The Magnitude and Pathophysiologyof Severe Sepsis

R. Phillip Dellinger, MDR. Phillip Dellinger, MDProfessor of MedicineProfessor of Medicine

Robert Wood Johnson Medical SchoolRobert Wood Johnson Medical SchoolUniversity of Medicine and Dentistry of New JerseyUniversity of Medicine and Dentistry of New Jersey

Head, Division of Critical Care MedicineHead, Division of Critical Care MedicineCooper University HospitalCooper University Hospital

Camden, New JerseyCamden, New Jersey

* Based on data for septicemia * Based on data for septicemia ††Reflects hospitalReflects hospital--wide cases of severe sepsis as defined by infection in the presewide cases of severe sepsis as defined by infection in the presence of organ dysfunction nce of organ dysfunction 11Sands KE, et al. Sands KE, et al. JAMAJAMA 1997;278:2341997;278:234--40.40.22Murphy SL. National Vital Statistics Reports. 1998.Murphy SL. National Vital Statistics Reports. 1998.33Angus DC, et al. Angus DC, et al. CritCrit Care MedCare Med 2001;29:13032001;29:1303--10. 10.

SEVERE SEPSIS:A Significant Healthcare Challenge

Major cause of morbidity and mortality Major cause of morbidity and mortality worldwideworldwide

Leading cause of death in Leading cause of death in noncoronarynoncoronary ICU (US)ICU (US)11

1111thth leading cause of death overall (US)leading cause of death overall (US)22**More than 750,000 cases of severe sepsis in More than 750,000 cases of severe sepsis in the US annuallythe US annually33

In the US, more than 500 patients die of In the US, more than 500 patients die of severe sepsis dailysevere sepsis daily33††

0

50

100

150

200

250

300

Severe Sepsis Stroke Breast Cancer Lung Cancer

IncidenceMortality

*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).

†Severe sepsis mortality rates range from 28%-50% (79/100,000 to 141/100,000 population).

SEVERE SEPSIS IS COMMON*R

ate

per

100,

000

Pop

ulat

ion

†

Patient Characteristics and Costof Severe Sepsis and

Septic Shock in Quebec

LetarteLetarte J, Longo CJ, Pelletier J, et alJ, Longo CJ, Pelletier J, et alJ J CritCrit Care Care 2002; 17(1):392002; 17(1):39--4949

Nonsurvivor$7,584 total/$1,724 daySurvivor$16,228 total/$877 day

Pathogenesis of Severe Sepsis

Infecting organismInfecting organism↓↓

Initiators (Initiators (endotoxin/exotoxinendotoxin/exotoxin))↓↓

MediatorsMediators↓↓

Organ dysfunction and shockOrgan dysfunction and shock

Balk RA. Crit Care Clin 2000;16:337-52.

IDENTIFYING ACUTE ORGAN DYSFUNCTION AS MARKERS OF SEPSIS AND SEVERE SEPSIS

TachycardiaTachycardiaHypotensionHypotensionAlteredAltered CVPCVP

AlteredAltered PAOPPAOP

OliguriaOliguriaAnuriaAnuria

↑↑ CreatinineCreatinine

↓↓ PlateletsPlatelets↑↑ PT/APTTPT/APTT↓↓ Protein CProtein C↑↑ DD--dimerdimer

JaundiceJaundice↑↑ EnzymesEnzymes↓↓ AlbuminAlbumin

↑↑ PTPT

Altered Altered ConsciousnessConsciousness

ConfusionConfusionPsychosisPsychosis

TachypneaTachypneaPaOPaO22 <70 mm Hg<70 mm Hg

SaOSaO22 <90%<90%PaOPaO22/FiO/FiO22 ≤≤300300

Figure B, page 948, reproduced with permission from Dellinger RP. Cardiovascular management of septic shock. Crit Care Med 2003;31:946-955.

Brun-Buisson C, Mehaka P, Pinton P, et al . Intensive Care Med. 2004; 30:580-588

Schrier R and Wang W. N Engl J Med 2004;351:159-169

Arterial Vasodilatation and Renal Vasoconstriction in Patients with Sepsis

Predictive value of microalbuminuria in medical ICU patients

Abid O, Sun, Q, Sugimoto K, et al.Abid O, Sun, Q, Sugimoto K, et al.Chest Chest 2001; 120:19842001; 120:1984--19881988

Bakker J, et al. Am J Surg 1996; 171:221-226

High Perfused Vessel Density (Sublingual OPS High Perfused Vessel Density (Sublingual OPS in normal individual)in normal individual)

Low Perfused Vessel Density (OPS in Septic Low Perfused Vessel Density (OPS in Septic Shock)Shock)

Organ Dysfunction and Mortality:Baseline and Dynamic Values

Marshall et al. Marshall et al. CCMCCM 1995; 23(10):16381995; 23(10):1638--16521652

ICU Outcome According to theMaximum Number of SIRS Criteria at Admission

Sprung et al. Intensive Care Med 2006; 32:421-427

The PIRO Model of Sepsis

OO

RR

II

PPGeneticsChronic Illness

Cultural Attitudes

ShockARDS, etc.

PhysiologicSpecific MediatorsGeneric Markers

INFECTION

Type of Organism

PREDISPOSITION

ORGAN DYSFUNCTION

RESPONSE

Site

Extent

Levy MM et al, CCM 2003; 31(4):1250-1256

37

38

39

40

[°C

]

0

10

20

30

40

[G/l]

0

6

12

18

24[n

g/m

l]

050

100150200250300350

[mg/

l]

NoneSIRS

Sepsis

Sev. Sepsis

Sept. Shock NoneSIRS

Sepsis

Sev. Sepsis

Sept. Shock

CRPPCT

LeukocytesTemperature

[n.s.]

[<0.0001]

[<0.0001]

[<0.0001]

20% 8% 7% 20% 72%

Outcome of Sepsis is Related to Severity of the Host Response

Rangel-Frausto et al. JAMA 1995.

3 7 1017 16 20

46

0

10

20

30

40

50

60M

orta

lity

(%)

NoSIRS

SIRS2 SIRS3 SIRS4 Sepsis SevereSepsis

SepticShock

Severity

Diagnostic Dilemma:Heart Attack vs. Sepsis

Heart AttackHeart AttackEKGEKGCardiac EnzymesCardiac Enzymes

CPKCPKMBMB

TroponinTroponinCRPCRPEchocardiogramEchocardiogramCardiac Cardiac CatheterizationCatheterization

SepsisSepsisSigns and symptomsSigns and symptoms

Fever, chills, Fever, chills, elevated WBC, elevated WBC, difficulty breathingdifficulty breathing

““Look sickLook sick””Objective Objective measurementsmeasurements……

CCM 2008; 36:1394-1396

CCM 2008; 36:1394-1396

The Future

More precise and earlier More precise and earlier identificationidentificationPrevention of organ dysfunction Prevention of organ dysfunction from occurringfrom occurringTargeting newly recognized and still Targeting newly recognized and still poorly understood mediatorspoorly understood mediators

Such as heat shock proteinSuch as heat shock protein