Septic Shock in 2004

Emergency Department Strategies for Reducing Mortality

Moritz Haager PGY-3May 13, 2004

Objectives Brief review of basic pathophysiology Overview of recent advances in treatment with focus

on those most relevant to ED care Initial resuscitation

Early goal directed therapy Which fluid? Which pressor? Blood transfusions?

Infection & source control Role of steroids Ventilatory strategies

Adjunctive pharmacologic therapies Activated Protein C Insulin therapy

Epidemiology

Incidence variable but on the rise ~ 1/1000 – 260/1000 pts days Larger # of elderly, HIV, chemotherapy, organ transplant,

and dialysis pts in addition to diabetics, alcoholics etc Mortality ranges from 3% for pts w/ no SIRS criteria

to 46% for septic shock Accounts for 215,000 deaths/yr in US = MI deaths or

9.3% of all deaths in 1995 Annual est cost in US $16.7 billion Locally ~250 ICU admissions for sepsis per year

Definitions

Old SIRS

T >38 or <36 HR > 90 RR > 20 or PCO2 < 32 WBC > 12 or < 4

Too sensitive & simplistic

Latest ACCP/SCCM Consensus Definitions

Infection = invasion of organ system(s) by microorganisms

Sepsis = systemic host response to infection requiring > 1 signs & symptoms of sepsis

Severe sepsis = sepsis w/ organ failure Septic shock = severe sepsis w/

cardiovascular failure requiring vasoactive medications

Vincent & Jacobs. Curr Opin Infect Dis 16: 309-13. 2003

Vincent & Jacobs. Curr Opin Infect Dis 16: 309-13. 2003

Classifications reflect disease severity

Diagnostic 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

PIRO Grading System

P – Predisposing factors Age, comorbidities, immune status etc

I – Infection Organism, site(s), degree

R – Response Degree of host response as judged by clinical & laboratory

parameters O – Organ dysfunction

Degree of organ involvement

Sepsis Etiology

> 90% bacterial etiology Gram negative ~42% Gram positive ~34% Anaerobes ~2-5% Mixed ~14%

Fungi ~5% Primarily Candida More common in ICU setting,

immunocompromised pts, 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: 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 rxns, anesthetics, NMS etc

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

SEPSIS

INFLAMMATION PATHOGENS

TF EXPOSURE ENDOTHELIAL INJURY

ANTI-COAGULANTSYSTEM INHIBITON

ACTIVATIONOF CLOTTING CASCADE

FIBRINOLYTICSYSTEM INHIBITION

PRO-COAGULANT EFFECT

MICROVASCULAR THROMBOSIS

MULTI ORGAN DYSFUNTION SYNDROME

TNF-α, IL-1, IL-6, IL-7,Proteases, Leukotrienes, ProstaglandinsBradykinin, Platelet activating factorsFree oxygen radicals

Endotoxins, ExotoxinsDirect endothelial invasion

↓ AT III, ↓ aPC, ↓ pS↓ thrombomodulin

↑ PAI-1

A tale of 2 theories

Hyperimmune response theory Sepsis is a state of uncontrolled inflammatory

response to infection Multiple (unsuccessful) trials of anti-inflammatory

agents Hypoimmune response theory

Sepsis leads to immunosuppression through anergic & apoptotic mechanisms

Hotchkiss & Karl. The pathophysiology and treatment of sepsis. N Eng J Med. 2003; 348: 138-50

Clinical Effects

Peripheral vasodilatation & capillary leak Intravascular volume depletion

Myocardial depression Hypermetabolic state – global tissue hypoxia DIC – coagulation > fibrinolysis

Treatment of Septic Shock

InfectionControl

SupportiveCare

Immuno-modulatoryTherapies

Septic Shock

EGDT

Ventilation

Antibiotics

Surgical Management

Steroids

rhAPC

SCCM Guidelines for Treatment of Septic Shock

Utilize EGDT in 1st 6 hrs Cultures before Abx Source control Aggressive rehydration with

colloid or crystalloid Use dopamine or

norepinephrine for refractory shock

Give stress dose steroids

Give rhAPC when appropriate

Keep Hb 70-90 Use low TV’s & minimal

peak pressure & PEEP vent strategy

Use insulin therapy

Avoid Supranormal oxygenation Bicarb

Dellinger et al. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004; 32: 858-73

Early Goal Directed Therapy

SCCM Guidelines “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

Rationale behind EGDT

Time is survival: Goal is to achieve balance b/w O2 delivery & consumption

Standardized approaches to ED Tx have improved outcomes in other Dz (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 as well as predicted

Earlier Trials No consistent benefit from using goal-directed

therapy to optimize oxygen delivery in ICU patients 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

Earlier Trials

Limitations: 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

Rivers et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Eng J Med. 2001; 345: 1368-77

Prospective RCT of 263 adult pts with sepsis treated either with traditional care or a standardized resuscitation protocol in the ED

All had arterial & central venous lines placed – the EGDT group got a catheter capable of continuous O2 sat measurement

EGDT discontinued once transferred to ICU – all ICU staff blinded to pts assignments

Primary endpoint was mortality

Edwards PreSep Central Venous Oximetry Catheter

EGDT Protocol

Rivers et al. 2001 (cont’d)

Found that 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

Rivers et al. 2001 (cont’d)

Differences in EGDT group More fluid early (4.9 L vs. 3.5L) More transfusions (64.1% vs. 18.5%) More inotropic support (13.7% vs. 0.8%) Less use of pulmonary artery catheters

later in ICU stay (18% vs. 31.9%)

Controversies

Conflicts with earlier studies showing lack of benefit from using hemodynamic goals

Hayes et al. N Eng J Med 1995; 330: 1717-22 Gattinoni et al. N Eng J Med 1995; 333: 1025-32

Different time points – all prior studies in ICU setting

More heterogeneous patient populations

Controversies

Transfusion practice How does this fit with the TRICC trial?

Need for IJ or SC lines Which part of protocol accounts for benefit? How will this affect department flow

Supporting data

Retrospective study of pediatric sepsis Early normalization of vitals associated with >9

fold improved odds of survival Odds of mortality increase >2-fold with every hour

of ongoing shock Only 45% of pts were adequately fluid

resuscitated Han et al. Early reversal of pediatric-neonatal septic

shock by community physicians is associated with improved outcome

Supporting data

Success of hemodynamic optimization appears time-dependent Meta-analysis of ICU pts Studies instituting PAC goal-directed therapy later

than 12 hrs or after onset of organ failure failed to show benefit

Studies that intervened early found to result in significant mortality reduction of 23% (95%CI 16-30)

Kern et al. Meta-analysis of hemodynamic optimization in high-risk patients. Crit Care Med 2002; 30: 1686-92

Fluids in Sepsis

SCCM Guidelines

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)

Crystalloids or colloids?

Controversial Many heterogeneous studies No evidence for superiority of one over other, but

trend towards increased mortality w/ colloids Choi et al. Crystalloids vs. colloids in fluid resuscitation: A

systematic review. Crit Care Med. 1999; 27: 200-10 Shierhout & Roberts. Fluid resuscitation with colloid or

crystalloid solutions in critically ill patients: A systematic review of randomized trials. BMJ. 1998; 316: 961-4

Crystalloids Cheaper, easily available, less risk of anaphylactoid rxns,

resuscitate intra- & extravascular space

VasopressorsJust need a little squeeze..

SCCM Guidelines 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) Dobutamine may be considered in refractory shock felt

to be due to low cardiac output (E)

Does “renal dose” dopamine work?

NO!! DBRCT multicenter trial of 328 ICU pts

randomized to placebo or dopamine at 2ug/kg/min

No difference in mortality, peak serum creatinine, need for renal replacement Tx, rise in serum creatinine, or length of stay

ANZICS clinical trials group. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomized trial. Lancet. 2000; 356: 2139-43

Norepinephrine or Dopamine 1st in septic shock? Tons of animal data; very few clinical studies

Decreased mortality w/ norepinephrine vs. dopamine in one NON-randomized trial

Theoretical benefits w/ norepinephrine Less tachycardia No effect on HPA or cerebral perfusion pressure Increased GFR Decreased lactate levels Improved splanchnic blood flow

Vincent & de Backer. Crit Care 2003; 7: 6-8 On the other hand dopamine is quickly available and

familiar Bottom line = either will do as an initial pressor

Transfusion

Why do sick pts become anemic?

95% of ICU pts are anemic by day 3 of ICU stay

Mechanisms Phlebotomy = 65 ml/day on average 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

What should be the transfusion threshold?

SCCM 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%

TRICC Trial

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

Herbert et al. A multicenter, randomized, controlled trial of transfusion requirements in critical care. N Eng J Med. 1999; 340: 409-17

TRICC Trial

Results No difference in 30d mortality

ARR 4.6% (95%CI -0.84 – 10.2%) No difference in 60d mortality No difference in mortality in sepsis sub-group 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

Why the TRICC trial does not contradict Rivers et al

Different patient population Euvolemic pts Enrolled within 72 hrs of ICU admission Only 6% had Dx of sepsis, and only 26.5% had

any infection at all

Antibiotic TreatmentThe war against bugs

SCCM Guidelines

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

Fatal Error

“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 indicate progressive increase in

mortality w/ each hour of delay to Abx 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

Mono- or Combination Therapy?

Combination Tx: theoretical advantages Broadens spectrum Synergism Decreases emergence of resistant strains

No good studies to document improved outcomes Paucity of relevant data and adequately powered

studies Bochd, Glauser, & Calandra. Antibiotics in sepsis. Int Care

Med. 2001; 27: S33-48

Mono- or Combination Therapy?

Meta-analysis 64 RCT’s (7586 pts) of monotherapy vs. Beta-lactam &

aminoglycosides combo No difference in all-cause mortality, treatment failure, or

resistance development Lack of benefit consistent in all subgroups analyzed Significant increased nephrotoxicity w/ combo Tx NNH

15 (14-17) Paul et al. Beta-lactam monotherapy versus beta-lactam

aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomized trials. BMJ 2004; 238: 668

Local ID recommendations: Quick reference guide

Undifferentiated febrile shocky pt w/ no focus Ceftriaxone

Respiratory Ceftriaxone + macrolide

or resp quinolone Urinary tract

Gentamicin or quinolone Meningitis

Ceftriaxone +/- vancomycin +/- ampicillin

Intraabdominal Ancef + flagyl +

gentamicin (24 hr dosing) Ceftriaxone + flagyl Pip-tazo Carbapenem

Necrotizing fasciitis IVIG + penicillin +

clindamycin + surgery Dr. Dan Gregson

personal communication

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

We still frequently fail to obtain cultures prior to initiating antibiotics in the ED

Yield of cultures ranges from 9-64% Bochd, Glauser, & Calandra. Antibiotics in sepsis. Int Care Med. 2001;

27: S33-48

Blood cultures

Limitations Colonization vs. infection Prior antimicrobial Tx Significance of

Rare or unfamiliar organisms Mixed culture results Organisms not usually associated w/ Dz

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

Source ControlGetting to the root of the cause

SCCM Guidelines

Arrange for appropriate studies & consults Choose intervention least disruptive to

unstable physiological status (e.g. percutaneous drainage rather than surgery)

Source control should occur as soon as possible after initial resuscitation

Remove lines & tubes if appropriate

Ya gotta do all the lil’ things right…that’s what wins games

When inserting central lines, chest tubes etc Wear a sterile gown Wear a mask Prep & drape a huge

area Communicate potential

‘dirty’ lines to admitting service

Ventilatory Strategies

SCCM Guidelines 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

Background

Traditional vent parameters TV 10 – 15 ml/kg, minimal PEEP to maintain normal

PCO2, PO2 & pH ARDS mortality as high as 90% in the 70’s (currently

30-40%) Gattinoni et al. Physiologic rationale for ventilator setting in

acute lung injury / acute respiratory distress syndrome patients. Crit Care Med. 2003; 31(S): S300-04

Mechanisms of VALI

Mechanisms of lung injury due to barotrauma & volutrauma Basic underlying effect due to high inspiratory pressures & resultant

shear forces on lung parenchyma Large Vt's, low PEEP, high peak pressure large gradient in lung

volume b/w inspiration & expiration cyclical collapse & distention of alveolar units

Lung heterogeneity – diseased portions collapse while healthy alveoli become overdistended Local inflammation Disruption of alveolar-capillary barrier Reduced clearance of edema fluid

Frank & Matthay. Science review: Mechanisms of ventilator-induced injury. Crit Care. 2003; 7: 233-41

Mechanisms of VALI Conventional ventilation increases

inflammatory mediators Reducing TV’s to 6-8 ml/kg decreases cytokine

levels Low TV’s and inspiratory pressures

significantly reduce mortality in human trials Vincent et al. Reducing mortality in sepsis: new directions. Crit Care.

2002. 6: S1-18

Excessively low TV’s & airway pressures also appear to lead to VALI likely due to propensity for alveolar collapse

Brower et al. Lung-protective ventilation strategies in acute lung injury. Crit Care Med 2003; 31(S): S312-16

Summary of trials

Frank & Matthay. Science review: Mechanisms of ventilator-induced injury. Crit Care. 2003; 7: 233-41

ARDS-Net trial

Multicenter RCT of 861 adults with ARDS Randomized within 36 hrs of intubation to:

Control group Vt 12 ml/kg predicted body wt on AC mode Adjusted Vt to keep plateau pressure b/w 45-50 cm H2O

Low Vt group Vt 6-8 ml/kg predicted body wt on AC mode Adjusted Vt to keep plateau pressure b/w 25-30 cm H20

Followed for 180 days

Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory

distress syndrome. N Eng J Med. 2000; 342: 1301-8

ARDS-Net trial (cont’d)

Primary outcomes In hospital mortality Ventilator-free days in first 28 days

Secondary outcomes Organ failure Barotrauma Plasma IL-6 levels

ARDS-Net trial (cont’d)

Results: Low Vt group had Sig 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

Criticisms

Vt or plateau pressure Control group had higher plateau pressures Recent meta-analysis argues that difference due

to increased mortality in control group & that plateau pressures are to blame (despite lower than average mortality in control group)

Eichacker et al. Meta-analysis of acute lung injury and acute respiratory distress syndrome trials testing low tidal volumes. Am J Resp Crit Care Med 2002; 166: 1510-14

Conclusions

General consensus in the literature that ARDS trial results are valid, and that VT should be 6-8 ml/kg

Plateau pressures should be kept to < 30 cm H2O PEEP should be used to minimize alveolar collapse at

pressures as low as possible (start 5-10 cm H2O)

Steroids

SCCM Guidelines

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)

Background Anti-inflammatory effects

Basis for large dose (primarily methylprednisolone 30 mg/kg followed by 5 mg/kg }steroid trials in 80’s

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

Background Concept of adrenal insufficiency

Stress steroid response essential Taking out adrenals increases septic & hemorrhagic shock

mortality in animals -- 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 pts 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

Annane et al cont’d

Results No significant difference in mortality for all pts Non-responders treated w/ steroids had decreased

28d mortality 53 vs. 63%; ARR 10%, OR 0.54 (95%CI 0.31-0.97) NNT = 10

Less reliance on vasopressors Non-responders: Median time to withdrawal 7 vs. 10 d; HR

1.91 (95%CI 1.29-2.84) All pts: Median time to withdrawal 7 vs. 9 d; HR 1.54 (95%CI

1.10-2.16) No significant differences in adverse events

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

Trend towards harm in responders needs clarification Avoid steroids for all approach

Change of entry criteria during study No analysis of pts recruited before & after

Diagnosis of adrenal insufficiency

No clear cut normal range: Serum cortisol levels variable & poorly reflective of biologic action during stress

Inc’d production (up to 6x normal) & loss of diurnal variation Dec’d concentration & binding affinity of corticosteroid-

binding globulin (CBG) Inc’d local concentration due to protease activity on CBG Up- or down-regulation of intracellular steroid receptors

Elevated and depressed cortisol levels are both associated w/ increased morbidity & mortality

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

Adrenals & sepsis

Adrenal responsiveness is normally maintained even during illness 25-59% of pts maintain corticotropin response Possible causes of adrenal insufficiency

Drugs (etomidate, fluconazole) Adrenal infarction / hemorrhage / abscess Dysregulation of HPA axis by high levels of

inflammatory cytokines steroid resistance Cooper & Stewart. Corticosteroid insufficiency in acutely

ill patients. N Eng J Med. 2003; 348: 727-34

Diagnosis of adrenal insufficiency

What is a normal serum cortisol during stress? Most controversial area Nobody knows – no good studies to compare

methods of testing for adrenal insufficiency w/ accepted gold standards

Accounts for variation in incidence from 1.4 – 54%

Current diagnosis based on limited data & consensus opinion on threshold cortisol levels & “appropriate” response to ACTH stim test

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

Interpreting results

Random cortisol < 414 nmol/L (15 ug/dL) – suggestive of adrenal

insufficiency – start steroids >938 nmol/L (34 ug/dL) – suggestive of steroid resistance

– replacement unlikely to help 414 – 938 nmol/L – base decision on ACTH stim test result

ACTH stim test >250 nmol/L (9 ug/dL) change adrenal insufficiency

unlikely <250 nmol/L (9 ug/dL) change suggestive of adrenal

insufficiency – start steroids Cooper & Stewart. Corticosteroid insufficiency in acutely ill

patients. N Eng J Med. 2003; 348: 727-34

What about serum free cortisol?

66 consecutive ICU pts w/ APACHE III > 15 Group 1: serum albumin ≤ 25 g/L Group 2: serum albumin > 35 g/L

Compared w/ 33 healthy volunteers 7 ICU pts w/ proven adrenal insufficiency

Looked at Total & free cortisol levels at baseline & after

cosyntropin test

Conclusions

Critically ill pts have elevated cortisol levels Free cortisol levels can change significantly

w/ less significant concomitant changes in total cortisol

Total serum cortisol levels in pts w/ hypoproteinemia can be misleading

Suggest baseline free cortisol of < 52.4 nmol/L identifies pts at risk for adrenal insufficiency

Steroid conclusions

Think of steroids in pts w/ apparent septic shock refractory to standard treatment

Draw baseline cortisol levels & do ACTH stim test

Use dexamethasone in the ED Do NOT give steroids card blanche Await trials on use of free cortisol

Recombinant Human Activated Protein C

(rhAPC = Drotrecogin alfa = Xigiris® aka superdrug)

SCCM Guidelines

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)

Background No pharmacologic agent shown to reduce in sepsis

mortality in phase III trials…. Ibuprofen NAC Anti-TNF-α mAb vs. placebo (NORASEPT II) IL-1 receptor antagonist vs. placebo PAF receptor antagonist vs. placebo High dose steroids Bradykinin antagonist (Deltibant) Tissue factor pathway inhibitor AT III vs. placebo (KYBERSEPT) Etc, etc

…until now (maybe)

Multiple 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

Protein C as Tx

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

Multicenter DBRCT of 1690 adult pts w/ severe sepsis

Randomized to rhAPC infusion @ 24 ug/kg/h for 96 hrs Placebo

Primary outcome All-cause mortality at 28d

Bernard et al. cont’d

Results rhAPC significantly reduced mortality

28d 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

Sounds great, but don’t forget to read the fine print…

Post hoc analyses

Pts w/ APACHE II scores <25 did worse w/ rhAPC than w/ placebo

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

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?

Cost $335 Cdn 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

Contraindications to rhAPC Active internal bleeding Recent (within 3 mo) hemorrhagic stroke Recent (within 2 mo) intracranial or intraspinal

surgery, or severe head trauma Trauma with an increased risk of life-threatening

bleeding Presence of an epidural catheter Intracranial neoplasm or mass lesion or evidence of

cerebral herniation

The Future

ADDRESS Trial Placebo-controlled trial of rhAPC in lower-risk pts

w/ severe sepsis Trials in pediatric populations Trials examining use of heparin in

conjunction w/ rhAPC Development of more defined criteria for

selecting pts likely to benefit from rhAPC

Insulin therapySugar: its not just bad for your teeth..

SCCM Guideline

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

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

RCT w/ blinded outcome assessment of 1548 pts admitted to surgical ICU

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

Van den Berghe et al cont’d

Results ARR 3.4% or NNT = 29, adjusted RRR 32%

(95%CI 2-55%) Greatest reduction in mortality due to decrease in

deaths due to MOF with septic focus (33 pts vs. 8 pts)

Decreased septicemia by 46% (95%CI 25-67%) Decreased need for renal replacement, ARR

3.4% Shorter ICU stay, less Abx, less vent support

Van den Berghe et al

Criticisms Generalizability

Virtually all post-op pts – is this applicable to all “sick’ pts?

Does prophylactic value of glycemic control in preventing sepsis translate into benefit as treatment for primary sepsis?

Single center trial Not really blinded

Is it the normoglycemia or the insulin that provided the benefit?

Multivariate analysis of the original study data suggests benefit primarily related to prevention of hyperglycemia than to exogenous insulin administration

Prevention of renal failure however appeared to be associated more with insulin Tx

Van den Berghe et al. Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control. Crit Care Med. 2003; 31: 359-66

Conclusions

We can reduce mortality in sepsis in the ED: EGDT: ARR 16.0% ARDSNet vent strategy ARR 8.8% Steroids ARR 10.0% rhAPC ARR 6.1% Insulin ARR 3.4% Dex in Meningitis ARR 8.0% Early appropriate Abx Source control