high impact concepts in the management of severe sepsis · 2010-11-04 · the impact of sepsis...
TRANSCRIPT
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:
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).
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:
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).
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:
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).
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).