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
1,800,000 600,000
Severe Sepsis Cases
1,600,000 US Population
500,000

Total US Population/1,000
1,400,000
Sepsis Cases

1,200,000 400,000

1,000,000
300,000
800,000

600,000 200,000

400,000
100,000
200,000

2001 2025 2050

Year
Angus DC et al. Crit Care Med 2001
 Antibiotics and Severe Sepsis:
Necessary but Not Sufficient for Survival

Infection
Appropriate antibiotics
Immune/Coagulation System reduce progression to
Activation
severe sepsis by ~50%
Severe Sepsis
Appropriate antibiotics
reduce mortality by
Death 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
Appropriate antibiotics
Immune/Coagulation System seduce progression to
Activation
severe sepsis by ~50%
Severe Sepsis
Appropriate antibiotics
reduce mortality by
Death 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 7
– TNF Receptors 4
– IL1ra , IVIG, or elastase inhibitors 7
– Growth hormone 1
– Soluble Phospholipase A2 Inhibitor 1
– 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
Inadequate
Parameter Preshock Warm Shock Resuscitation
Heart Rate
Blood Pressure WNL
Systemic
Vascular WNL or
Resistance
Cardiac Output (and Sv02)
Pulmonary Artery
Occlusive WNL or WNL or
Pressure
Other 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

Cellular dysfunction
Organ tissue

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 Goal- Standard

Directed Therapy Therapy
CVP > 8-12 mm Hg CVP > 8-12 mm Hg
MAP > 65 mm Hg MAP > 65 mm Hg
Urine Output > 0.5 ml/kg/hr Urine Output > 0.5 ml/kg/hr

If ScvO2 < 70% PRBC

If Hct < 30% Dobutamine

At least 6 hours As soon as

of EGDT Transfer to ICU possible
ICU MDs blinded to
study treatment Rivers et al NEJM 2001
Edwards “Sepsis Catheter”
 EGDT Results: First Six Hours

6000 75%

5000

50%

Percent of Patients
4000

ml 3000

2000 25%

1000

0 0%
RBCs Pressors Dobutamine
Fluids in ml
(mean) 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
P=0.009 P=0.01 P=0.03
70
60

50
40

30
20

10
0
In-hospital 28-day mortality 60-day mortality
mortality (all
patients) EGDT
Standard Therapy

Rivers et al NEJM 2001

 Case Presentation

100
 72 year old woman 90
urinary sepsis 80
70
Resuscitation 60

ScvO2

50
continued in MICU with 40
normal saline 30
20
10
 1 unit PRBC
0
0 1 2 3 4 5
 Low-dose dobutamine
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
Relative Risk 95% (C.I.)
Luce et al. 1.07 (0.72 – 1.60)
(1988)
VASSCg 0.95 (0.57 – 1.58)
(1987)
Bone et al. 1.35 (0.98 – 1.84)
(1987)
Sprung et al. 1.11 (0.74 – 1.67)
(1984)
Thompson 1.01 (0.77 – 1.31)
(1976)
Lucas et al. 1.09 (0.36 – 3.27)
(1984)
Schumer et al. 0.30 (0.13 – 0.72)
(1976)
Klastersky et al. 0.97 (0.65 – 1.45)
(1971)
CS group 1.72 (1.23 – 2.41)
(1963)
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

Non-Responders (n=229)* All Patients (299)

1.00 1.00

0.80 0.80

Survival
0.60
Survival

TREATMENT 0.60 TREATMENT

0.40 0.40
PLACEBO PLACEBO
0.20 0.20

0.00 P = 0.02 0.00

P = 0.03
0 7 14 21 28 0 7 14 21 28
Time days 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

Non-Responders (n=229)* All Patients (299)

1.00 1.00

0.80 0.80

Survival
0.60
Survival

TREATMENT 0.60 TREATMENT

0.40 0.40
PLACEBO PLACEBO
0.20 0.20

0.00 P = 0.02 0.00

P = 0.03
0 7 14 21 28 0 7 14 21 28
Time days 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

Non-Responders (n=229)* All Patients (299)

1.00 1.00

0.80 0.80

Survival
0.60
Survival

TREATMENT 0.60 TREATMENT

0.40 0.40
PLACEBO PLACEBO
0.20 0.20

0.00 P = 0.02 0.00

P = 0.03
0 7 14 21 28 0 7 14 21 28
Time days 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 pro-
inflammatory, 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 80-110

Insulin (median) 33 u/d 71 u/d

Duration (% ICU Days) 67% 100%

AM Glucose 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) 6 pts 39 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 (p=.0001)
- Polyneuropathy (p=.0001)
- Bacteremia (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
0.9
Proportion of Patients

0.8
0.7
0.6
0.5
Lower tidal volumes
0.4 Survival
0.3 Discharge
0.2 Traditional tidal values
Survival
0.1
Discharge
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
50
6 ml/kg
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 Murakami, Am J Physiol 1997

Taylor, J Clin Invest 1987 Joyce, JBC 2001
Activated Protein C Function
rhAPC for 4 days in Patients with
Severe Sepsis (PROWESS)
100

90
Survivors (%)

Drotrecogin alfa
(activated)
80 (N=850)

Placebo
(N=840)
70

60 P=0.006

0 7 14 21 28
Days from Start of Infusion to Death

Bernard et al. NEJM 2001

 PROWESS: Alteration of Inflammatory
and Thrombotic Markers

IL-6 Change D-Dimer Change

from Baseline from Baseline

D-Dimer Change (g/mL) (Median)

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

100 1
Placebo
Placebo
0 Drotrecogin alfa
Drotrecogin alfa (activated)
(activated)
-100
0
-200

-300

-400 -1
Pre- 1 2 3 4 5 6 7 Pre- 1 2 3 4 5 6 7
infusion infusion
Time (days) Time (days)

Bernard GR, et al. N EJM 2001

Bleeding Events Reported as Serious
Adverse Events (EVAD)
Drotrecogin Alfa
3.5%
(n=30)
(Activated)
3.5 N=850
3.0 Placebo
2.4% N=840
2.5 (n=20)
2.0%
Patients (%)

(n=17)
2.0
1.5 1.0%
(n=8)
1.0
0.5
0.0
Study Drug 28-Day
Infusion Period Study Period
p=0.024 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