 or <360
Heart rate >90 beats/min
Respiratory rate >20 or PaCO2 < 32 mmHg
WBC >12,000, <4,000, or left-shift (>10%)
* Can result from a variety of insults (infection, trauma, pancreatitis, etc)
3
SIRS
Sepsis
Severe Sepsis
Old Sepsis Definitions
Septic Shock
SIRS
+
Suspected Infection
SIRS
Sepsis
Severe Sepsis
Old Sepsis Definitions
Septic Shock
All 3 criteria met within 6 hrs of each other
1.Documentation of suspected source of infection (“possible”)
2.SIRS
3.Organ dysfunction (need only one)
• SBP < 90 or MAP < 65 mm Hg within 1st hr
• Creatinine > 2 or urine output < .5 ml/kg/hr for > 2hr
• Bilirubin > 2 mg/dl
• Platelets < 100,000
• Coagulopathy (INR > 1.5 or PTT > 60 sec)
• Lactate > 2 mmol/L
SIRS
Sepsis
Severe Sepsis
Old Sepsis Definitions
Septic Shock
Severe Sepsis with:
Hypoperfusion despite “adequate” fluid resuscitation
(SBP < 90 or MAP < 65 mm Hg or 40% reduction from
baseline)
OR
Lactate > 4.0 mmol/L
SIRS
Sepsis
Severe Sepsis
Sepsis Definition 2017 (Sepsis 3)
Septic Shock
Quick SOFA
2 or more of
Resp Rate ≥ 22
Altered Mentation (GCS ≤13)
Systolic BP ≤ 100 mmHg
SIRS
Sepsis
Severe Sepsis
Sepsis Definition 2016
Septic Shock
Evidence of Infection
+
Change in baseline
SOFA score of ≥ 2
(assume baseline of 0)
SEPSIS
Clinical Handbook of Interstitial Lung DiseaseClinical Handbook of Interstitial Lung Disease
Sequential Organ Failure Assessment (SOFA) Score
4
SIRS
Sepsis
Severe Sepsis
Sepsis Definition 2016
Septic Shock
Vasopressors to maintain MAP ≥65
mmHg
And
Lactate > 2 mmol/L despite volume
resuscitation
A 62 year-old female presents to the ED with fever, cough,
dyspnea. She has a history of diabetes and CHF.
T 102, HR 130, RR 24, BP 100/50, SaO2 = 94% on 6L.
CXR shows right lower lobe consolidation.
Wbc 14, Creatinine 2.1, Lactate 2.1
What is the patient’s diagnosis (old definition)?A. SIRS
B. Sepsis
C. Severe sepsis
D. Septic shock
A 62 year-old female presents to the ED with fever, cough,
dyspnea. She has a history of diabetes and CHF.
T 102, HR 130, RR 24, BP 100/50, SaO2 = 94% on 6L.
CXR shows right lower lobe consolidation.
Wbc 14, Creatinine 2.1, Lactate 2.1
What is the patient’s diagnosis (old definition)?A. SIRS
B. Sepsis
C. Severe sepsis
D. Septic shock
A 62 year-old female presents to the ED with fever, cough,
dyspnea. She has a history of diabetes and CHF.
T 102, HR 130, RR 24, BP 100/50, SaO2 = 94% on 6L.
CXR shows right lower lobe consolidation.
Wbc 14, Creatinine 2.1, Lactate 2.1
What is the patient’s diagnosis (new definition)?A. Not Septic
B. Sepsis
C. Septic shock
A 62 year-old female presents to the ED with fever, cough,
dyspnea. She has a history of diabetes and CHF.
T 102, HR 130, RR 24, BP 100/50, SaO2 = 94% on 6L.
CXR shows right lower lobe consolidation.
Wbc 14, Creatinine 2.1, Lactate 2.1
What is the patient’s diagnosis (new definition)?A. Not Septic
B. Sepsis
C. Septic shock
A 62 year-old female presents to the ED with fever, cough,
dyspnea. She has a history of diabetes and CHF.
CXR shows right lower lobe consolidation.
Wbc 14, Creatinine 2.1, Lactate 2.1
The patient’s blood pressure on recheck is 85/45. She is given 1.5 L of saline but remains hypotensive (She weighs 75 kg)
What are the next best steps?A. Get blood cultures
B. Give broad spectrum antibiotics
C. Place a central line to measure CVP
D. A and B
E. All the above
5
Prompt Administration of Antibiotics Saves Lives
0
20
40
60
80
100
<0.5 .5-1 1-2 2-3 3-4 4-5 5-6 6-9 9-12 12-24 24-36
Kumar. Crit Care Med 2006
% S
urv
ivin
g
Time to Antibiotic Administration (hrs)
N = 2731 patients
10 hospitals, 14 ICUs
Prompt Administration of Antibiotics Saves Lives
0
20
40
60
80
100
<0.5 .5-1 1-2 2-3 3-4 4-5 5-6 6-9 9-12 12-24 24-36
Kumar. Crit Care Med 2006
% S
urv
ivin
g
Time to Antibiotic Administration (hrs)
Each hour of delay is associated
with an 8% decrease in survival
NEJM November 8, 2001; 345:1368-77.
• Has become a de facto standard
of care for the last 14 years for
how to resuscitate patients in
severe sepsis and septic shock.
• Has led to sepsis “bundles” of
care
– 3 hour bundle
– 6 hour bundle
Early Goal Directed TherapySevere Sepsis or
Septic Shock
CVP
MAP
SvO2
Goals
Met ?
IV Fluids
Vasopressors
< 8 mm Hg
8-12 mm Hg
< 65 mm Hg
> 65 mm Hg
Transfuse blood until
Hct > 30%
< 70%
> 70%
Dobutamine
< 70%
> 70%
No
ICU AdmissionYes
Rivers. NEJM 345:1368-1377,2001
0
10
20
30
40
50
60
In-hospital 28 Day 60 Day
Control
EGDT
**
*
Mort
ality
Rivers. NEJM 345:1368-1377,2001
**
* p<0.05
** p<0.01
Early Goal Directed Therapy - Mortality
2015 UPDATE
• 3 major large randomized trials
• Looking to determine if there REALLY is any benefit to using
the approach of EGDT vs. “usual care” in patients with septic
shock
PROCESS TRIAL
PROMISE TRIAL
ARISE TRIAL
6
ProCESS Trial
N Engl J Med 2014;370:1683-93.
ProCESS trial
• In 31 EDs across USA, randomly assigned patients with
septic shock to one of three groups for 6 hr of
resuscitation (1341 patients):
– Protocol-based EGDT
– Protocol-based standard therapy that did not require
placement of CVP, inotropes, or blood transfusions
– Usual care
Early Goal Directed TherapySevere Sepsis or
Septic Shock
CVP
MAP
SvO2
Goals
Met ?
IV Fluids
Vasopressors
< 8 mm Hg
8-12 mm Hg
< 65 mm Hg
> 65 mm Hg
Transfuse blood until
Hct > 30%
< 70%
> 70%
Dobutamine
< 70%
> 70%
No
ICU AdmissionYes
Rivers. NEJM 345:1368-1377,2001
Shock index = HR/SBP
Values ≥ 0.8 suggestive
of shock
• 60-day mortality
– Protocol EGDT: 21%
– Protocol standard therapy:
18.2%
– Usual care: 18.9%
• Relative Risk of death:
– Protocol v. usual care: 1.04
(0.82-1.31, p=0.83)
– EGDT v. prot. standard: 1.15
(0.88-1.51, p=0.31)
ProCESS: Conclusions
• “In our multicenter, randomized trial, in which patients
were identified early in the ED as having septic shock
and received abx and other non-resuscitation aspects of
care promptly, we found no significant advantage,
with respect to mortality or morbidity, of protocol-
based resuscitation over bedside care provided
according to the treating physician's judgment.
• We also found no significant benefit of the mandated
use of central venous catheterization and central
hemodynamic monitoring in all patients.”
7
• Enrolled 1600 patients at 51 centers to EGDT vs usual care in
Australia and New Zealand
• Primary outcome:
– 90-day mortality
• 90-day mortality:
– EGDT: 18.6%
– Usual care: 18.8% ( P=0.90 )
• EGTD had more vasopressors, RBC transfusions and dobutamine
• Pragmatic randomized trial of 1260 patients in 56 hospitals in
England
• Patients with early septic shock were randomized to receive either:
– 6 hours of Early Goal-directed Therapy (EGDT)
– 6 hours of usual care
• 90 day mortality the same (29.5% vs 29.2%)
• EGDT had more IVF, vasoactive drugs, RBC
• EGDT had worse organ failure scores, more days with CV support,
longer ICU stays
Study Setting Patients EGDT Usual Care Protocol
Based
Rivers Single Center 263 44.3 56.9
ProCESS
ARISE
ProMISE
% Mortality
Study Setting Patients EGDT Usual Care Protocol
Based
Rivers Single Center 263 44.3 56.9
ProCESS USA (31) 1341 21 18.9 18.2
ARISE Aus/NZ (51) 1591 18.6 18.8
ProMISE England (56) 1251 29.5 29.2
% Mortality
Study EGDT Usual Care EGDT Usual Care
Rivers 27 30 100 NA
ProCESS 55 44 97 58
ARISE 66 58 98 62
ProMISE 53 46 99 51
% with CVC% on Pressors
CVP is useless for assessing volume status
Marik P. Chest. 2008;134(1):172-178.Shippy CR. Crit Care Med 1984. 12:107-112.
8
CVP is useless for assessing volume status
Shippy CR. Crit Care Med 1984. 12:107-112.
A 62 year-old female presents to the ED with fever, cough,
dyspnea. She has a history of diabetes and CHF.
CXR shows right lower lobe consolidation.
Wbc 14, Creatinine 2.1, Lactate 2.1
The patient’s blood pressure on recheck is 85/45. She is given 1.5 L of saline but remains hypotensive (She weighs 70 kg)
What are the next best steps?A. Get blood cultures
B. Give broad spectrum antibiotics
C. Place a central line to measure CVP
D. A and B
E. All the above
A 62 year-old female presents to the ED with fever, cough,
dyspnea. She has a history of diabetes and CHF.
CXR shows right lower lobe consolidation.
Wbc 14, Creatinine 2.1, Lactate 2.1
The patient’s blood pressure on recheck is 85/45. She is given 1.5 L of saline but remains hypotensive (She weighs 70 kg)
What are the next best steps?A. Get blood cultures
B. Give broad spectrum antibiotics
C. Place a central line to measure CVP
D. A and B
E. All the above
A 62 year-old female presents to the ED with fever, cough,
dyspnea. She has a history of diabetes and CHF.
CXR shows right lower lobe consolidation.
Wbc 14, Creatinine 2.1, Lactate 2.1, Hgb 8
The patient’s blood pressure on recheck is 85/45. She is given 1.5 L of saline but remains hypotensive (She weighs 70 kg)
What should we do about fluids?A. Give saline 30cc/kg based on CMS guidelines
B. Give fluids until you think she’s had enough
C. Give blood to volume expand and improve oxygenation
D. A and B
E. All the above
Study Setting EGDT Usual Care
Rivers Single Center 4.4 3.9
ProCESS USA (31) 2.8 2.2
ARISE Aus/NZ (51) 2.5 1.7
ProMISE England (56) 2.2 2.0
After enrollment (L)
Fluid Administration
Study Setting EGDT Usual Care EGDT Usual Care
Rivers Single Center 4.4 3.9 7.4 6.9
ProCESS USA (31) 2.8 2.2 4.9 4.3
ARISE Aus/NZ (51) 2.5 1.7 5.1 4.3
ProMISE England (56) 2.2 2.0 4.2 4.0
After enrollment (L) Total in 6hrs (L)
Fluid Administration
9
Study EGDT Usual Care
Rivers 64.1 18
ProCESS 14.4 7.5
ARISE 13.6 7.0
ProMISE 8.8 3.8
% Transfused
Blood Administration
TRISS Study
•Multicenter randomized
controlled trial
•998 patients with septic shock
•Transfused for Hgb < 9 or Hgb
< 7
•No benefit to higher Hgb
Fluid Administration
Summary and Additional Notes
• Starch is bad – leads to renal failure and increased mortality
• Albumin appears to be safe but no benefit over crystalloid
(ALBIOS and SAFE studies)
• Don’t use blood to volume expand
• Crystalloids are best studied
– Give a minimum of 30 cc/kg in first 6 hrs (CMS guidelines)
– Most patients needed at least 4L in multicenter trials
– Use your clinical skills to determine the optimum amount
• LR may be better than saline (pH 3-6, chloride 150)
A 62 year-old female presents to the ED with fever, cough,
dyspnea. She has a history of diabetes and CHF.
CXR shows right lower lobe consolidation.
Wbc 14, Creatinine 2.1, Lactate 2.1, Hgb 8
The patient’s blood pressure on recheck is 85/45. She is given 1.5 L of saline but remains hypotensive (She weighs 70 kg)
What should we do about fluids?A. Give saline 30cc/kg based on guidelines
B. Give fluids until you think she’s had enough
C. Give blood to volume expand and improve oxygenation
D. A and B
E. All the above
A 62 year-old female presents to the ED with fever, cough,
dyspnea. She has a history of diabetes and CHF.
CXR shows right lower lobe consolidation.
Wbc 14, Creatinine 2.1, Lactate 2.1, Hgb 8
The patient’s blood pressure on recheck is 85/45. She is given 1.5 L of saline but remains hypotensive (She weighs 70 kg)
What should we do about fluids?A. Give saline 30cc/kg based on guidelines
B. Give fluids until you think she’s had enough
C. Give blood to volume expand and improve oxygenation
D. A and B
E. All the above
Septic Shock Bundle
0 6 hr3 hr
1. measure lactate level
2. obtain blood cultures prior to
antibiotics
3. administer broad spectrum
antibiotics
4. 30 cc/kg crystalloid for
hypotension or lactate ≥4
1. apply vasopressors for
hypotension that does not respond
to initial fluid resuscitation
(MAP≥ 65)
2. re-assess volume status and
tissue perfusion and document
findings.*
3. Re-measure lactate if initial level
was elevatedPhysical exam or 2 of
CVP
ScVO2
Echo
Dynamic assessment
10
Sepsis Survivors
• Of those who lived independently prior to sepsis:– 1/3 die by 6 months
– 1/3 of 6 month survivors have not returned to independence
– 45% of those with problems at 6 m die or continue with problems at 1y
Yendi et al. Crit Care 2016
Jutte et al. SRCCM 2015
Conclusions • New definitions of sepsis and septic shock
• No need for routine CVL and CVP
• Less transfusion (target hg > 7)
• ? Protocol to use but EGDT is not necessary
• Crucial points – early recognition, early antibiotics, lot of fluid
• Survivors of sepsis have a tough road ahead of them
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