Surviving Sepsis

Eloise Harman

The SEPSIS CASCADE

Balk , adapted from R Bone

The Sepsis Continuum

SIRS Sepsis

Severe Sepsis

Septic Shock

A clinical response arising from a nonspecific insult, with 2 of the following: o o T >38 C or <36 C HR >90 beats/min RR >20/min 3 WBC >12,000/mm or <4,000/mm3 or >10% bands

SIRS with a presumed or confirmed infectious process

Sepsis with organ failure

Refractory hypotension

SIRS = systemic inflammatory response syndrome

Chest 1992;101:1644.

Sepsis: A Major Cause of ICU Death

More than 750,000 cases of severe sepsis in the US each year Mortality about 20% (recent decline) Economic cost of $17 billion each year Incidence is projected to increase by 1.5% yearly Although prognosis has improved, because of increased incidence, actual deaths will increase

Surviving Sepsis Campaign

Launched in Fall 2002 as a collaborative effort of European Society of Intensive Care Medicine, the International Sepsis Forum, and the Society of Critical Care Medicine Goal: reduce sepsis mortality by 25% in the next 5 years Guidelines revealed at SCCM in Feb 2004

Critical Care Medicine March 2004 32(3):858-87. Website: survivingsepsis .org

Key Components
Fluid resuscitation Appropriate cultures prior to antibiotic administration Early targeted antibiotics and source control Use of vasopressors/inotropes when fluid resuscitation optimized

Key Components
Evaluation for adrenal insufficiency Stress dose corticosteroid administration Recombinant human activated protein C (xigris) for severe sepsis Low tidal volume mechanical ventilation for ARDS Tight glucose control

Key Components: Prevent Complications of Critical Illness

Prophylaxis for DVT Stress ulcer prophylaxis Prevention of nosocomial pneumonia by elevation of head to 45 degrees Facilitate extubation by daily interruption of sedation and early SBT Narrowing of antibiotic spectrum when appropriate

Key Components: Infection Control

Appropriate cultures prior to antibiotic administration Early targeted antibiotics and source control

Early Appropriate Antibiotics and Source Control

Gram positive organisms have surpassed gram negatives as the most common source of sepsis Therapy targeted to the suspected site (eg, CAP, intra-abdominal source) Drainage, debridement and device removal as indicated

Therapy Across the Sepsis Continuum Severe Septic SIRS Sepsis Sepsis Shock
Drainage Debridement
28%
62%

Device removal
Definitive control resection amputation

Antibiotics and Source Control

Chest 2000;118(1):146 Chest 1992;101:1644.

Therapy Across the Sepsis Continuum

SIRS Sepsis

Severe Sepsis

Septic Shock

Early Goal Directed Therapy

Antibiotics and Source Control

Early Goal-Directed Therapy (EGDT): involves adjustments of cardiac preload, afterload, and contractility to balance O2 delivery with O2 demand
Chest 1992;101:1644.

Goal Directed Therapy

Administration of fluids, pressors and transfusion based upon targets for CVP, blood pressure, urine output, mixed venous oxygen saturation and hematocrit

Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock Study purpose: to evaluate the efficacy of early goal-directed therapy in patients presenting to an emergency department with severe sepsis or septic shock (prior to ICU admission) Study design: prospective, randomized controlled, partially blinded, single center trial

Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. NEJM 2001;345:1368.

Early goal directed therapy N=130

Patient randomized N=263

Antibiotics given at discretion of treating clinicians

Standard therapy N=133

CVP > 8-12 mm Hg MAP > 65 mm Hg Urine Output > 0.5 ml/kg/hr ScvO2 > 70% SaO2 > 93% Hct > 30%

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

At least 6 hours of EGDT Mean 8hrs

Transfer to ICU
ICU MDs blinded to study treatment

As soon as possible Mean 6.2hrs

NEJM 2001;345:1368-77.

Early GoalDirected Therapy

CVP: central venous pressure MAP: mean arterial pressure ScvO2: central venous oxygen saturation

NEJM 2001;345:1368-77.

Early Goal-Directed Therapy Results: 28 Day Mortality

60 50 40
Sudden CV Collapse

49.2%

P = 0.01*
33.3%

Mortality

30
20 10 0

21% vs 10%
p=0.02
MODS

22% vs 16%
P=0.27

Standard Therapy N=133

EGDT N=130
NEJM 2001;345:1368-77.

*Key difference was in sudden CV collapse, not MODS

Fluid Resuscitation
Crystalloids and colloids are equally effective in restoring intravascular volume

SAFE Study
In a randomized, controlled trial conducted in 16 ICUs in Australia and New Zealand 6997 patients were randomized to receive either saline or 4% albumin for fluid resuscitation The albumin group received less fluid volume, but required more transfusion in the first 48h
NEJM 2004; 350:2247

Kaplan-Meier Estimates of the Probability of Survival

The SAFE Study Investigators, N Engl J Med 2004;350:2247-2256

Primary Endpoint was 28 day mortality

SAFE STUDY
There were also no differences in duration of mechanical ventilation or ICU stay, development of single or multiple organ failure or duration of hospitalization.

Relative Risk of Death from Any Cause among All the Patients and among the Patients in the Six Predefined Subgroups

The SAFE Study Investigators, N Engl J Med 2004;350:2247-2256

What Pressors for Septic Shock ?

Several non-randomized studies and one small prospective randomized study of dopamine vs norepinephrine for septic shock suggest that survival may be improved with the use of norepinephrine

Norepinephrine vs Dopamine+/_ Epinephrine in Septic Shock

Results of a prospective observational study

Claude, Critical Care Med 2000;28:2758

If cardiac output is inadequate with norepinephrine, as indicated by a reduced mixed venous oxygen saturation, dobutamine may be added Vasopressin is emerging as a valuable addition to therapy for septic shock in patients with catecholamine refractory hypotension

Why Vasopressin ?
There is vasopressin deficiency in vasodiltory shock

VASOPRESSIN DEFICIENCY OCCURS IN SHOCK

A. Normal

B. After one hour of hemorrhagic shock

Why Vasopressin ?
Patients with septic shock have increased sensitivity to its pressor effects Vasopressin restores vascular tone in catecholamine resistant shock by several mechanisms including potentiation of adrenergic agents Low dose vasopressin increases urine output in septic patients, and increases creatinine clearance

Therapy Across the Sepsis Continuum

SIRS Sepsis

Severe Sepsis

Septic Shock

Early Goal Directed Therapy

Antibiotics and Source Control

Chest 1992;101:1644.

* Insulin and tight glucose control

Glucose Control: Mechanisms

Stress hyperglycemia is common in sepsis Glucose has pro-inflammatory effects Insulin resistance is common in sepsis Insulin has an anti-inflammatory effect, possibly via NOS. Benefit is likely related to both insulin itself and lowering of blood glucose

Tight Glucose Control

In a Belgian study, 1548 SICU patients on mechanical ventilation were prospectively randomized to tight glucose control (80110) vs standard control (180-200) Tight glucose control had a dramatic effect on morbidity in mortality, especially for patients in the ICU for>5 days

Van den Burghe, NEJM 2001; 345: 1359

Intensive Insulin Therapy in Critically Ill Patients

Randomization Conventional
Blood glucose level when insulin infusion was started Infusion adjusted to maintain blood glucose

Intensive
>110 mg/dL
80 to 110 mg/dL (4.4 to 6.1 mmol/L)
99% Received Insulin

>215 mg/dL
180 to 200 mg/dL (10.0 and 11.1 mmol/L)
39 % Received insulin

van den Berghe G, et al. NEJM 2001;345:1359-1367.

Tight Glucose Control Improved Survival

Intensive Insulin Therapy in Critically Ill Patients: Mortality

ICU Mortality was reduced by 42%
15%

In-Hospital Mortality was reduced by 34%

15%

p < 0.04 (adjusted)

p = 0.01
10.9%

Mortality (%)

10%

8.0% 4.6%

10% 7.2% 5%

5%

0%

N=783

N=765

0%

N=783

N=765

Conventional

Intensive NEJM 2001;345:1359-1367.

Tight Glucose Control

Other dramatic effects: 46% decrease in bacteremias, 41% in acute renal failure requiring dialysis, 50% reduction in blood transfusion and a 44% decrease in critical illness polyneuropathy Patients with bacteremia had a mortality of 12.5% vs 29.5% and a decreased risk of MSOF

Effect of Intensive Insulin Therapy on Morbidity In MICU Patients

Van den Berghe, G. et al. N Engl J Med 2006;354:449-461

Tight Glucose Control in the MICU: Effect on Mortality

Van den Berghe, G. et al. N Engl J Med 2006;354:449-461

Therapy Across the Sepsis Continuum

SIRS Sepsis

Severe Sepsis

Septic Shock

* Xigris (Drotrecogin)
Early Goal Directed Therapy

Antibiotics and Source Control Insulin and tight glucose control

Chest 1992;101:1644.

Activated Protein C in Sepsis

Protein C: 1. Inactivates clotting factors limiting the generation of thrombin 2. Inhibits prodn of inflammatory cytokines

PROWESS Study Design

1690 Patients : Known or suspected infection > 3 of the SIRS criteria > 1 acute (< 24hr in duration) organ failures
RANDOMIZED

Placebo 96 hr infusion + standard treatment

Drotrecogin (xigris) 24 mcg/kg/hr 96 hour infusion + standard treatment

Primary Endpoint: All-Cause Mortality at 28 days

NEJM 2001;344:699-709.

PROWESS Results
Primary Stratified Intention-to-Treat Analysis
40.0%

p=0.0054
30.0%

30.8%
20.0% 10.0% 0.0% Placebo Drotrecogin alfa (activated)

(n=850)

24.7%
(n=840)

6.1% in absolute mortality 19.4% in RR of death

NEJM 2001;344:699-709.

Adverse Events with Drotrecogin alfa

Mortality as a Function of APACHE II at Study Entry

Placebo 60%
0.49

Drotrecogin alfa (activated)

50%

28-Day Mortality Rate

40% 30% 20% 10% 0% 1st 2nd

0.12 0.15 0.26 0.22

0.36 0.24

0.38

3rd

4th

APACHE II Quartile Survival benefit was confined to patients with APACHE >25

Xigris (Drotrecogin)
Mortality increased in patients with one organ failure who underwent surgery within the previous 30 days, and is contraindicated in this group

Therapy Across the Sepsis Continuum

SIRS Sepsis

Severe Sepsis

Septic Shock

* Steroids
Drotrecogin
Early Goal Directed Therapy

Antibiotics and Source Control Insulin and tight glucose control

Chest 1992;101:1644.

Adrenal Insufficiency in Septic Shock

There is significant disagreement about how to best evaluate adrenal function in critical illness General agreement that a random cortisol of less than 25 is abnormal in this population Some screen with random cortisol and reserve ACTH stim test for those with low levels Use of total rather than free cortisol in those with hypoalbuminemia may overestimate the incidence of adrenal insufficiency

Stress Dose Corticosteroids in Sepsis

In a double-blind, placebo controlled study in France, 300 patients were randomized to receive stress dose steroids (hydrocortisone 50 mg q6h) and fludrocortisone (50 mcg daily) or placebo for 7 days Patients first underwent a cortrosyn stimulation test to determine relative adrenal insufficiency
Annane, JAMA 2002;288:862

Low Dose Steroid Treatment in Septic Shock: Study Design

Onset of shock Randomization

Time 0

Cortrosyn stimulation

Hydrocortisone IV 50mg every 6 hours x 7 days

Placebo X 7 days

+
Fludrocortisone 50mcg NG daily x 7 days Primary Outcome: 28-day survival
Annane D, et. al. JAMA 2002;288(7):862.

Relative adrenal insufficiency was defined as a failure to increase serum cortisol by greater than 9mcg/dl after a 250 mcg ACTH stimulation test. Using this criteria, 77% of patients in this study were adrenally insufficient

Low Dose Steroid Treatment in Septic Shock: 28 Day Mortality (Non-responders vs. Responders)
100%
28-day Mortality Patients with Relative Adrenal Insuffiency (ACTH Test Nonresponders) (77%) p = 0.04 Patients Without Relative Adrenal Insufficiency (ACTH 100% Test Responders) (23%) p = 0.96 80%

80% 63% 60% 40%

N=114 N=115

61% 60% 40%

N=36 N=34

53%

53%

20% 0%

20% 0%

Low-dose Steroids

Placebo

Annane D, et. al. JAMA 2002;288(7):862.

Corticosteroids in Sepsis
Obtain a baseline cortisol or ACTH stimulation Start stress dose steroids (hydrocortisone 200-300mg +/- fludrocortisone 50 mcg) Discontinue if levels are adequate

SURVIVING SEPSIS
Fluid resuscitation, goal-directed Appropriate cultures prior to antibiotic administration Early targeted antibiotics and source control Use of vasopressors/inotropes when fluid resuscitation optimized

SURVIVING SEPSIS
Evaluation for adrenal insufficiency Stress dose corticosteroid administration Recombinant human activated protein C (xigris) for severe sepsis Insulin drip for tight glucose control Low tidal volumes (6cc/kg) for mechanical ventilation in ARDS

PREVENT COMPLICATIONS
Stress ulcer and DVT prophylaxis Narrow antibiotic spectrum Prevent VAP: 45 degree elevation Facilitate early discontinuation of mechanical ventilation: sedation interruption, early SBT

Acknowledgement
Michelle Allen Pharm D Henry J. Mann, U of Minnesota