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

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• 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

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 (2)

Cellular Conservation of Glucose

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

Relationship: Serum Lactate & Cardiac Index

0

1

2

3

4

5

6

7

Admission 6 12 18 24

Lactate

C.I.

Serum Lactate & Cardiac Index

0

1

2

3

4

5

6

7

8

Admit 12 hrs 24 hrs 72 hrs

LactateC.I.

Gastric Tonometry: pH(a) vs. pH(R)

6.9 7 7.1 7.2 7.3 7.4

Admit

8

16

24

36

48 pH(a)

pH(R)

Serum Lactate & Cardiac Index

0

2

4

6

8

10

12

14

16LactateC.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 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

APC: PROWESS

[NEJM 2001;344(10)]

Risks

vs.

Benefit

APC: “Economic Evaluation”

NEJM 2002;347(13)

Can we afford NOT to treat ?

Can we afford to treat ?

Mortality Rates as a Baseline

The clinical utility of APACHE Scores…and do we track at BMC ?

SEPSIS: A Targeted Approach

Severe Sepsis -----------------------Septic Shock

Antibiotics

Active Infection

Antioxidants

Toxic Metabolites

Aggressive Volume &

Tissue Perfusion

APC

Inflammatory Response

Circulatory Stasis

SIRS & Sepsis in 2003: Questions ?

Bradley J. Phillips, M.D.

Critical Care Medicine

Boston Medical Center

Boston University School of Medicine

ICU EDUCATIONAL SERIES