surviving sepsis talk

7/30/2019 Surviving Sepsis Talk

1/56

Surviving SepsisEloise Harman


2/56

The SEPSIS CASCADE

Balk , adapted from R Bone


3/56

The Sepsis Continuum

A clinical responsearising from anonspecific insult, with2 of the following:

T >38oC or 90 beats/min

RR >20/min

WBC >12,000/mm3or 10% bands

SIRS = systemic inflammatoryresponse syndrome

SIRS with apresumedor confirmed

infectiousprocess

Chest 1992;101:1644.

SepsisSIRSSevere

Sepsis

Septic

Shock

Sepsis withorgan failure

Refractoryhypotension


4/56

Sepsis: A Major Cause of ICUDeath

More than 750,000 cases of severe sepsisin 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, actualdeaths will increase


5/56

Surviving Sepsis Campaign

Launched in Fall 2002 as a collaborative effort ofEuropean Society of Intensive Care Medicine,the International Sepsis Forum, and the Society

of Critical Care MedicineGoal: reduce sepsis mortality by 25% in the next5 years

Guidelines revealed at SCCM in Feb 2004

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

Website: survivingsepsis.org


6/56

Key Components

Fluid resuscitation

Appropriate cultures prior to antibiotic

administration

Early targeted antibiotics and sourcecontrol

Use of vasopressors/inotropes when fluidresuscitation optimized


7/56

Key Components

Evaluation for adrenal insufficiency

Stress dose corticosteroid administration

Recombinant human activated protein C(xigris) for severe sepsis

Low tidal volume mechanical ventilationfor ARDS

Tight glucose control


8/56

Key Components: PreventComplications of Critical Illness

Prophylaxis for DVT

Stress ulcer prophylaxis

Prevention of nosocomial pneumonia byelevation of head to 45 degrees

Facilitate extubation by daily interruption

of sedation and early SBTNarrowing of antibiotic spectrum whenappropriate


9/56

Key Components: Infection Control


administration

Early targeted antibiotics and sourcecontrol


10/56

Early Appropriate Antibiotics andSource Control

Gram positive organisms have surpassedgram negatives as the most commonsource of sepsis

Therapy targeted to the suspected site(eg, CAP, intra-abdominal source)

Drainage, debridement and deviceremoval as indicated


11/56

Therapy Across the Sepsis Continuum

Chest1992;101:1644.

SepsisSIRSSevere

Sepsis

Septic

Shock

Antibiotics and Source Control

Chest2000;118(1):146

62%

28%

Drainage

Debridement

Deviceremoval

Definitivecontrol

resection

amputation


12/56


Chest1992;101:1644.

SepsisSIRSSevere

Sepsis

Septic

Shock

Early Goal Directed Therapy


Early Goal-Directed Therapy (EGDT): involves adjustments of cardiacpreload, afterload, and contractility to balance O2 delivery with O2 demand

*


13/56

Goal Directed Therapy

Administration of fluids, pressors andtransfusion based upon targets for CVP,blood pressure, urine output, mixed

venous oxygen saturation and hematocrit


14/56

Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the

treatment of severe sepsis and septic shock. NEJM2001;345:1368.

Early Goal-Directed Therapy in the Treatment ofSevere Sepsis and Septic Shock

Study purpose: to evaluate the efficacy of earlygoal-directedtherapy in patients presenting to anemergency department with severe sepsis or

septic shock (prior to ICU admission)

Study design: prospective, randomizedcontrolled, partially blinded, single center trial


15/56

Patientrandomized

N=263Early goaldirected therapyN=130

Standardtherapy N=133

CVP > 8-12 mm Hg

MAP > 65 mm HgUrine Output > 0.5 ml/kg/hr

CVP > 8-12 mm Hg

MAP > 65 mm HgUrine Output > 0.5 ml/kg/hrScvO2 > 70%SaO2 > 93%Hct> 30%

Antibiotics given atdiscretion of

treating clinicians

As soon aspossibleMean 6.2hrs

ICU MDs blinded to

study treatment NEJM2001;345:1368-77.

At least 6 hoursof EGDTMean 8hrs

Transfer to ICU


16/56

CVP: central venouspressure

MAP: mean arterialpressure

ScvO2: central venousoxygen saturation

Early Goal-

Directed Therapy

NEJM2001;345:1368-77.


17/56

49.2%

33.3%

0

10

20

30

40

50

60

Standard TherapyN=133

EGDTN=130

P = 0.01*

*Key difference was in sudden CV collapse, not MODS

Early Goal-Directed Therapy Results:28 Day Mortality

Sudden CV Collapse

MODS

21% vs 10%

p=0.02

22%vs16%

P=0.27

NEJM2001;345:1368-77.

Mortality


18/56

Fluid Resuscitation

Crystalloids and colloids are equallyeffective in restoring intravascular volume


19/56

SAFE Study

In a randomized, controlled trial conductedin 16 ICUs in Australia and New Zealand6997 patients were randomized to receive

either saline or 4% albumin for fluidresuscitation

The albumin group received less fluidvolume, but required more transfusion inthe first 48h

NEJM 2004; 350:2247


20/56

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

Kaplan-Meier Estimates of the Probability of Survival

Primary Endpoint was 28 day mortality


21/56

SAFE STUDY

There were also no differences in durationof mechanical ventilation or ICU stay,development of single or multiple organ

failure or duration of hospitalization.


22/56

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

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


23/56

What Pressors for Septic Shock ?

Several non-randomized studies and onesmall prospective randomized study ofdopamine vs norepinephrine for septic

shock suggest that survival may beimproved with the use of norepinephrine


24/56

Norepinephrine vs Dopamine+/_ Epinephrine in Septic Shock

Results of a prospective observational study

Claude, Critical Care Med 2000;28:2758


25/56

If cardiac output is inadequate withnorepinephrine, as indicated by a reducedmixed venous oxygen saturation,

dobutamine may be added

Vasopressin is emerging as a valuableaddition to therapy for septic shock in

patients with catecholamine refractoryhypotension


26/56

Why Vasopressin ?

There is vasopressin deficiency invasodiltory shock


27/56
http://content.nejm.org/content/vol345/issue8/images/large/07f4.jpeg


28/56

A. Normal B. After one hour of hemorrhagic shock

VASOPRESSIN DEFICIENCY OCCURS IN SHOCK
http://content.nejm.org/content/vol345/issue8/images/large/07f3.jpeg


29/56

Why Vasopressin ?

Patients with septic shock have increasedsensitivity to its pressor effects

Vasopressin restores vascular tone in

catecholamine resistant shock by severalmechanisms including potentiation ofadrenergic agents

Low dose vasopressin increases urineoutput in septic patients, and increasescreatinine clearance


30/56


SepsisSIRSSevereSepsis

Septic

Shock

Insulin and tight glucose control



Chest1992;101:1644.

*


31/56

Glucose Control: Mechanisms

Stress hyperglycemia is common in sepsis

Glucose has pro-inflammatory effects

Insulin resistance is common in sepsisInsulin has an anti-inflammatory effect,possibly via NOS.

Benefit is likely related to both insulin itselfand lowering of blood glucose


32/56

Tight Glucose Control

In a Belgian study, 1548 SICU patients onmechanical ventilation were prospectivelyrandomized to tight glucose control (80-

110) vs standard control (180-200)Tight glucose control had a dramatic effecton morbidity in mortality, especially for

patients in the ICU for>5 days

Van den Burghe, NEJM 2001; 345: 1359


33/56

Randomization

Conventional Intensive

>215 mg/dL

180 to 200 mg/dL

(10.0 and 11.1mmol/L)

>110 mg/dL

80 to 110 mg/dL

(4.4 to 6.1mmol/L)

Blood glucose levelwhen insulin infusion

was started

Infusion adjusted to

maintain bloodglucose

van den Berghe G, et al. NEJM2001;345:1359-1367.

Intensive Insulin Therapy in Critically Ill Patients

39 % Received insulin 99% Received Insulin


34/56

Tight Glucose Control ImprovedSurvival


35/56

10.9%

7.2%

0%

5%

10%

15%

8.0%

4.6%

0%

5%

10%

15%

ICU Mortality was reducedby 42%

In-Hospital Mortality wasreduced by 34%

Mortality(%)

p = 0.01p < 0.04 (adjusted)

N=783 N=765

Conventional Intensive

N=783 N=765

NEJM

2001;345:1359-1367.

Intensive Insulin Therapy in Critically Ill Patients:Mortality


36/56

Tight Glucose Control

Other dramatic effects: 46% decrease inbacteremias, 41% in acute renal failurerequiring dialysis, 50% reduction in

blood transfusion and a 44% decreasein critical illness polyneuropathy

Patients with bacteremia had a mortality

of 12.5% vs 29.5% and a decreasedrisk of MSOF


37/56

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

Effect of Intensive Insulin Therapy on Morbidity In MICUPatients


38/56

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

Tight Glucose Control in the MICU: Effect on Mortality


39/56


SepticShock

Xigris (Drotrecogin)




Chest1992;101:1644.


*


40/56

Activated Protein C in Sepsis

Protein C:

1. Inactivates

clotting factorslimiting

the generation

of thrombin

2. Inhibits prodnof inflammatory

cytokines


41/56

PROWESS Study Design1690 Patients : Known or suspected infection > 3 of the SIRS criteria > 1 acute (< 24hr in duration) organ failures

Primary Endpoint: All-Cause Mortality at 28 days

Placebo96 hr infusion

+ standard treatment

Drotrecogin (xigris)24 mcg/kg/hr

96 hour infusion+ standard treatment

NEJM2001;344:699-709.

RANDOMIZED


42/56

30.8%

24.7%

0.0%

10.0%

20.0%

30.0%

40.0%

Placebo Drotrecogin alfa (activated)

p=0.0054

PROWESS Results

6.1% inabsolute

mortality 19.4% inRR of death

Primary Stratified Intention-to-Treat Analysis

(n=850)(n=840)

NEJM2001;344:699-709.

Ad E t ith


43/56

Adverse Events withDrotrecogin alfa


44/56

Mortality as a Function of APACHE II at Study Entry

0.120.15

0.26

0.22

0.36

0.24

0.49

0.38

0%

10%

20%

30%

40%

50%

60%

1st 2nd 3rd 4th

Placebo Drotrecogin alfa (activated)

APACHE II Quartile28-Day

MortalityR

ate

Survival benefit was confined to patients with APACHE >25


45/56

Xigris (Drotrecogin)

Mortality increased in patients with oneorgan failure who underwent surgerywithin the previous 30 days, and is

contraindicated in this group


46/56


SepticShock

Drotrecogin



Steroids


Chest1992;101:1644.


*


47/56

Adrenal Insufficiency in Septic

Shock

There is significant disagreement about how tobest evaluate adrenal function in critical illness

General agreement that a random cortisol of

less than 25 is abnormal in this populationSome screen with random cortisol and reserve

ACTH stim test for those with low levels

Use of total rather than free cortisol in those withhypoalbuminemia may overestimate theincidence of adrenal insufficiency

Stress Dose Corticosteroids in


48/56

Stress Dose Corticosteroids inSepsis

In a double-blind, placebo controlledstudy in France, 300 patients wererandomized to receive stress dosesteroids (hydrocortisone 50 mg q6h)and fludrocortisone (50 mcg daily) orplacebo for 7 days

Patients first underwent a cortrosyn

stimulation test to determine relativeadrenal insufficiency

Annane, JAMA 2002;288:862


49/56

Low Dose Steroid Treatment in Septic Shock:Study Design

Time 0Onset of shock

Randomization

Hydrocortisone IV 50mgevery 6 hours x 7 days

+Fludrocortisone 50mcg NG

daily x 7 days

PlaceboX 7 days

Cortrosyn stimulation

Primary Outcome:28-day survival

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


50/56

Relative adrenal insufficiency was definedas a failure to increase serum cortisol bygreater than 9mcg/dl after a 250 mcg

ACTH stimulation test.Using this criteria, 77% of patients in thisstudy were adrenally insufficient


51/56

Low Dose Steroid Treatment in Septic Shock:28 Day Mortality (Non-responders vs. Responders)

61%53%

0%

20%

40%

60%

80%

100%

53%63%

0%

20%

40%

60%

80%

100%

Low-dose Steroids Placebo

Patients with Relative AdrenalInsuffiency (ACTH Test Non-

responders) (77%)

Patients Without RelativeAdrenal Insufficiency (ACTH

Test Responders) (23%)

p = 0.04 p = 0.96

N=114 N=36 N=34N=11528-dayMort

ality

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


52/56

Corticosteroids in Sepsis

Obtain a baseline cortisol or ACTHstimulation

Start stress dose steroids (hydrocortisone

200-300mg +/- fludrocortisone 50 mcg)

Discontinue if levels are adequate


53/56

SURVIVING SEPSIS

Fluid resuscitation, goal-directed


administrationEarly targeted antibiotics and sourcecontrol

Use of vasopressors/inotropes when fluidresuscitation optimized


54/56

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 mechanicalventilation in ARDS


55/56

PREVENT COMPLICATIONS

Stress ulcer and DVT prophylaxis

Narrow antibiotic spectrum

Prevent VAP: 45 degree elevationFacilitate early discontinuation ofmechanical ventilation: sedation

interruption, early SBT


56/56

Acknowledgement

Michelle Allen Pharm D

Henry J. Mann, U of Minnesota

surviving sepsis talk

Documents