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Sepsis: still misunderstood
after all these years...
Naeem Ali, MD
Assistant Professor
Director, Medical Intensive Care Unit
The Ohio State University Medical Center
2008
Ann Surg. 1886 April; 3(4): 321–333.
Objectives
1. To identify the severe sepsis
syndrome
2. To prioritize treatments for patients
with septic shock
3. To understand the current
controversies and upcoming studies in
severe sepsis
• What is sepsis?
• How common is sepsis?
• What causes sepsis?
• How do you treat sepsis?
Recognition
6 hours
Resuscitation
Initial Management
24 hours
Maintenance
Hospitalization
Recovery
Pre and post-discharge
What is sepsis?
I shall not today attempt further to define the
kinds of material…[b]ut I know it when I see it…
•Justice Potter Stewart, 1964
RECOGNITION
• 84yo Caucasian male with h/o
Parkinson’s and remote history of gun
shot wound
• Presents to the ED from his residence
with altered mental status, fever and
smelly urine
• Temp 102.3 P 118 R 32 BP 78/34
• 84% SPO2
Karol Wojtyla (1920-2005)
Sepsis:
Defining a Disease Continuum
SIRS = Systemic Inflammatory Response Syndrome
Infection/
Trauma
SIRS
Sepsis Severe Sepsis
A clinical response arising from a nonspecific
insult, including  2 of the following:
•
•
•
•
Temperature 38oC or 36oC
HR 90 beats/min
Respirations 20/min
WBC count 12,000/mm3 or
4,000/mm3 or >10% immature neutrophils
Adapted from: Bone RC, et al. Chest 1992;101:1644
Opal SM, et al. Crit Care Med 2000;28:S81
?
Sepsis:
Defining a Disease Continuum
SIRS = Systemic Inflammatory Response Syndrome
Infection/
Trauma
SIRS
Sepsis Severe Sepsis
SIRS with a
presumed or
confirmed
infectious process
Adapted from: Bone RC, et al. Chest 1992;101:1644
Opal SM, et al. Crit Care Med 2000;28:S81
• 84yo Caucasian male with h/o
Parkinson’s and remote history of gun
shot wound
• Presents to the ED from his residence
with altered mental status, fever and
smelly urine
• Temp 102.3 P 118 R 32 BP 78/34
• 84% SPO2
Does he have sepsis?
Is he sick or not sick?
Sepsis:
Defining a Disease Continuum
Infection/
Trauma
SIRS
Sepsis Severe Sepsis
Sepsis with 1 sign of organ
failure
Cardiovascular (refractory
hypotension)
Renal
Respiratory
Hepatic
Hematologic
CNS
Metabolic acidosis
Bone et al. Chest 1992;101:1644; Wheeler and Bernard. N Engl J Med 1999;340:207
Neurologic
Altered
Consciousness
Confusion
Psychosis
Tachycardia
Hypotension
Altered CVP
Altered PAOP
Cardiovascular
Tachypnea
PaO2 <70 mm Hg
SaO2 <90%
PaO2/FiO2 300
Respiratory
Jaundice
 Enzymes
 Albumin
 PT
Hepatic
Oliguria
Anuria
 Creatinine
Renal
 Platelets
 PT/APTT
 Protein C
 D-dimer
Coagulation
Sepsis:
Timing of Organ Failures
Wheeler et al. NEJM 1999; 340: 207-14
Mortality increases with increasing
organ failure
Hebert et al. Chest 1993;104:230-5
Neurologic
Altered
Consciousness
Confusion
Psychosis
Sepsis:
Tachycardia
Hypotension
Altered CVP
Altered PAOP
Defining a Disease Continuum
Infection/
SIRS
Tachypnea
Trauma
PaO <70 mm Hg
2
SaO2 <90%
PaO2/FiO2 300
Respiratory
Jaundice
 Enzymes
 Albumin
 PT
Hepatic
Cardiovascular
Sepsis Severe Sepsis
Oliguria
Anuria
 Creatinine
Sepsis withRenal
1 sign of organ
failure
Cardiovascular (refractory
hypotension)
 Platelets
Renal
 PT/APTT
Respiratory
 Protein C
Hepatic
 D-dimer
Hematologic
CNS
Metabolic acidosis
Coagulation
Bone et al. Chest 1992;101:1644; Wheeler and Bernard. N Engl J Med 1999;340:207
Mortality Increases in Septic Shock Patients
Incidence
Mortality
Sepsis
400,000
7-17%
Severe Sepsis
300,000
20-53%
Septic
Shock
53-63%
Balk, R.A. Crit Care Clin 2000;337:52
How sick is he?
•
•
•
•
•
•
•
WBC 30K with 20% bands
Shock
ABG 7.20/28/42/15 on 100% FiO2
Platelets normal, INR 1.7
LFTs normal
BUN 32, Creatinine 1.9
Delirious
This seems kind of bad.
Glad it doesn’t happen much
RECOGNITION
http://www.cnn.com/2004/SHOWBIZ/Movies/10/11
/obit.reeve/index.html Accessed 8/23/05
1,800
600
Severe Sepsis Cases
US Population
500
1,400
1,200
400
1,000
300
800
2001
2025
At LEAST the
10th Leading
Cause of Death
Rate per
100,000 Population
Year
Angus DC, et al. JAMA 2000;284:2762-70.
Angus DC, et al. Crit Care Med 2001;29:1303-10.
300
Total US Population (million)
Sepsis Cases (x103)
1,600
Severe Sepsis
is common and
increasing in
incidence
2050
Incidence
Mortality
250
200
150
100
50
0Severe
Sepsis Stroke Breast CA Lung CA
Severe Sepsis
Stroke
Breast Cancer
Lung Cancer
*Calculated data based on information compiled from the American Heart Association, American
Cancer Society, National Center for Health Statistics and the US Census Bureau (1995-1999)
Mortality rate is decreasing but
more are dying overall
• 1979 – 1984 – 27.8%
– 43,579
– 21.9/100,000
population
MORTALITY
• 1995 – 2000 – 17.9%
– 120,491
– 43.9/100,000
population
• Mortality dropped
most with Gram+
infections
Martin et al, NEJM 2003:348;1546-54.
215,000 deaths a year in US
~590 Deaths Every day
Severe Sepsis Costs a Lot
Average per-patient cost
Total national cost
Age
•Average LOS 19.6 days
•Average cost $22,100/case
•Total national hospital cost was $16.7 BILLION
•52.3% of costs in those >64 years
•30.8% total costs in those >74 years
Angus et al, Crit Care Med 2001; 29: 1303-10
OSUMC-Specific Data:
January 1995 – August 26, 2006
• ICD9 codes for sepsis
– NPV 80%, PPV 90%
• 12,518 admissions
– 2.9 admissions/day
• 2856 deaths (23%)
– One death every 1.5
days
• Average hospital LOS 17.5 days
– 219,246 hospital days
– 18,807 hospital days/yr
• 4725 with ICU stay (37.7%)
– Average ICU LOS 11.7 days
– 4742 ICU days/yr
– 13 ICU beds with septic
patients/day
• Total charges of
$1,028,675,176.43
• Yearly charge of $88,241,231.35
• Average charge of $82,175.68
This doesn’t sound that great
Maybe we should figure out what
causes this
Risk factors and Pathogenesis
The Pathogenesis of Sepsis
Infectious Agents
•Endotoxin/LPS
•Lipopeptides
•Lipoteichoic acid
•DNA
•Flagellin
Response to Stimulus
•Inflammation
•Immunosuppression
•Coagulopathy
•Mitochondrial dysfunction
Susceptible Host
•Co-morbidities
•Age
•Genetic polymorphisms
A Theoretical Picture of Sepsis
Infection
Inflammation
Organ Failure
Cellular Failure
Infection factors
Host factors
Cytokines
Dysregulated Coagulation
Poor Perfusion
Apoptosis
Mitochondrial Dysfunction
Metabolic Derangement
MOSF
Death
Microvascular Blood Flow
Normal
Septic shock
De Backer et al, AJRCCM 2002; 166:98-104.
Organisms Found in Sepsis
Gram
negative
bacteria
Gram positive bacteria
Fungi
Only about 30% have a positive blood culture
Martin et al, NEJM 2003:348;1546-54.
Sites of Infection in Severe Sepsis
Other/Unknown
Endocarditis
Central nervous system
Wound/soft tissue
Device-related
Abdominal
Genitourinary
Primary Bacteremia
Respiratory
0
5
10
15
20
25
Angus et al, Crit Care Med 2001; 29: 1303-10
30
35
40
Extremes of age are associated with higher
incidence
Cases
OR if >65 is 13!
Incidence
AGE
Angus et al, Crit Care Med 2001; 29: 1303-10
Population-Adjusted Incidence of Sepsis,
According to Sex, 1979-2000
MEN (OR 1.3)
WOMEN
38.8%
sever
e
sepsis
659,935 cases
240.4 cases/100K
Martin, G. S. et al. N Engl J Med 2003;348:1546-1554
Race is associated with Incidence of Sepsis
Black
Other
OR 1.9
White
Martin et al N Engl J Med 2003;348:1546-1554
Highest incidence
Youngest age at onset
Highest mortality
was among
African-American men
Important Patient-Related Factors
CO-MORBIDITIES
•Immunosuppression
•AIDS (OR 5.1)
•Cancer
•Any (OR 2.8)
•Solid (OR 1.8)
•Liquid (OR 15.7)
GENETIC PRE-DISPOSITION
•Innate immune system
•Cytokine genes
•Other polymorphisms
•Cirrhosis (OR 2.6)
•Alcohol dependence (OR 1.5)
•Chronic catheters (OR 64)
•TRANSFUSIONS (OR 6.0)
•Diabetes
All right, all right, I get it.
But isn’t that guy dying on us?
Shouldn’t we do something about that?
TREATMENT
Treatment of Inflammation
Failed Strategies
•
•
•
•
•
•
•
•
•
High-dose corticosteroids
PLA2 inhibitors
Pentoxifylline
Prostaglandin E1
Ketoconazole
Anti-endotoxin antibodies
Anti-TNF antibodies
Interleukin-1 receptor antagonist
Tissue factor pathway inhibitor
American Association of Critical-Care Nurses
American College of Chest Physicians
American College of Emergency Physicians
Canadian Critical Care Society
European Society of Clinical Microbiology and
Infectious
Diseases
European Society of Intensive Care Medicine
European Respiratory Society
International Sepsis Forum
Japanese Association for Acute Medicine
Japanese Association of Intensive Care Medicine
Society of Critical Care Medicine
Society of Hospital Medicine
Surgical Infection Society
World Federation of Societies of Intensive and Critical
Care
Medicine
German Sepsis Society
Latin America Sepsis Institute
RESUSCITATION PHASE
GOAL: Keep him alive for 24 hours
• A – Airway
– Intubation
Treat the
Infection
• B – Breathing
– Mechanical ventilation
• C – Circulation
– IV access
– Goal directed therapy
– Steroids
Antibiotics – Go BIG early
•Every hour in delay of appropriate atbx = 7.6% lower survival
•Median time to appropriate atbx = 6h
Kumar et al. Crit Care Med 2006; 34: 1589-96.
Surviving Sepsis Campaign Level 1
Recs re ATBX
• Get cxs before atbx if WON’T DELAY ATBX
• ≥2 blood cxs (≥1 peripheral, 1 from each
CVC), other sites as indicated
• Begin IV atbx ASAP and ALWAYS within 1h of
recognizing severe sepsis/septic shock
• Use broad-spectrum atbx, ≥1 agents with
activity against likely bugs and penetration into
site
• Reassess choices daily
• Duration can probably be 7-10d
• Stop atbx if not infected
How do you know when you’ve addressed “C” in
ABCs?
Early Goal-Directed
Therapy
CVP: central venous pressure
MAP: mean arterial pressure
ScvO2: central venous oxygen
saturation
N Engl J Med 2001;345:1368
Early Goal-Directed Therapy Results
60
50
28-day Mortality
49.2%
40
P = 0.01*
33.3%
30
20
10
0
Standard Therapy
n=133
N Engl J Med 2001;345:1368-77.
EGDT
n=130
Limitations
• Single center and a single group of
investigators
– Is it generalizable?
• Is the whole protocol necessary?
– Blood?
– Inotropes?
– Continuous ScvO2 monitoring?
ProCESS Study Design
• Three Arms
– Usual Care Arm
– Early Goal-Directed Therapy (EGDT) Arm
– Protocolized Standard Care (PSC) Arm
• 24 Centers, 1935 Subjects
– 645 in each arm
ProCESS Objectives
• Aim 1: Clinical Efficacy
– Is any protocolized care superior to usual care?
– Is EGDT arm superior to PSC arm?
• Aim 2: Mechanisms of Action
–
–
–
–
Inflammation
Cellular hypoxia
Oxidative stress
Coagulation / thrombosis
• Aim 3: Costs and Cost-effectiveness
A Comparison of Albumin and Saline for Fluid
Resuscitation in the Intensive Care Unit
•N=6997
•Randomized to NS or
4% albumin for any
resuscitation
•In patients with severe
sepsis:
•30.7% mortality with
albumin
•35.3% mortality with
NS
NEJM 2004; 350: 2247-56
Vasopressors In Septic Shock
Heart Rate
Contractility Vasoconstrict
Dopamine
Low dose
0
0
1-
Med dose
2+
2+
0
Hi dose
2+
2+
3+
Dobutamine
1+
4+
1-
Norepinephrine
2+
2+
4+
Phenylephrine
2-
0
4+
Epinephrine
4+
4+
4+
Vasopressin
1-
1-
4+
Original Article
Vasopressin versus Norepinephrine Infusion in
Patients with Septic Shock
James A. Russell, M.D., Keith R. Walley, M.D., Joel Singer, Ph.D., Anthony C. Gordon,
M.B., B.S., M.D., Paul C. Hébert, M.D., D. James Cooper, B.M., B.S., M.D., Cheryl L.
Holmes, M.D., Sangeeta Mehta, M.D., John T. Granton, M.D., Michelle M. Storms,
B.Sc.N., Deborah J. Cook, M.D., Jeffrey J. Presneill, M.B., B.S., Ph.D., Dieter Ayers,
M.Sc., for the VASST Investigators
N Engl J Med
Volume 358(9):877-887
February 28, 2008
Study Overview
• In a multicenter trial, 778 patients with
septic shock who were being treated
with catecholamine vasopressors were
randomly assigned to either
norepinephrine or vasopressin in
addition to open-label vasopressors
Kaplan-Meier Survival Curves for Patients Who Underwent Randomization and Infusion
Russell JA et al. N Engl J Med 2008;358:877-887
Rates and Risks of Death from Any Cause According to the Severity of Shock
Russell JA et al. N Engl J Med 2008;358:877-887
Surviving Sepsis Campaign Level 1
Recs re Resuscitation and Pressors
• Begin resuscitation immediately if low bp or lactate >4
• Goals include:
– CVP 8-12 (higher if on vent)
– MAP ≥65
– UO ≥0.5mL/kg/h
– CvO2 ≥70% or SvO2 ≥65%
• Use crystalloids or colloids
• Give “fluid challenge” and monitor response – at least 1L
crystalloid or 300mL colloid over 30min
• Reduce fluid administration if filling pressures rise without
hemodynamic improvement
• Norepi or dopa are initial pressors of choice
• DON’T use “renal dose” dopamine
• Insert an a-line in those on pressors
• Use dobutamine in patients with myocardial dysfxn (elevated
filling pressures, low CO)
• Do not increase CI to supranormal levels
Corticosteroids
Steroids
Placebo
N=300
•Sick
•Sbp<90 for 1h despite vasopressors
•Mechanical ventilation
•Another organ failure
•Treated within 8h
•77% unresponsive to ACTH
•ACTH unresponsiveness predicted benefit
Annane, D. JAMA, 2002; 288 (7): 868.
Not steroids again….
N=499
•Less Sick
Sprung. NEJM, 2008; 358: 111.
•Sbp<90 or vasopressors despite fluids
•Hypoperfusion or OF due to sepsis
•Treated within 72h (77% within 12h)
•47% unresponsive to ACTH
•ACTH unresponsiveness did NOT predict benefit
•25% had misclassification of ACTH response
Surviving Sepsis Campaign Level 1
Recs re Steroids
• Use hydrocortisone dose ≤300mg/d
• Do not use steroids without shock
LEVEL 2
• Consider steroids if hypotension poorly responsive to fluids and
pressors
• ACTH stim test DOES NOT identify those who will benefit from
steroids
• Fludrocortisone may be included
• Steroids may be weaned
INITIAL MANAGEMENT PHASE
GOAL: Let’s get him better
• Supportive care
– Identify organ failures
– Customize antibiotics
based on
cultures/sensitivities
– Additional diagnostic
testing
– Goals of care
discussions
• Specific care
– Drotrecogin alfa
(activated) [Xigris®]
– Lung protective
ventilation
– Conservative fluid
management
APC Links Coagulation & Inflammation
Coagulation cascade
Inflammation
N Engl J Med 2001;344:699-709.
Inhibition of
fibrinolysis
Drotrecogin Alfa (Activated) Significantly
Reduced Mortality in PROWESS
100
Percent Survivors
NNT = 17
90
Drotrecogin alfa (activated)
(n=850)
80
Placebo
(n=840)
6% Absolute
mortality
difference
70
P=.006 (stratified log-rank test)
0
0
7
14
21
Days from Start of Infusion to Death
Bernard GR, et al. N Engl J Med 2001;344:699-709.
28
Patient selection is important
• “High risk” of dying
• “Low risk” of bleeding
– APACHE II score >24
– serious bleeding: 2 to 5%
– ICH: 0.2 to 0.5%
– Bleeding associated with:
• NNT = 8
– Multi-organ failure
• NNT=14
– Respiratory failure
• NNT=17
– Shock
• NNT=15
– 40% probability of dying?
•
•
•
•
•
Instrumentation
Trauma
Thrombocytopenia (<30)
Meningitis
INR >3
Management of Acute Lung
Injury and the Acute
Respiratory Distress
Syndrome…to be continued
MAINTENANCE AND RECOVERY
GOAL: Don’t kill him
• Avoid nosocomial
complications
– Ventilator-induced
lung injury
– Get tubes and lines
out of him
– Clots and bleeding
• Avoid new infection
– Hand washing
– Semi-recumbent
position
– Get tubes and lines out
of him
– Minimize transfusions
Glucose
SICU
Managed by Endo
fellow
Conventional
Treatment
(180-200)
Intensive
Treatment
(80-110)
ICU Deaths
63/783 (8.0%)
35/765 (4.6%)
0.005
Hospital Deaths
85/783 (10.9%)
55/765 (7.2%)
0.01
Hypoglycemia (<40)
6/783 (0.8%)
39/765 (5.1%)
MICU
Managed by RN
protocol
Conventional
Treatment
(180-200)
Intensive
Treatment
(80-110)
<0.000
1
ICU Deaths
162/605 (26.8%)
144/595 (24.2%)
0.31
Hospital Deaths
242/605 (40.0%)
222/595 (37.3%)
0.33
19/605 (3.1%)
111/595 (18.7%)
<0.000
1
Hypoglycemia
Van den Berghe et al, NEJM 2001; 345:1359 and 2006;354:449.
Glucose, Part Deux
•Severe sepsis
•80-100 v 180-200
•Stopped after 488 pts
•Hypoglycemia
•17.0% v 4.1%
p=0.36
•Hypoglycemia was assoc
with death HR 3.3
Brunkhorst et al., NEJM 2008; 358:125-39.
Probability of Survival and Odds Ratios for Death, According to Treatment Group
The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297
Probability of Survival and Odds Ratios for Death, According to Treatment Group
The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297
Surviving Sepsis Campaign Level 1
Recs re Maintenance
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Target Hgb 7-9
Do not use epo to treat sepsis-assoc anemia
Do not use antithrombin
Use sedation protocol with goals
Use intermittent bolus sedation or daily awakenings
Avoid neuromuscular blockers
Use IV insulin to control hyperglycemia
Provide glucose and monitor every 1-2h if receiving IV insulin
Interpret with caution POC glucose
Do not use HCO3 to treat lactic acidosis with pH>7.15
Use UFH or LMWH prophylaxis
Use mechanical device when heparin contraindicated
Use H2blocker or PPI for stress ulcer prophylaxis
Discuss goals of care and set realistic expectations
What is it?
•
•
•
•
SIRS + Infection = Sepsis
Sepsis + Organ Failure = Severe Sepsis
Sepsis + Shock = Septic Shock
Mortality increases with more organ failure
How common is it?
•
•
•
•
Significant mortality – Top 10 cause of death
Significant morbidity
Significant cost
Is getting more common
What causes it?
•
•
•
•
•
•
Inflammation
Coagulopathy
Blood flow
Cell failure
Organ failure
Death
• Host factors
• Infection factors
• Nosocomial
complications
– VAP/BSI
– Ventilators
How do you treat it?
• Recognition
• Resuscitation = ABCs + Atbx
– Goal-directed therapy
• Initial Management
– Customize care
– Drotrecogin alfa (activated)
• Maintenance
– Avoid complications
• Transfusion
• Sedation
• Ventilation
• For questions/comments, please feel
free to contact me:
[email protected]
• 292-6933