Sepsis: A New Look at an Old Problem

Nathan Shapiro, MD, MPH Beth Israel Deaconess Medical Center Harvard 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 Incidence of Severe Sepsis Mortality of Severe Sepsis 300 250 200 150 100 50 250,000 200,000 150,000 100,000 50,000 0 0 AIDS* Colon Breast Cancer § CHF † Severe Sepsis ‡ AIDS* Breast Cancer § AMI † Severe Sepsis ‡

† National Center for Health Statistics, 2001.

2000.

‡ Angus DC et al.

Crit Care Med.

§ American Cancer Society, 2001. *American Heart Association. 2001 (In Press).

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 following 1. 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

SIRS Sepsis Severe Sepsis Septic Shock

Mortality

2.2% (2.3-4.1) 2% 9% 15% (1.0-3.5) (7.2-10.7) (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

No SIRS SIRS/Sepsis Severe Sepsis Septic Shock

Mortality

3.2% (2.3-4.1%) 8% (1.1-3.5%) 10% 27% (7.4-10.8%) (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

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

Mediators of Sepsis

LPS TNF IL-1 IL-6/IL-8 NO,PAF, others Local Inflammation (low levels) Sepsis (medium levels) Severe Sepsis (high levels)

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

Patient Enrollment

3,179 (96%) Enrolled 2/3 2,070 Derivation Set Visits randomly assigned 1/3 122 (4%) missed 1,109 Validation Set Regression and Prediction Rule

Independent Predictors Identified by Multivariate Analysis __________________________________________________ Variable Odds Ratio 95% CI Points __________________________________________________ Terminal illness (<30d) 6.3 Tachypnea or hypoxia Platelets < 150,000 /mm 3 2.6 2.6 Bands > 5% Age > 65 2.3 2.3

Suspected pneumonia 2.0 Nursing home resident 1.9 Septic Shock 2.6 Altered mental status 1.7 (3.7 to 10.4) (1.6 to 4.2) (1.6 to 4.4) (1.4 to 3.5) (1.4 to 3.7) (1.3 to 3.2) (1.2 to 3.1) (1.0 to 3.3) (1.1 to 2.7)

Shapiro et al/ Critical Care Medicine. March 2003

3 3 2 2 6 3 3 3 2

**ROC Area = .81

Mortality by MEDS score

60% 50% 40% 30% 20% 10% 0%

.6% .7% 2.3% 4.7% 8% 9.1%

0-4 5-7 8-12

MEDS score 18% 16%

12-15

51% 39%

>15 Derivation Validation

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 /mm 3 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 Protein C Coagulation Infection

Sepsis: A Network of Cascading Events INFLAMMATION PROINFLAMMATORY MEDIATORS INFECTION ANTI-INFLAMMATORY MEDIATORS Activated Protein C T TM Protein C Activated Protein C COAGULATION TF TAF-1 T-PA PAI-1 ENDOTHELIAL INJURY FIBRINOLYSIS

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

Homeostasis Carvalho AC et al.

J Crit Illness.

Thromb Hemost.

1998;24:33-44.

1994;9:51-75; Kidokoro A et al.

Shock.

1996;5:223-8; Vervloet MG et al.

Semin

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 30.8% VS Protein C Group 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

1 Cost-Benefit

• All patients: $27,936 per life-year • APACHE II > 25 • APACHE II < 24 $24,484 per life-year $575,054 per life-year 1 Manns et al. NEJM:347:13:993-1000