High Impact Concepts in the Management of Severe Sepsis · 2010-11-04 · The Impact of Sepsis...

High Impact Concepts in the Management of

Severe Sepsis

Rolando Berger M.D., FACP, FCCP

Professor of Medicine

Director of MICU

University of Kentucky Medical Center

Five Learning Objectives

The nature and the scope of the problem

Antimicrobials and Source Control: timing is all!

Hemodynamic management: what, when, and how…Does it matter?

The role of corticosteroids in severe sepsis.

New therapies to prevent “late death”:

the coagulation and inflammation cascades

preventing ATP-depletion and cell death.

SEPSIS: THE NATURE AND THE SCOPE OF THE

PROBLEM

Sepsis: A Complex Disease This Venn diagram

provides a conceptual

framework to view

the relationships

between various clinical

“septic” syndromes.

The inflammatory

changes of sepsis and

SIRS are tightly linked to

a disturbed coagulation

and fibrinolysis process.

Adapted from: Bone RC et al. Chest. 1992;101:1644-1655.Opal SM et al. Crit Care Med. 2000;28:S81-S82

shock

severe

severe

Sepsis: A Clinical Continuum

“focal” HR, WBC oxygenation BP oxygenation

symptoms fever, BP coagulopathy urine output

BUN/cr, LFTs CNS

INFECTION SEPSIS SEVERE SEPSIS MODS DEATH

supportive care fluids supplemental O2 vasopressors mechanical ventilation

dialysis

HIGH RISK

antimicrobials drotrecogin alfa

source control cytoprotective interventions

Severe Sepsis Concept

So, in plain English, severe sepsis simply

means that clinically significant

dysfunction of one or more organs and/or

systems has resulted as a consequence of

the SIRS process, and not as a direct

result of the infection per se.

The Impact of Sepsis• Major cause of morbidity and mortality worldwide

• Leading cause of death in noncoronary ICU (USA) *

• 11th leading cause of death overall (USA) † §

• More than 750,000 annual cases in the USA ‡

• In the USA, more than 500 patients die of severe

sepsis each day (1 every 3 minutes) ‡

* Sands KE et al. JAMA. 1997;278:234-240

† Based on data for septicemia.

§ Murphy SL. National Vital Statistics Reports.

‡ Angus DC et al. Crit Care Med 2001;29:1303-1310

Severe Sepsis: Comparison With

Other Major Diseases

† National Center for Health Statistics, 2001. § American Cancer Society, 2001. * American Heart

Association. 2000. ‡ Angus DC et al. Crit Care Med 2001;29:1303-1310

0

50

100

150

200

250

300

AIDS † Colon

CancerBreast

Cancer §CHF * Severe

Sepsis ‡

Cases/1

00,0

00

Incidence of Severe Sepsis Mortality of Severe Sepsis

0

50,000

100,000

150,000

200,000

250,000

Death

s/Y

ear

AIDS † Severe

Sepsis ‡AMI *Breast

Cancer §

* Angus DC. Crit Care Med 2001;29:1303-1310

Severe Sepsis: A Growing Challenge

Today

> 750,000

cases of severe

sepsis/year

in the US*

Future

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1,400,000

1,600,000

1,800,000

2001 2025 2050

Year

100,000

200,000

300,000

400,000

500,000

600,000

Severe Sepsis Cases

US Population

Sep

sis

Cases

To

tal U

S P

op

ula

tio

n/1

,000

E ND RE S ULT :

shock , M OF, death

COAG ULOPAT HY:

ce ll apoptosis and ongoing inflam m ation

INFLAM M AT ION AND E NDOT HE LIAL INJURY:

these events in turn activa te

coagula tion and inhibit fibrinolysis

CE LLULAR RE S PONS E :

re lease of throm boxanes, leukotriens, PAF,

ox idases (NO, sPLA2), k inins, and the

cytok ines(T NF, IL1 , IL6 , IL8)

INFE CT ION:

endo/exo-tox ins, peptidoglycans

Treat infection;

block toxins;

source control!!

Block mediators and/or

receptor sites

Restore coagulation and

fibrinolytic homeostasis

Cytoprotective interventions

(phenanthridinone, Mg-adenosine

triphosphate, and others).

E ND RE S ULT :

shock , M OF, death

COAG ULOPAT HY:









INFE CT ION:


Treat infection;

block toxins;

source control!!


receptor sites






Treating the Underlying Cause of Severe Sepsis

Means Adequate Antimicrobials

and SourCE Control…..

but Timing is All !!

Choice and Timing of Antimicrobials

Prompt and correct antimicrobial therapy is

essential to improve outcome.

As far as timing is concerned, any delay translates

into worse outcome for any severe infection. For

severe sepsis the recommended maximal interval

between diagnosis and initiation of antimicrobial

therapy is < 60 minutes!!Surviving Sepsis Campaign Management Guidelines Crit Care

Med 2004; 32:858-873 --- Revised International Guidelines Crit

Care Med 2008;36:296-327

tImInG IS All….or At lEASt Half Of It !!

A large (2,154 ICU patients), multicenter (10 hospitals, 14 ICUs), and multinational (US and Canada), cohort study of ICU patients with severe sepsis.

By multivariable analysis, for every hour delay (from the onset of hypotension) in administering antimicrobials there was a 7.6% decrease in survival rate, for an adjusted odds ratio for death of 1.12 per hour of delay (up to 6 hours) (95% CI of 1.10 to 1.13, p < 0.001).

Kumar A et al: Crit Care Med 2006;34:1589-1596

Time Kills !!!

0

10

20

30

40

50

60

70

80

1 2 3 4 5 6

Hours From Onset of Hypotension

Su

rviv

al

Ra

te (

%)

Graphic depiction of the slope of expected decrease in survivalfor every hour of delay in startingantimicrobials after the onset ofhypotension (7.6% per hour) in atheoretical scenario that assumes an initial survival rate of 76%.

AnD morE DAtA…

A single-center cohort study of 261 patients with

severe sepsis or septic shock.

All treated with EGD by medical team in the ER.

Timing from EGD to antimicrobial administration

was a main determinant of mortality: 25% vs.

38.5% when treated in < 1 hour vs. in > 1 hour.

Odds ratio for death if treated in < 1 hour was 0.50

(95% CI of 0.27 to 0.92)

Crit Care Med 2010;38:1045-1053

But…It HAS to BE FASt andIt Has To Be Right

There Never Is A Second Chance

To Make A First Impression!

The Only Antibiotic Dose That

Saves Your Life Is The First

One….

“WronG” InItIAl Antimicrobials:

A Very Serious Problem!

The cumulative evidence for the harmful effect of inadequate initial antimicrobial therapy for allserious infections (not only septic shock) is overwhelming and beyond discussion.

“Correcting” antimicrobial therapy after 48-72 hrs is not adequate. “Wrong” initial therapy translates into a major increase in the risk of death: the best mortality odds-ratio reported so far is 1.6; that is a 60% increase in the mortality risk….. and this is the best result!

Inappropriate AntibioticsAnd Mortality

Study of 5,715 patients with sepsis by

SCCM/ACCP criteria (in 83% bacterial sepsis

confirmed – in 17% the diagnosis was suspected).

Initial inappropriate antimicrobials (48 to 72

hours) yielded on average a 5-fold reduction in

survival rates: range 2.3 to 17 depending on site

and type of infection. The p value was 0.0001, and

the 95% CIs were narrow and far away from 1.From the University of Manitoba – Presented at the SCCM

annual meeting- Feb 2008 – Honolulu, Hawaii

The New Clinical Paradigm

Escalation is Dead!

Long Live

De-Escalation!

rEmEmBEr…..

The Only Antibiotic Dose That

Saves Your Life Is The First

One….

HEMODYNAMIC MANAGEMENT IN SEPSIS

What Have We Learned ?Time to correction of shock is crucial! Strictly timed

goal-directed therapy has the best outcome.

Volume resuscitation must be done first. Add transfusion of RBCs if SvO2 remains low and/or if there is persistent lactic acidosis.

Myocardial depression is common in sepsis, and significant RV failure may occur. Inotropes are often needed to maintain adequate CO.

In septic shock alpha-pressors increase splanchnicperfusion if used correctly, with the possible exception of dopamine (CCM 2003;31:1659-1667 – CCM

1997;25:399-404).

“Stress-dose” corticosteroids may help

Shock, Survival, and Cumulative O2 Deficit

0

20

40

60

80

100

120

0 20 30 40 60 80 100 120 140 160 180 200

Oxygen Debt in mL/kg/min

Per

cen

t S

urv

ival

Adapted from:

JW Crowell & EE Smith

Am J Physiol 1964; 206:313n = 100 dogs

Shock, Survival, and Serum Lactic Acid

0

20

40

60

80

100

120

1 2 3 4 6 11 16 17>

Per

cen

t S

urv

iva

l

Plasma Lactate Level in mMol/L

n = 142 patients

Modified from:

MH Weil & AA Afifi

Circulation 1970; 41:989

The Goal of Treating Shock

It is to achieve and maintain proper

oxygenation and function of vital

organs.

It is not to achieve any “magical”

value of systemic blood pressure,

pulmonary wedge pressure, SVR,

and/or cardiac index !

HoW to tEll IF tHE “GoAl” is Being Achieved

End-organ function: urine, CNS, heart, liver

Acid-Base Balance:

Gastric tonometry (research tool – value?)

pH, lactic acid levels, AG, serum HCO3-

Perfusion markers: color, warmth, capillary

filling of skin, fingers, and toes.

Blood Pressure: traditionally MAP > 60 mm Hg

SvO2: ≥ 60% (in PA) or ≥ 70% (in SVC).

6070

80

50

40

SvO2

Good!Bad!

O2 demands O2 delivery

Goal-Directed Therapy

Martin, Saux and colleagues in 1990

(Marseilles Medical School, France) Acta Anesthesiol Scand 1990; 34:413-417

Rivers, Nguyen and colleagues in 2001

(The Early Goal-Directed Therapy

Collaborative Group – Detroit, MI) N Engl J Med 2001; 345:13681377

A Recipe For Septic Shock Reduce oxygen needs: cool down, mechanical

ventilation, sedation, analgesia, paralysis, etc.

Volume resuscitation to CVP > 10 or PWP > 12 mm

Hg. Usually 4 – 6 liters of cristalloids in first 1-2 hours.

Use RBCs if Hgb < 10 g/dL.

If SvO2 still low (< 70%), add dobutamine at

increments of 5 mcg/kg/min q 15-20 mins.

May give RBCs if SvO2 remains < 60%-70% on

“maximal” dobutamine, regardless of Hgb.

If MAP < 60 mm Hg, start levarterenol (Levophed™)

at increments of 5 mcg/min q 15-20 mins.

Consider vasopressin at fixed dose of 0.004 units/min.

Consider hydrocortisone 100 mg IV q 8 hours x 7 days.

Is There A Role For Steroids In Severe Sepsis

and Septic Shock?

How Did This Get Started?

High-dose steroids for

septic shock became

popular in the late

1970’s and early 1980’s

after William

Schumer’s paper was

published

Schumer W: "Steroids in the

Treatment of Septic Shock".

Ann Surgery 1976;

1845:333-341

Aren’t steroids

great?

AnD tHEn tHE BuBBlE BurSt….Five large prospective, controlled studies (and 2 meta-analysis) “killed” this practice:

Sprung et al: NEJM 1984; 311:1137-11432.

Bone et al: NEJM 1987; 317:653-6583.

VA Cooperative Study: NEJM 1987; 317:659-6654.

Luce et al: ARRD 1988; 138:62-685.

Slotman et al: CCM 1993; 21:191-1951.

Lefering & Neugebauer: "Steroid Controversy in Sepsis and Septic Shock: A Meta-Analysis". CCM 1995; 23:1294-13032.

Cronin et al: "Corticosteroid Therapy for Sepsis: A Critical Appraisal and Meta-Analysis of the Literature". CCM 1995; 23:1430-1439

But……. In the mid 1990’s clear

evidence of adrenal insufficiency occurring in patients with severe sepsis was published

Anita Soni et al: "Adrenal Insufficiency Occurring During Septic Shock: Incidence, Outcome, and Relationship to Peripheral Cytokine Levels". Am J Med 1995; 98:266-271

A nEW BEGInnInG….? Thus, in the late 1990’s two

studies reported benefit from stress-dose steroids in severe refractory septic shock

• Briegel J et al: "Effect of Hydrocortisone on Reversal of Hyperdynamic Septic Shock: A Randomized, Double-Blind, Placebo-Controlled Single-Center Study". Shock 1997; 7:165 (Abstract). Then Crit Care Med 1999; 27:723-732

• Bollaert P-E et al: "Reversal of Late Septic Shock with Supraphysiologic Doses of Hydrocortisone". Crit Care Med 1998; 26:645-650

Two More Recent StuDIES…

A study by Annane and colleagues (Paris

University) confirmed this finding (JAMA 2002;

288:862-871), using fludrocortisone (50 mcg/d)

and hydrocortisone (50 mg IV q 6 h).

However, the multi-center trial “Corticus”

yielded conflicting results and showed no

clear benefit, although it did not show any

harm either (N Engl J Med 2008;358(2):111-124).

So tHE DEBAtE ContInuES…There is no agreement on how to define or test for

clinically significant adrenal insufficiency in severe sepsis.

The current recommendation is to NOT do any kind of testing but to treat everyone who does not rapidly improve and stabilize with conventional therapy (within 6 hours or less).

Treatment should be 200 to 300 mg of hydrocortisone a day.

Treatment should be for ≥ 7 days based on a meta-analysis that showed that the survival benefit was only seen in patients treated for at least one week (Annane et al; British Medical Journal, August 2004 ).

THE NEW THERAPIES: PREVENTING MORBIDITY

AnD “lAtE” DEAtH

E ND RE S ULT :

shock , M OF, death

COAG ULOPAT HY:









INFE CT ION:


Treat infection;

block toxins;

source control!!


receptor sites






Severe Sepsis: A Truly Vicious Cycle

ACUTE ORGAN DYSFUNCTION(Severe Sepsis)

DEATH

SEPSIS

ATIII= antithrombin 3

TFPI= tissue factor pathway inhibitor

Activated Protein C

Activated Protein C

Protein C

Sepsis: A Network of Cascading Events

Courtesy of Eli Lilly and Co.

TFPI

AT-III

ATIII=

antithrombin 3

TFPI= Tissue

factor pathway

inhibitor

Homeostasis Of Coagulation Is Unbalanced in Severe

Sepsis

Carvalho AC, Freeman NJ. J Crit Illness. 1994;9:51-75; Kidokoro A et al. Shock. 1996;5:223-228; Vervloet MG et al. Semin Thromb Hemost. 1998;24:33-44.

Homeostasis

Fibrinolysis Coagulation Inflammation

Modulating Coagulation, Fibrinolysis, and Inflammation

Activated Protein C Activated Protein C

Carvalho AC et al. J Crit Illness. 1994;9:51-75; Kidokoro A et al. Shock. 1996;5:223-228; Vervloet MG et al. Semin Thromb Hemost. 1998;24:33-44

APC, ATIII, TFPI APC, ATIII, TFPI

tHrEE mAIn rCt’S (Advances in Sepsis 2001;1(4):114-124)

PROWESS TRIAL:

recombinant human activated

protein C or drotrecogin alpha

(Xigris®) (NEJM 2001;344:699).

KYBERSEPT TRIAL: human

antithrombin, formerly

antithrombin III (JAMA 2001;

286:1869).

OPTIMIST TRIAL:

Tifacogin® or Tissue Factor

Pathway Inhibitor (JAMA 2003;

290:238-247).

proWESS’ rESultS

0

5

10

15

20

25

30

35

Placebo Drotrecogin

alfa

2-sided p value: 0.005

Absolute risk reduction: 6.1%

Adjusted relative risk reduction: 19.4%

Increase in survival odds: 38.1%

30.8%

24.7%

Apache II Score and Mortality

Patient

Group

Mortality

APC

group

Mortality

Placebo

Group

Absolute

Difference

Relative

Risk Ratio

(RRR)

95% CI

for

RRR

All 24.7% 30.8% - 6.1% 0.810.70

to 0.93

Apache II

0 to 2419% 19% 0% 0.99

0.75

to 1.30

Apache II

> 2531% 44% - 13% 0.71

0.59

to 0.85

E ND RE S ULT :

shock , M OF, death

COAG ULOPAT HY:









INFE CT ION:


Treat infection;

block toxins;

source control!!


receptor sites






Cytoprotection: Phenanthridinone

Shock/reperfusion states cause cellular DNA injury, which in turn induces the release of poly(adenosine 5’-diphosphate-ribose) synthetase (known as PARS or PARP) to repair the damage.

This repair-enzyme can rapidly deplete NAD and ATP stores through its energy-costly cycle of transferring ADP-ribose units to nuclear proteins.

NAD and ATP depletion results in decreased glycolysis and mithocondrial respiration, eventually culminating in cell death.

Phenanthridinone inhibits PARS in animals.

Crit Care Med 2002; 30:1071-1082

Cytoprotection: Adenosine Tri-Phosphate – MgCl2

Septic states lead to decrease intracellular

production of ATP, which coupled with the

increased use also associated to severe

sepsis, can result in cell death. In animal

studies adenosine triphosphate-magnesium

dichloride (ATP-MgCl2) restored cell

function in severely endotoxemic pigs.

Crit Care Med 2002; 30:1826-1833

TIME IS UP!

ANY QUESTIONS?

The Prowess TrialRandomized, double-blind, placebo-controlled,

multi-center (164 hospitals), and multi-national (11 countries) study.

1,728 patients recruited – the study was prematurely terminated because of achieved benefit at pre-determined level of significance for second interim review (June 2000): p < 0.0118

There were 857 patients in the placebo arm, and 840 completed the study. There were 871 patients in the drotrecogin-alfa arm, and 850 completed the study: thus, 1690 of 1,728 patients (97.8%) completed the study as per protocol.

The KYBERSEPT TrialFrom March 1977 to January 2000 a

multicenter prospective, randomized, controlled, and blinded clinical trial of anti-thrombin III in severe sepsis was conducted in 211 hospitals in 19 countries, eventually including a total of 2,314 adult patients. No overall benefit in 28-day mortality found.

Increased risk of hemorrhage in patients receiving concomitant heparin: 23.8% vs. 13.5%, p < 0.001.

“Trend” toward possible survival benefit in those not on heparin was noted post-hoc, but p = 0.08 for mortality at 28 days and survival difference did not reach significance until day 90 (p = 0.03).

JAMA 2001; 286:1869

The TFPI OPTIMIST TrialRecombinant Tissue Factor Pathway Inhibitor

(TFPI) or Tifacogin® was developed in partnership

by Pharmacia Corp. and Chiron and appeared

promising in an initial clinical trial (CCM 2001;29:2081).

A much larger phase III trial (“OPTIMIST trial”) was

carried out in slightly over 2,000 patients, enrolled in

about 16 different countries. The reported data from

this study indicated that no mortality advantage at 28

days was found in the group as a whole (JAMA 2003;

290:238-247).

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High Impact Concepts in the Management of Severe Sepsis · 2010-11-04 · The Impact of Sepsis...

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