Sepsis Syndromes Aric Storck October 5, 2006.

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 Epidemiology slide 3 Sepsis kills more people per year in the US than stroke and MI. The actual death rate in sepsis is likely underestimated given the cofounding effect of the fact that most of these pts have other co-morbidities to which one could attribute their demise. What is important to realize is that this mortality rates have not changed in the past 25 yrs! Compare this with the reduction of AMI mortality from 25-30% in the 1960’s to less than 8% currently.

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 Severe sepsis Septic shock
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 & Mortality
Diagnostic category Mortality (%) SIRS criteria none 3 Sepsis Severe sepsis 20 Septic shock 46 McCoy & Matthews. Drotrecogin Alfa (Recombinant Human Activated Protein C) for the treatment of severe sepsis. Clin Ther 2003; 25:

Sepsis Etiology > 90% bacterial Fungi ~5% Gram negative ~42%
Gram positive ~34% Anaerobes ~2-5% Mixed ~14% Fungi ~5% Primarily Candida More common in ICU, immunocompromise, steroids, diabetics Sepsis Etiology slide 9 Gram (+) bugs: staph aureus (12%), coag (-) staph 7%, enterococci 8% Gram (-) bugs: E.coli 13%, Klebsiella 8%, Pseudomonas 8% 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: Can be identified in ~92% of pts
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 Not all that is febrile & shocky is infectious Unfortunately the Dx remains mostly clinical. There are a few tests like procalcitonoin being looked at but so far they lack the required specificity & sensitivity to reliably distinguish infection 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 Evidence based recommendations. Graded according to strength of evidence

Treatment of Septic Shock
Antibiotics Surgical Management EGDT Steroids rhAPC Ventilation

Case 1 76 F – from nursing home O/E 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 Lactate 4

Case 1 - continued Diagnosis? Does this patient have SIRS? Sepsis?
Severe Sepsis? Septic Shock? Initial Management?

EGDT Protocol EGDT Protocol slide 24
Intubation & mechanical ventilation as indicated 500 cc crystalloid boluses q30 min to achieve CVP 8 – 12 mm Hg Vasopressors if MAP < 65 mm Hg Vasodilators if MAP > 90 mm Hg If CV SPO2 < 70% then got PRBC’s to Hcg at least 30% If the CV SPO2 still < 70% then start dobutamine at 2.5 ug/kg/min and inc dose by 2.5 ug/kg/min q30 min until CV SPO2 > 70% or max dose (20) reached, MAP < 65, or HR > 120

Which fluid are you going to give?
Fluid Resuscitation Which fluid are you going to give?

Amount titrated to clinical status and response to fluids
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

All-comers no difference in mortality
Traumatized patients strong trend towards increased risk of death.

SAFE Trial Conclusion: “trend” towards improved survival with albumin, interpret with caution as study not powered or designed to test this difference

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? There are inherent problems with meta-analysis: heterogeneity of patients and endpoints and interventions.

EGDT – Fluid Resuscitation
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 to account for increased intrathoracic pressure

Surviving Sepsis Guidelines - Fluids
No evidence for choosing colloid over crystalloids (Grade C) Administer crystalloids as cc over 30 mins & repeat prn based on response (E) Administer colloids at cc over 30 mins & repeat prn based on response (E) SCCM Guidelines SCCM Guidelines slide 32 Lack of good prospective studies specific to sepsis; extrapolated from other similar pt populations Need more crystalloid than colloid therefore more likely to become edematous

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:

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?

Vasopressors Goals Which vasopressor do you choose?
MAP >65 Improvement in indicators of end organ perfusion Which vasopressor do you choose? What is your starting dose?

Vasopressors Dopamine Dosing Norepinephrine Dosing
Precursor of epi/norepi Release of norepi from presynaptic terminals Dosing Dopaminergic <5ug/kg/min Vasodilation coronary, renal, mesenteric beds Beta ug/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) SCCM Guidelines Slide 35 Once pressure drops below a certain point you lose autoregulation in a number of organs – flow becomes directly dependant on perfusion pressure & you may need to boost this with meds Renal dose dopamine has been shown to be of no utility in one large RCT and a meta-analysis

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? What antibiotic?

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:

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 ) Adequate Tx dec’d risk of death in surgical sepsis (OR 0.37, 95%CI ) Do Antibiotics make a difference? Slide 47 Obviously a antibiotics vs. placebo trial in sepsis will never happen for sound ethical reasons. The studies suggest that antibiotic administration also decreases progression to shock by about 50% 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:

Bug Juice What’s the MC site of infection?
Lungs>abd>UTI>soft tissue>other

CHR Sepsis Protocol Recommendations
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

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 SCCM Guidelines slide 45 Spectrum should be narrowed based on susceptibility testing hrs later – once causative organism identified no evidence that monotherapy is worse than combination therapy. Tx for 7-10 days based on clinical response Combination therapy is favored by some for Pseudomonas infections and neutropenic pts All this evidence received the lowest grade Meaning expert opinion only

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. Grade E

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? Central line insertion

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 ScvO2 comes back
Normal pO2 ~40 ScvO2 comes back ScvO2 = 64% What does this result mean?

What is the physiological rationale for transfusion
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) + ( 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 Why do sick pts become anemic? Slide 39 Studies have shown that inflammatory cytokine production actually interferes with expression of the eryhtropoeitin gene– this mechanism is felt to be similar to that seen in the anemia of chronic disease. 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% What should be the transfusion threshold? Slide 40 There is a lack of benefit for immediate impact of transfused pRBC’s on improving oxygen delivery – transfused pRBC’s are not normal due to storage defects such as decreased 2,3-diphosphoglycerate levels, and duration of storage has been shown to correlate with efficacy in humans as well as in animal models of sepsis – the newer the red cell concentrate the better.

Multicenter RCT of 838 ICU pts w/ Hb <90
Randomized to Liberal strategy Transfusion threshold 100 g/L – aim for g/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 slide 41 Setting: 22 tertiary & community ICU’s in Canada Inclusion criteria: ICU pts w/ Hb < 90 g/L within 72 hrs of admission Euvolemic Exclusion criteria: Age , 16 yo Inability to receive blood products Active bleeding at enrollment (dec in Hb of 30 or need for 3 or more units in preceding 12 hrs) Chronic anemia (Hb < 90 at least once 1 mo prior to admission) Pregnancy Brain death Imminent death (24h) Admission post cardiac surgery Secondary outcomes All cause mortality at 60d and during hospitalization & ICU stay Organ failure Did a power calculation estimating they needed 2300 pts to detect a 4% difference in 30d mortality – this was decreased to 1620 pts based on a higher than expected overall mortality rate during interim analysis ITT analysis

TRICC Trial Results Conclusion 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
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 ” 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%

Inotropes Dobutamine Overall effect NB – BP can go up or down
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 Rationale behind EGDT slide 19 One suggestion for why many similar EGDT trials & perhaps trials of other Tx modalities, have failed to show benefit is that the pts were enrolled up to 72 hrs post admission – they may have missed the golden hours during which a crucial difference may be made Trials in the 60s and 70s observed that people who survived septic shock not only had physiologic hemodynamic indices that were higher than those who died of their disease, but also that the values were in the supranormal range.

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: Hayes et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Eng J Med 1994; 330: 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: Tuchschmidt et al. Elevation of cardiac output and oxygen delivery improves outcome in septic shock. Chest 1992; 102: Shoemaker et al. prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 1988; 94:

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 Earlier Trials slide 21 Many of the pts enrolled in these studies were post-op pts The numbers of pats enrolled tended to be very small as reflected in very wide confidence intervals often from 1 – 40% -- does not rule out benefit. All of them began their study intervention after admission to the ICU suggesting that for many this was too late – interestingly it was observed in many of these studies that a very large proportion of pts whose hemodynamics were optimized by fluid resus alone survived Virtually all of theses studies focused on one intervention at a time, and almost always this consisted of inotropic intervention in the form of dobutamine to raise cardiac index, often to supranormal levels, as a means to increase oxygen delivery. Lastly as these were ICU-based studies they relied on PA caths to guide their treatment – there is considerable controversy about whether of not PAC’s possibly increase mortality. however one 2003 NEJM paper of which Dr. Dean Sandham is the lead author, a multicenter RCT of PAC’s in ICU pts failed to show any difference in outcome b/w the groups.

All had arterial & IJ central venous lines
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 Rivers et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. Slide 22 Landmark paper: First study of its kind to initiate goal-directed Tx in the ED rather than after ICU admission Inclusion criteria: 2 or more SIRS criteria and SBP 90 or lower after fluid challenge or lactate > 4 mmol/L Exclusion criteria: -< 18 yo -pregnant -acute CVA -ACS -acute pulmonary edema -status asthmaticus -primary Dx of cardiac arrhythmia -central venous catheterization contraindicated -active GIB -seizure -drug OD -burns -trauma -need for immediate surgery -uncured actively treated (chemo) CA -immunosuppression for TX pts -DNR status Their sample size was based on a power calculation to give 80% power to detect a 15% reduction in mortality (not that imp given difference detected) ITT analysis

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 d) Baseline SVO2 was 48% despite only 50% ventilated Rivers et al (cont’d) slide 25 No significant baseline differences b/w the 2 study groups. NNT = 100/ARR The EGDT spent longer time in the Ed – why is this? Didn't they all go to the ICU ASAP One thing to note is that the incidence of organ failure was NOT significantly different b/w the groups The very low SVO2 values were surprising and imply severe more than appreciated hypovolemia in these pts – Rivers feels this is a very sensitive early indicator in pts whose vitals & appearance would suggest that they are not that sick but in fact are on the verge of spiraling and showed some video examples of this at CAEP

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%) Rivers et al (cont’d) slide 26 Overall the groups got similar amounts of fluid cumutively when measured at 72 hrs but the EGDT group got more early on while the standard Tx group got more after the initial 6 hr period suggesting incomplete ED resuscitation

EGDT - Controversies Has never been replicated
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? Controversies Slide 27 The most clear consensus in the literature and most likely explanation is that the difference b/w this trial and those that preceded it is the early timing of the intervention. The feeling is that although SVO2 is an imperfect (due to inability to tell u about regional hypoperfusion – just gives an overall picture), together with lactate these are more sensitive markers to follow than vitals and urine output etc A lot of trials tried to increase oxygen delivery to supernormal levels and this may have missed the mark – establishing normalized hemodynamics appears a more valid goal, especially if you are using vasoactive meds to achieve your ends (and the resultant complications). The rationale behind these trials was the inconsistent observation that in some series (but not others) septic shock survivors were more likely to have high CI’s & DO2’s. It would be nice to see some further corroborating studies especially ones looking to elucidate which part of this protocol gives the greatest benefit and what we can do without

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?

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 Diffuse disease Normal cap wedge Fi02:pa02 <300 <36hrs since intubated

ARDS Network Primary outcomes Secondary 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) slide 64 Barotrauma was any new PTX, pneumomediastinum, SC emphysema, or pneumatocoele > 2cm in diameter

ARDS Network - Results Low Vt group Significantly decreased mortality
31.0% vs. 39.8% ARR 8.8% (95%CI %); 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 ARDS-Net trial (cont’d) slide 65 Study was stopped early after an interim analysis revealed sig dec in mortality in experimental group

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: 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: 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:

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 Background Slide 71 The recent use of steroids in septic shock partially owes its renaissance to etomidate – introduction of etomidate infusions in Glasgow coincided with increased mortality rates in ICU pts w/o changing the injury severity scores. Etomidate selectively inhibits 11-beta hydroxylase which converts deoxycortisol to cortisol. This suggested that reduced cortisol levels can increase mortality in septic shock pts. Mechanism for reversal of vascular catecholamine resistance may be inhibition of nitric oxide synthase, increased expression of catecholamine receptors, dec’d production of inflammatory compounds, and stimulation of guanylate cyclase Prigent et al. Clinical review: Corticotherapy in sepsis. Crit Care 2004; 8:

Annane et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288: 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. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock slide 72 The largest of three RCT’s to show benefit from low dose steroids in septic shock. French study in 19 different ICUs Inclusion criteria 18 yo or older All of Documented or strongly suspected infection Temp >38.3 or < 35.6 HR > 90 SBP < 90 for at least 1 hr despite adequate fluid replacement & > 5 ug/kg/min dopamine or epi/norepi use U/O < 0.5 ml/kg/h for at least 1 hr or PaO2 / FiO2 < 280 mm Hg or Lactate > 2 mmol/L Need for mechanical ventilation Exclusion criteria Pregnant Acute MI or PE Advanced CA Advanced AIDS Contraindication to steroids Etomidate 6 hrs prior to enrollment Randomized w/in 3-8 hrs of shock onset (amended) All had short corticotropin test prior to randomization = giving 250 ug of IV tetracosactrin and taking cortisol levels immediately prior, at 30 & 60 mins. Relative adrenal insufficiency (nonresponders) was defined as a change of 90 ug/L or less, a value they derived from earlier studies suggesting that pts w/ an increase less than this correlated with increased mortality Calculated a sample size of 270 pts to detect a 20% difference in 28d mortality w/ 90% probability assuming 95% mortality in nonresponder placebo group and a frequency of 40% nonresponders ITT analysis

Results Mortality Reliance on vasopressors Overall Non-responders
No difference in 28 day mortality Non-responders 28 day mortality - 53 vs 63%; ARR 10%, OR 0.54 (95%CI ) NNT = 10 Reliance on vasopressors No difference Median time to withdrawal 7 vs 10 d, HR 1.91 (95%CI ) Annane et al cont’d slide 73 The mortality benefit faded out of statistical significance at 1 yr in the non-responders ARR 9% OR 0.57 (95%CI ) P = 0.07

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 Criticisms slide 74 Could the results have been due to increased mortality in the placebo group due to inclusion of pat w/ true primary adrenal insufficiency mimicking septic shock causing inc’d mortality in the placebo group rather than dec’d mortality in the steroid group? Possibly but the trial reflects real life practice – would expect some missed diagnoses to occur. CORTICUS trial = Corticotherapy for septic shock, a European multicenter phase III trial Although the change in the entry criteria (making inc’d lactate optional, and increasing time to enrollment to 8 hrs) likely had little impact we don’t really know b/c it was never looked at by the investigators Power calculation based on higher than observed mortality causing Study to likely be underpowered – none the less they detected a difference

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 Suggested diagnostic approach slide 78 Test results can be confusing and may need to be repeated so give dex 2 mg is approx same as 50 mg of hydrocortisone but it lacks the mineralcorticoid activity so its not ideal R

Steroid Algorithm Draw baseline cortisol and do ACTH stim test
Give dexamethasone in ED Does not interfere with ACTH stim test <414nmol/L >938nmol/L <250nmol/L >250nmol/L Cooper & Stewart. Corticosteroid insufficiency in acutely ill patients. N Eng J Med. 2003; 348:

Surviving Sepsis Guidelines - Steroids
IV hydrocortisone 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) SCCM Guidelines slide 69 High dose steroids first popularized in the 70’s were subsequently shown to be ineffective, or harmful in 2 RCT’s and 2 meta-analyses.

Glycemic Control in Sepsis
Skip over this Need to know for ICU Also give insulin to hyperglycemic pts in the ED who you are treating for a critical illness (ie septic shock)

RCT N=1548 Randomized to Primary outcomes
Van den Berghe et al. Intensive insulin therapy in critically ill patients. N Eng J Med. 2001; 345: 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 mmol/L Primary outcomes All-cause ICU mortality Van den Berghe et al. Intensive insulin therapy in critically ill patients slide 103 This was a study conducted in Belgium in a surgical ICU. They included all pts who were intubated & ventilated. They excluded only 14 pts who were either in other trials, moribund, or DNR. The pt population was primarily post-op pts – 62% were post cardiac surgery – only 6% were post abdominal surgery. There appeared to be no pts w/ a primary Dx of septic shock. 13% had preexisting Dx of diabetes Secondary outcomes looked at were in-hospital death, LOS in ICU, need for prolonged mech vent or ICU (>14d) or readmission, renal replacement Tx, vasoactive meds, critical illness polyneuropathy, markers of inflammation, bloodstream infections & need for abx, transfusion requirements, hyperbilirubinemia. They calculated a sample size of 2500 pts to detect an ARR of 5% b/w/ treatment groups – the study was stopped early b/c of dec’d mortality in the experimental group. All analyses were done in ITT fashion

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

Intensive Insulin Therapy and Sepsis
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) Prolonged antibiotics = >10d

Criticisms Generalizability Not blinded
Van den Berghe et al. Intensive insulin therapy in critically ill patients. N Eng J Med. 2001; 345: 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 slide 105 Other concerns are hypoglycemia which occurred more frequently in intensive Tx group (39 vs. 6 pts) but w/o any serious consequences (most were asymptomatic). Also the details on nutritional support were not provided – if caloric intake differed b/w groups then this could confound things

Surviving Sepsis Guidelines – Glucose Control
IV infusions of insulin should be used to maintain serum glucose levels < 8.3 mmol/L (D) Based on post-op cardiac surgery pts & generalized to all critically ill pts

Recombinant Human Activated Protein C

RhAPC - Pharmacologic Actions
Anti-inflammatory Inhibits TNF-α, IL-1, IL-6 production Inhibits monocyte & neutrophil migration Inhibits lipid A activation of monocytes Inhibits tissue factor activation 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 Multiple pharmacologic actions Slide 87 Some have suggested the multi-faceted actions of apc may explain why it’s the first such agent to show decrease in mortality. PAI = plasminogen activator inhibitor type 1 TAFI = thrombin-activatable fibrinolysis inhibitor McCoy & Matthews. Drotrecogin Alfa (Recombinant Human Activated Protein C) for the treatment of severe sepsis. Clin Ther 2003; 25:

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 Protein C as Tx Slide 88 The conversion of protein C to activated protein C is impaired during sepsis secondary to dec’d levels of thrombomodulin & endothelial protein C receptors.

RCT – N=1690 Randomized to Primary outcome Severe sepsis
PROWESS Trial: Bernard et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Eng J Med 2001; 344: RCT – N=1690 Severe sepsis Randomized to rhAPC 24 ug/kg/h for 96 hrs Placebo Primary outcome All-cause mortality at 28d PROWESS Trial Slide 90 Conducted in 164 centers in 11 countries Inclusion criteria: -known or strongly suspected infection (defined as WBC’s in normally sterile body fluids, perf’d viscus, radiographic evidence of pneumonia in association w/ purulent sputum, or a syndrome w/ high risk of associated infection e.g. cholangitis) AND the following w/in a 24 hr period: 3 of 4 SIRS criteria Sepsis-induced dysfunction of at least one organ system <24 hrs prior to enrollment Exclusion criteria Pregnant or breast feeding <18 yo or wt > 135 kg At increased risk of bleeding Surgery 12 hrs prior to infusion Potential need for surgery Active post-op bleeding Severe head trauma, intracranial surgery, or stroke w/in 3 mos Any intracerebral AVM, cerebral aneurysm, CNS mass lesion Congenital bleeding disorder GIB w/in 6 wks unless corrective surgery performed Trauma considered to increase risk of bleeding Known Hypercoagulable state Activated protein C resistance Hereditary protein C, S, ATIII deficiency Anticardiolipin or antiphospholipid ab’s Lupus anticoagulant Homocysteinemia Known or suspected DVT or PE w/in 3mo Pt family or physician not in favor of aggressive Tx or advance directive to same extent Moribund – death felt to be imminent Less than 28d expected survival b/c of underlying dz (e.g. advanced neoplasm) HIV & last CD4 count <50/mm3 Hx of bone marrow, lung, liver, pancreas, or small bowel transplant Chronic renal failure requiring dialysis (HD or PD) Known or suspected portosystemic HTN, chronic jaundice, cirrhosis, or chronic ascites Acute pancreatitis w/ no established source of infection Participation in another study w/in 30d before current study Use of any of the following meds: UFH to tx active thrombosis 8h before APC gtt LMWH at doses > prophylactic w/in 12 hrs Coumadin w/in 7d and if INR not in normal range ASA >650 mg/d w/in 3d GPIIbIIIa’s w/in 7d ATIII >10,000 U w/in 12 hrs Protein C w/in 24h APC was given as continuous infusion of 24 ug/kg/h for 96 hrs which was interrupted 1 h before any procedures and resume 1h later (12 h for surgery)

PROWESS Trial - Results
rhAPC significantly reduced mortality 24.7% APC vs. 30.8% placebo ARR 6.1% (95% CI ); NNT = 16 rhAPC had non-significant increase in risk of serious bleeding 3.5% vs. 2.0% (p=0.06), NNH = 67 Bernard et al. cont’d slide 91 Results remained consistent with ITT analysis & Kaplan-Meier analysis They also saw concomitant decreases in IL-6 & D-dimer levels in the APC group The risk of serious bleeding was increased in the APC group approaching statistical significance – serious bleeds occurred primarily in pts w/ identifiable risk factors such as gastric ulceration. The increased bleeding risk did reach statistical significance during the infusion period and returned to baseline once the infusion was stopped. – this is in keeping with its short half life. Review of the safety data reveals the following: 4 deaths due to bleeding, related to the study drug per the investigators, occurred in the rhAPC, and none in the placebo arm. There was an increased rate of bleeding adverse events and bleeding serious adverse events in the rhAPC treated patients compared to placebo. There was a higher mortality rate in the first APACHE II quartile in the rhAPC group compared to placebo. There was a higher rate of serious bleeding events in the first APACHE II quartile in the rhAPC group compared to placebo. There was a higher mortality in patients requiring emergency surgery in the rhAPC group compared to placebo. There was a higher mortality rate in the rhAPC steady state 4th quartile (highest concentration) when compared to the first 3 quartiles. Anti-APC antibody detection was rare, though one of the two patients with positive results developed superficial and deep vein thrombosis. This patient reportedly died after the 28-day study period. Other than bleeding events, there were no other patterns of adverse event noted in the rhAPC group compared to placebo. Because of the nature of this population, significant adverse events may have been subsumed in the underlying illness of the patients. Current surveillance of commercial use put the incidence of intracranial hemorrhage at 0.2%

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 Post hoc analyses Slide 93 Of note, the exploratory analyses of important patient subgroups showed a reverse mortality trend in the first APACHE II quartile and less benefit in patients who fell into the second APACHE II quartile compared to the third and fourth APACHE II quartiles. Among the adult patients studied, there was a smaller treatment effect in those younger than 50 years of age. This may have implications for labeling to pediatric patients, where data in the pediatric population are limited. In addition to the APACHE II subgroups, other exploratory analyses indicate a treatment effect in patients with DIC at baseline and no effect in those without DIC at baseline, and almost no treatment effect in patients with less than two organ failures. Also of note was a significant difference in mortality among patients randomized to rhAPC between the first and second half of the study. This finding resulted in extensive FDA analyses to assess the potential impact of the manufacturing change and the protocol amendment, both of which were instituted at similar time approximately half way through the study. 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:

Tqo main points here are the different outcomes seen in pts with APACHE II scores <25 and >25 & pts w/ single vs multiple organ dysfunction. As a result the FDA has limited use fo rhAPC to pts at significant risk of death as evidenced by higher APACHE II scores, and the European Agency for the Evaluation of Medicinal Products limits it to pts severe sepsis and MOD 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:

Prowess - Criticisms Face Validity Validity of the results
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 Slide 95 Entry criteria were modified to exclude pts who were likely to die from causes other than sepsis (Tx pts, end-stage liver dz etc) as well as pts w/ organ failure >24h at enrollment. They changed the placebo from saline to 0.1% albumin. And they cahnged the cell line from which they made the rhAPC. The end result was a post-amendment study populations that had less severe underlying illness & more acute infection. The subsequent FDA analysis revealed that the efficacy before & after the protocol amendment was significantly different: The mortality rates for the 720 patients enrolled under the original protocol were 30% for placebo and 28% for rhAPC. Under the revised protocol, the mortality rates for the 970 enrolled patients were 31% for placebo and 22% for rhAPC (Table 25). The mortality rates for rhAPC the original and newly manufactured product were 29% compared to 19%. The implementation of this manufacturing change occurred in about half way through the study, at about the same time as the changes in the protocol. Overall, an analysis of the two protocol versions showed that under the amended version of the protocol there were fewer patients: with malignancies, experiencing non-sepsis deaths, with chronic APACHE II health points, who had with life support withdrawn, who were immunocompromised (including patient on chemotherapy and radiotherapy), at nursing facility prior to entry, and with disabilities and more patients were at home prior to the onset of sepsis 81 patients or 11% eligible for the original protocol would not have been eligible for the amended version of the protocol. This highlights the fact that the amended protocol did enroll a different patient population compared to the original protocol. Analysis of the pt populations before & after amendment suggests they do not account for observed inc’d efficacy The pts enrolled prior to protocol change who would not have made it into the study under the new exclusion criteria acutally had greater benefit than those who still would have met the new entry criteria 2. The pts who had more chronic health points (and therefore were more likely to be excluded in the second half of the study) actually derived more benefit. Differences in mortality rates between the first and second half of the study may also be due to the smaller sites enrolling fewer patients. The relative risks of the patients at individual sites are presented in Appendix 8. Patients enrolled in sites ultimately dropped from the study before its completion were more likely to have a more severe SIRS, as reflected in organ dysfunction scores, have greater PC activity levels and were more independent and required little or no assistance as reflected by the activities of daily living (ADL) scores. An analysis conducted of 705 patients enrolled at US sites, showed a mortality rate of 25% on rhAPC compared to 33% on placebo It is impossible to say if the differences before & after protocol change was due to differences in the drug, the pts enrolled, chance, or bsome combination of these variables based on the available data. Thought the amino acid structure of rhAPC is very similar to the wild type, differences exist due to extensive post-translational modification primarily in the form of glycosylation. Post-translational modification is largely determined by the cell type in which a protein is expressed. Therefore it is conceivable that despite the drug company being unable to detect any structural difference b/w the new & old lots of rhAPC, one may indeed exist possibly accounting for the marked change in efficacy. The following are some of the changes: Simplify the primary analysis such that the primary analysis was confined to patients meeting the diagnosis of severe sepsis. Eliminate a primary planned analysis of Protein C deficiency (analyze as secondary instead) and “septic shock” from the primary and secondary analyses. Clarify exclusion criteria for patients with esophageal varices. Add exclusion criteria for patients having undergone bone marrow, lung, liver, pancreas, or small bowel transplantation. Add exclusion criteria for patients who were considered moribund and where death was imminent (within 24 hours). Add exclusion criteria for patients whose family had not committed to aggressive management of the patient. Add exclusion criteria for patients with acute pancreatitis without known infection. Clarify exclusion criteria for patients with a history of malignancy. Add exclusion criteria for patients having organ failure for greater than 24 hours at the time of meeting all inclusion criteria. Change placebo from normal saline to 0.1% HSA. Replace “septic shock status” with “Protein C activity class” as a covariate for the primary analysis. They also changed the cell line used to produce the APC

Criticisms External validity Other concerns
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? Remaining questions Slide 97 Of particular concern to me is that many of the groups excluded from PROWESS are the exact same groups accounting for some of the increase in incidence of sepsis e.g. Tx pts, HIV pts

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 Cost Slide 98 The economic ananlyses concluded that rhAPC is reasonably cost effective ehen used in the appropriate pts: ie.e pts w/ more severe disease as evidenced by APACHE II scores of 25 mor more, criteria for severe sepsis, and a reasonable life expectancy if they survive.; Manns et al. An economic evaluation of activated protein C for severe sepsis. N Eng J Med. 2002; 347:

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 SCCM Guidelines for Treatment of Septic Shock Slide 16 Guidelines developed through critical review of the literature & consensus conference by experts from 11 international critical care & ID organizations. Ranked the evidence similarly to the way AHA ranks evidence in ACLS. Importantly there were no industry members on the committee, no industry presence at the meetings, and no industry input into the guidelines. Note in text that “although these recommendations are written primarily for the pt in the ICU setting, many recommendations are appropriate targets for the pre-ICU setting”. They had very rigorous methodology for grading literature & resolving differences in opinion (e.g. consulting an outside epidemiologist when there was disagreement on how to rate a study) They acknowledge that “the majority of the recommendations are not supported by high level evidence. Most are supported by expert opinion only”

CHR Sepsis Protocol

CHR Severe Sepsis Algorithm

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Sepsis Syndromes Aric Storck October 5, 2006.

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Sepsis Syndromes Aric Storck October 5, 2006.

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