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

invasion of organ system(s) by microorganisms Sepsis

SIRS + infection Severe sepsis

Sepsis with organ dysfunction Lactic acidosis, oliguria, ALOC, etc.

Responsive to fluids Septic shock

Severe sepsis requiring vasopressors/inotropes to maintain normotension

Sepsis Spectrum & MortalityDiagnostic category Mortality (%)

SIRS criterianone 32 73 104 17

Sepsis 16Severe sepsis 20Septic shock 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: S10-32Bochd, Glauser, & Calandra. Antibiotics in sepsis. Int Care Med. 2001; 27: S33-48

Sources of Infection Specific sites:

Respiratory 36% Blood 20% Abdomen 19% Urinary tract 13% Wounds & Skin 7% Other 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

Surgery, trauma, DVT, MI, PE, pancreatitis, etc Metabolic

Thyroid storm, adrenal insufficiency Malignancy

Tumor lysis syndrome, lymphoma CNS

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 Initial resuscitation Source control Drugs Fluid therapy Blood products Mechanical ventilation

Treatment of Septic Shock

InfectionControl

SupportiveCare

Immuno-modulatoryTherapies

Septic Shock

EGDT

Ventilation

Antibiotics

Surgical Management

Steroids

rhAPC

Case 1 76 F – from nursing home

Increasing confusion x 3 days Not eating Complaining of lower abdominal tenderness

O/E 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

Hb 94; WBC 11 (bands 2); platelets 154 Lytes

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)

“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

Surviving Sepsis Guidelines - Fluids

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 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 Dosing

Dopaminergic <5ug/kg/min Vasodilation coronary,

renal, mesenteric beds Beta - 5-10ug/kg/min

Increase contractility and HR

Alpha - >10ug/kg/min vasoconstriction

Norepinephrine Alpha agonist Increases BP by

vasoconstriction, little effect on HR or cardiac output

Dosing 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 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

increased mortality with each hour of delay to antibiotics

Few prospective RCT’s 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

Community Acquired Pneumonia Ceftriaxone 2gm IV PLUS Azithromycin 500mg IV OR Levofloxacin 500mg IV

Intra-abdominal Infection 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 Gentamicin 6mg/kg IV OR Ceftriaxone 2gm IV

Meningitis Dexamethasone 10 mg IV at or before antibiotics

given Ceftriaxone 2 gm IV PLUS Vancomycin 1 gm IV

Cellulitis/Bone/Joint Cefazolin 2 gm IV OR Cloxacillin 1 gm IV

Fasciitis Clindamycin 600 mg IV PLUS Penicillin 4 MU IV

PLUS IVIG PLUS Surgery

Endocarditis Ensure Blood Culture x THREE are done Ceftriaxone 2gm IV ADD Vancomycin 1 gm IV if MRSA suspected

Infected Central Line Pull Line Vancomycin 1 gm IV

Neutropaenic 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

CHR Sepsis Protocol Recommendations

Blood cultures

Important to establish Dx for: Guiding antimicrobial Tx Guiding adjunctive Tx Microbiological epidemiological surveillance

Llewelyn & Cohen. Diagnosis of infection in sepsis. Int Care Med. 2001; 27: S10-32

Yield of cultures ranges from 9-64% 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

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

Source control ASAP after initial resuscitation

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

blood from SVC or right atrium SmvO2

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

Normal ~75% Normal pO2 ~40

ScvO2 comes back 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 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 Transfuse to keep hematocrit at least 30%

Multicenter RCT of 838 ICU pts w/ Hb <90 Randomized to

Liberal strategy Transfusion threshold 100 g/L – aim for 100 -120g/L

Restrictive strategy (study group) Transfusion threshold 70 g/L – aim for 70 – 90 g/L

Primary outcome All cause mortality at 30 days

TRICC Trial Results

No difference in 30 or 60 day mortality Lower in-hospital mortality in restrictive group

22.2% vs 28.1% (p=0.005) 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 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

Hypovolemic patients Actual measurement of suboptimal O2 delivery Early resuscitation phase

TRICC 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 B1 – increases contractility, minimal effect on HR B2 – vasodilation

Overall effect 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 non-survivors

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

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

Previous trials of goal directed therapy

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 Placebo Hydrocortisone 50 mg q6h IV & fludrocortisone 50 ug PO

OD for 7 days Primary outcome

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 No difference in 28 day mortality

Non-responders 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 High mortality rate in placebo group

Use of fludrocortisone in addition to hydrocortisone 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 Does not interfere with

ACTH stim test

<414nmol/L 414-938 >938nmol/L

<250nmol/L >250nmol/L

Cooper & Stewart. Corticosteroid insufficiency in acutely ill patients. N Eng J Med. 2003; 348: 727-34

Surviving Sepsis Guidelines - Steroids

IV hydrocortisone 200-300 mg/day for 7 days should be given to adequately fluid-resuscitated 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

Continuous IV insulin initiated if glucose >6.1 mmol/L & adjusted to maintain glu b/w 4.4 – 6.1 mmol/L

Traditional Tx 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 group Lower rate of developing septicemia

4.2% vs 7.8% (p=0.003) Lower requirement for prolonged antibiotics

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)

Intensive Insulin Therapy and Sepsis

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?

Van den Berghe et al. Intensive insulin therapy in critically ill patients. N Eng J Med. 2001; 345: 1359-67

Surviving Sepsis Guidelines – Glucose Control

IV infusions of insulin should be used to maintain serum glucose levels < 8.3 mmol/L (D)

Recombinant HumanActivated Protein C

RhAPC - Pharmacologic Actions Anti-thrombotic

Inhibits FVa & FVIIIa

Anti-fibrinolytic Inhibits PAI-1 & TAFI Decreases thrombin

production

Anti-apoptotic Induces Bcl-2 & inhibitor

of apoptosis-1 gene expression

Anti-inflammatory Inhibits TNF-α, IL-1, IL-

6 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 Severe sepsis

Randomized to 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 anti-thrombotic 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 ARR 16.0% Steroids ARR 10.0% ARDS Net vent strategy ARR 8.8% rhAPC ARR 6.1% Insulin ARR 3.4% Dex in Meningitis ARR 8.0% Early appropriate Abx Source control

Surviving Sepsis – Summary Utilize

EGDT in 1st 6 hrs Cultures before Abx Source control Fluid resuscitation

Crystalloid = colloid Vasoactive medications

when fluid fails Dopamine = norepinephrine

Steroids replacement

rhAPC when appropriate Keep Hb 70-90 Ventilate with low TV and

peak pressures Euglycemia

Avoid Supranormal oxygenation Bicarbonate

q Pneumonia, emphysemaq Urinary tract infectionq Acute abdominal infectionq Meningitisq Skin/soft tissue infectionq Bone/joint infectionq Wound infectionq Bloodstream catheter infectionq Endocarditis (IVDA)q Implantable device infectionq No known source other than

clinical suspicion***q Other

Suspected or Proven Infection

Draw and send: q CBC with diff, electrolytes q Glucose, creatinine

q O2 saturation <90%n on Room Airq Hypotensive: systolic BP <90 or MAP <60q Oliguria – urine output <0.5ml/kg/hrq Mottledq Increased Creatinine >60 umol/l from baselineq Coagulation Abn: INR >1.5, PTT > 60secq Thrombocytopenia PLT <100q Hyperbilirubinemia: >70 mmol/lq Hyperlactatemia: >4 mmol/l

S.I.R.S. criteria:q Hyperthermia > 38 Cq Hypothermia < 36 Cq Tachycardia > 90 bpmq Tachypnea > 20 bpmq Acutely altered mental status (GCS < 15)q Leukocytosis (WBC count >12.0 x 10E9/L)q Leukopenia (WBC count <4.0 x 10E9/L)q Normal WBC with bands > 0q Hyperglycemia (plasma glucose > 7.7 mmol/L in

the absence of diabetes

Draw and send: q Bilirubin q Lactate

Does the patient have any evidence of new end organ dysfunction

· Ensure patient is in a monitored bed· Initiate Severe Sepsis Order Set and Algorithm

Does the patient have 2 or more S.I.R.S. criteria

Addressograph:

Complete:q Urinalysis, Chemstripq Order Old Charts

Complete the following

Complete the followingq Blood Cultures x2q PTT/INRYES

YES

PHYSICIAN SCREENING TOOL for SEVERE SEPSISPilot Form- Please retain on patient chart

YES

Time Severe Sepsis Diagnosed: _________

*** High Risk PatientsImmunocompromised

Substance AbuseChronic Disease

DiabeticSplenectomy

Elderly and neonatesPostoperative

CHR Sepsis Protocol

Severe Sepsis:

· 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

Septic Shock:

Acute circulatory failure due to suspected infection.

Hypotension: SBP <90 mmHg or MAP <60 mmHg

S.I.R.S:(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 ornormal WBC with bands >0

Severe Sepsis/Septic Shock Algorithm

ASSESSMENT

Continuous: · O2 Saturation· ECG Monitoring · Urine output

(Foley catheter)

Intermittently: · B/P, HR, RR

q15 mins· Temp q1h

O2 Sat < 90% on Room Air

q Supplement O2

q Maintain O2

Saturation >90%q Call for ABGs.

Consider Intubation

SBP <90 or MAP <65(manual BP)

MAP = DBP + (SBP – DBP) 3

2 large bore I.V.sFluid Resuscitation

Give:Crystalloid 500ml bolus q5-10min

Titrate to:SBP > 90HR <100

Do Not Exceed:40cc/kg to a maximum of 4 litres of crystalloid

Maintenance fluids:Crystalloid 150cc/hr

Draw appropriate labs and blood cultures as per the Severe Sepsis order set

**INITIATE ANTIBIOTIC**

Initiate Consult

q ICU (attending) and MTU (senior resident) on all severe sepsis/septic shock patients.

q If MTU senior resident not available or at RGH, call attending directly.

q Intubated patients consult ICU only.

Hospitalist: Palliative Patients Only

Advanced Goal Directed Therapy Central Line Required

CVP 8-12 mm Hg

MAP >65 mm Hg

SV02 >70% from central

line

Give Fluid bolus: Crystalloid 500mlMaintanience Fluids: 150 ml/hr

Start Norepinephrine infusion at 0.1ug/kg/min and titrate to effect or max 2.0ug/kg/min.

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.

ADMIT ICU

ADMIT ICU

Transfusion 1 unit PRBC

Hgb <100 g/l

YES

YES

YES

NO

YES

NO

NO

CHR Severe Sepsis Algorithm

the end