Reducing Sepsis Mortality
Richard Crowell, MD
Senior Vice Chair
Department of Internal Medicine
Professor and Chief
Pulmonary, Critical Care, and Sleep Medicine
UNM School of Medicine
Objectives
• Discuss pathophysiology and treatment of
sepsis and septic shock, and advent of
Early Goal-Directed Therapy
• Describe approach to Early Goal-Directed
Therapy at UNM Hospital: SMITe
Severe Sepsis vs. Other Critical Illnesses
In the US, more than 500 patients die of severe
sepsis daily (Angus, Crit Care Med 2001)
Condition
Prevalence
Deaths
Mortality
AMI (1)
900,000
225,000
25%
Stroke (2)
Trauma (3)
700,000
163,500
23%
2.9 million
42,643
1.5%
751,000
215,000
29%
(Motor Vehicle)
Severe
Sepsis (4)
Source: (1) Ryan TJ, et al. ACC/AHA Guidelines for management of patients with AMI. JACC.
1996; 28: 1328-1428. (2) American Heart Association. Heart Disease and Stroke Statistics –
2005 Update. Available at: www.americanheart.org. (3) National Highway Traffic Safety
Administration. Traffic Safety Facts 2003: A Compilation of Motor Vehicle Crash Data from the
Fatality Analysis Reporting System and the General Estimates System. Available at
http://www.nhtsa.dot.gov/. (4) Angus DC et al. Crit Care Med 2001;29(7): 1303-1310.
Age Related Incidence of Severe Sepsis
25
20
60,000
15
40,000
10
20,000
5
0
0
85
80,000
<1
1-4
510 9
-1
15 4
-1
20 9
-2
25 4
-2
30 9
-3
35 4
-3
40 9
-4
45 4
-49
50
-5
55 4
-5
60 9
-6
65 4
-69
70
-7
75 4
-7
80 > 9
-84
No. of Cases
100,000
Cases
Incidence
Incidence (per 1000 pop)
30
120,000
Age (y)
Angus DC, et al. Crit Care Med. 2001.
Sepsis: A Complex Disease
Other
Sepsis
Pancreatitis
Infection
Severe
Sepsis
SIRS
Trauma
Burns
Adapted from: Bone RC et al. Chest. 1992;101:1644-55.
Used with permission, S.Simpson, MD, KU, 2008
Sepsis: A Deadly Continuum
SIRS
• A clinical response
arising from a
nonspecific insult, with
2 of the following:
• T >38oC or <36oC
• HR >90 beats/min
• RR >20/min
• WBC >12,000/mm3 or
<4,000/mm3 or >10%
bands
Sepsis
SIRS with a
presumed
or confirmed
infectious
process
Severe
Sepsis
Sepsis with
organ
dysfunction
Shock
Septic
Refractory
Hypotension
Related to
Sepsis
Chest 1992;101:1644.
Natural History of SIRS
• Prospectively enrolled 2527 patients who met SIRS criteria
• Followed for 28 days or discharge for development of any
stage of the sepsis continuum
Incidence (No. pts, (%))
Mortality (%)
No progression
1301 (52%)
7%
Sepsis
649 (26%)
16%
Severe Sepsis
467 (18%)
25%
Septic Shock
110 (4%)
46%
•Note: median interval from SIRS to sepsis was inversely
related to number of SIRS criteria
Rangel-Frausto MS, et.al. JAMA 273:117-23, 1995
Prognosis based sepsis severity
Mortality
Severe Sepsis: 20-35%
Septic shock: 35-60%
Figure B, page 948, reproduced with permission from Dellinger RP. Cardiovascular
management of septic shock. Crit Care Med 2003;31:946-955.
Clinical Alterations in Severe Sepsis
• Vasculopathy
• Loss of regional autoregulation
• Vasodilation
• Relative intravascular hypovolemia
• Cardiopathy
• ↓ contractility, ↑ compliance
• ↑ CO, but ↓ EF
• Acute organ dysfunction
• Toxin and cytokine actions on
vascular / tissue barriers
Inflammatory Mediators
Cardiovascular Insufficiency
Global Tissue Hypoxia
Increased Metabolic
Demands
O2 Demand
Hypovolemia Vasodilation
Myocardial Depression
Microvascular Alterations
Used with permission, S.Simpson, MD, KU, 2008
O2 Delivery
After Fink. Crit Care Clin 2002.
Acute Organ Dysfunction as the Hallmark of
Severe Sepsis
Altered
Consciousness
Confusion
Psychosis
Tachycardia
Hypotension
Tachypnea
PaO2 <70 mm Hg
SaO2 <90%
PaO2/FiO2 300
Oliguria
Anuria
 Creatinine
Jaundice
 Enzymes
 Albumin
 PT
 Platelets
 PT/APTT
 Protein C
 D-dimer
Lactic acidosis
Used with permission, S.Simpson, MD, KU, 2008
Treatment of Sepsis
•
Address cause: Treat infection
•
Intravascular volume resuscitation
•
Cardiovascular support
•
Support of dysfunctional organ systems
Figure 2
Has the mortality of septic shock changed with time?
Friedman, Gilberto; Silva, Eliezer; Vincent, Jean-Louis;
MD, PhD
Critical Care Medicine. 26(12):2078-2086, December
1998.
.
Time Sensitive Interventions
• Patients enrolled on entry into ED
• Evidence of Infection
• Met SIRS criteria
• Hypotensive
OR
• Lactic acidosis (>4 mmol/L)
• Rapid recognition
• Protocol of treatment w/in 6 hours:
• Cultures and appropriate antibiotics
• Fluid resuscitation to CVP 8-12
• Cardiovascular support with
pressors, augmented O2 delivery
The Importance of Early Goal-Directed
Therapy for Sepsis Induced Hypoperfusion
NNT to prevent 1 event (death) = 6-8
Mortality (%)
60
50
Standard therapy
EGDT
40
30
20
10
0
In-hospital
mortality
(all patients)
28-day
mortality
60-day
mortality
Adapted from Table 3, page 1374, from Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy
in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-1377
Surviving Sepsis Campaign
www.survivingsepsis.org
Surviving Sepsis Campaign: International
Guidelines for Management of Severe
Sepsis and Septic Shock 2012
Crit Care Med 2013; 41:580-637
Institute for Healthcare Improvement
www.IHI.org
Early Goal-Direct Therapy (EGDT)
EGDT is designed to:
Recognize patients with severe sepsis as early as
possible and begin treatment quickly
Assess laboratory and clinical variables for acute
organ dysfunction, hemodynamic instability
Delineate time targets for delivery of treatment of
patients with sepsis
Develop hospital-specific bundled protocols
 Earlier treatment leads to better outcomes
Surviving Sepsis Campaign
Recommendations for EGDT Bundle
Bundles should be developed based on the systems and
expertise available to providers
Goal: perform all indicated tasks 100% of the time within
the first 6 hours of identification
Good Evidence-based Data for EGDT
• Mortality improvement
• Use of lactate as severity and prognostic indicator
• Bundled protocols improve outcomes
• But not all individual bundle elements have been shown
to specifically improve mortality
• Early and appropriate antibiotics
• Aggressive fluid resuscitation improve outcomes
• But how much fluid?
• Enough to improve end organ dysfunction
• But not too much…
Best current, generally available measure of
Global Tissue Hypoxia is Lactate
• What is role of lactate ?
• Patient assessment
• Assigning prognosis
• Guiding treatment decisions
Serum Lactate as a predictor of mortality in
patients with infection
•Retrospective analysis of patients with dx of infection and lactate measured
•Did not evaluate +/- shock
Trzeciak S, et.al. Intensive Care Medicine 33:970-77, 2007
Lactate is associated with mortality in Severe Sepsis
Independent of organ failure and shock
Prospective cohort study
Critical Care Medicine. 37(5):1670-1677, May 2009.
© 2009 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc.
4
Figure 3.
Lactate is associated with mortality in Severe
Sepsis Independent of organ failure and shock
Critical Care Medicine. 37(5):1670-1677, May 2009.
© 2009 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc.
7
Lactate is associated with mortality in Severe Sepsis
Independent of organ failure and shock 2.
Critical Care Medicine. 37(5):1670-1677, May 2009.
© 2009 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc.
6
Good Evidence-based Data for EGDT
• Mortality improvement
• Use of lactate as severity and prognostic indicator
• Bundled protocols improve outcomes
• Even though not all individual bundle elements have
been shown to specifically improve mortality
• Early and appropriate antibiotics
• Aggressive fluid resuscitation improve outcomes
• But how much fluid?
• Enough to improve end organ dysfunction
• But not too much…
EGDT: Bundled approaches to protocols
• Use is evidence-based:
• Combine multiple effective elements
• Outcome is additive or synergistic
• Framework that leverages change
• Avoids a piecemeal approach
Do Bundles Work?
Gao, et al. Critical Care 2005, 9:R764-R770.
With Permission from S. Simpson, MD,, Kansas University, 2008
A. All subjects with
Severe Sepsis/Septic Shock
B. Only subjects with Septic
Shock
Multicenter implementation of a severe sepsis
and septic shock treatment bundle.
Miller RR, et.al. Am Journal Respir
Crit Care Med, 2013; 188, 77-82
Good Evidence-based Data for EGDT
• Mortality improvement
• Use of lactate as severity and prognostic indicator
• Bundled protocols improve outcomes
• Even though all individual bundle elements have not
been shown to specifically improve mortality
• Early and appropriate antibiotics
• Aggressive fluid resuscitation improve outcomes
• But how much fluid?
• Enough to improve end organ dysfunction
• But not too much…
Good Evidence-based Data for EGDT
• Mortality improvement
• Use of lactate as severity and prognostic indicator
• Bundled protocols improve outcomes
• But not all individual bundle elements have been shown
to specifically improve mortality
• Early and appropriate antibiotics
• Aggressive fluid resuscitation improve outcomes
• But how much fluid?
• Enough to improve end organ dysfunction
• But not too much…
Timeliness of Antibiotics in Septic Shock
• Kumar, et.al. reviewed medical records of 2731 adults with
septic shock over 25 years in Manitoba, Canada
• Focused on 2,154 patients who received Ab ONLY
after onset of hypotension
• Clinical site infections
• 37.2% lung
• 29.3% intraabdominal
• 10.7% genitourinary
• Documented infection (by cx) in 78% of cases
• Others by definitive xray, surgical, biopsy, or
autopsy evidence
• Microbiology: Gram (-) 47.9%, Gram (+) 38.3%
Kumar A, et.al. Crit Care Med 34:1589, 2006
Kumar et al, CCM. 2006:34:1589-96
Septic Shock: Timing of Antibiotics
Percent of total pts
1.00
% Survival
% Total receiving antibiotics
14 ICUs; n = 2,731
.80
.60 50% of patients in Septic Shock
Only
received antibiotics w/in 6 hrs.
.40
.20
0.0
Time (hrs) from hypotension onset
Timeliness of Antibiotics in Septic Shock
• Antibiotics w/in first hour: 79.9% survival
• Every hour delay decreased survival by 7.6%
• OR of in-hospital mortality increased by 12% for
each hour delay in administration
• In Multivariate analysis:
• Time to antimicrobial therapy most strongly
associated with survival
• Others: APACHE score, volume of fluid in first
hour of resuscitation
•Kumar A, et.al. Crit Care Med 34:1589, 2006
Antibiotic administration, UNMH ED → MICU
May 1, 2011 thru May 31, 2012; 296 total cases
Mortality (%)
* Percent of Bundle patients who received Ab in this time frame
% patients Ab <3hrs
Antibiotics in < 3 hrs
100
Percent
80
60
40
20
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Month
With Permission of Jon Femling, MD
A n tib io tic s < 6 0 m in u te s
100
The challenge
Antibiotics within 60 minutes is the
goal. As this data reveals we meet this
goal less than 50% of the time.
P e rc e n t
80
60
40
20
0
6
7
8
9
10
11
12
13
14
15
M o n th
With Permission of Jon Femling, MD
Time to Antibiotics
Percent of patients who receive Antibiotics in less than 1 Hour
(monthly)
80
Percent
60
40
20
6/11
9/11
12/11
3/12
6/12
9/12
12/12
Month
Intervention begins
3/13
Time to Antibiotics (individual patients)
March - present,
2013
Minutes
July 2012 – Feb 2013
88 min
66 min
Individual patients
Intervention begins
Good Evidence-based Data for EGDT
• Mortality improvement
• Use of lactate as severity and prognostic indicator
• Bundled protocols improve outcomes
• But not all individual bundle elements have been shown
to specifically improve mortality
• Early and appropriate antibiotics
• Aggressive fluid resuscitation improve outcomes
• But how much fluid?
• Enough to improve end organ dysfunction
• But not too much…
Cardiovascular Resuscitation-Based EGDT
Lin, et.al. 2006
• 241 consecutive patients enrolled, randomized to
protocol vs no protocol
• Protocol focused on rapid fluids to:
• 1) attain CVP ≥ 8-12
then
2) MAP ≥ 65 (pressors, steroids as needed)
then
• 2) urine output ≥ 0.5 ml/kg/hr
• All patients got antibiotics per clinician; no differences
in groups
Lin SM, et.al. Shock 6:551-7, 2006
Cardiovascular Resuscitation-Based EGDT
Outcome
Protocol
(n=108)
No Protocol
(n=116)
p
53.7 %
71.6%
0.006
Shock reversal (hrs)
47 ± 22.8
65.4 ± 32.1
0.006
Resuscitation fluids
136.2 ± 119
88.6 ± 57.7
0.034
78 22.2
104.4 29
0.001
Length of ICU stay
14.3 ± 11.7
20.3 ± 16.6
0.003
Renal failure
42 (38.9%)
64 (55.2%)
0.015
CNS failure
20 (18.5%)
42 (36.2%)
0.003
Hosp Mortality
Time to pressors
Lin SM, et.al. Shock 6:551-7, 2006
Good Evidence-based Data for EGDT
• Mortality improvement
• Use of lactate as severity and prognostic indicator
• Bundled protocols improve outcomes
• But not all individual bundle elements have been shown
to specifically improve mortality
• Early and appropriate antibiotics
• Aggressive fluid resuscitation improve outcomes
• But how much fluid?
• Enough to improve end organ dysfunction
• But not too much…
Successful fluid resuscitation in EGDT
• What are appropriate endpoints for “successful”
volume resuscitation?
• Depends on “volume responsiveness”
• where is the patient on the Starling curve?
• CVP: may not be best measure for volume
responsiveness
• Pulse pressure variation: accurate only in nonspontaneously breathing patients
• IVC diameter before/after fluid challenges:
limited by body habitus
Is optimization of oxygen delivery/utilization
necessary for successful EGDT?
• Is ScVO2 the appropriate surrogate measure for
optimizing oxygen delivery/utilization in septic
shock?
• Role of transfusion, inotropic support
• Can lactate clearance be used as a measure of
successful EGDT ?
Surviving Sepsis Campaign:
Early Recognition is Crucial!!!
• Use of screening tools improves overall
awareness, educates, and increases
recognition
• UNM:
• Wards/MICU: qshift screening by
nursing staff
• ED: Triage nurses, EMS do initial
evaluation
Figure 1
Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012
Dellinger, R. Phillip; Levy, Mitchell M.; Rhodes, Andrew; Annane, Djillali; Gerlach, Herwig; Opal, Steven M.; Sevransky, Jonathan E.; Sprung, Charles L.;
Douglas, Ivor S.; Jaeschke, Roman; Osborn, Tiffany M.; Nunnally, Mark E.; Townsend, Sean R.; Reinhart, Konrad; Kleinpell, Ruth M.; Angus, Derek C.;
Deutschman, Clifford S.; Machado, Flavia R.; Rubenfeld, Gordon D.; Webb, Steven A.; Beale, Richard J.; Vincent, Jean-Louis; Moreno, Rui; and the Surviving
Sepsis Campaign Guidelines Committee including the Pediatric Subgroup
Figure 1. Surviving Sepsis Campaign Care
Critical Care Medicine. 41(2):580-637, February 2013.
Bundles.
doi: 10.1097/CCM.0b013e31827e83af
Copyright © 2013 Critical Care Medicine. Published by Lippincott Williams & Wilkins.
49
Table 2
Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012
Dellinger, R. Phillip; Levy, Mitchell M.; Rhodes, Andrew; Annane, Djillali; Gerlach, Herwig; Opal, Steven M.; Sevransky, Jonathan E.; Sprung, Charles L.;
Douglas, Ivor S.; Jaeschke, Roman; Osborn, Tiffany M.; Nunnally, Mark E.; Townsend, Sean R.; Reinhart, Konrad; Kleinpell, Ruth M.; Angus, Derek C.;
Deutschman, Clifford S.; Machado, Flavia R.; Rubenfeld, Gordon D.; Webb, Steven A.; Beale, Richard J.; Vincent, Jean-Louis; Moreno, Rui; and the Surviving
Sepsis Campaign Guidelines Committee including the Pediatric Subgroup
Critical Care Medicine. 41(2):580-637, February 2013.
doi: 10.1097/CCM.0b013e31827e83af
TABLE 2. Severe Sepsis
Copyright © 2013 Critical Care Medicine. Published by Lippincott Williams & Wilkins.
50
UNM 6 Hour Sepsis Resuscitation Bundle
Completed ASAP (w/in 6 hrs) after (+) SIRS/Sepsis screen
1. Organ function labs, Serum lactate
measured
2. Blood Cultures obtained
3. Appropriate antibiotics administered
(within 1 hr)
UNM 6 Hour Sepsis Resuscitation Bundle
Completed ASAP (w/in 6 hrs) after (+) SIRS/Sepsis screen
4. If Lactate >4, SBP<90, MAP <65, or SBP
>30mm decrease from baseline:
a. Give 30 ml/kg IVF bolus
b. Transfer to MICU
UNM 6 Hour Sepsis Resuscitation Bundle
Completed ASAP (w/in 6 hrs) after (+) SIRS/Sepsis screen
5. Place central venous catheter
6. Apply vasopressors for hypotension not
responding to initial fluid resuscitation to
maintain mean arterial pressure > 65 mmHg
• Norepi, then vasopressin
• Avoid dopamine
7. Consider SvO2 measurement, improve
oxygen delivery if <65-70%
Identification of sepsis
severity !!
3 pathways
Green (sepsis)
Yellow (lactate 2-4)
Red (severe sepsis or
septic shock)
• Protocol was based
on literature and input
from all areas involved
• Several revisions
before consensus
Electronic Order
Set
IHI Severe Sepsis Collaborative
Expanded SMITe to ED
• Fall 2009  Joined IHI collaborative
• Aims:
• Improve ED recognition of severe sepsis
• Facilitate transfers to the MICU
• Improve communication between both units
• ED-specific screening tool for triage
• Concurrent patient tracking
• Still have twice-monthly group meeting
“If you’re not keeping score, you’re just
practicing”
EGDT: Outcomes Measures
• Establish institutional data baselines
“where are we starting from?”
• UNM: In 2007 ~38% of all deaths on Medicine
service were coded for sepsis or infection as
primary cause of death
• Severe sepsis/septic shock mortality: 46%
Our ED->MICU EGDT Performance
(2/12 -5/13)
~24 patients / month
30% Mortality
With Permission of Jon Femling, MD
Lactate
Cultures
Fluids
Antibiotics
Pressors
CVP
100%
94%
97%
88%
79%
68%
Observed Severe Sepsis Mortality
% Mortality Adult Severe
Sepsis Observed
Severe Sepsis: UNMH
Mortality Index (O/E Ratio)
Documentation of Disease Severity:
Severe Sepsis/Septic Shock
• Severe sepsis w/o MV 96+ hours
with MCC
• DRG 871
RW: 1.9090
Est. Payment: $17,654
• Severe sepsis w/o MV 96+ hours
without MCC
• DRG 872
RW 1.1339
Est. Payment: $10,486
61
Severity of Illness and Risk of
Mortality
Comorbidity and/or Complication (CC)
• Comorbitidy: A pre-existing condition/illness
that will cause an increase in length of stay
because of its presence with the condition that
caused the admission.
• Complication: A condition that arises during
the hospital stay that may prolong the length of
stay.
• Major comordibity/complication (MCC)
62
MCCs for Sepsis
Example of MCCs for Sepsis
•Respiratory Failure due to Sepsis
•
•
•
•
Acute Respiratory Failure
Lung Abcess
Empyema
Ventilator Dependent (can’t use unable to wean)
63
Summary of recent data on EGDT
• EGDT bundle completion improves mortality
• Antibiotics within 1 hour saves lives
• Hospital-derived Sepsis much higher mortality
than if present on admission
• UH Sepsis mortality NOT POA 2x that if
Present On Admission (PAO)
Brought to you by
SMITe
Sepsis
Mortality
Improvement
Team
at UNM