1. Septic Shock in 2004 Emergency Department Strategies for Reducing Mortality Moritz Haager PGY-3 May 13, 2004

2. 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

3. 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

4. Definitions Old SIRS T >38 or <36 HR > 90 RR > 20 or PCO 2 < 32 WBC > 12 or < 4 Too sensitive & simplistic

5. 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

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

7. Classifications reflect disease severity Diagnostic categoryMortality (%) SIRS criteria none3 27 310 417 Sepsis16 Severe sepsis20 Septic shock46  McCoy & Matthews. Drotrecogin Alfa (Recombinant Human Activated Protein C) for the treatment of severe sepsis. Clin Ther 2003; 25: 396-421

8. 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

9. 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

10. Sources of Infection Specific sites: Respiratory 36% Blood20% Abdomen19% Urinary tract13% Wounds & Skin7% Other5% 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

11. 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

12. SEPSIS INFLAMMATIONPATHOGENS TF EXPOSUREENDOTHELIAL INJURY ANTI-COAGULANT SYSTEM INHIBITON ACTIVATION OF CLOTTING CASCADE FIBRINOLYTIC SYSTEM INHIBITION PRO-COAGULANT EFFECT MICROVASCULAR THROMBOSIS MULTI ORGAN DYSFUNTION SYNDROME TNF-α, IL-1, IL-6, IL-7, Proteases, Leukotrienes, Prostaglandins Bradykinin, Platelet activating factors Free oxygen radicals Endotoxins, Exotoxins Direct endothelial invasion ↓ AT III, ↓ aPC, ↓ pS ↓ thrombomodulin ↑ PAI-1

13. 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

14. Clinical Effects Peripheral vasodilatation & capillary leak Intravascular volume depletion Myocardial depression Hypermetabolic state – global tissue hypoxia DIC – coagulation > fibrinolysis

15. Treatment of Septic Shock Septic Shock Infection Control Supportive Care Immuno- modulatory Therapies EGDT Ventilation Antibiotics Surgical Management Steroids rhAPC

16. SCCM Guidelines for Treatment of Septic Shock Utilize EGDT in 1 st 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

17. Early Goal Directed Therapy

18. SCCM Guidelines “resuscitation…should not be delayed pending ICU admission.” Goals of resuscitation in 1 st 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

19. Rationale behind EGDT Time is survival: Goal is to achieve balance b/w O 2 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

20. 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

21. 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

22. 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 O 2 sat measurement EGDT discontinued once transferred to ICU – all ICU staff blinded to pts assignments Primary endpoint was mortality

23. Edwards PreSep Central Venous Oximetry Catheter

24. EGDT Protocol

25. 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 SVO 2 was 48% despite only 50% ventilated

26. 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%)

27. 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

28. 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

29. 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

30. 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

31. Fluids in Sepsis

32. 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)

33. 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

34. Vasopressors Just need a little squeeze..

35. SCCM Guidelines Should be used when shock refractory to fluid resuscitation Life-threatening hypotension (E) Dopamine or norepinephrine are 1 st 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 2 nd line agent in refractory shock (E) Dobutamine may be considered in refractory shock felt to be due to low cardiac output (E)

36. 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

37. Norepinephrine or Dopamine 1 st 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

38. Transfusion

39. 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

40. 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%

41. 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

42. 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

43. 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

44. Antibiotic Treatment The war against bugs

45. 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

46. 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

47. 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

48. 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

49. 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

50. 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

51. 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

52. 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

53. Source Control Getting to the root of the cause

54. 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

55. 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

56. Ventilatory Strategies

57. 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 45 o to prevent VAP

58. Background Traditional vent parameters TV 10 – 15 ml/kg, minimal PEEP to maintain normal PCO 2, PO 2 & 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

59. 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

60. 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

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

62. 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 H 2 O 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 H 2 0 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

64. 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

65. 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

66. 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

67. Conclusions General consensus in the literature that ARDS trial results are valid, and that V T should be 6-8 ml/kg Plateau pressures should be kept to < 30 cm H 2 O PEEP should be used to minimize alveolar collapse at pressures as low as possible (start 5-10 cm H 2 O)

68. Steroids

69. 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)

70. 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

71. 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

72. 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

73. 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

74. 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

75. 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

76. 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

77. 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

78. 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

79. 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

80. 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

82. 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

83. 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

84. Recombinant Human Activated Protein C (rhAPC = Drotrecogin alfa = Xigiris® aka superdrug)

85. 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)

86. 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)

87. 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

88. 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

90. 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

91. 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

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

93. 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

94.  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

95. 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

96. 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

97. 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?

98. 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

99. 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

100. 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

101. Insulin therapy Sugar: its not just bad for your teeth..

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

103. 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

104. 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

105. 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

106. 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

107. Conclusions We can reduce mortality in sepsis in the ED: EGDT:ARR 16.0% ARDSNet vent strategyARR 8.8% SteroidsARR 10.0% rhAPCARR 6.1% InsulinARR 3.4% Dex in MeningitisARR 8.0% Early appropriate Abx Source control