Transcript 2006_10_05-Storck

Sepsis Syndromes
Aric Storck
October 5, 2006
Objectives

Review of basic pathophysiology

Overview of treatment with focus on ED care





Initial resuscitation
Infection & source control
Early goal directed therapy
Ventilatory strategies
Pharmacologic therapies
Epidemiology

Most common non-cardiac cause of death in ICU

Disproportionately affects elderly, HIV, chemotherapy,
transplant, dialysis, diabetes, alcoholics

Accounts for 215,000 deaths/yr in US = MI deaths or
9.3% of all deaths in 1995

Annual cost in US $16.7 billion

Locally ~250 ICU admissions for sepsis per year
Systemic Inflammatory Response
Syndrome

“a systemic inflammatory response to a variety of
clinical insults.”

Diagnostic Criteria = 2 or more of





T >38 or <36
HR > 90
RR > 20 or PCO2 < 32
WBC > 12 or < 4 or >10% bands
Problems

Too simplistic & extremely non-specific
SIRS & Sepsis

Infection


Sepsis


invasion of organ system(s) by microorganisms
SIRS + infection
Severe sepsis

Sepsis with organ dysfunction


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Lactic acidosis, oliguria, ALOC, etc.
Responsive to fluids
Septic shock

Severe sepsis requiring vasopressors/inotropes to
maintain normotension
Sepsis Spectrum & Mortality
Diagnostic category
SIRS criteria
none
2
3
4
Sepsis
Severe sepsis
Septic shock
Mortality (%)
3
7
10
17
16
20
46
McCoy & Matthews. Drotrecogin Alfa (Recombinant Human
Activated Protein C) for the treatment of severe sepsis. Clin
Ther 2003; 25: 396-421
Sepsis Etiology

> 90% bacterial
 Gram negative ~42%
 Gram positive ~34%
 Anaerobes ~2-5%
 Mixed ~14%

Fungi ~5%
 Primarily Candida
 More common in ICU, immunocompromise,
steroids, diabetics
Llewelyn & Cohen. Diagnosis of infection in sepsis. Int Care Med. 2001; 27: S10-32
Bochd, Glauser, & Calandra. Antibiotics in sepsis. Int Care Med. 2001; 27: S33-48
Sources of Infection

Specific sites:
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


Respiratory
Blood
Abdomen
Urinary tract
Wounds & Skin
Other
36%
20%
19%
13%
7%
5%
Can be identified in ~92% of pts
Extremely important in choosing Abx
Bochd, Glauser, & Calandra. Antibiotics in sepsis. Int
Care Med. 2001; 27: S33-48
Not all that is febrile & shocky is
infectious…

Non-infectious causes of SIRS
 Tissue damage


Metabolic


Tumor lysis syndrome, lymphoma
CNS


Thyroid storm, adrenal insufficiency
Malignancy


Surgery, trauma, DVT, MI, PE, pancreatitis, etc
SAH
Iatrogenic

Transfusion rx, anesthetics, NMS, etc
Llewelyn & Cohen. Diagnosis of infection in
sepsis. Int Care Med. 2001; 27: S10-32

International consensus guidelines

Provide guidance on


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Initial resuscitation
Source control
Drugs
Fluid therapy
Blood products
Mechanical ventilation
Treatment of Septic Shock
Antibiotics
Infection
Control
Surgical Management
Septic
Shock
Steroids
rhAPC
Immunomodulatory
Therapies
Supportive
Care
EGDT
Ventilation
Case 1
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76 F – from nursing home
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Increasing confusion x 3 days
Not eating
Complaining of lower abdominal tenderness
O/E
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
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HR 105 RR 30 BP 95/62 Sats 91% T 38.1
CVS – Normal HS
Chest – Decreased A/E to bases, no distress
Abdo - soft, +BS, Moderate periumbilical and
suprapubic tenderness
Case 1 - Investigations

ECG – sinus tach

CXR – cardiomegaly, hyperinflation, nil acute

Lab

CBC


Lytes



Hb 94; WBC 11 (bands 2); platelets 154
Na 133 K 4.9 Cl 98 HCO3 18
LFT’s – normal
Urine - +nitrites, + leuks, >30 WBC
Case 1 - continued

Diagnosis?

Does this patient have SIRS?

Sepsis?

Severe Sepsis?

Septic Shock?

Initial Management?
EGDT Protocol
Fluid Resuscitation
Which fluid are you
going to give?

DBRCT, N=6997.




4% albumin vs crystalloid
Amount titrated to clinical status and
response to fluids
Primary outcome: 28d mortality
18% patients had severe sepsis
SAFE Trial
Crystalloid vs Colloid

Cochrane Systematic Reviews, 2005.
 Albumin or plasma protein fraction.



19 Trials reported data on mortality
N= 7576
RR from these trials was 1.02 (0.93, 1.11).

No evidence of meaningful benefit to colloids
vs crystalloids

Normal Saline
 Cheap, available
 USE IT FIRST

How much are you going to give?
EGDT – Fluid Resuscitation

EGDT

Step 1 – Fill the tank

Normal Saline

500ml bolus then 500ml q30min until CVP 8-12

How can you measure CVP in the ED?

What if the patient is intubated

Target a CVP 12-15 to account for increased
intrathoracic pressure
Surviving Sepsis Guidelines - Fluids

No evidence for choosing colloid over
crystalloids (Grade C)

Administer crystalloids as 500-1000 cc over
30 mins & repeat prn based on response (E)

Administer colloids at 300-500 cc over 30
mins & repeat prn based on response (E)
Surviving Sepsis Guidelines - Fluids

“resuscitation…should not be delayed pending ICU
admission.”

Goals of resuscitation in 1st 6 hrs of recognition: (B)
 CVP: 8-12 mm Hg (12-15 if ventilated)
 MAP: > 65 mm Hg
 Urine output: > 0.5 ml/kg/hr
 SVO2 > 70%
 If unable to attain SVO2 >70% despite above then:


Transfuse to keep Hct > 30%
Dobutamine
Dellinger et al. Surviving sepsis campaign guidelines for
management of severe sepsis and septic shock. Crit Care
Med. 2004; 32: 858-73
Back to Case 1

After 2500ml of NS CVP is ~10

You reassess the patient

O/E

HR 100 RR 32 BP 80/50 Sats 91% T 38.4

What is their MAP?

What is your next move?
EGDT Protocol
Vasopressors

Goals
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
MAP >65
Improvement in indicators of end organ perfusion

Which vasopressor do you choose?

What is your starting dose?
Vasopressors

Dopamine




Precursor of epi/norepi
Release of norepi from
presynaptic terminals
Norepinephrine


Dosing

Dopaminergic <5ug/kg/min


Dosing


Beta - 5-10ug/kg/min


Vasodilation coronary,
renal, mesenteric beds

Increase contractility and
HR
Alpha - >10ug/kg/min

vasoconstriction
Alpha agonist
Increases BP by
vasoconstriction, little effect
on HR or cardiac output

Start at 0.1 ug/kg/min
Double every five minutes
to effect
Maximum ~ 2ug/kg/min
Dopamine vs Norepinephrine

Theoretical advantages to norepinephrine
 Direct acting, works in catecholamine depleted patients
 Less tachycardias & dysrhythmias

Indirect evidence of benefit over dopamine in multiple small trials
 Improved hemodynamics
 Improved gastric pH
 Improved lactate

Single non-randomized trial showing mortality benefit

No RCT showing mortality benefit
Surviving Sepsis Guidelines - Vasopressors

Should be used when

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shock refractory to fluid resuscitation
Life-threatening hypotension (E)

Dopamine or norepinephrine are 1st line agents (D)

‘Renal dose’ dopamine does not work & should not be
used (B)

Invasive BP monitoring & central IV lines should be
placed as soon as possible (E)

Vasopressin may be considered as a 2nd line agent in
refractory shock (E)
Back to our case

Our patient now on dopamine 10ug/kg/min

VS 120 RR 30 BP 95/65 Sats 92% T 38.1

You now have a few moments to think

You’re pretty sure this patient has Urosepsis?

What else would you like to do?
Antibiotics & Source Control
“Autopsy studies in persons who died in the
intensive care unit show that failure to
diagnose and appropriately treat
infections with antibiotics or surgical
drainage is the most common avoidable
error”
Hotchkiss & Karl. The pathophysiology and treatment of
sepsis. N Eng J Med. 2003; 348: 138-50
Do Antibiotics make a difference?

Animal models

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Few prospective RCT’s



increased mortality with each hour of delay to antibiotics
most outcome data based on retrospective analyses
ARR 16 – 26% when initial Abx were appropriate
Virtually all studies in ICU setting


Prospective cohort study of 406 pts w/ sepsis found
inadequate initial Abx Tx significantly increased risk of
death in non-surgical sepsis (OR 8.15; 95%CI 1.98-33.5)
Adequate Tx dec’d risk of death in surgical sepsis (OR
0.37, 95%CI 0.18-0.77)
Garnacho-Montero et al. Impact of adequate empirical
antibiotic therapy on the outcome of patients admitted
to the intensive care unit with sepsis. Crit Care Med
2003; 31: 2742-51
Bug Juice
CHR Sepsis Protocol Recommendations
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Community Acquired Pneumonia
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Intra-abdominal Infection
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Cellulitis/Bone/Joint
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Cefazolin 2 gm IV
OR Cloxacillin 1 gm IV
Pull Line
Vancomycin 1 gm IV
Neutropaenic

Dexamethasone 10 mg IV at or before antibiotics
given
Ceftriaxone 2 gm IV PLUS Vancomycin 1 gm IV
Ensure Blood Culture x THREE are done
Ceftriaxone 2gm IV
ADD Vancomycin 1 gm IV if MRSA suspected
Infected Central Line


Clindamycin 600 mg IV PLUS Penicillin 4 MU IV
PLUS IVIG PLUS Surgery
Endocarditis


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Fasciitis

Gentamicin 6mg/kg IV
OR Ceftriaxone 2gm IV
Meningitis
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Piperacillin/Tazobactam 3.375gm IV
OR Ceftriaxone 2gm IV PLUS Flagyl 500mg IV
OR Ampicillin 2gm IV PLUS Gentamicin 6mg/kg IV
PLUS Metronidazole 500mg IV
Urosepsis


Ceftriaxone 2gm IV PLUS Azithromycin 500mg IV
OR Levofloxacin 500mg IV
Piperacillin/Tazobactam 3.375gm IV PLUS
Gentamycin 6 mg/kg IV
Sepsis Source Unknown


Treat for MOST likely source
Treat as per Intra-abdominal Infection
Blood cultures

Important to establish Dx for:
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Guiding antimicrobial Tx
Guiding adjunctive Tx
Microbiological epidemiological surveillance


Yield of cultures ranges from 9-64%


Llewelyn & Cohen. Diagnosis of infection in sepsis. Int Care
Med. 2001; 27: S10-32
Bochd, Glauser, & Calandra. Antibiotics in sepsis. Int Care Med. 2001;
27: S33-48
Don’t forget to draw cultures before antibiotics!
Blood cultures

Limitations



Colonization vs. infection
Prior antimicrobial Tx
Significance of


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Rare or unfamiliar organisms
Mixed culture results
Organisms not usually associated with disease
Llewelyn & Cohen. Diagnosis of infection in sepsis. Int
Care Med. 2001; 27: S10-32
Surviving Sepsis Guidelines-Antibiotics




Draw appropriate cultures first
Give antibiotics within 1 hr of recognition of septic
syndrome
Antibiotics should be broad-spectrum & chosen to
cover most likely organisms based on presentation
& local resistance patterns
Arrange for further diagnostic studies to rule out
surgically correctable foci of infection once
appropriate
Surviving Sepsis Guidelines - Source
Control

Get appropriate study to find the source (CT,
U/S, etc.)

Choose least invasive effective intervention

eg. CT guided percutaneous drainage vs surgery
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Source control ASAP after initial resuscitation
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Remove any possible iatrogenic sources

Central lines, foley catheters, etc.
Back to our case

You started our patient on gentamicin

He’s still on dopamine 10ug/kg/min

VS 120 RR 30 BP 95/65 Sats 92% T 38.1

What would you like to do now?
EGDT Protocol
Measurement of ScvO2

What is ScvO2?

Reflects oxygenation at tissue level

How are you going to measure ScvO2?

What is the difference between mixed venous and
central venous SvO2?

ScvO2


SmvO2


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blood from SVC or right atrium
blood from pulmonary artery
Contains blood from IVC (lower extremity) and coronary sinus
ScvO2 and SmvO2 correlate well
Edwards Central Venous Oximetry
Catheter
ScvO2

What is a normal ScvO2



ScvO2 comes back

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Normal ~75%
Normal pO2 ~40
ScvO2 = 64%
What does this result mean?

Repeat CBC


Hb 81 Hct 0.25
What do you do

Transfuse patient to Hct of 0.3

What is the physiological rationale for transfusion

O2 content = (1.34 x Hb x SaO2) + (0.0031 x PO2)
Transfusion in Sepsis

95% of ICU pts anemic by day 3 of ICU stay

Mechanisms



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Phlebotomy = average 65 ml/day
Ongoing bleeding
Fluid resuscitation
Underproduction anemia


Blunted erythropoietin response secondary to
inflammatory cytokine production
Abnormal iron metabolism due to immune activation

Low iron levels & elevated ferritin
Corwin et al. Transfusion practice in the critically ill.
Crit Care Med 2003; 31(S): S668-71
When should you transfuse?

Surviving Sepsis Guidelines



Transfuse to keep Hb > 70 g/L unless extenuating
circumstances (e.g. CAD) (B)
Based on TRICC trial
Rivers et al. 2001
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Transfuse to keep hematocrit at least 30%
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Multicenter RCT of 838 ICU pts w/ Hb <90
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Randomized to

Liberal strategy

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Restrictive strategy (study group)


Transfusion threshold 100 g/L – aim for 100 -120g/L
Transfusion threshold 70 g/L – aim for 70 – 90 g/L
Primary outcome

All cause mortality at 30 days
TRICC Trial
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Results


No difference in 30 or 60 day mortality
Lower in-hospital mortality in restrictive group


No difference in mortality in sepsis sub-group


But only 5% of patients had sepsis
Less sick pts (APACHE II score <20) did better
with restrictive strategy

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22.2% vs 28.1% (p=0.005)
ARR 7.4% (95%CI 1.0 – 13.6%)
Conclusion

Restrictive strategy equivalent to, and possibly
better than keeping Hb > 100 g/L
Reconciling EGDT and TRICC

EGDT

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
TRICC
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Hypovolemic patients
Actual measurement of suboptimal O2 delivery
Early resuscitation phase
Euvolemic pts enrolled within 72 hours of ICU
Only 6% sepsis, only 27% had any infection
Bottom Line

Use EGDT in acute resuscitation, use TRICC
afterwards when stabilized
Surviving Sepsis Guidelines - Transfusion

“Once tissue hypoperfusion has resolved
and in the absence of extenuating
circumstances, such as significant coronary
artery disease, acute hemorrhage, or lactic
acidosis (see recommendations for initial
resuscitation), red blood cell transfusion
should occur only when hemoglobin
decreases to 70 to a target Hb of 70-90.”

Recommends EGDT in initial resuscitation
Back to our case


You gave our patient one unit of blood
Repeat CBC

Hb 91 Hct 0.31

What now?

Repeat ScvO2


ScvO2 = 68%
What now?
Inotropes

Dobutamine

Beta adrenergic agonist



Overall effect





B1 – increases contractility, minimal effect on HR
B2 – vasodilation
Increased stroke volume
Increased HR
Increased cardiac output
= increased O2 delivery
NB – BP can go up or down
Survivng Sepsis Guidelines - Inotropes

“In patients with low cardiac output despite
adequate fluid resuscitation, dobutamine may
be used to increase cardiac output. If used in
the presence of low blood pressure, it should
be combined with vasopressor therapy.”
Early Goal Directed
Therapy

Rationale


Time is survival:
Goal is to achieve balance b/w O2 delivery & consumption

Standardized approaches to ED Tx have improved outcomes
in other diseases (e.g. MI)

Traditional parameters to guide resus (vitals, mental status,
urine output) appear to be too insensitive for ongoing tissue
hypoxia

Early observational trials found survivors to have
hemodynamic parameters that were both higher than nonsurvivors
Previous trials of goal directed therapy

Gattinoni et al. A trial of goal-directed hemodynamic therapy in
critically ill patients. N Eng J Med 1995; 333: 1025-32

Hayes et al. Elevation of systemic oxygen delivery in the treatment of
critically ill patients. N Eng J Med 1994; 330: 1717-22

Yu et al. Effect of maximizing oxygen delivery on morbidity and
mortality rates in critically ill patients: a prospective randomized
controlled study. Crit Care Med. 1993; 21: 830-8

Boyd et al. A randomized clinical trial of the effect of deliberate
perioperative increase of oxygen delivery on mortality in high-risk
surgical patients. JAMA. 1993; 270: 2699-707

Tuchschmidt et al. Elevation of cardiac output and oxygen delivery
improves outcome in septic shock. Chest 1992; 102: 216-20

Shoemaker et al. prospective trial of supranormal values of survivors
as therapeutic goals in high-risk surgical patients. Chest 1988; 94:
1176-86
Previous trials of goal directed therapy

No convincing benefit

Limitations






NOT EARLY
Heterogeneous study populations
Small sample sizes & wide CI’s
Enrollment after ICU admission
Tended to focus on one intervention in isolation
Most used PA catheters

Prospective RCT – N=263



Patients with SIRS and sBP<90 or lactate >4
Randomized to EGDT protocol or standard care
All had arterial & IJ central venous lines

EGDT group had catheter capable of ScvO2 monitoring

EGDT discontinued once transferred to ICU

ICU staff blinded to patient assignments

Primary endpoint was mortality
EGDT Protocol
EGDT - Results

EGDT did significantly better

In-hospital mortality 30.5% vs. 46.5%,



ARR 16%; NNT = 6; OR 0.58 (95%CI 0.38 – 0.87)
60d mortality 44.3% vs. 56.9%
 Primarily explained by reduction in sudden CVS
collapse deaths (10.3% vs. 21.0%)
Various secondary outcomes (labs & severity
scores) significantly better in EGDT group



EGDT pts spent longer time in the ED
EGDT survivors spent less time in hospital than
standard Tx survivors (14.6 d vs. 18.4 d)
Baseline SVO2 was 48% despite only 50% ventilated
EGDT - Results

Differences in EGDT group
 More fluid early (4.9 L vs. 3.5L)




No difference in overall fluids at 72h (13 vs 13L)
More early transfusions (64.1% vs. 18.5%)
More early inotropes (13.7% vs. 0.8%)
Less use of pulmonary artery catheters
later in ICU stay (18% vs. 31.9%)
EGDT - Controversies

Conflicts with earlier studies showing lack of
benefit from using hemodynamic goals
 all prior studies in ICU setting

Has never been replicated

A whole package of interventions

Which one(s) actually matter?
Back to the case

You start our patient on dobutamine at
10ug/kg/min

Repeat ScvO2

ScvO2 = 69%

Patient becoming more confused, no urine
output

What now?
EGDT Protocol
Intubating the Septic Patient

What do you use for




Pretreatment
Induction agent
Paralytic agent
You successfully intubate the patient
What Vent Setting Doctor?
ARDS Network

RCT – N=861 (stopped early)



Patients with strictly defined ARDS
27% of patients had sepsis
Used A/C ventilation mode

Traditional ventilatory parameters


12cc/kg, plateau pressures <50
Intervention (=low Tv)
6cc/kg, plateau pressures <30
 RR variable to achieve near normal pH

ARDS Network

Primary outcomes



In hospital mortality
Ventilator-free days in first 28 days
Secondary outcomes



Organ failure
Barotrauma
Plasma IL-6 levels
ARDS Network - Results

Low Vt group

Significantly decreased mortality







31.0% vs. 39.8%
ARR 8.8% (95%CI 2.4-15.3%); NNT = 11
More ventilator free days
More organ-failure free days
More pts breathing w/o assistance at 28d
Greater decreases and lower absolute levels of
IL-6 at day 3
No difference in barotrauma
Surviving Sepsis Guidelines –
Ventilation Strategy

Avoid high tidal volumes & high plateau pressures
(B)


Target TV 6 ml/kg
Target end-inspiratory plateau pressure < 30 cm H20

Small levels of PEEP should be used to prevent
atelectasis (E)

Utilize permissive hypercapnea to help minimize TV
& plateau pressures if necessary (C)

In absence of contraindications, position intubated &
ventilated pts w/ HOB 45o to prevent VAP

The patient is transferred to the ICU

You are the ICU resident

What other therapies have proven mortality
benefit in sepsis?
Steroids in Sepsis

Initially proposed for anti-inflammatory effects


Large dose (methylprednisolone 30 mg/kg then 5 mg/kg)
2 large RCT’s failed to show benefit



Veterans administration. Effect of high-dose glucocorticoid
therapy on mortality in patients wit clinical signs of systemic
sepsis. N Eng J Med. 1987; 317: 659-65
Bone et al. A controlled clinical trial of high dose
methylprednisolone in the treatment of severe sepsis and
septic shock. N Eng j Med. 1987; 317: 653-58
Meta-analysis of 9 RCT’s found no benefit, and possibly
increased mortality w/ large dose steroids RR 1.13, 95%CI
0.99 – 1.29

Cronin et al. Corticosteroid treatment for sepsis: A critical
appraisal and meta-analysis of the literature. Crit Care Med.
1995; 23: 1430-39
Adrenal insufficiency

Stress steroid response essential





Removing adrenals increases septic shock mortality in
animal models -- reversible with exogenous steroids
Bilateral adrenal necrosis or infarction noted in ~30%
of septic pts at autopsy
Multiple factors affect HPA axis during stress
Studies of sepsis have shown that up to 42% have
adrenal or HPA dysfunction which correlates w/
increased mortality
Multiple studies document improved catecholamine
response in steroid-treated septic shock
Prigent et al. Clinical review: Corticotherapy in sepsis.
Crit Care 2004; 8: 122-29
Annane et al. Effect of treatment with low doses of
hydrocortisone and fludrocortisone on mortality in patients
with septic shock. JAMA 2002; 288: 862-71

Multicenter DBRCT of 300 adult septic shock pts
tested with short corticotropin test & randomized to



Primary outcome


Placebo
Hydrocortisone 50 mg q6h IV & fludrocortisone 50 ug PO
OD for 7 days
28d survival
Secondary outcomes




28d survival in responders vs. nonresponders
28d, 1 yr, ICU, & hospital mortality
Time to vasopressor Tx withdrawal
Adverse events
Results

Mortality

Overall


Non-responders


No difference in 28 day mortality
28 day mortality - 53 vs 63%; ARR 10%, OR 0.54 (95%CI
0.31-0.97) NNT = 10
Reliance on vasopressors

Overall


No difference
Non-responders

Median time to withdrawal 7 vs 10 d, HR 1.91 (95%CI
1.29-2.84)
Criticisms

Possible inclusion of true adrenal insufficiency


Use of fludrocortisone in addition to hydrocortisone




High mortality rate in placebo group
Not widely practiced
CORTICUS trial ongoing to evaluate hydrocortisone alone
in septic shock
Underpowered to detect harm in responders
Change of entry criteria during study

No analysis of pts recruited before & after
Suggested diagnostic approach


Draw a random cortisol level
Perform a ACTH stim test



Administer 250 ug of cosyntropin IV
Draw serum cortisol levels at 0, 30, and 60 min
Give dexamethasone 2-4 mg in ED


Does not interfere w/ ACTH stim test
Treatment should be stopped if test negative
 Serum cortisol levels >1242 nmol/L have been found to
be associated w/ significantly greater mortality
 Suggests that exogenous steroids could be harmful

Sam et al. Cortisol levels and mortality in severe sepsis. Clin
Endo. 2004; 60: 29-35
Steroid Algorithm


Draw baseline cortisol
and do ACTH stim test
Give dexamethasone in
ED

<414nmol/L
414-938
>938nmol/L
Does not interfere with
ACTH stim test
<250nmol/L
Cooper & Stewart. Corticosteroid insufficiency in
acutely ill patients. N Eng J Med. 2003; 348:
727-34
>250nmol/L
Surviving Sepsis Guidelines - Steroids



IV hydrocortisone 200-300 mg/day for 7 days
should be given to adequately fluidresuscitated pts in refractory shock (C)
Doses of > 300 mg/day should not be used
(A)
Use dexamethasone in ED & consider use of
ACTH stim test to identify pts in need of
continued steroids (E)
Glycemic Control in Sepsis
Van den Berghe et al. Intensive insulin therapy in critically
ill patients. N Eng J Med. 2001; 345: 1359-67

RCT N=1548


Mostly surgical patients
Randomized to

Intensive insulin Tx


Traditional Tx


Continuous IV insulin initiated if glucose >6.1 mmol/L &
adjusted to maintain glu b/w 4.4 – 6.1 mmol/L
Continuous IV insulin initiated if glucose >11.9 mmol/L &
adjusted to maintain glu b/w 10-11.1 mmol/L
Primary outcomes

All-cause ICU mortality
Intensive Insulin Therapy and Sepsis

Intensive Insulin group

Lower rate of developing septicemia


Lower requirement for prolonged antibiotics


4.2% vs 7.8% (p=0.003)
11.2% vs 17.1% (p<0.001)
Patients with bacteremia had trend towards
lower mortality with intensive insulin therapy

29.5% vs 12.5% (NS)
Van den Berghe et al. Intensive insulin therapy in critically
ill patients. N Eng J Med. 2001; 345: 1359-67

Criticisms

Generalizability

Mostly post-surgical patients





Does this apply to septic or other medically sick patients?
Does use of insulin to prevent sepsis translate into mortality
benefit when treating primary sepsis?
Single center trial
Not blinded
Is the benefit related to euglycemia or to insulin?
Surviving Sepsis Guidelines –
Glucose Control

IV infusions of insulin should be used to
maintain serum glucose levels < 8.3 mmol/L
(D)
Recombinant Human
Activated Protein C
RhAPC - Pharmacologic Actions



Anti-thrombotic
 Inhibits FVa & FVIIIa
Anti-fibrinolytic
 Inhibits PAI-1 & TAFI
 Decreases thrombin
production
Anti-apoptotic


Anti-inflammatory




Induces Bcl-2 & inhibitor
of apoptosis-1 gene
expression
Inhibits TNF-α, IL-1, IL6 production
Inhibits monocyte &
neutrophil migration
Inhibits lipid A
activation of
monocytes
Inhibits tissue factor
activation
McCoy & Matthews. Drotrecogin Alfa (Recombinant Human Activated
Protein C) for the treatment of severe sepsis. Clin Ther 2003; 25: 396-421
RhAPC

Most septic pts have low levels of protein C


Associated with increased M & M
Pharmacologic properties

Anti-inflammatory, anti-thrombotic, anti-fibrinolytic

Increased survival in primate model of septic shock

Improved outcomes suggested in non-randomized
trial of meningococcemia

Administration associated w/ dec’d levels of
proinflammatory mediators & D-dimer in humans
PROWESS Trial: Bernard et al. Efficacy and safety of
recombinant human activated protein C for severe sepsis.
N Eng J Med 2001; 344: 699-709

RCT – N=1690


Randomized to



Severe sepsis
rhAPC infusion @ 24 ug/kg/h for 96 hrs
Placebo
Primary outcome

All-cause mortality at 28d
PROWESS Trial - Results

rhAPC significantly reduced mortality



24.7% APC vs. 30.8% placebo
ARR 6.1% (95% CI 1.9-10.4); NNT = 16
rhAPC had non-significant increase in risk of
serious bleeding

3.5% vs. 2.0% (p=0.06), NNH = 67
Post hoc analyses

APACHE II scores <25 did worse with rhAPC

Benefit dec’d w/ less organ dysfunction


ARR single organ system 1.7%
ARR multi-organ failure 7.4%

More benefit in pts w/ septic shock rather
than sepsis

Pts not in DIC did worse w/ rhAPC than w/
placebo
Dhainaut et al. Drotrecogin alfa (activated) in the treatment of severe
sepsis patients with multiple-organ dysfunction: data from the
PROWESS trial. Int Care Med 2003; 29: 894 - 903
Dhainaut et al. Drotrecogin alfa (activated) in the treatment of severe
sepsis patients with multiple-organ dysfunction: data from the
PROWESS trial. Int Care Med 2003; 29: 894 - 903
Prowess - Criticisms

Face Validity


When multiple other trials of anti-cytokine or antithrombotic meds have not worked why does this one?
Validity of the results
 Entry criteria where changed ½ way through
 Cell line used to produce rhAPC was changed
½ way through


Changes not mentioned anywhere in methods
Changes coincided w/ significant difference in
observed efficacy
Criticisms

External validity



Exclusion criteria extensive & included many pt
groups relevant to increasing incidence of sepsis
What is mortality beyond 28d? What is status of
survivors?
Other concerns


Sponsored by Eli Lilly
3 authors are Eli Lilly employees, 2 are stockholders,
5 have served as consultants leaving only 3/11
primary authors as having no ties
Remaining questions






What is the mortality benefit beyond 28d? What
about morbidity?
What is the best method to identify pts most likely to
benefit from rhAPC?
Can we use rhAPC in any of the pt populations
excluded from PROWESS?
Would giving rhAPC earlier = greater efficacy?
Would a longer Tx period = greater efficacy?
How does rhAPC interact w/ other existing or novel
sepsis therapies?
Is it cost effective?

CAD$335 per 5 mg vial



0.024 mg x 70g kg x 96 hrs = ~161 mg or 32 vials
= $10,800 Cdn per treatment
Is it cost-effective? Yes, if used selectively.


Cost per life-year gained
 APACHE II <25 $19,723 USD
 APACHE II >25 $575,054 USD
Total cost to our system
 CHR ICU pharmacy budget 2001: $1.6 million USD
 Cost if rhAPC was used in pts w/ APACHE II > 25:
$482,800 USD
Manns et al. An economic evaluation of activated protein C
for severe sepsis. N Eng J Med. 2002; 347: 993-1000
Surviving Sepsis Guidelines - rhAPC

rhAPC should be given to severely ill pts:





APACHE II score > 25
Sepsis-induced MOF
Septic shock
ARDS
In the absence of absolute or significant
relative contraindications (B)
We can reduce mortality in sepsis in the ED








EGDT
Steroids
ARDS Net vent strategy
rhAPC
Insulin
Dex in Meningitis
Early appropriate Abx
Source control
ARR 16.0%
ARR 10.0%
ARR 8.8%
ARR 6.1%
ARR 3.4%
ARR 8.0%
Surviving Sepsis – Summary

Utilize




EGDT in 1st 6 hrs
Cultures before Abx
Source control
Fluid resuscitation





rhAPC when appropriate
Keep Hb 70-90
Ventilate with low TV and
peak pressures
Euglycemia
Crystalloid = colloid
Vasoactive medications
when fluid fails



Dopamine = norepinephrine
Steroids replacement

Avoid


Supranormal oxygenation
Bicarbonate
PHYSICIAN SCREENING TOOL for SEVERE SEPSIS
Pilot Form- Please retain on patient chart
CHR Sepsis
Protocol
Suspected
or
Proven
Infection
Pneumonia, emphysema
Urinary tract infection
Acute abdominal infection
Meningitis
Skin/soft tissue infection
Bone/joint infection
Wound infection
Bloodstream catheter infection
Endocarditis (IVDA)
Implantable device infection
No known source other than
clinical suspicion***
Other
YES Complete the following
*** High Risk Patients
Immunocompromised
Substance Abuse
Chronic Disease
Diabetic
Splenectomy
Elderly and neonates
Postoperative
Draw and send:
 CBC with diff, electrolytes
 Glucose, creatinine
Complete:
 Urinalysis, Chemstrip
 Order Old Charts
S.I.R.S. criteria:
 Hyperthermia > 38 C
 Hypothermia < 36 C
 Tachycardia > 90 bpm
 Tachypnea > 20 bpm
 Acutely altered mental status (GCS < 15)
 Leukocytosis (WBC count >12.0 x 10E9/L)
 Leukopenia (WBC count <4.0 x 10E9/L)
 Normal WBC with bands > 0
 Hyperglycemia (plasma glucose > 7.7 mmol/L in
the absence of diabetes
Does the
patient
have
2 or more
S.I.R.S.
criteria
YES
Addressograph:
Complete the following
Does the
patient
have any
evidence of
new end
organ
dysfunction
 Blood Cultures x2
 PTT/INR
Draw and send:
 Bilirubin
 Lactate
O2 saturation <90%n on Room Air
Hypotensive: systolic BP <90 or MAP <60
Oliguria – urine output <0.5ml/kg/hr
Mottled
Increased Creatinine >60 umol/l from baseline
Coagulation Abn: INR >1.5, PTT > 60sec
Thrombocytopenia PLT <100
Hyperbilirubinemia: >70 mmol/l
Hyperlactatemia: >4 mmol/l
YES
·
·
Ensure patient is in a monitored bed
Initiate Severe Sepsis Order Set and Algorithm
Time Severe Sepsis Diagnosed: _________
Severe Sepsis/Septic Shock Algorithm
CHR Severe
Sepsis Algorithm


ASSESSMENT
O2 Sat < 90% on Room Air
Continuous:
·
O2 Saturation
·
ECG Monitoring
·
Urine output
(Foley catheter)

Intermittently:
·
B/P, HR, RR
q15 mins
·
Temp q1h
Consider
Intubation
SBP <90 or MAP <65
(manual BP)
MAP = DBP + (SBP – DBP)
3
2 large bore I.V.s
Draw appropriate labs and
blood cultures as per the
Severe Sepsis order set
**INITIATE
ANTIBIOTIC**



Initiate Consult
Supplement O2
Maintain O2
Saturation >90%
Call for ABGs.
Fluid
Resuscitation
Give:
Crystalloid 500ml
bolus q5-10min
Titrate to:
SBP > 90
HR <100
Do Not Exceed:
40cc/kg to a
maximum of 4 litres
of crystalloid
ICU (attending) and MTU (senior resident) on all
severe sepsis/septic shock patients.
If MTU senior resident not available or at RGH,
call attending directly.
Intubated patients consult ICU only.
Maintenance fluids:
Crystalloid 150cc/hr
Hospitalist:
Palliative Patients Only
Central Line
Required
Advanced Goal Directed Therapy
YES
CVP 8-12 mm
Hg
NO
Give Fluid bolus: Crystalloid 500ml
Maintanience Fluids: 150 ml/hr
YES
MAP >65 mm
Hg
NO
Start Norepinephrine infusion at 0.1ug/kg/min
and titrate to effect or max 2.0ug/kg/min.
ADMIT ICU
YES
Start Dobutamine infusion at 2.5ug/kg/min.
increase by 2.5 ug/kg/min q30 min to effect
or max of 20 ug/kg/min.
NO
SV02 >70%
from central
line
ADMIT ICU
Hgb <100 g/l
YES
Transfusion 1 unit PRBC
S.I.R.S:
Severe Sepsis:
Septic Shock:
(Systemic Inflammatory Response Syndrome)
·
2 or more of the following:
·
Temp >38 or <36
·
Hr >90
·
RR >20
·
Altered Mental Status (GCS <15)
·
Hyperglycemia – Glucose > 7.7mmol/l
in the absence of diabetes
·
Abn CBC diff:
WBC > 12.0 x 10E9/L or
WBC < 4.0 x 10E9/L or
normal WBC with bands >0
·
·
·
·
·
·
·
·
S.I.R.S. associated with evidence of new
end organ dysfunction
O2 Saturation <90%
Oliguria (urine output <0.5 ml/kg/hr)
Mottled
Increased Creatinine > 60 umol/l from pt
known baseline
Coag Abn: INR >1.5, PTT >60 sec
Thrombocytopenia: PLT <100
Hyperbilirubinemia: > 70 mmmol/l
Hyperlactatemia: >4mmol/l
Acute circulatory
failure due to
suspected infection.
Hypotension:
SBP <90 mmHg
or
MAP <60 mmHg
the end