Transcript Sepsis: Unraveling the Puzzle - Kathleen Vollman, RN, MSN

Nurse’s role In
Comprehensive
Sepsis Management
Kathleen M. Vollman RN, MSN, CCNS, FCCM
Clinical Nurse Specialist/Educator/Consultant
ADVANCING NURSING
[email protected]
Northville, Michigan
www.vollman.com
© Vollman 2009
Overview
• Significance of the Problem
• Defining the continuum
• Brief overview of Pathophysiologic
derangements
• Prevention
• Early Recognition & Resuscitation
Severe Sepsis:
A Significant Healthcare Challenge
• Major cause of morbidity and mortality
worldwide
– Leading cause of death in noncoronary
ICU (US)1
– 10th leading cause of death overall (US)2*
• More than 750,000 cases of severe sepsis
in the US annually3
• In the US, more than 500 patients die
of severe sepsis daily3†
* Based on data for septicemia
†Reflects hospital-wide cases of severe sepsis as defined by infection in the presence of organ dysfunction
1 Sands KE, et al. JAMA 1997;278:234-40.
2 National Vital Statistics Reports. 2005.
3 Angus DC, et al. Crit Care Med 2001;29:1303-10.
Severe Sepsis Is Common
• 1 in 10 patients admitted to the ICU has
severe sepsis.*
• 2.26% of total hospital discharges nationally
• Incidence is expected to increase by nearly 17%
by 2014.
•All analyses were performed using the 2000 MEDPAR Hospital Discharge Database. The information presented
represents national averages, and similar analyses performed at an individual institution may provide different
results.
1. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome and
associated costs of care. Crit Care Med. 2001;29(7):1303-1310. 2. Data of file, Eli Lilly and Company: XIG20070405b.
Severe Sepsis Is Common
 Severe sepsis is more common than AIDS, colon cancer,
and breast cancer combined.
Cases/100,000
Incidence
AIDS1
Colon
Cancer2
Breast
Cancer2
CHF3
Severe
Sepsis4
1. National Center for Health Statistics, 2001. 2. American Cancer Society, 2001.
3. American Heart Association. 2000. 4. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States:
Analysis of incidence, outcome and associated costs of care. Crit Care Med. 2001;29(7):1303-1310.
Begin Proven Care Strategies
•
•
•
•
•
•
Early appropriate antibiotic use
EGDT: Early Goal-Directed Therapy
Low-tidal volume ventilation/ARDS/ALI
Xigris if not contraindicated
Tight glycemic control
Low-dose steroid administration for refractory
septic shock particularly in patients with relative
adrenal insufficiency
Implementation Through Proven
Change Strategies
IHI/VHA Change Strategy
• Care Bundles
– Grouping of care elements
for particular symptoms,
procedures or treatments
– Strong science, good
methodology, poor process
– Bundle characteristics
•
•
•
•
Solid evidence
Relatively easy &
inexpensive
Individual components
defined well
Process not defined well
How Does Severe Sepsis
Compare to Your Current Care
Priorities?
Quality
Projects
US
Incidence
# of Deaths
Mortality
Rate
AMI1
895,000
171,000
19%
Stroke1
700,000
157,800
23%
Pneumonia2
1,300,000
61,800
4.8%
Severe Sepsis3
751,000
215,000
29%
Why do you think that severe sepsis has not received
the same focus as these other common disease states?
1. American Heart Association. Heart Disease and Stroke Statistics 2006 Update. 2. National Center for Health Statistics. Available at:
www.cdc.gov/nchs/fastats/pneumonia.htm. Accessed February 4, 2005. 3. Angus DC, et al. Crit Care Med 2001;29(7):1303-1310.
4-Tier Process for
Severe Sepsis Program Implementation
Measuring
Success
Implementation of
the Sepsis Bundle
Early Screening with
Tools and Triggers
Organizational Consensus that Severe Sepsis
Must be Managed Early and Aggressively
2004-2006 Severe Sepsis Report
National-All Hospital, Medicare Reporting-3670
Top Ten Severe Sepsis Diagnosis-Related Groups *†
(53.5% of all cases with severe sepsis fell within 10 DRGs)
Severe Sepsis
Cases
All Others
(average)
(average)
Mortality
27%
7%
Ventilator Use
30%
2%
Hospital Length of Stay
11.1 days
7.2 days
ICU Length of Stay
6.5 days
4.2 days
$22,000
$12,000
Cost per Case‡
(costs exceeds payment)
Payment-to-Cost Ratio
-24%
8%
*
All analyses were performed using the 2004 through 2006 MEDPAR Hospital Discharge Databases. Cost and charge data are reported in year-appropriate
†
Severe sepsis patients were identified by looking for combinations of ICD-9-CM codes indicating infection and new onset of acute organ failure following SCCM/ACCP
guidelines as described in Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome and
associated costs of care. Crit Care Med. 2001;29 (7):1303-1310.
‡
Copyright © 2007, Eli Lilly and Company. All rights reserved
Average total hospital costs for patients treated in the ICU.
US Dollars.
Organization Support
 Executive management at hospital actively
supports the program
 Managing severe sepsis is aligned with hospital ‘s
current year goals
 Willingness to align resources with program
 Understanding that this is a 2-3+ year program to
make this the standard of practice for this patient
population
 Existing culture that supports change
• Successfully implemented other major change
programs—eg: vent bundle, tight glucose
control, CR-BSI
 Established team in place with ICU physician and
nurse champion, ED physician and nurse champion
that are respected by staff
Building a Severe Sepsis Tool Kit:
Project Team Charter
Problem Statement: Severe Sepsis is Common and Deadly
Team Members
ED, ICU, Patient Care Unit
Representatives, Administration,
Medical Staff, Nursing,
Pharmacy, Performance Improvement,
Case Management, Laboratory
Business Case
In comparison to other ICU patients,
severe sepsis patients have a higher
mortality rate, increased LOS, and an
increased need for a ventilator
Goals
Reduce severe sepsis mortality (make
the goal specific and measurable)
Scope
Severe sepsis patients in the ED, ICU,
and patient care units
Benefits
Milestones
Potential to improve outcomes
Implementation of tiers 1, 2, 3, and 4
The Team is KEY!!
Can Be Major Barrier If Not
Functioning Well
• Must have nurse and physician champions
from ED and ICU (need at least one physician
at all meetings)
• Must be linked in the organization’s quality or
operational structure
• Must meet at least 2 times per month
• Team members must be well educated on
the evidence and armed with tools and
knowledge to change behavior at the bedside
• MUST have bedside nurses on team—
provide reality check and best knowledge of
barriers
Severe Sepsis: Defining a Disease
Continuum
Infection or
Trauma
SIRS
Adult Criteria
A clinical response arising from a
nonspecific insult, including ≥ 2
of the following:
Temperature:> 38°C or < 36°C
Heart Rate: > 90 beats/min
Respiration:> 20/min
WBC count: > 12,000/mm3,
or < 4,000/mm3,
or > 10% immature
neutrophils
SIRS = Systemic Inflammatory Response Syndrome
Bone et al. Chest.1992;101:1644-1654.
Sepsis
SIRS
with a
presumed or
confirmed
infectious
process
Severe Sepsis
Sepsis
with 1 sign of organ
dysfunction,
hypoperfusion or
hypotension.
Examples:
• Cardiovascular
(refractory hypotension)
• Renal
• Respiratory
• Hepatic
Shock
• Hematologic
• CNS
• Unexplained metabolic
acidosis
Severe Sepsis: Defining a
Disease Continuum
Infection or
Trauma
SIRS
Sepsis
Severe Sepsis
Adult Criteria
A clinical response arising from a nonspecific
insult, including ≥ 2 of the following:
Temperature:> 38°C or < 36°C
Heart Rate:
> 90 beats/min
Respiration: > 20/min
WBC count: > 12,000/mm3,
or < 4,000/mm3,
or > 10% immature neutrophils
SIRS = Systemic Inflammatory Response Syndrome
Bone et al. Chest.1992;101:1644-1654.
Signs & Symptoms of Sepsis
Chills
Alteration in LOC
Tachypnea
Unexplained metabolic
31
acidosis
Heart rate
Altered blood pressure
 Platelets
 Bands
 Skin perfusion
 Urine output
Skin mottling
Poor capillary refill
Hyperglycemia
Purpura/petechia
Levy M, et al. Crit Care Med 2003;31:1250-6.
Severe Sepsis: Defining a
Disease Continuum
Infection or
Trauma
SIRS
Sepsis
SIRS
with a
presumed or
confirmed
infectious
process
SIRS = Systemic Inflammatory Response Syndrome
Bone et al. Chest.1992;101:1644-1654.
Severe Sepsis
Severe Sepsis: Defining a
Disease Continuum
Infection or
Trauma
SIRS
Examples:
Sepsis
Severe Sepsis
Sepsis
.
with 1 sign of organ
dysfunction, hypoperfusion
or hypotension
• Cardiovascular
(refractory hypotension)
• Renal
• Respiratory
• Hepatic
• Hematologic
• CNS
• Unexplained metabolic acidosis
SIRS = Systemic Inflammatory Response Syndrome
Bone et al. Chest.1992;101:1644-1654.
Shock
Identifying Acute Organ
Dysfunction as a Marker of
Severe Sepsis
Respiratory
PaO2/FiO2 200 if lung
only dysfunction/site of
infection
PaO2/FiO2 250 with
other organ
dysfunction/lung not site
of infection
Metabolic
Unexplained
metabolic acidosis
•Lactate > 1.5 times
upper normal
Cardiovascular
Tachycardia
SBP<90mmHg
MAP < 70mmHg
(despite fluid)
Need for Vasopressors
Renal
UO <0.5 ml/kg per hr
(despite fluid)
Hematologic
Platelets <80,000/mm3
Decline in platelet
count of 50% over 3
days
Deterioration of Cardiovascular Function on Day 1
was Associated with Increased Mortality in Placebo
Patients
Change in Vasopressor Dose on Day 1*†
70
P<0.00
01
% Mortality
60
58%
54%
50
37%
40
30
20%
20
n=294
0
No Vasopressor
n=41
No Vasopressor
to Low Dose
n=36
No Vasopressor
to High Dose
n=46
CV SOFA Increased by  1
* 28-day mortality for standard therapy patients enrolled in PROWESS and a Phase II study of an investigational anti-sepsis drug.
† Vasopressor requirement at study entry through day 1. Based on the Sequential Organ Failure Assessment (SOFA) score, low dose was
dopamine 6-15 µg/kg/min, epinephrine  0.1 µg/kg/min, or norepinephrine  0.1 µg/kg/min. High dose was defined as dopamine
> 15 µg/kg/min, epinephrine > 0.1 µg/kg/min, or norepinephrine >0.1 µg/kg/min.
defined as
21
Levy, M., Macias, W., Vincent, J., et al. Early changes in organ function predict eventual survival
in severe sepsis. Crit Care Med. 2005; 33:1-8.
PaO2/FiO2 Ratio
• User friendly tool
• Crude assessment of the
severity of lung injury
• May be used in the
assessment of Acute
Respiratory Dysfunction
due to Severe Sepsis
• Also used in the
definition of Acute Lung
Injury (ALI) and Acute
Respiratory Distress
Syndrome (ARDS)
PaO2 = 70 torr
FiO2 = 60% or .60
P/F Ratio = 70/.60
Answer: 117
Respiratory Dysfunction
(Mortality by Change in SOFA Score) in Placebo
Patients
Severe sepsis mortality predictors (Baseline to Day 1)
Population-based outcomes observed in severe sepsis patients
60%
p=0.0004
57%
50%
40%
30%
27%
30%
20%
10%
N=355
N=398
N=94
0%
IMPROVED BY DAY
1
UNCHANGED AT
DAY 1
WORSENED BY DAY
1
24
Levy, M., Macias, W., Vincent, J., et al. Early changes in organ function predict eventual survival in severe sepsis. Crit Care Med. 2005; 33:1-8.
Renal Dysfunction
(Mortality by Change in Serum Creatinine) in Placebo Patients
Severe sepsis mortality predictors (Baseline to Day 1)
Population-based outcomes observed in severe sepsis patients
In PROWESS, patients with chronic kidney failure on dialysis were excluded. The following was observed
in patients with acute kidney dysfunction at baseline (renal SOFA = 2)†‡
70
60
CMH Trend Test
P<0.0001
61%
50
40
35%
30
20
19%
10
N=129
N=109
N=38
0
1.2 TO 1.9 mg/dL
TO
< 1.2 mg/dL
1.2 TO 1.9 mg/dL
TO
1.2 TO 1.9 mg/dL
† Renal SOFA Score = 2 equivalent to creatinine range 2.0 - 3.4 mg/dL.
‡ APACHE (Acute Physiology And Chronic Health Evaluation). For more information on
26
using the APACHE II scoring system, please see
http://www.sfar.org/scores2/scores2.html.
1.2 TO 1.9 mg/dL
TO
> 1.9 mg/dL
Levy, M., Macias, W., Vincent, J., et al. Early changes in
organ function predict eventual survival in severe sepsis.
Crit Care Med. 2005; 33:1-8.
Data on file, Eli Lilly and Company: XIG20060922a.
Homeostasis Is Unbalanced
in Severe Sepsis
FIBRINOLYSIS
COAGULATION
INFLAMMATION
Homeostasis
Carvalho AC, Freeman NJ. J Crit Illness 1994;9:51-75.
Kidokoro A, et al. Shock 1996;5:223-8.
Vervloet MG, et al. Semin Thromb Hemost 1998;24:33-44.
SEVERE SEPSIS
PATHOPHYSIOLOGY
Microvascular
dysfunction  Hypoperfusion/hypoxia  Organ dysfunction
 Inflammation
 Coagulation
 Fibrinolysis
Microvascular thrombosis
Endothelial dysfunction
Global tissue hypoxia
Direct tissue damage
Inflammation, Coagulation and
Impaired Fibrinolysis In Severe Sepsis
Endothelium
COAGULATION CASCADE
Tissue Factor
Factor VIIIa
PAI-1
IL-6
IL-1
TNF-
Monocyte
Factor Va
Suppressed
fibrinolysis
THROMBIN
Neutrophil
Fibrin
IL-6
Fibrin clot
Tissue Factor
Inflammatory Response
to Infection
Thrombotic Response
to Infection
Adapted from Bernard GR, et al. N Engl J Med. 2001;344:699-709.
Fibrinolytic Response
to Infection
The Role Of Endogenous Activated
Protein C In Severe Sepsis
Endothelium
Activated Protein C
COAGULATION CASCADE
Tissue Factor
Factor VIIIa
IL-6
Inactivation
PAI-1
Activated Protein C
Organisms
Inhibition
Monocyte
Inactivation
Factor Va
Inactivation
Suppressed
fibrinolysis
Activated
Protein C
THROMBIN
Inhibition
Neutrophil
Fibrin
IL-6
Tissue Factor
Inflammatory Response
to Infection
Activated Protein C
Thrombotic Response
to Infection
Adapted from Bernard GR, et al. N Engl J Med. 2001;344:699-709
Fibrin clot
Fibrinolytic Response
to Infection
Pathophysiologic
Characteristics in Severe
Sepsis
• Maldistribution of blood flow
• Imbalance of oxygen supply & demand
• Metabolic alterations & activation of the
stress response
© Vollman 2001
Maldistribution of Blood
Flow
• Mechanical obstruction
– Micro-emboli
– Increased blood viscosity
– Compression
• Systemic & local mediator &
ion influence
– Constriction vs. dilation
• Loss of regulatory
activities/endothelial cell injury
– Reactive hyperemia
– Anticoagulation
© Vollman 2001
Imbalance of Oxygen Supply &
Demand
SUPPLY
DEMAND
© Vollman 2001
OXYGEN SUPPLY/DEMAND
DYNAMICS
ScvO2
CVP,
CO, CI,
SV, SVI
O 2 Supply/Demand
Compensatory Mechanisms
Improve pulmonary gas exchange
Increase oxygen delivery
Alter the distribution of blood flow
O2 Supply Debt
Metabolic Alterations & The
Stress Response
Initiation of the Stress Response
Sympathetic Nervous
System Activation
Hypothalamus
Activation
Metabolic Alterations & The
Stress Response
• Hypothalamus
• SNS Activation
Activation
• Gut hypothesis
• Adrenal cortex
•  BMR
stimulation
• Inhibition of
• Changes in
insulin secretion
carbohydrate, protein
& fat metabolism
• Inhibition of
resulting in  glucose
glucose uptake
concentration
by the tissues
Except on few occasions,
the patient appears to die from
the body's response to infection
rather than from it."
Sir William Osler – 1904
The Evolution of Modern Medicine
The Nurse’s Role
• Prevention of infection
• Early recognition of patients with signs
of sepsis
• Early initiation of evidence-based
practice therapies appropriate for your
area of practice (antibiotics,
fluids/blood, and vasopressors)
• Swift disposition to care areas
where the rest of the bundle
can be started
Prevention of Infection
• Ventilator-associated pneumonia
• Hospital acquired pneumonia
• Bloodstream infection related to an
invasive catheter
• Are you currently working on strategies
to prevent infections?
PREVENTING THE INVASION

Handwashing

Line care

Oral care

HOB
© Vollman 2001
EARLY MANAGEMENT
Early Recognition
Prompt/Aggressive
Resuscitation
Early Antibiotics
ICU/Additional Evidence
Based Therapies
2nd-Tier
Implementation of Early Screening
Tools and Triggers
Screens and triggers developed
to ID Severe Sepsis
patients in the ED, ICU, and
on patient care units
Organizational Consensus that Severe Sepsis
Must be Managed Early and Aggressively
Early Recognition: A
Screening Process
• TIME IS TISSUE!!
– If you identify patients early then you can
intervene and prevent further tissue damage
• To screen effectively, it must be part of the
nurses’ daily routine
• Must define a process for what to do with the
results of the screen
If you don’t screen you will miss patients that could
have benefited from the interventions
Make it Process Dependent
• Weave into fabric of current
practice
• Assess for daily
• Identify strategies for initiation of
therapy response once patient is
identified
“Triggers” for Identifying Severe Sepsis
Location/
Trigger Type
Standard Procedure
Manual Alert Message
Computerized
Alert Message
• Triage: Criteria-Based • Concurrent coder
Early Response
or case manager
• Upon pharmacy
entry of vasopressor/
antibiotic
• Lactate drawn as
a screen
• Order sheets
antibiotic/
vasopressor
• Upon withdrawal of
med from Automated
Dispensing Cabinet
• Change in lactate
• Change in lab
values (lactate)
• Upon scanning of
medication at bedside
Emergency
Department
“Triggers” for Identifying Severe Sepsis
Location/
Trigger Type
ICU
Computerized
Alert Message
Standard Procedure
Manual Alert Message
• Upon admission
• From concurrent
coder or case
manager
• Upon pharmacy
entry of vasopressor/
antibiotic
• By nurse at shift
change
• Nurse MAR review
(for antibiotic/
vasopressor)
• In note field on
computerized MAR
• Change in lactate
• During MD, RN, RPh,
rounds
note field of
• Change in lab values • In
vasopressor
(lactate)
computerized label
• Criteria-Based Early
Response
• Place on all ICU
charts (daily)
• Upon withdrawal of
med from Automated
Dispensing Cabinet
• Upon scanning of
medication at bedside
“Triggers” for Identifying Severe Sepsis
Location/
Trigger Type
Patient
Care Units
Computerized
Alert Message
Standard Procedure
Manual Alert Message
• Upon admission
• From concurrent
coder or case
manager
• Upon pharmacy
entry of antibiotic
• During MD, RN, RPh,
rounds
• Nurse MAR review
for antibiotic
• In note field on
computerized MAR
• Criteria-Based Early
Response teams
• Change in patient
hemodynamics
• In note field of
vasopressor
computerized label
• Need to mobilize
MET
• Upon withdrawal of
med from Automated
Dispensing Cabinet
• Change in lab values
(e.g., elevated WBC,
decreased platelet
count)
• Upon scanning of
medication at bedside
Reaching Outside the ICU:
Early Recognition Models
• Shock Program
• Medical Emergency Response Team (MET)
• Critical Care Nurse Consultant Service
Screening:
Barriers/Strategies
 Barriers
 Time for nurses to do it (perception vs reality)
 Screening is not sensitive only for severe sepsis
 Positive screen is not a diagnosis of severe sepsis
 Strategies
 Must assign responsibility and hold them
accountable- Perform audits to measure compliance and
identify problems
 Round on unit and ask nurses how it is going and
discuss issues
Screening:
Barriers/Strategies
• Lesson Learned: Bedside nurse must do
screening
• Education/Simulation/Education
- Every 6 months
- Build into orientation
- Must be part of their documentation structure
- Practice-Practice-Practice
The END RESULT—anytime patient has 2 or more
SIRS—will think that this patient might have sepsis
and can screen at that time
EARLY MANAGEMENT
Early Recognition
Prompt/Aggressive
Resuscitation
Early Antibiotics
ICU/Additional Evidence
Based Therapies
3rd-Tier
Implementation of Evidence-Based
Sepsis Bundles
Implementation of
the Sepsis Bundle with
protocol & order sets
Early Screening with
Tools and Triggers
Organizational Consensus that Severe Sepsis
Must be Managed Early and Aggressively
The Severe Sepsis Bundles: Surviving
Sepsis Campaign/IHI
Resuscitation Bundle
Management Bundle
(To be accomplished as soon as possible and scored
over first 6 hours):
(To be accomplished as soon as possible
and scored over first
24 hours):
 Serum lactate measured.
 Blood cultures obtained prior to antibiotics
administered. (1C)
 Perform imaging studies promptly to fine source
(1C)
 From the time of presentation, broad- spectrum
antibiotics within 3 hours for ED admissions and
1 hour for non-ED ICU admissions. (1D/1B)
 For hypotension and/or lactate > 4 mmol/L:
Deliver an initial minimum of 20 mL/kg of
crystalloid (or colloid equivalent) (1C)
Apply vasopressors for hypotension not
responding to initial fluid resuscitation to
maintain MAP > 65 mmHg.
 For persistent hypotension despite initial fluid
resuscitation (septic shock) and/or lactate
> 4 mmol/L: 1C
Achieve CVP > 8 mmHg & MAP > 65 mmHg &
UO >0.5mL/kg/hr
Achieve ScvO2 of > 70% or SvO2 > 65%.
 if ScvO2 not > 70% blood or dobutamine (2C)
 Low-dose steroids administered for
septic shock in accordance with a
standardized ICU policy. (Given to
patients who respond poorly to fluids
or vasopressors) (2C)
 Drotrecogin alfa (activated)
administered in accordance with a
standardized ICU policy. (Given to
patients with sepsis induced organ
dysfunction at high risk of death (2B)
 Glucose control maintained
to < 150 mg/dL (8.3 mmol/L). (2C)
 Tidal volume 6 ml/kg (1B) Inspiratory
plateau pressures
< 30 cmH2O for mechanically
ventilated patients. (1C)
Adapted from the revised guidelines: CCM
2008;36:296-327.
Bleeding is the most common adverse effect
associated with Xigris therapy.
See Important Safety Information in this presentation.
SURVIVING SEPSIS
GUIDELINES 2008
• The GRADE system is based on a sequential assessment of the quality
of evidence, followed by assessment of the balance between benefits
versus risks, burden, and cost and, based on the above, development
and grading of a management recommendations.
• Keeping the rating of quality of evidence and strength of
recommendation explicitly separate constitutes a crucial and defining
feature of the GRADE approach.
• This system classifies quality of evidence as high (Grade A), moderate
(Grade B), low (Grade C), or very low (Grade D).
• The GRADE system classifies recommendations as strong (Grade 1) or
weak (Grade 2).
• The grade of strong or weak is considered of greater clinical importance
than a difference in letter level of quality of evidence.
1. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: International guidelines for management
of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36:296-327.
Strength of the Science:
Part 1 of Grading System
Grading of Recommendations:
A.
Supported by at least two level I
investigations
B.
Supported by one level I investigation
C.
Supported by level II investigations only
D.
Supported by at least one level III
investigation
E.
Supported by level IV or V evidence
Recommendations are published in groups by category and not by hierarchy
Dellinger RP, et al. Crit Care Med. 2008;36:296-327.
New Grading System
• Quality of the evidence process = no change
• Recommendation process = new
Which components
of the bundle do you
believe will encounter
the most resistance?
PROMPT AGGRESSIVE
RESUSCITATION
“Early Goal Directed Therapy”
Sepsis Resuscitation Bundle
(To be accomplished as soon as possible over first 6 hours):
1. Serum lactate measured.
2. Blood cultures obtained prior to antibiotic administration.
3. From the time of presentation, broad-spectrum antibiotics administered within
3 hours for ED admissions and 1 hour for non-ED ICU admissions.
4. In the event of hypotension and/or lactate > 4 mmol/L (36 mg/dl):
a) Deliver an initial minimum of 20 ml/kg of crystalloid (or colloid equivalent*).
b) Apply vasopressors for hypotension not responding to initial fluid
resuscitation to
maintain mean arterial pressure (MAP) > 65 mm Hg.
5. In the event of persistent hypotension despite fluid resuscitation (septic
shock) and/or
lactate > 4 mmol/L (36 mg/dl):
a) Achieve central venous pressure (CVP) of > 8 mm Hg.
b) Achieve central venous oxygen saturation (ScvO2) of > 70%.**
Early Goal Directed Therapy
Methodology: 263 severe sepsis patients
• Early Goal-Directed
Therapy (EGDT)
• Continuous ScvO2
monitoring & tx with fluids,
blood, inotropes &/or
vasoactives to maintain:
ScvO2 >70%, SaO2 >
93%, Hct > 30%, CI/VO2
CVP > 8-12
MAP > 65
UO > .5ml/kg/hr
• Standard Therapy
• CVP > 8-12
• MAP > 65
• UO > .5ml/kg/hr
Rivers et. al. N Engl J Med. 2001;345;19:1368-1377.
Early Goal-Directed Therapy Results
28-day Mortality
NNT = 7-8
60
50
49.2%
P = 0.01*
40
33.3%
30
20
10
0
Standard Therapy
EGDT
n=133
n=130
*Key difference was in sudden CV collapse, not MODS
Rivers E. N Engl J Med 2001;345:1368-77.
Evidence of Early Goal
Directed Therapy
• First 6 hours of EGDT:
– 1500cc more fluid
– 64% received blood products vs. 18.5%
– 13.7% received inotropes vs. 0.8%
– No difference in vasopressor use or
mechanical ventilation
Rivers et. al. N Engl J Med. 2001;345;19:1368-1377.
Initial Resuscitation (1C)
 Protocolized resuscitation should begin as soon as
sepsis induced tissue hypoperfusion is recognized
or
 Elevated Serum lactate identifies tissue
hypoperfusion in patients at risk who are not
hypotensive
-
 Initial fluid challenges be started at > 1000 mL/kg
or 300-500 mL of colloid over 30 minutes (1C)
Dellinger, et. al. Crit Care Med 2008, 36:296-327.
Rivers E. N Engl J Med 2001;345:1368-77.
Early Goal-Directed Therapy:
SSC Recommendations
• Goals of therapy within first 6 hours are: (1C)
• Central Venous Pressure  8 - 12 mmHg
• Mean arterial pressure  65 mmHg
• Urine output  0.5 mL/kg/hr
• ScvO2  70%; if not achieved with fluid
resuscitation during first 6 hours (2C)
- Transfuse PRBC to hematocrit >27% and/or
- Administer dobutamine (max 20
mcg/kg/min) to goal
Dellinger RP, et al. Crit Care Med. 2008;36:296-327.
Potential Emergency
Department Challenges
• Screening in Triage
• Drawing lactic acid level with less than one
hour turn around time
• When and who will place the central line?
Physician skill level ?
• Monitoring CVPs and ScvO2-nurses skill level
and available resources?
• When to transfer to ICU? ED-ICU handoff
• If long ED LOS---does the ED implement both
resuscitation and management bundles
EGDT: Revisited
 Outcomes Survey: 12 programs
 1,298 patients with severe sepsis and septic
shock
 Treated with EGDT and/or the sepsis bundles
 Pre implementation mortality: 44.8 + 7.8%
 Post implementation mortality: 24.5 + 5.5 %
20.3% Reduction in Mortality, NNT 5
Otero RM. et al Chest; 2006:130:1579-1595
EGDT: Revisited
 Cost Effectiveness of EGDT/Guideline Based
Care (ED, ICU or RRT initiated)
23.4% reduction in hospital cost (incorporated
additional training, personnel and equipment)
Huang et al Crit Care Med 2003:7(suppl S116)
Henry Ford Hospital:  4 day Hospital LOS
(32.6% reduction)
Reduction in hospital charges from $135,199
to $82,233 (39.2% reduction) Trzeciak S et al, Chest
2006:129:225-232
Otero RM. et al Chest; 2006:130:1579-1595
Peer Review Publications
Favors No
EGDT
Before
1104
Favors
EGDT
After
1175
Abstracts and Publications
Abstracts
Chen, 2007
Sebat, 2007
Jones, 2007
Nguyen, 2007
Qu, 2006
Shu-Min Lin, 2006
Micek, 2006
Trzeciak, 2006
Shapiro, 2006
Kortgen, 2006
Sebat, 2005
Gao, 2005
Rivers, 2001
Abstracts
Chen, 2007
Sebat, 2007
Jones, 2007
Nguyen, 2007
Qu, 2006
Shu-Min Lin, 2006
Micek, 2006
Trzeciak, 2006
Shapiro, 2006
Kortgen, 2006
Sebat, 2005
Gao, 2005
Rivers, 2001
0
10
20
30
40
50
Absolute Risk Reduction (%)
3311 Before
0.00
0.25
0.50
0.75
Relative Risk Reduction (%)
3223 After
1.00
Abstracts and Publications
Rivers, 2001
1 of every 6
Patients
Publications
Abstracts
0.0
2.5
5.0
7.5
Number Need To Treat
4125 Before
3328 After
10.0
Vasopressors
• Recommend that MAP be maintain > 65 mmhg (1C)
• Ideally adequate fluid resuscitation should be achieved
before vasopressors and inotropes are used, but use early in
septic shock may need to occur. When it does the goal
should be to try and wean with continuing fluid resuscitation.
• Norepinephrine or dopamine as first choice. (1C)
• Epinephrine, phenylephrine or vasopression should not be
used as the initial vasopressor. (2C) Vasopresion may be
added to norepinephrine at 0.03 units/min.
• Suggest that epinephrine be the first chosen alternative. (2B)
• Low dose dopamine not be used for renal perfusion. (1A)
Dellinger RP, et al. Crit Care Med. 2008;36:296-327
Vasopressin vs Norepinephrine
Infusion in Septic Shock
VASST Study
• Design: Multicenter, randomized, doubleblinded
• Population: 778 patients with septic shock and
were receiving a minimum of 5mcq/min of
norephinephrine (or equivalent) for 6 hours
(excluded pts with underlying heart disease)
• Methods: Received either low dose
vasopressin (0.01-0.03U per minutes) or
norepinephrine in addition to open-label
vasopressors
• End point: 28 day mortality
Russell et al NEJM, 2008; Vol. 58, No 9
VASST Study Results
• No significant difference in 28 day or 90 day mortality
between the two groups
– Among patients who had less severe septic
shock(on norepinephrine between 5-15 mcq/min)
there was a trend toward improved mortality with
vasopressin (hypothesis generating)
• No significant difference in rates of organ dsyfunction
between the two groups
• No significant difference in overall rates of serious
adverse events between the two groups
– Trend toward higher rate of cardiac arrest in
norepinephrine group
– Trend toward higher rate of digital ischemia in the
vasopressin group
Russell et al NEJM, 2008; Vol. 58, No 9
Additional Findings
• Vasopressin infusion allowed a rapid
decrease in the total norepinephrine dose
while maintaining mean arterial pressure
• Overall rates of serious adverse events were
approximately 10% each in the vasopressin
and norepinephrine groups.
• The MAP at baseline was 72-73mmHg—
essentially making this a study of the effects
of low dose vasopressin as a “catecholaminesparing drug” not an evaluation of
vasopressin in patients with catecholamineunresponsive refractory shock
Russell et al NEJM, 2008; Vol. 58, No 9
EARLY MANAGEMENT
Early Recognition
Prompt/Aggressive
Resuscitation
Early Antibiotics
ICU/Additional Evidence
Based Therapies
Antibiotic Therapy
• Start intravenous antibiotic therapy within the
•
•
first hour of recognition of severe sepsis after
obtaining appropriate cultures (1D) for Septic
shock (1B)
Board spectrum: include one or more agents
active against likely bacterial/fungal pathogens,
& with good penetration into presumed source
(1B)
Reassess regimen daily to optimize efficacy,
prevent resistance, avoid toxicity & minimize
costs. (1C)
Kreger BE. Am J Med 1980;68:344-355.
Ibrahim EH. Chest 2000;118:146-155.
Dellinger, et. al. Crit Care Med 2008, 36: 296-327. Hatala R. Ann Intern Med 1996;124-717-725.
Mortality as a Function of Adequacy
of Empiric Antimicrobial Therapy
Inadequate Therapy
60
P<0.001
Adequate Therapy
P<0.001
50
40
30
20
10
0
All causes
Kollef MH, et al. Chest 1999;115:462-74.
Infection-related
Duration of hypotension before initiation of effective
antimicrobial therapy is the critical determinant of survival in
human septic shock
*Effective antimicrobial
administration within the
1st hour of documented
hypotension was
associated with increased
survival in patients with
septic shock.
*Each hour of delay over
the next 6 hours was
associated with an
average decrease in
survival of 7.6% (range
3.6-9.9%)
CCM 2006 Vol. 34 No.6
Antibiotic Challenges
 Appropriate selection – determined based upon
consensus guidelines and pathogen sensitivity
at your institution
 Timing issues
 How? Delivery time challenges of
antibiotics
 Possible solutions
Case Study
• Disclaimer:
– This is intended for education purposes
– Judgment of physician/clinician should always be the deciding factor
– The following case represents individual experience that are specific to
these patients and may not reflect the typical course of recovery
Clinical Scenario 2 : Early
Identification and Intervention
• 88 year old, 51.6kg,white, female presented
to ED at 1345 from ECF
• History: CAD, COPD, dementia, Alzheimer
disease, depression, SVT
• Chief Complaint: rib pain, chest congestion
and SOB
• Awake, alert and oriented, slight combative
(history of combative behavior)
Case Study 2: Early
Identification and Intervention
• Initial VS:
– Temp: 101.6 F
– RR: 31
– HR: 109, atrial fib with occasional SVT
– B/P: 79/51
– 2L of O2, O2 sat of 96%
• Positive Screen for severe sepsis:
– SIRS: HR >90; RR> 20; Temp > 38
– Organ dysfunction: SBP<90mmHg
• Early Treatment
– IV started
– Received 500cc NS bolus over 30 minutes
– Labs drawn
Advanced Treatment Guidelines
Department of Emergency Services
PURPOSE: To provide prompt, consistent nursing interventions for the patient with SIRS or
sepsis prior to physician evaluation, to enable rapid diagnosis and slow the
progression of illness.
IMPLEMENTATION:
The nursing staff may implement these interventions for patients who present with all three
of the following criteria. The nurse should take into consideration the patient’s baseline vital
signs when evaluating as a potential candidate. Also, these interventions should not conflict
with the patient/family goals. (i.e. DNR, comfort care)
1.
Clinical suspicion of systemic infection
2.
At least two of the following:
» Hyperthermia :Temperature greater than 38 °C (100.4 °F)
» Hypothermia: Temperature less than < 36 °C (96.8 °F)
» Tachycardia Pulse > 90 bpm
» Tachypnea RR > 20
SBP < 90
3.
–
Patients who meet all three criteria will be placed in a room immediately after
consultation with charge nurse and/or attending.
Advanced Treatment Guidelines
Department of Emergency Services
TREATMENT
1. Notify Physician
2. Place Intermittent Infusion Device (large bore catheter) in 2
sites
3. Place on cardiac monitor
4. Continuous pulse oximetry
5. Vital signs every 15 minutes
6. Administer oxygen at 2 L/min per nasal cannula if O2 sat <92%
7. Draw and hold blood cultures x 2, Type & screen
8. Draw tube for serum lactate and place on ice.
9. Collect CCMS urine sample in the non-menstruating patient.
Send for Urinalysis and urine culture.
10. Portable CXR
11. Intravenous hydration: Administer 500ml bolus of normal
saline over 15 minutes.
Case Study 2: Early
Identification and Intervention
• Labs:
– WBC: 11.5
– Hgb: 15.8
– Hct: 47.4
– BUN: 28 Creatinine:1.6
– Glucose:158
– BNP:78 (moderate CHF); troponin:0.03
– Lactic acid: 4.6
– U/A: positive for bacteria
– ScvO2: 49.1%
– Blood cultures X 2 drawn
Case Study 2: Early
Identification and Intervention
• CXR: RLL consolidation
• Additional Interventions:
– Broad spectrum antibiotics given within 3 hours of
presentation
– Lactic acid >4mmol/L so CVP inserted
– Fluid resuscitation continued
– Foley inserted
• Received total of 3 Liters of NS during 3 hour ED
stay
• ED diagnosis: Severe sepsis, Pneumonia , UTI,
CHF
• Transferred to MICU
Case Study 2 : Early Identification
and Intervention--MICU
• Additional Interventions: Day 1
– Continued fluid resuscitation—7 L
– Low dose vasopressor
– Low dose steroids
– Remained on 2 L nasal canula
– Not eligible for Xigris (renal failure resolved and
vasopressor weaned off within 12hours after ICU
admission)
• Labs:
– ScvO2: 72.8 (after resuscitation)
– Lactic acid: 4 hours after ICU admission: 6.7
12 hours after ICU admission: 3.0
Bleeding is most common adverse effect associated with Xigris therapy,
please see important safety information in this presentation
Case Study 2: Early
Identification and Intervention
• Day 2:
– Vasopressor weaned off
– Lasix to assist with fluid mobilization
– Lactic acid: 3.0
• Day 3:
– Lactic acid: 1.2
– O2 sat 93% on room air
– Central line discontinued
• Transferred to intermediate care on Day 3
• Discharged from hospital on day 7
EARLY MANAGEMENT
Early Recognition
Prompt/Aggressive
Resuscitation
Early Antibiotics
ICU/Additional Evidence
Based Therapies
Management Bundle
Components
Recombinant human Activated
Protein C (2B)
• Recombinant human Activated Protein C
[Drotrecogin alfa (activated)] is recommended in
patients at a high risk of death (APACHE II score  25,
or Sepsis-induced multiple organ failure) if there are no
contraindications.
• Within 30 days of surgery with the above indications
(2C)
• Drotrecogin alfa (activated) is not indicated in adult
patients with severe sepsis and lower risk of death. (1A)
• Relative contraindications/warnings should be consider
Dellinger, et. al. Crit Care Med 2008, 36: 296-327.
Drotrecogin Alfa (Activated) In
Severe Sepsis: PROWESS Results
PROWESS 28-Day Mortality –
High Risk of Death Patients*
 29% reduction
in relative risk
of death with
Xigris†
60%
Mortality Rate
50%
44%
Absolute Risk = 13%
Reduction
40%
31%
30%
20%
10%
0%
*as defined by APACHE II 25
†relative risk reduction at 28 days
Data on file, Eli Lilly and Company.
Placebo Drotrecogin
alfa
(activated)
See important safety information in this presentation.
Survival Benefit Consistent across
High-risk Severe Sepsis Patients
Xigris® (drotrecogin alfa [activated]) benefits consistent
28-DAY MORTALITY
FAVORS XIGRIS
FAVORS PLACEBO
TOTAL
RELATIVE RISK
XIGRIS
PLACEBO
(CONFIDENCE
INTERVAL)
APACHE II* ≥ 251
817
0.70(0.59 - 0.85)
30.9
43.7
ORGAN DYSFUNCTION ≥ 22
1271
0.78(0.66 - 0.93)
26.5
33.9
CAP WITH APACHE II ≥ 253
321
0.60(0.44 - 0.82)
26.2
43.5
CAP S. PNEUMONIAE
WITH APACHE II ≥ 254
92
0.40(0.20 - 0.78)
18.0
45.2
INTRA-ABDOMINAL SURGERY
WITH APACHE II ≥ 251
116
0.60(0.36 - 1.00)
26.8
45.0
OVERT DIC6
454
0.71(0.55 - 0.91)
30.5
43.0
0.0
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
Relative Risk of Death (95% CI)
The 95% relative risk confidence interval for each subgroup included the point estimate for the
overall PROWESS population (0.80). The point estimate of relative risk of death in each subgroup
is indicated by a solid circle, and the 95% confidence interval is indicated by the horizontal lines.
Note the consistency between the overall trial result and the subgroup analyses.
*APACHE (Acute Physiology And Chronic Health Evaluation). For more information on using the APACHE II scoring system, please see
http://www.sfar.org/scores2/scores2.html †Nonprospectively defined population 1. Barie P, et al. Am J Surg. 2004; 188:212-220.
2. Dhainaut JF MD, PhD, et al. For the PROWESS Study Group. Intensive Care Med. 2003;29(6):894-903.3. Laterre P-F et al. Crit Care Med.
2005;33(5):952-961. 4. Data on file, Eli Lilly and Company. 6. Dhainaut JF, Yan SB, Joyce DE, et al. J Thromb Haemost 2004; 2:1924-33.
See Important Safety Information in this presentation.
6
Fine-Tuning Xigris Therapy in Adult
High-Risk Severe Sepsis Patients
Right Patient, Right Drug, Right Time
New: Clinical trials to help advance care of adult
patients with severe sepsis at high risk of death:
RESPOND Targeted Enrollment = 500
Enrollment started in Nov. 2006
Phase 2 trial investigating a biomarker (Protein C) to help guide
Xigris therapy in adult patients with severe sepsis at high risk of death.
NEW Placebo Controlled Trial
in Adult High-Risk Severe Sepsis
Help clinicians better identify patients who are most likely to benefit
from Xigris, as well as to further clarify the benefit/risk profile of the drug.
Contact 1-800-LILLY-RX for more information.
Bleeding is the most common adverse effect associated with Xigris therapy.
Please see Important Safety Information in this presentation and accompanying full Prescribing Information.
What are the Challenges to
Appropriate Screening and Administration
of Xigris® (drotrecogin alfa [activated])?
• Concerns about risk of bleeding
• Restrictive order set
• Inconsistent screening process
• Cost issues
Safety Profile
 Low incidence of serious bleeding events*
 Rate of serious bleeding events during infusion in high-risk
patients:
 PROWESS: 2.2% (9 of 414) in drotrecogin alfa
(activated) patients vs 0.7% (3 of 403) in standard
therapy patients
 Rate of ICH in high-risk patients during infusion:
 PROWESS: 0.2% (1 of 414) in drotrecogin alfa (activated) patients
 Associated with severe thrombocytopenia (platelet count
< 30,000/mm3)†
 Not associated with other adverse events
*Serious bleeding events were defined as any intracranial hemorrhage, any life-threatening bleeding, any bleeding event requiring
the administration of ≥3 units of packed red blood cells per day for 2 consecutive days, or any bleeding event assessed as a
serious adverse event.
†At the time of enrollment in the PROWESS study, the patient had a platelet count above 30,000/mm 3. The patient’s platelet
count fell to less than 30,000/mm3 after drotrecogin alfa (activated) therapy was initiated.
Data on file, Eli Lilly and Company
See important safety information and full prescribing information in this presentation.
Drotrecogin Alfa (Activated) Has a
Favorable Risk/Benefit Profile
8 times more likely to save an additional life than
observe an additional serious bleeding event *
* Based on a 13% 28-day survival benefit and a serious bleeding rate during infusion attributable to Xigris
of 1.5% (13% ÷ 1.5% = 8.7) in patients with an APACHE II score > 25.
Data on file, Eli Lilly and Company.
Important Safety Information
CONTRAINDICATIONS
Drotrecogin alfa (activated) increases the risk of bleeding. Drotrecogin alfa
(activated) is contraindicated in patients with the following clinical situations
in which bleeding could be associated with a high risk of death or significant
morbidity.
– Active internal bleeding
– Recent (within 3 months) hemorrhagic stroke
– Recent (within 2 months) intracranial or intraspinal
surgery, or severe head trauma
– Trauma with an increased risk of life-threatening
bleeding
– Presence of an epidural catheter
– Intracranial neoplasm or mass lesion or evidence of
cerebral herniation
Drotrecogin alfa (activated) is contraindicated in patients with known
hypersensitivity to drotrecogin alfa (activated) or any component of this product.
See full Prescribing Information available at this presentation.
Important Safety Information
WARNINGS
Bleeding
• Bleeding is the most common serious adverse effect associated with drotrecogin alfa
(activated) therapy. Each patient being considered for therapy with drotrecogin alfa
(activated) should be carefully evaluated and anticipated benefits weighed against
potential risks associated with therapy
•
Certain conditions, many of which led to exclusion from the Phase 3 trial, are likely to
increase the risk of bleeding with drotrecogin alfa (activated) therapy. For individuals
with one or more of the following conditions, the increased risk of bleeding should be
carefully considered when deciding whether to use drotrecogin alfa (activated) therapy:
–
–
–
–
–
–
–
–
–
–
–
–
Concurrent therapeutic dosing of heparin to treat an active thrombotic or embolic event
Platelet count < 30,000 x 106/L, even if the platelet count is increased after transfusions
Prothrombin time-INR > 3.0
Recent (within 6 weeks) gastrointestinal bleeding
Recent administration (within 3 days) of thrombolytic therapy
Recent administration (within 7 days) of oral anticoagulants or glycoprotein IIb/IIIa inhibitors
Recent administration (within 7 days) of aspirin > 650 mg per day or other platelet inhibitors
Recent (within 3 months) ischemic stroke
Intracranial arteriovenous malformation or aneurysm
Known bleeding diathesis
Chronic severe hepatic disease
Any other condition in which bleeding constitutes a significant hazard or would be particularly
difficult to manage because of its location
See full Prescribing Information available at this presentation.
Additional
Management Bundle
Components
Low Tidal Volume Ventilation:
SSC Recommendations
• Target tidal volumes to < 6 mL/kg (predicted body
weight) in patients with ALI/ARDS (1B)
• Initial upper limit goal for plateau pressures in a
passively inflated patient be < 30 cm H2O (1C)
• Hypercapnia can be tolerated in patients with
ALI/ARDS if required to minimize plateau pressures
and tidal volumes (1C)
• Recommend that positive end expiratory pressure
be set as to avoid extensive lung collapse at endexpiration (1C)
• Suggest prone positioning in ARDS patients
requiring potentially injurious levels of FiO2 or
plateau pressures in facilities that have experience
with the practice (2C)
Dellinger RP, et al. Crit Care Med. 2008;36;296-327.
ARDS Network
ALI/ARDS Ventilator Study
Methodology:
–Inclusion criteria: p/f ratio < 300, bilateral
infiltrates, no cardiac cause, receiving
mechanical ventilation
–Outcomes: mortality/VFD
–841 patients randomized
–12 ml/kg TV group – Plat < 50 cm H2O
–6 ml/kg TV group - Plat < 30 cm H2O
ARDS Network, N Engl J Med 2000;342:1301-8.
ARDS Network
ALI/ARDS Ventilator Study
Results:
PEEP:
no difference in average amount used
Mortality:
31% ( 6 ml/kg TV) vs. 40% (12 ml/kg
TV) p=0.007
VFD:
12+ 11 vs. 10+11 (p=0.007)
Greater
organ failure free days in protective
group
Reduction
Difficulty
in IL-6 levels by day 3
with agitation/high rates in the 6 ml/kg
group
ARDS Network, N Engl J Med 2000;342:1301-8.
Additional Mechanical
Ventilation Recommendations
• Unless contraindicated, maintain HOB elevated
to limit aspiration and prevent VAP (1B).
Elevation should be 30 to 45 degrees (2C)
• Non-invasive mask ventilation only be
considered in that minority of mild to moderate
hypoxemic respiratory failure patients who are
able to protect their airway & are
hemodynamically stable. A low threshold for
intubation should be maintain (2B)
Dellinger RP, et al. Crit Care Med. 2008;36;296-327
Additional Mechanical
Ventilation Recommendations
• Weaning protocol in place where patients
undergo SBT if the satisfy criteria (1A)
• Recommend against the routine use of PA
catheters (1A)
• Recommend a conservative fluid strategy for
patients with established ALI/ARDS who do not
have evidence of tissue hypoperfusion (1C)
Dellinger RP, et al. Crit Care Med. 2008;36;296-327
Corticosteroids In Septic Shock:
SSC Recommendations (2C)
• Intravenous corticosteroids should only be given to adult
septic shock patients after it has been confirmed that their
blood pressure is poorly responsive to fluid resuscitation
and vasopressor therapy
• Suggest that the ACTH stimulation test should NOT BE
used to identify the subset of adult with septic shock who
should receive hydrocortisone. (2B)
• We suggest that patients with septic shock should not
receive dexamethasone if hydrocortisone is available. (2B)
– Administer intravenous hydrocortisone <300 mg daily (1A)
– Fludrocortisone is optional if hydrocortisone is used (2C)
Dellinger RP, et al. Crit Care Med. 2008;36:296-327.
Hydrocortisone Therapy for
Patients with Septic Shock
• Design: Multicenter, randomized, doubleblind, placebo-controlled trial
• Population: 499 patients with septic shock—
BP<90 systolic despite adequate fluid
replacement or vasopressors for at least one
hour (onset of shock within previous 72 hrs)
• Method: 2 groups: one group received 50mg
hydrocortisone every 6 hrs for 5 days, then
tapered; other group received a placebo.
• End Point: 28 day mortality
Sprung, NEJM,2008; Vol 358 No 2
Hydrocortisone Therapy for Patients
with Septic Shock--Results
• No significant difference between 2 study groups in
rate of death at 28 days (no matter if responded or
not to corticotropin)
• Duration of time to reversal of shock was significantly
shorter among all pts receiving hydrocortisone (3.3
days vs 5.8 days; p<0.001)
• Pts in this study who has a SBP of< 90mmHg at 1
day after fluid and vasopressor resuscitation had
mortality of 56% if received placebo and mortality of
44.9 if received hydrocortisone (difference of
11.4%)—similar to Annane et al results.
• In hydrocortisone group there was an increased
incidence of superinfections, including new episodes
of septic shock
Sprung, NEJM,2008; Vol 358 No 2
Glucose Control: SSC
Recommendations
• Initial stabilization of patients with severe sepsis and
hyperglycemia who are admitted to the ICU receive IV
insulin therapy to reduce blood glucose levels. (1B)
• Use of a validated protocol and target glucose levels
to < 150 mg/dL range. (2C)
• All patients receiving IV insulin should receive a
glucose calorie source and blood glucose values
should be initially assesses every 1-2 hrs, then q 4
hours after stabilization. (1C)
• Low glucose levels obtained by Point of Care testing
should be interpreted with caution (1B)
Dellinger RP, et al. Crit Care Med. 2008;36:296-327.
NICE Study
• 6104 Critically Ill Patients within 24
hrs of admission to ICU randomized
• Data evaluated on 3010 pts in
intensive control group (target 81108 mg/dL) & 3012 pts to
conventional group (target < 180
mg/dL)
• Similar characteristics at baseline
• Results:
• Conventional group has
significantly lower number of
deaths
• Severe hypoglycemia (blood
glucose < 40mg per dL greater
in intensive control group (6.8%
vs. .5% (p<0.001
27.5% vs. 24.9% (p =0.02)
NICE-SUGAR Investigators, N Engl J Med;2009:1283-97.
Procedure or Population
Breakdown
NICE-SUGAR Investigators, N Engl J Med;2009:1283-97.
What to Do Now?
Continue to Optimize Management of Glucose to Prevent
Hyperglycemic & Hypoglycemic Events…range target to < 180
mg/dL, stop infusion at 140 mg/dL
Do NOT Return to Sliding Scale
Inzucchi SE, Siegel MD. N Engl J Med;2009;360(13):1346-48.
Additional Management Bundle
Components Barriers
• TGC:
• Lack of tested nomogram
• What target range to pick?
• Evaluating success
• Increase nursing time
• Not enough monitors
• Low TV ventilation
• Lack of knowledge of research by
physicians, RT and nursing
• No defined policy
• Lack of accountability
• Identifying patients who have ALI or
ARDS?
Sepsis Evidence
Implementation
Making it a Reality
Sepsis Bundle
Sepsis Bundles
Yes
Screen for Severe Sepsis
No
Standard care
Resuscitation Sepsis Bundle (6-Hour)
•Obtain Cultures before antibiotic administration
•Lactate Level
•In the event of hypotension (SBP < 90, MAP < 70) or lactate
> 4 mmol/L, begin initial fluid resuscitation with 20-40 ml of
crystalloid (or colloid equivalent) per estimated kg of body
weight
•Vasopressors employed for hypotension ((MAP) Less than 65
mm Hg) during and after initial fluid resuscitation
•Board spectrum antibiotics administered Within 3 hours of
presentation
•In the event of septic shock or lactate > 4 mmol/L, CVP and
ScvO2 or SVO2 measured.
•In the event of septic shock or lactate > 4 mmol/L, CVP
maintained 8-12 mmhg
•Inotropes (and/or PRBC’s if hematocrit <= 30 percent)
delivered for ScvO2 < 70 percent or SVO2 < 65 percent if
CVP >= 8 mmhg
If on Antibiotic, then Monitor
Q24H FL Monitor Per shift ICU
Management Sepsis Bundle (24 hour)
•
•
•
•
Maintain serum glucose levels on
average < 150 mg/dl. (8.3 mmol/L )
Drotrecogin alfa (activated)
administered in accordance with
hospital guidelines
Steroids given for septic shock
requiring continued use of
vasopressors for equal to or greater
than 6 hours
Adoption of a lung protective strategy
(tidal volumes < 6ml/kg) with plateau
pressures of 30 cm H2O for
mechanically ventilated patients
Develop Protocols & Order Sets to
Implement
Resuscitation in Medical-Surgical Area
• Draw blood
– Lactate Level
– Obtain blood cultures before administration of
antibiotic
• In the event of hypotension (SBP < 90, MAP < 70) or
lactate > 4 mmol/L, begin initial fluid resuscitation with
20-40 ml of crystalloid (or colloid equivalent) per
estimated kg of body weight
• Vasopressors employed for hypotension ((MAP)
Less than 65 mm Hg) during and after initial fluid
resuscitation
• Broad spectrum antibiotics administered within three
hours of presentation
www.ihi.org
Within 6 hrs (Transport to the ICU
is Key)
• In the event of septic shock or lactate > 4
mmol/L, CVP and ScvO2 or SVO2
measured. (line inserted)
• In the event of septic shock or lactate > 4
mmol/L, CVP maintained 8-12 mmhg
• Inotropes (and/or PRBC’s if hematocrit
<= 30 percent) delivered for ScvO2 <
70 percent or SVO2 < 65 percent if CVP
>= 8 mmhg
www.ihi.org
Develop Protocols & Order Sets to Implement
Management 24-Hour Severe Sepsis Bundles
 Adoption of a lung protective strategy (tidal
volumes < 6ml/kg) with plateau pressures
of 30 cm H2O for mechanically ventilated
patients with ALI/ARDS
 Drotrecogin alfa (activated) administered in
accordance with hospital guidelines
 Maintain serum glucose levels on average
< 150 mg/dl. (8.3 mmol/L)
 Consider steroids given for septic shock
requiring continued use of vasopressors
and fluid resuscitation and remains
www.IHI.org
unstable
Fourth Tier:
Measuring Process and
Outcomes Changes
Measuring
Success
Implementation of
the Sepsis Bundle
Early Screening with
Tools and Triggers
Organizational Consensus that Severe Sepsis
Must be Managed Early and Aggressively
Sepsis Measurement tool
found at www.ihi.org &
www.survivingsepsis.org
Data Collection
• Outcome
– Mortality (ICU and Hosp)
– Hosp LOS
– Cost per case (total and direct)
• Process
– SSC database
– Data elements that measure implementation
of resuscitation and management bundle
Role of Data
• Outcome data
– Share with staff and administration to keep
momentum going
– Helps convince/move skeptics
• Process data
– Celebrate small successes
– Helps identify where opportunities for
improvement still exist
Implementation
• Hospital resources often focused on planning
phase and then back off after implementation.
• The implementation phase is the most critical
• Frequent rounds recommended on unit by
project champion to support staff and answer
questions.
• Defined resources for bedside nurse-IE:
– Project champion has pager to be available
24/7 initially
– Clinical nurse champions identified on each
ICU unit and ED to be resources to bedside
staff (these staff should be a member of the
sepsis team/committee from the beginning)
Severe Sepsis Bundle
Implementation Results
•
•
•
•
Loma Linda, California
England
Germany
St. Louis, Missouri
Surviving Sepsis Campaign
•
•
•
•
252 hospitals in 18 countries
Data from January 2005-March 2008
Observational; time series
Baseline is first quarter data was
collected
• Use of standardized screening tool
• Excluded site if less than 20 patients or
less than 3 months of results
M Levy, presented at SCCM 02/2009 Nashville
Surviving Sepsis Campaign
Results
• Final Sample Size: 15,022 patients
from 166 sites (95% of total)
– North America: 58%
– Europe: 31%
– South America: 10%
M Levy, presented at SCCM 02/2009 Nashville
Surviving Sepsis
Campaign Results
Entry Point
Subjects
ED
52%
Mortality
(hosp)
27.6
ICU
12.8%
41.3
Ward
34.8%
46.8
Hospital mortality went from 37% to 30%
7% ARR; 19% RRR; p< 0.007
M Levy, presented at SCCM 02/2009 Nashville
Surviving Sepsis Campaign
Bundle Compliance
Bundle
Baseline
2 year
Resuscitation
10.9 %
31.3 %
Management
18 %
36 %
Risk Adjusted Hospital Mortality decreased by 5.4%
20 % improvement in compliance with bundles
M Levy, presented at SCCM 02/2009 Nashville
A Prospective Multi-Center Collaborative
Study
Before and After Implementation of an
Early Sepsis Initiative
The Multi-Center Severe Sepsis &
Septic Shock Collaborative Group
Presented by Emanuel Rivers at the World Federation of Critical care Medicine,
Florence Italy 08/09
Methods
 Pre-implementation analysis occurred from
2003-2005 with post-implementation observation
from 2005-2008.
 11 centers ranging from community (N=6) to
academic tertiary care (N=5) settings were
included in the study.
 In this intention-to-treat evaluation, all patients
including DNR were examined.
Presented by Emanuel Rivers at the World Federation of
Critical care Medicine, Florence Italy 08/09
Fluid Administration
Pre- & Post Sepsis Initiative Implementation
11.2
12
10.4
Fluid Volume (L)
10
8
Fluids admin. 0-6 hours, L
6
Fluids admin. 6-24 hours, L
4
2
Fluids admin. 0-72 hours, L
2.5
2.5
2.8
2.3
0
PRE-Implementation POST-Implementation
Presented by Emanuel Rivers at the World Federation of Critical care Medicine, Florence Italy 08/09
In-Hospital Mortality:
M SS/SS C vs. SSC
M SS/SS C
SSC
PRE %
POST %
ARR %
RRR %
39.1
28.9
10.2
26.0
1st Q
Last Q
37.0
30.0
7.0
19.0
Presented by Emanuel Rivers at the World Federation of Critical care
Medicine, Florence Italy 08/09
Mortality by Lactate & SBP
Subsets
Lactate > 4 Only
SBP < 90 Only
Lactate > 4 & SBP
< 90
PRE40.4
42.4
57.3
POST32.9
30.9
39.5
Presented by Emanuel Rivers at the World Federation
of Critical care Medicine, Florence Italy 08/09
Bundle Implementation:
Decreased Mortality
Methodology
• 2 year prospective study in academic tertiary care facility,
with majority of care delivered in the ED
• 330 patient enrolled
• Measured 5 quality indicators related to management of
Severe sepsis & septic shock population. CVP/ScvO2 by 2
hrs, antibiotics by 4 hours, EGDT completed at 6 hours,
appropriate steroids, lactate clearance
Nguyen et al CCM, 2007 Vol 35, No. 4,
Bundle Implementation:
Decreased Mortality
Results:
• In hospital mortality in patients who completed the bundle
was significantly lower then those who did not complete the
bundle (20.8 vs 39.5; p<0.01)
• 14% of patients that completed the bundle received rhAPC.
• Completing EGDT in 6 hours was the only quality indicator
with a significant odds ratio for decreased mortality using
multivariate regression analysis
• After 2 years, achieved 51% compliance with all five
indicators
Nguyen et al CCM, 2007 Vol 35, No. 4,
Bundle Component Compliance
and Impact on Mortality
Nguyen et al CCM, 2007 Vol 35, No. 4
Prospective External Validation of
Effectiveness of EGDT
• Prospective interventional
study conducted over 2
years
• Compared 79 patients in
pre-intervention year and
77 patients in post
intervention year
• Intervention group
received significantly
more fluid (2L), less
vasopressors
• Mortality 18% vs. 27%
Jones AE, et al. Chest, 2007;132:425-432
Sepsis Bundles:
Significant Impact on Hospital Outcomes
•
Two acute National Health Service Trust Teaching Hospitals in England
performed a prospective observational study with 101 adult patients with
severe sepsis or septic shock
•
Outcomes measures
– Rate of compliance with 6-hour and 24-hour bundles adapted from 2004
SSC guidelines
– Hospitality mortality between compliant and noncompliant groups
Compliance with Bundles
Bundle Mortality
6-hour bundle 52%
24-hour bundle 30%
Noncompliant 49% (p=.001)
Compliant 23% (p=.001)
 More than two-fold increase in hospital mortality associated with
noncompliant group
 Assessed compliance as “all or none” for the bundle elements
Is a two-fold mortality improvement a possibility in your institution?
Source: Gao F, Melody T, Daniels D, et al. The impact of compliance with 6-hour and 24-hour sepsis bundle on hospital mortality in
patients with severe sepsis: A prospective observational study. Crit Care Med. 2005;9(6):R764-R770.
Compliance with 6hr
Bundle
Gao F, et al. Critical Care, 2005;9:R764-770
84%
100%
74%
80%
74%
70%
60%
52%
40%
20%
0%
lactate
blood culture
antibiotics
fluid+/vasopressors
Hb 7-9g/dl
6hr Bundle & Hosp Mortality
Gao F, et al. Critical Care, 2005;9:R764-770
RR=2.12 (1.2-3.8)
P=0.01
50%
49%
40%
30%
N=24/49
20%
23%
10%
N=12/52
0%
6hr Bundle
Yes
6hr Bundle
No
NNT = 3.9
Compliance with 24hr Bundle
Gao F, et al. Critical Care, 2005;9:R764-770
100%
85%
80%
60%
64%
43%
40%
30%
20%
0%
Glucose < 8.3
Steroids
Pp < 30
RhAPC
24hr Bundle & Hosp Mortality
Gao F, et al. Critical Care, 2005;9:R764-770
50%
RR=1.75(0.84-3.6)
P=0.16
50%
40%
30%
29%
N=24/48
20%
N=6/21
10%
0%
24hr Bundle
Yes
24hr Bundle
No
NNT = 4.8
Severe Sepsis Protocol in
Use Germany
• Retrospective cohort study in 10 bed mixed ICU in Germany
• 60 patients (30 consecutive receiving SOP severe sepsis
management compared to historical controls)
• Measured: Primary endpoint 28 day mortality
• Measured: Secondary endpoints; ABG’s, lactate, glucose,
creat, WBC, Plat, time to dx & 7am on day 2 & 4 SOFA
scores
• Results: In SOP group: ↑ use of dobutamine, glucose
control, steroids & rhAPC
• Mortality: Control vs SOP (53% vs. 27% p <.05)
• Independent predictors of survival: lactate on admission, age,
gender, blood glucose < 150 mg/dl, adm of rhAPC & steroids
Kortgen A et al. Crit Care Med, 2006:34:943-949
Standardized Order Set-Sepsis
Bundles
St. Louis, Missouri
• Before-after study design with prospective consecutive
data collection of 120 patients
• 1,200 bed academic medical center
• Primary endpoint: 28 day mortality
• Other measures: hospital LOS, IV fluid intact for shock,
appropriate antibiotic
• Results: after group: received more IV fluids in ED
(p=0.002); more likely to receive >20ml/kg of fluid prior to
vasopressors; had lower risk of mortality (48.3% vs 30%,
p=0.04); lower hospital LOS (12.1 vs 8.9 days, p=0.038)
• Independent predictors of survival: increased pt age and
not receiving >20 ml/kg of IV fluid prior to vasopressors
Micek, Scott et al., Critical Care Medicine, 2006; 34:2707-2714
Standardized Order Set-Sepsis
Bundles Decreases Cost
St. Louis, Missouri
• Before-after study design with prospective consecutive
data collection of 120 patients to determine financial
impact of sepsis protocol
• 1,200 bed academic medical center
• Primary endpoint: Overall Hospital costs
• Secondary endpoint: Hospital LOS
• Results: after group: Hospital costs $16,103 vs. $21,985,
p = .008; LOS 5 days less in the protocol group (p= .023)
• Use of protocol independently associated with less per
patient cost.
Shorr AF, et al. Critical Care Medicine, 2007; 35:1257-1262
Case Study
• Disclaimer:
– This is intended for education purposes
– Judgment of physician/clinician should always be the deciding factor
– The following case represents individual experience that are specific to
these patients and may not reflect the typical course of recovery
Case Study 3: Early
Identification and Intervention
• 63 year old white female directly admitted to
a med-surg floor from a free standing urgent
care at 2130
• Hx: NIDDM, COPD, HTN
• Chief complaint: pain right lower sternal
border times 2 days, worse with deep breath,
SOB.
• CXR: right pleural effusion
• Orthostatic hypotension, renal insufficiency
(creatinine 3.4—previously 1.2)
Case Study 3: Early Identification
And Intervention
•
•
•
•
•
•
•
Initial VS: stable BP, HR-102, RR-WNL
On 2L nasal cannula, IV at 150/hr
Labs: WBC-7.5, plat 197, D-dimer: 273
Resp distress at 0600 next am
Transferred to MICU
Possible PE—heparin gtt started
Broad spectrum antibiotics started
Case Study 3: Early
Identification And Intervention
• ICU course:
– 2000: BP: 79/34, HR: 123 , WBC: 3.3
– Dx of severe sepsis at 2000
– 2 liter fluid bolus
– Intubated and ventilated
– Lactic acid 0.9
– Levophed started, heparin gtt d/c’d
– CVP inserted
Case Study 3: Early
Identification And Intervention
•
ICU course-continued:
–
–
–
–
Xigris started at 0600 (still on vasopressors,
vent, creat-3.9)
1000: Stopped Xigris for CT guided pleural
aspirtation
1200: CT- 2 loculated cavities in right lung;
Cardio thoracic surgery consulted
OR at 1700 for drainage of empyema
• Right mini-thorocotomy, empyema
drainage, decortication and bronchoscopy.
CT (2) inserted
Case Study 3: Early
Identification And Intervention
•
Post-op
–
–
•
Post-op Day 1
Levophed off at 0400
– Bicarb gtt off at 0400
– Vasopressin gtt off at 1000
– Vent FiO2 decreased to 55% @ 0800
Full course of Xigris
Off vent/extubated in 6 days (hx of COPD)
Transfer out of ICU- post-op day 11
Discharge home- post-op day 25
–
•
•
•
•
Temp-97, HR: 84, BP-139/69 on levophed and
vasopressin and bicarb gtt.
Xigris restarted
The Nurses Role
• Early recognition of
patients with signs of
sepsis
• Early initiation of
evidence based practice
therapies appropriate for
your area of practice
(antibiotics, fluids/blood &
pressors)
• Swift disposition to care
areas where the rest of
the bundle can be started.