Sepsis: A New Look at an Old Problem

Nathan Shapiro, MD, MPH

Beth Israel Deaconess Medical CenterHarvard Medical School

Sepsis

• 750,000 cases per year in US• Mortality ranges 10-60%• 215,000 deaths/year• More than 640 deaths/day in US• $22,000 per case• $16.7 billion per year in US

Angus et al. Crit Care Med. 2001;29:7:1303-1309

Severe Sepsis: Comparison With Other Major Diseases

†National Center for Health Statistics, 2001. §American Cancer Society, 2001. *American Heart Association.

2000. ‡Angus DC et al. Crit Care Med. 2001 (In Press).

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What is sepsis?

Host Infection

Systemic Inflammatory Response

Pro-inflammatory/Anti Inflammatory Activity

Accelerated Inflammatory Cascade

Sepsis Syndromes

Sepsis Definitions

Systemic Inflammatory Response Syndrome:

(SIRS): two or more of the following1. T>38 or <36

2. HR > 90 beats/min

3. RR>20 beats/min or pCo2<32 torr

4. WBC>12,000 or < 4,000 or >10% bands

SEPSIS – SIRS due to an infection

ACCM/SCCM Consensus Conference:Chest :1992:20:6

Sepsis Definitions

SEVERE SEPSIS - Sepsis + Organ Dysfunction,signs of organ dysfunction in the following systems:

– Cardiovascular– Renal– Respiratory– Hepatic– Hemostasis– CNS– Unexplained metabolic acidosis

SEPTIC SHOCK – Severe Sepsis + hypotension (despite adequate fluid resuscitation)

The Natural History of the Systemic Inflammatory Response Syndrome

• 3708 patients, multi-center prospective study in ICU/inpatient population

Syndrome Mortality

SIRS 2.2% (2.3-4.1)

Sepsis 2% (1.0-3.5)

Severe Sepsis 9% (7.2-10.7)

Septic Shock 15% (9.5-20.3)

Rangel-Frausto et. al. JAMA:1995:273:117-123.

Sepsis Syndromes in the Emergency Department

• 3179 patients, prospective, ED based study

Syndrome Mortality

No SIRS 3.2% (2.3-4.1%)

SIRS/Sepsis 8% (1.1-3.5%)

Severe Sepsis 10% (7.4-10.8%)

Septic Shock 27% (16.5-41.2%)

Shapiro et al. 2001 SCCM Meeting

“Patients die of complications of their

disease, rather than the disease itself”

Sir William Osler

Mediators of Sepsis

LPS

TNF

IL-1

IL-6/IL-8

NO,PAF, others

Local Inflammation Sepsis Severe Sepsis(low levels) (medium levels) (high levels)

Anti-InflammatoryIL-4IL-6 (both)IL-10IL-11IL-13

Approach to Sepsis

• Recognition of SIRS/Sepsis• Identify etiology• Early and Aggressive Treatment

“Sick, or not sick?That is the question!”

(Adapted from) Shakespeare

“Hectic Fevers at its inception is difficult to recognize, but easy to treat; Left untended, it becomes easy to recognize, but difficult to treat.”

Niccollo Machievielli, in “The Prince”(1513)

What are the RED FLAGS in Emergency Department patients

with sepsis?

Mortality in Emergency Department Sepsis (MEDS) Score

• Objective: To identify predictors of death from sepsis present in Emergency Department (ED) patients

• Prospective Study of 3179 ED patients admitted to hospital with suspected infection

• Logistic regression to identify “predictors of death”

Shapiro et al/ Critical Care Medicine. March 2003

3,301 Patient Encounters

3,179 (96%) Enrolled

122 (4%)missed

Visits randomly assigned

2/3 1/3

2,070 Derivation Set

1,109 Validation Set

Regression andPrediction Rule

Patient Enrollment

Independent Predictors Identified by Multivariate Analysis__________________________________________________

Variable Odds Ratio 95% CI Points

__________________________________________________

Terminal illness (<30d) 6.3 (3.7 to 10.4) 6

Tachypnea or hypoxia 2.6 (1.6 to 4.2) 3

Platelets < 150,000 /mm3 2.6 (1.6 to 4.4) 3

Bands > 5% 2.3 (1.4 to 3.5) 3

Age > 65 2.3 (1.4 to 3.7) 3

Suspected pneumonia 2.0 (1.3 to 3.2) 2

Nursing home resident 1.9 (1.2 to 3.1) 2

Septic Shock 2.6 (1.0 to 3.3) 3

Altered mental status 1.7 (1.1 to 2.7) 2 Shapiro et al/ Critical Care Medicine. March 2003

Mortality by MEDS score

.6% 2.3% 8%

18%

51%

.7% 4.7%9.1%

16%

39%

0%

10%

20%

30%

40%

50%

60%

0-4 5-7 8-12 12-15 >15

MEDS score

DerivationValidation

Mor

tali

ty %

**ROC Area = .81

ED Predictors of death from Sepsis

Host Status• Terminal illness (<30d) • Age > 65• Nursing home resident

Infection Type• Suspected pneumonia

Findings:• **Tachypnea or hypoxia• **Septic Shock• Altered mental status

Lab Abnormalities• Platelets < 150,000 /mm3

• Bands > 5%

Therapy

“Over 13,000 patients have been enrolled in 23 multi-center, placebo-controlled, clinical trials……results have been generally disappointing with some spectacular failures”

From “Clinical Trials for Severe Sepsis. Past Failures and Future Hopes, 1999

Opal et al. Infectious Disease Clinics of North America. 1999:13:2.

Sepsis

Systemic Inflammation

Infection

Coagulation

Protein C

Sepsis: A Network of Cascading Events

FIBRINOLYSIS

PROINFLAMMATORYMEDIATORS

INFECTION

TF

ANTI-INFLAMMATORYMEDIATORS

INFLAMMATION

Activated Protein C

Protein C

Activated Protein C

T TM

COAGULATION

PAI-1T-PATAF-1

ENDOTHELIAL INJURY

Homeostasis

Anti-Inflammatory

Anti-Inflammatory

Pro-Inflammatory

Pro-Inflammatory

Endogenous Activated Protein C Modulates Coagulation, Fibrinolysis, and Inflammation in

Severe Sepsis

Carvalho AC et al. J Crit Illness. 1994;9:51-75; Kidokoro A et al. Shock. 1996;5:223-8; Vervloet MG et al. Semin Thromb Hemost. 1998;24:33-44.

Pro-Coagulant

Pro-Coagulant

FibrinolyticFibrinolytic

Recombinant Human Activated Protein C

• 1690 patients, double blind, placebo controlled

• Inclusion: – known/suspected sepsis– > 3 SIRS criteria– dysfunction > 1 organ systems

Bernard et.al. NEJM. March 8, 2001:344:10:699-709.

Results

Mortality

Control Protein C Group

30.8% VS 24.7%

6.1% absolute reduction in DEATH

(Number needed to treat = 17)

Bernard et.al. NEJM. March 8, 2001:344:10:699-709.

APC “PROS”

• Well designed RANDOMIZED, DOUBLE BLIND, MULTICENTER, PLACEBO CONTROLLED study showing benefit in meeting primary objective

• Makes good biological sense

APC CONS

• Single Study• Numerous exclusion criteria• Altered exclusion criteria mid-study• Very expensive• Unclear benefit in patients with lower

APACHE Scores

FDA mandated follow-up study (lower acuity) starting soon

1Cost-Benefit

• All patients: $27,936 per life-year

• APACHE II > 25 $24,484 per life-year• APACHE II < 24 $575,054 per life-year

1Manns et al. NEJM:347:13:993-1000