Transcript Sepsis

SIRS & Sepsis:
what are we doing and why ?
Bradley J. Phillips, MD
Burn-Trauma-ICU
Adults & Pediatrics
“Sepsis”
the difference between
infection and inflammation
• We must try to differentiate between the two…
If we consider signs of inflammation (fever, leukocytosis) as actual
evidence of infection, we clinically fuse two distinct
entities…leading to the possibility of errors in decision-making
and potentially, altering outcome-events.
The Inflammatory Response
• Complex series initiated by an insult to the host
–
–
–
–
•
Microbial invasion
Physical trauma
Burns
Chemical irritants
Purpose is to protect the host
200 yrs ago, John Hunter pointed out that this
response can actually injure the host
Inflammation: Protection vs. Injury
Marino, 2nd ed.
Clinical Syndromes
The relationship between infection, inflammation, and
organ injury
•
•
•
•
Fever + Leukocytosis
=
SIRS
SIRS + Infection
=
Sepsis
Sepsis + Multiorgan Dysfunction
=
Severe Sepsis + Refractory hypotension =
Severe Sepsis
Septic Shock
[ACCP/ SCCM]
SIRS: definition
ACCP/SCCM Consensus Conference on Sepsis & Organ Failure.
(Chest 92;101:1644-1655.)
SIRS
• In one study of 170 patients in a SICU, 93%
satisfied the criteria for SIRS.
[Pittet et al. ICMed 95;21:302-309]
• Of those with SIRS, infection is identified in only
25 – 50% of patients.
[Pittet et al. ICMed 95;21:302-309]
[Rangel et al. JAMA 95;273:117-123]
Multiple Organ Dysfunction Syndrome
•
•
•
•
Triggering Insult…
Activated neutrophils in the circulating stream
Endothelial activation and expression of adhesion molecules
Once adherent, the neutrophils release their granular contents
– Proteolytic enzymes
– Oxygen metabolites
damages the endothelium
(which directly decreases thrombomodulin levels),
permitting infiltration of the tissue parenchyma
with the plasma contents and inflammatory mediators,
leading to organ dysfunction
MODS
Organ System
Clinical Syndrome
Lungs
Kidneys
Heart
Central nervous system
Peripheral nervous system
Coagulation system
GI Tract
Liver
Adrenal glands
ARDS
ATN / ARF
Hyperdynamic Hypotension
Metabolic Encephalopathy
ICU Polyneuropathy
DIC
Gastroparesis / Ileus
Noninfectious Hepatitis
Acute Adrenal Insufficiency
MODS: mortality
directly related to
the number of
organs
that fail
Severe Sepsis & Septic Shock
Both of these are conditions in which
multiorgan dysfunction is due to INFECTION
• The only difference between these two is the presence of
volume-resistant hypotension in septic shock…
• The tendency to develop one (or both) of these conditions
is NOT a function of the organism involved in the actual
infectious process…but rather, the degree of HOST
RESPONSE.
Nosocomial Septicemia: ICU Patients
Pittet D et al. [JAMA 94;271:1598-1601]
Hemodynamics in Sepsis
(1)
• Early Stages
– Hypovolemia
• Relative - venous pooling
• Absolute – transudation of fluid
– Hypodynamic state
• Low cardiac output due to BOTH systolic &
diastolic impairment
• Intrinsic decrease in contractile function
– Though the mechanism has yet to be understood
– Mysterious “myocardial depressant factor”
Hemodynamics in Sepsis
(2)
“but I thought sepsis was a hyperdynamic process…”
• It is, early on – but only AFTER intravascular volume has been
restored
– The subsequent increase in Cardiac Output is due to a reflexive
tachycardia NOT an actual increase in stroke volume
• Late stages: sepsis becomes a hypodynamic state
– Due to a reduced blood flow & peripheral vasoconstriction
Oxygen Transport in Sepsis
(1)
• Severe sepsis & septic shock are classically characterized
by a defect in the peripheral extraction of oxygen
“ OXYGEN DEBT ”
• As peripheral blood flow decreases, the normal ability to extract
molecular oxygen is impaired leading to a decrease in VO2
This cellular hypoxia decreases pyruvate metabolism
and leads to anaerobic conversion of
glucose to lactate
in an attempt to salvage energetic losses
Oxygen Transport in Sepsis
Cellular Conservation of Glucose
(2)
Why is sepsis “so critical” ?
The current rate of death from Severe Sepsis
ranges from 30 – 50 %.
• In the U.S., there are ~ 750,000 cases of sepsis
each year.
• Of these, at least, 225,000 are fatal.
[NEJM 2001;344(10)]
Sepsis: how should we treat it ?
Mainstay of Early Treatment:
Aggressive Volume Infusion
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•
•
•
•
Crystalloid vs. Colloid ?
Tx of Hypoalbuminemia ?
End-point of volume infusions (what numbers are right ?)
CVP or Swan ?
Role of Vasotonics to treat associated hypotension ?
– Dopamine, Levophed, Neo…
(1)
Sepsis: how should we treat it ?
(2)
Oxygen Transport:
is there a role for the transport variables ?
• Target parameters ?
– Normal whole-body oxygen uptake… (VO2 > 100)
– Supranormal delivery approach…(DO2 > 600, VO2 > 170)
• Supply-dependence ?
• Role of dobutamine ?
is the treatment of “septic shock” similar to
“major resuscitation”
Resuscitation Efforts: Patient Scenarios
• 76 yr. old Female
• 36 % TBSA Burn: 2nd / 3rd Degree with Inhalation
• Caught in a Housefire - carried out by Firefighters
• Medical Hx: “Hypertension”
• Intubated/Supportive Ventilation
• Hyperdynamic Protocols Initiated
– 42 Hours Post-Admission: coded
– Autopsy: Acute MI with Rupture of Left Ventricle
(Phillips, Matthews, Schiller, Malone, & Shoemaker. in press)
20
Hemodynamic
Parameters
15
10
48
36
24
16
0
8
5
2
C.I.
CVP
PWP
60
LVSWI
40
20
0
4
8
12
16
20
24
30
36
42
48
Relationship: Serum Lactate & Cardiac Index
7
6
Lactate
5
C.I.
4
3
2
1
0
Admission
6
12
18
24
Patient Scenarios (2)
• 42 yr. old Female
• 30 % TBSA, 3rd Degree Burn
– Barbecue Gas-Explosion
– Compartment Syndrome to Right U.E.
• Followed with Tissue Pressures
• 8 hours after injury, required escharotomy
• Resuscitated without event
• Survived injury - transferred to E.C.F.
(Phillips, Matthews, Schiller, Malone, & Shoemaker. in press)
Serum Lactate & Cardiac Index
Lactate
C.I.
8
7
6
5
4
3
2
1
0
Admit
12 hrs
24 hrs
72 hrs
Patient Scenarios (3)
• 60 yr. old Male
• 35 % TBSA Burn, 3rd Degree
• Seized and fell into a bonfire
• Compartment Syndrome to Right Upper Extremity
• E.D. Fasciotomy (by phone)
• 20 hour-delayed presentation to Burn Center
• Shock State - Rhabdomyolysis/ATN
• Unresponsive to Resuscitative Efforts
• Eventual End-organ Collapse
(Phillips, Matthews, Schiller, Malone, & Shoemaker. in press)
VO2 & DO2 vs. Time
1600
VO2
1400
DO2
1200
1000
800
600
400
200
0
Admit
2 Hrs
12 Hrs
16 Hrs
18 Hrs
24 Hrs
Gastric Tonometry: pH(a) vs. pH(R)
48
pH(a)
pH(R)
36
24
16
8
Admit
6.9
7
7.1
7.2
7.3
7.4
Serum Lactate & Cardiac Index
hr
48
42
36
30
24
18
16
12
8
4
A
dm
it
16
14
12
10
8
6
4
2
0
s
Lactate
C.I.
so, even with all that information & all
those tools,
we still can’t treat sepsis…
???
there must be a way - other options ?
Critical Care Medicine
Boston Medical Center
Sepsis: how should we treat it ?
(3)
Empiric Antibiotics
• Yes or No ?
• Which antimicrobial agents should be used…
– Early stages ?
– Late-stages ?
• Given that “septic shock”, by definition carries evidence of multiorgan
dysfunction, how should we dose the antibiotics
– would this have any effect on subsequent organ failure ?
• What is the expected course & rationale management for “empiric”
treatment…when, if ever, do we stop the antibiotics ?
Sepsis: how should we treat it ?
(4)
Steroids
• 1960’s: High-dose steroids directly employed
• American Infectious Disease Society:
– “steroids should be avoided in patients with sepsis”
Any new studies or approaches ?
Sepsis: Treatment Arms
Marino, 2nd ed.
Sepsis: novel ideas
(1)
Anti-Inflammatory Antibodies
• Anti-endotoxin antibody
• Anti-TNF antibody
• Anti-IL1 antibody
• Large clinical studies have not shown a benefit…
– McCloskey et al. Ann Intern Med 94;121:1-5
– Abraham et al. JAMA 95;273:934-941
– Fischer et al. JAMA 94; 271:1836-1843.
Sepsis: novel ideas
(2)
Antioxidant Therapy
• Academically, seems to be a sound approach to limit
metabolite-induced organ injury
• PROBLEM: very little clinical science or investigation…
– IV N-acetylcysteine may help with A.R.D.S….but confirmation is
needed on a large-scale basis
Anti-oxidant Therapy
Selenium
(glu. Peroxidase)
Glutathione
(acts via reduction)
N-acetylcysteine
(a glutahione analog)
Vit. E
(blocks lipid peroxidation)
Vit. C
(pro-oxidant to maintain
iron as Fe(II)
Aminosteroids
(? lipid peroxidation)
Sepsis: novel ideas
(3)
Activated Protein C
APC, an endogenous protein that promotes fibrinolysis,
is an important modulator of the coagulation and inflammation
associated with severe sepsis.
APC is converted from its inactive precursor, protein C,
by thrombin coupled to thrombomodulin.
The conversion of protein C to APC may be impaired during sepsis as a
result of down-regulation of thrombomodulin
by inflammatory cytokines.
[NEJM 2001;344(10)]
Sepsis: novel ideas
(4)
Activated Protein C
Reduced levels of protein C are found in the majority of
patients with sepsis and are associated with an
increased risk of death
[NEJM 2001;344(10)]
Activated Protein C: PROWESS
19.4% decrease
in the R.R.
of death
6.1% decrease
in the A.R.
of death
[NEJM 2001;344(10)]
APC: PROWESS
Risks
vs.
Benefit
[NEJM 2001;344(10)]
APC: “Economic Evaluation”
Can we
afford to
treat ?
NEJM 2002;347(13)
Can we
afford NOT
to treat ?
Mortality Rates as a Baseline
The clinical utility of APACHE Scores…and do we track it ?
SEPSIS in the Year 2002
what should
we be doing & why ?
SEPSIS: A Targeted Approach
Aggressive Volume &
Tissue Perfusion
Antioxidants
Antibiotics
Active Infection
APC
Toxic Metabolites
Inflammatory Response
Circulatory Stasis
Severe Sepsis-----------------------Septic Shock
SIRS & SEPSIS
what should
we be doing & why ?
Shriners Hospital for Children
UTMB