Treatment of Sepsis

Ednan K. Bajwa, M.D.

Massachusetts General
Hospital

Severe Sepsis: Definitions and

Magnitude of the Problem

Sepsis = Infection with Systemic Inflammation

Severe Sepsis = Sepsis plus shock or organ

failure

More than 750,000 new cases of severe

sepsis/year

30% to 50% Mortality even with appropriate

treatment, increases to ~70% with ARF

Projected Incidence of Severe Sepsis

in the US: 2001-2050
600,000

Severe Sepsis Cases

US Population

1,600,000

500,000

Sepsis Cases

1,400,000
1,200,000

400,000

1,000,000
300,000
800,000
600,000

200,000

400,000
100,000
200,000

2001

2025

Year

Total US Population/1,000

1,800,000

2050

Angus DC et al. Crit Care Med 2001

Antibiotics and Severe Sepsis:

Necessary but Not Sufficient for Survival
Infection
Immune/Coagulation System
Activation

Appropriate antibiotics
reduce progression to
severe sepsis by ~50%

Severe Sepsis

Death

Appropriate antibiotics
reduce mortality by
10-15%

Kreger BE, et al. Am J Med 1980;

Simon D, et al. Crit Care Clin 2000
Pittet D, et al. AJRCCM 1996; Opal SM, et al. CCM 1997.

Antibiotics and Severe Sepsis:

Necessary but Not Sufficient for Survival
Infection
Immune/Coagulation System
Activation

Appropriate antibiotics
seduce progression to
severe sepsis by ~50%

Severe Sepsis

Death

Appropriate antibiotics
reduce mortality by
10-15%

Kreger BE, et al. Am J Med 1980;

Simon D, et al. Crit Care Clin 2000
Pittet D, et al. AJRCCM 1996; Opal SM, et al. CCM 1997.

Clinical Trials of Immune Modulation

for Severe Sepsis

Phase II-III Placebo-Controlled Trials Showing No

Benefit or Harm:
Anti-LPS (Polyclonal Ab, HA-1A, E5)

13

Anti-TNF Monoclonal Antibodies

TNF Receptors

IL1ra , IVIG, or elastase inhibitors

Growth hormone

Soluble Phospholipase A2 Inhibitor

rhAPC for lower risk severe sepsis

1
34

Treatment of Severe Sepsis: Levels of

Evidence for Improved Outcome

Early, goal-directed resuscitation

Corticosteroid therapy

Glycemic control

Lower tidal volume

Xigris (rhAPC)

Treatment of Severe Sepsis: Levels of

Evidence for Improved Outcome

Early, goal-directed resuscitation

Corticosteroid therapy

Glycemic control

Lower tidal volume

Xigris (rhAPC) for higher risk

Choice of Vasopressor?

When an appropriate fluid challenge fails to

restore adequate blood pressure and organ
perfusion, therapy with vasopressor agents
should be started.

Little outcomes data to suggest ideal pressor

Norepinephrine or dopamine preferred

Pathophysiology of Organ Dysfunction

in Early Septic Shock

Shock represents the failure of the circulatory system to

maintain adequate delivery of oxygen and other
nutrients to tissues, causing cellular and then organ
dysfunction

Previous trials of goal-directed resuscitation ineffective

Early resuscitation may restore effective tissue perfusion

and normalize cellular metabolism
Task force of the SCCM 1999

Hemodynamic Alterations of Septic

Shock
Parameter

Preshock

Warm Shock

Inadequate
Resuscitation

Heart Rate
Blood Pressure

WNL

Systemic
Vascular
Resistance

WNL or

Cardiac Output
Pulmonary Artery
Occlusive
Pressure
Other

(and Sv02)
WNL or

WNL or

1. Loss of Autoregulatory Mechanisms with Maldistribution of Blood Flow

2. Decreased Vascular Sesitivity to Catecholamines

Modified from: Lanken PN. The Intensive Care Manual. 2001, p.95.

Organ Dysfunction in Early Septic Shock

Decreased Perfusion
Organ tissue

Organ Dysfunction in Early Septic Shock

Organ tissue

Cellular dysfunction

Cells + mitochondria irreversibly

injured

Early Goal-Directed Therapy for

Septic Shock

Early Goal-Directed Therapy (EGDT): Goal to balance

O2 delivery with demand for patients presenting in the
ER with:
Septic shock, or
Sepsis with Lactic acidosis (lactate > 4 mmol/l)

Study Design: Prospective, randomized controlled,

partially blinded, single center trial

263 Patients (133 standard therapy; 130 EGDT)

Rivers et al NEJM 2001

Early Goal Directed Therapy (EGDT)

Patient Randomized
Early GoalDirected Therapy

Standard
Therapy

CVP > 8-12 mm Hg

MAP > 65 mm Hg
Urine Output > 0.5 ml/kg/hr
If ScvO2 < 70%
If Hct < 30%

At least 6 hours
of EGDT

CVP > 8-12 mm Hg

MAP > 65 mm Hg
Urine Output > 0.5 ml/kg/hr

PRBC
Dobutamine

Transfer to ICU
ICU MDs blinded to
study treatment

As soon as
possible
Rivers et al NEJM 2001

Edwards Sepsis Catheter

EGDT Results: First Six Hours

75%

6000

Percent of Patients

5000
4000

ml 3000
2000
1000

50%

25%

0%

0
Fluids in ml
(mean)

RBCs

Pressors Dobutamine

EGDT
Traditional

Rivers et al NEJM 2001

EGDT: Results at 7 to 72 hours

Higher Disease Severity (APACHE II) and more

organ failures (MODS) with standard therapy

More DIC with Standard Rx:

PT (P=0.001),
FSP concentration (P<0.001)
D-dimer levels (P=0.006)

Rivers et al NEJM 2001

Improved Survival with Early Goal-Directed

Therapy for Septic Shock
80
70

P=0.009

P=0.01

P=0.03

In-hospital
mortality (all
patients)

28-day mortality

60-day mortality

60
50
40
30
20
10
0

EGDT
Standard Therapy

Rivers et al NEJM 2001

72 year old woman

urinary sepsis

Resuscitation
continued in MICU with
normal saline

1 unit PRBC

Low-dose dobutamine

ScvO2

Case Presentation
100
90
80
70
60
50
40
30
20
10
0

Time (Hrs)

Treatment of Severe Sepsis: Levels of

Evidence for Improved Outcome

Early, goal-directed resuscitation

Corticosteroid therapy

Glycemic Control

Lower tidal volume

Xigris (rhAPC) for higher risk

Mckay, Endo Reviews 1999

High Dose Corticosteroid Treatment

for Sepsis
FAVORS TREATMENT

FAVORS CONTROL

Luce et al.
(1988)

Relative Risk 95% (C.I.)

1.07 (0.72 1.60)

VASSCg
(1987)

0.95

(0.57 1.58)

Bone et al.
(1987)

1.35

(0.98 1.84)

Sprung et al.
(1984)

1.11

(0.74 1.67)

Thompson
(1976)

1.01

(0.77 1.31)

Lucas et al.
(1984)

1.09

(0.36 3.27)

Schumer et al.
(1976)

0.30

(0.13 0.72)

Klastersky et al.
(1971)

0.97

(0.65 1.45)

CS group
(1963)

1.72

(1.23 2.41)

Common Relative Risk

1.13

(0.99 1.29)

0 .5 1 1.5 2 2.5 3 3.5 4

LOG ODDS RATIO

Cronin L et al. Crit Care Med 1995.

Success in science is defined as

moving from failure to failure with
undiminished enthusiasm
Winston Churchill

Replacement Dose Steroids for Sepsis

In sepsis, adrenal glands become stressed

Hydrocortisone 100-400 mg/day for > 5 days

Increased vasopressor responsiveness

Three RCTs demonstrate improved survival

Hoffman (n=38), Bollaert (n=41), Annane (n=299)

No evidence for increased secondary infections or GI

bleed by meta-analysis
Thompson CCM 2003, Annane BMJ 2004

Prognostic Value of Plasma Cortisol

189 consecutive pts with septic shock

Failure of plasma cortisol to increase

by > 9 g/dl in response to 250 ug
ACTH was independently associated
with a poor prognosis

? Adrenal injury vs. resistance to ACTH

Annane JAMA 2000

Corticosteroids for Early Severe Sepsis

RCT of Hydrocortisone 50mg Q6 + fludrocortisone for 7d
A priori goal to improve outcome in ACTH non-responders
All patients had shock and respiratory failure
1.00

Non-Responders (n=229)*

All Patients (299)

1.00
0.80

0.60

TREATMENT

0.40
PLACEBO

0.20
0.00
0

14

21

Time days

28

P = 0.02

Survival

Survival

0.80

0.60

TREATMENT

0.40

PLACEBO

0.20
0.00
0

P = 0.03
7

14

21

28

Time days

Annane JAMA 2002.

Corticosteroids for Early Severe Sepsis

RCT of Hydrocortisone 50mg Q6 + fludrocortisone for 7d
A priori goal to improve outcome in ACTH non-responders
All patients had shock and respiratory failure
1.00

Non-Responders (n=229)*

All Patients (299)

1.00
0.80

0.60

TREATMENT

0.40
PLACEBO

0.20
0.00
0

14

21

Time days

28

P = 0.02

Survival

Survival

0.80

0.60

TREATMENT

0.40

PLACEBO

0.20
0.00
0

P = 0.03
7

14

21

28

Time days

Annane JAMA 2002.

Corticosteroids for Early Severe Sepsis

RCT of Hydrocortisone 50mg Q6 + fludrocortisone for 7d
A priori goal to improve outcome in ACTH non-responders
All patients had shock and respiratory failure
1.00

Non-Responders (n=229)*

All Patients (299)

1.00
0.80

0.60

TREATMENT

0.40
PLACEBO

0.20
0.00
0

14

21

Time days

28

P = 0.02

Survival

Survival

0.80

0.60

TREATMENT

0.40

PLACEBO

0.20
0.00
0

P = 0.03
7

14

21

28

Time days

Annane JAMA 2002.

Steroids for Sepsis:

Summary and Recommendations

High-dose, short course steroids are not effective

Surviving Sepsis Recommendations:

Hydrocortisone for all patients with septic shock*
Minority view: ACTH testing (250ug) + HC (50 Q6h x 7d) for
patients with severe sepsis. Taper HC if cortisol increment >9
ug/dl.

* Guidelines for management of severe sepsis CCM 2004

Treatment of Severe Sepsis: Levels of

Evidence for Improved Outcome

Early, goal-directed resuscitation

Corticosteroid therapy

Glycemic Control

Lower tidal volume

Xigris (rhAPC) for higher risk

Toxic Effects of Hyperglycemia

Impairs neutrophil chemotaxis, adhesion, oxidant

burst, and phagocytosis

Advanced glycation endproducts (AGE) and/or FFA

may lead to oxidant stress in vascular endothelial
and smooth muscle cells producing a proinflammatory, pro-thrombotic, vasoconstrictor
response

Hyperglycemia may induce myocardiocyte apoptosis

Schmidt Circ Res 1999, Cai Diabetes 2002

Role of Intensive Insulin Therapy in

Critical Illness

1548 Mechanically Ventilated CSICU Patients

randomized to intensive vs. conventional insulin Rx
Conventional

Intensive

Target Glucose

180-200

Insulin (median)

33 u/d

71 u/d

Duration (% ICU Days)

67%

100%

AM Glucose

80-110

173 mg/dl

103 mg/dl

Van den Berghe NEJM 2001

Intensive Insulin Therapy

Conventional Intensive*
Patients in ICU >5d

(n=243)

(n=208)

ICU Mortality 20% 11%

Hosp Mortality 26% 17%
Dialysis 8.2%

4.8%

Polyneuropathy

52% 29%

Blood Stream Infections 17.1%

11.2%

Hypoglycemia (<40mg/dl)

39 pts

6 pts

*p<0.05 for all comparisons

Van den Berghe NEJM 2001

Improvement due to Glycemic Control

or Insulin Dose?
Multivariate Analysis of 1,548 patients (post hoc)
Improvement a/w Glucose Control
- Mortality
- Polyneuropathy
- Bacteremia

(p=.0001)
(p=.0001)
(p=.02)

Improvement a/w Insulin Dose

- Prevention of acute renal failure (p=.03)
Van den Berghe CCM 2003

Mortality/Glucose Dose Response:

> 150

110-50

< 110

Van den Berghe CCM 2003

Prospective Evaluation of an Insulin

Protocol in a Medical ICU AJRCCM 2003A

Average glucose values day =11.6

Six episodes of blood glucose < 60mg/dl in

three patients during 258 patient/days (~3000
glucose determinations); none < 40mg/dl

The protocol was well accepted by the MICU

nursing staff (qualitative assessment)

Computerized Bedside Decision Support

for Glycemic Control

Treatment of Severe Sepsis: Levels of

Evidence for Improved Outcome

Early, goal-directed resuscitation

Corticosteroid therapy

Glycemic Control

Lower tidal volume

Xigris (rhAPC) for higher risk

ARDS Net: Improved Survival

with Low Tidal Volume
1.0

Proportion of Patients

0.9
0.8
0.7
0.6
0.5

Lower tidal volumes

Survival
Discharge
Traditional tidal values
Survival
Discharge

0.4
0.3
0.2
0.1
0.0
0

20

40

60

80

100

120

140

160

180

Days after Randomization

ARDS Net N Engl J Med 2000.

Mortality in Low vs Traditional Tidal

Volume by Cause of ARDS
60

12 ml/kg
6 ml/kg

50
40

Mortalit 30
y
(%)

20
10
0

Sepsis

Pneumonia

Overall

(N=236)

(N=330)

(N=902)

Eisner et al. AJRCCM 2001

ARDS Network: Lower Tidal Volume

Additional Findings:
Reduced non-pulmonary organ failures
Lowered circulating IL-6, IL-8, IL-10 levels
Lower airway pressures a/w less systemic
inflammatory response syndrome (SIRS)

ARDS Net. NEJM 2000, Parsons CCM (in press)

ARDS Network: Lower Tidal Volume

Conclusion:
Barotrauma is a major factor contributing to
multisystem organ failure and death in patients with
sepsis and ARDS.
Barotrauma may mimic the syndrome of severe sepsis
Higher tidal volumes may predispose to development of
ARDS
Starting with low tidal volumes may decrease severity if
ARDS develops

ARDS Net. NEJM 2000, Parsons CCM 2004, Shock 2004

Treatment of Severe Sepsis: Levels of

Evidence for Improved Outcome

Early, goal-directed resuscitation

Corticosteroid therapy

Glycemic Control

Lower tidal volume

Xigris (rhAPC) for higher risk

Antiinflammatory Effects of Activated

Protein C

Activated Protein C (APC)

Anticoagulant
Inhibits factor Va and VIIIa as well as PAI-1

Anti-inflammatory
Blocks TNF induced activation of NF-kB
Blocks expression of adhesion molecules

Anti-apoptotic
Esmon, Crit Care Med 2000
Taylor, J Clin Invest 1987

Murakami, Am J Physiol 1997

Joyce, JBC 2001

Activated Protein C Function

rhAPC for 4 days in Patients with

Severe Sepsis (PROWESS)
100

Survivors (%)

90
Drotrecogin alfa
(activated)
(N=850)

80
Placebo
(N=840)

70

P=0.006

60
0

14

21

28

Days from Start of Infusion to Death

Bernard et al. NEJM 2001

IL-6 Change (pg/mL) (Median)

IL-6 Change
from Baseline
100
Placebo
0

Drotrecogin alfa
(activated)

-100
-200
-300
-400

Pre- 1
infusion

Time (days)

D-Dimer Change (g/mL) (Median)

PROWESS: Alteration of Inflammatory

and Thrombotic Markers
D-Dimer Change
from Baseline
1
Placebo
Drotrecogin alfa
(activated)
0

-1

Pre1
infusion

Time (days)

Bernard GR, et al. N EJM 2001

Bleeding Events Reported as Serious

Adverse Events (EVAD)
3.5

Patients (%)

3.0
2.5

Placebo
N=840

2.4%
(n=20)

2.0%
(n=17)

2.0
1.5
1.0

Drotrecogin Alfa
(Activated)
N=850

3.5%
(n=30)

1.0%
(n=8)

0.5
0.0

Study Drug
Infusion Period
p=0.024

28-Day
Study Period
p=0.060

Bernard GR, et al. N EJM 2001

Drotrecogin alfa (activated) (Xigris)

FDA approved November 21, 2001

Xigris is indicated for the reduction of mortality in
adult patients with severe sepsis (sepsis
associated with acute organ dysfunction) who
have a high risk of death (e.g., as determined by
APACHE II.)
Efficacy has not been established in adult
patients with severe sepsis and lower risk of
death.
From : Product labeling

Severe Sepsis: Summary

Early antibiotics are essential

Restoration of blood flow to organs is essential

Level I evidence supports

Control of blood glucose
Lower tidal volume ventilation
Xigris (rhAPC) for patients with severe sepsis

Level II evidence supports

Early goal directed resuscitation
hydrocortisone for ACTH non-responders

Thank you