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SIRS & Sepsis
Bradley J. Phillips, M.D.
Critical Care Medicine
Boston Medical Center
Boston University School of Medicine
TRAUMA-ICU NURSING EDUCATIONAL SERIES
“Sepsis”
the difference between
infection and inflammation
• We must try an 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 thisresponse can actually injure the host
Clinical Syndromes
The relationship between infection, inflammation, and organ injury
• Fever + Leukocytosis = SIRS• SIRS + Infection = Sepsis• Sepsis + Multiorgan Dysfunction = Severe Sepsis• Severe Sepsis + Refractory hypotension = 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 ARDS
Kidneys ATN / ARF
Heart Hyperdynamic Hypotension
Central nervous system Metabolic Encephalopathy
Peripheral nervous system ICU Polyneuropathy
Coagulation system DIC
GI Tract Gastroparesis / Ileus
Liver Noninfectious Hepatitis
Adrenal glands Acute Adrenal Insufficiency
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.
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
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 ? (1)
Mainstay of Early Treatment: Aggressive Volume Infusion
• 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…
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)
Hemodynamic Parameters
2 8 16 24 36 48
0
5
10
15
20
C.I.CVPPWP
0
20
40
60
4 8 12 16 20 24 30 36 42 48
LVSWI
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: 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 TherapySelenium(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
[NEJM 2001;344(10)]
19.4% decrease
in the R.R.
of death
6.1% decrease
in the A.R.
of death
SEPSIS: A Targeted Approach
Severe Sepsis -----------------------Septic Shock
Antibiotics
Active Infection
Antioxidants
Toxic Metabolites
Aggressive Volume &
Tissue Perfusion
APC
Inflammatory Response
Circulatory Stasis