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ATS Clinical Year in Review Sepsis Charles L. Sprung, M.D.

Department of Anesthesiology and Critical Care Medicine Hadassah Medical Center. ATS Clinical Year in Review Sepsis Charles L. Sprung, M.D. Presenter Disclosures.

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ATS Clinical Year in Review Sepsis Charles L. Sprung, M.D.

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  1. Department of Anesthesiology and Critical Care MedicineHadassah Medical Center ATS Clinical Year in Review Sepsis Charles L. Sprung, M.D.

  2. Presenter Disclosures Part 1: Personal financial relationships with commercial interests relevant to this presentation during the past 12 months: 1. Eli Lilly & Co – Consultancies 2. Novartis Corp- Other- Data Monitoring Committee 3. Takeda- Industry-sponsored grants 4. Eisai, Corp- Other- Steering Committee + Industry-sponsored grants 5. Artisan Pharma, Inc- Other- Data Monitoring Committee 6. Hutchinson Technology Incorporated- Other- Data Monitoring Committee

  3. Presenter Disclosures Part 2: Personal financial relationships with non-commercial interests (e.g., government or other nonprofit funding) relevant to this presentation, within past 12 months: No relationships to disclose Part 3: Relevant institutional financial interests: No relationships to disclose Part 4: Personal financial relationships with tobacco industry entities within the past 3 years: No relationships to disclose

  4. Clinical Year in Review- Sepsis • Russell JA, et al and the VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-87. • Ferrer R, et al and Edusepsis Study Group. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA. 2008;299:2294-2303. • Moreno RP, et al and SAPS 3 Investigators. Sepsis mortality prediction based on predisposition, infection and response. Intensive Care Med 2008; 34:496–504. • Dulhunty JM, et al and for the ANZICS Clinical Trials Group. Does severe non-infectious SIRS differ from severe sepsis? Results from a multi-centre Australian and New Zealand intensive care unit study. Intensive Care Med. 2008;34:1654-61.

  5. Surviving Sepsis Campaign Guidelines Vasopressors • Either norepinephrine or dopamine as the first choice vasopressor agent to correct hypotension in septic shock. Grade 1C • Epinephrine, phenylephrine, or vasopressin should not be administered as the initial vasopressor in septic shock. Grade 2C • Vasopressin 0.03 units/min may be subsequently added to norepinephrine with anticipation of an effect equivalent to norepinephrine alone. • Epinephrine be the first chosen alternative agent in septic shock that is poorly responsive to norepinephrine or dopamine. Grade 2B • Dellinger P. Crit Care Med 2008;36:296-327

  6. Clinical Year in Review- Sepsis • In this multicenter, randomized, double-blind placebo-controlled study, patients in septic shock receiving a minimum of 5 μg of norepinephrine per minute were randomized to receive either low-dose vasopressin (0.01-0.03 U per minute) or norepinephrine (5 to 15 μg per minute) in addition to open-label vasopressors. Russell JA. N Engl J Med 2008;358:877

  7. VASST PRIMARY HYPOTHESIS • Low dose vasopressin (0.03 U/min) infusion compared to norepinephrine infusion decreases 28 day mortality from 60% to 50% in severe septic shock. • N= 776 (power = 80%, α= 0.05) Russell JA. N Engl J Med 2008;358:877

  8. VASST SECONDARY HYPOTHESES • The beneficial effects of vasopressin are more pronounced in the subgroup of patients with more severe septic shock. More Severe septic shock: ≥ 15 μg/min norepinephrine Less Severe septic shock: 5 - 14 μg/min norepinephrine • 90-day mortality, days alive & free of organ dysfunction, length of stay (ICU & hospital) Russell JA. N Engl J Med 2008;358:877

  9. CENTRES • 27 centres in Canada, Australia and US

  10. NE AVP Off AVP Plasma Vasopressin Norepinephrine vs. Vasopressin 140 120 100 (pmol/L, median +IQR) 80 60 Plasma vasopressin level 40 20 0 Baseline 6 hours 24 hours 72hours 7days Timepoint Russell JA. N Engl J Med 2008;358:877

  11. 120 100 80 60 MAP (mmHg, mean +/-SD) NE AVP 40 20 0 0 5 10 15 20 25 30 Time from study drug infusion (days) Mean Arterial PressureVasopressin vs Norepinephrine Russell JA. N Engl J Med 2008;358:877

  12. 130 120 110 100 NE AVP 90 Herat rate (beats / min, mean +/-SD) 80 70 60 50 0 5 10 15 20 25 30 Time from study drug infusion (days) Heart rate Vasopressin vs Norepinephrine (p < 0.001) Russell JA. N Engl J Med 2008;358:877

  13. 130 120 110 100 90 Herat rate (beats / min, mean +/-SD) NE AVP 80 70 60 50 0 5 10 15 20 25 30 Time from study drug infusion (days) Heart rate AVP vs. NE (Days 1 - 4, p < 0.001) Russell JA. N Engl J Med 2008;358:877

  14. Survival - All Patients Log-rank statistic p = 0.27 day 28 p = 0.10 day 90 Russell JA. N Engl J Med 2008;358:877

  15. Serious Adverse Events Russell JA. N Engl J Med 2008;358:877

  16. Survival - Less Severe Shock Log-rank statistic p = 0.05 day 28 p = 0.03 day 90 Russell JA. N Engl J Med 2008;358:877

  17. Survival - More Severe Shock Log-rank statistic p = 0.77 day 28 p = 0.92 day 90 Russell JA. N Engl J Med 2008;358:877

  18. Clinical Year in Review- Comments • This study demonstrates the comparable effectiveness of vasopressin to norepinephrine therapy for vasopressor treatment of septic shock. • Vasopressin was used as an addition to norepinephrine and/or other vasopressor therapy for patients with relatively stable blood pressures on vasopressors, not rescue therapy for shock unresponsive to vasopressors. • Similar adverse events in the two groups may have been due to the exclusion of patients with acute heart disease in the study. • Vasopressin plus norepinephrine may decrease mortality compared to norepinephrine alone in less severe septic shock. • Treatment started 12 hours after septic shock may be too late for a vasopressor or any other therapeutic agent to affect mortality.

  19. Clinical Year in Review- Comments • Recent septic shock studies demonstrate lower mortalities- this study - 37%, Sprung (N Engl J Med. 2008;358:111-124 )- 33% and Annane (Lancet 2007; 360: 767−84)- 37% than those previously reported- Annane (JAMA 2002;288:862-870 )- 58% and Annane (Am J Respir Crit Care Med 2003;168:165-72)- 60%. • Physicians should be aware of the less recognized detrimental effects of catecholamines including stimulation of bacterial growth, increasing factors related to bacterial virulence and biofilm formation, affects on immune-cell populations and metabolic derangements which may not be present with alternatives such as vasopressin (Singer M. Lancet 2007;370:636-637).

  20. Survival - All Patients Log-rank statistic p = 0.27 day 28 p = 0.10 day 90 Russell JA. N Engl J Med 2008;358:877

  21. Outcomes: Mortality NICE SUGAR Study Finfer S. N Engl J Med 2009;360:1283

  22. Interaction of Vasopressin Infusion, Corticosteroid Treatment and Mortality of Septic Shock Russell et al. Crit Care Med 2009;37:811 - 818

  23. Vasopressin /Corticosteroid Mortality Interaction 1. Interaction statistic by logistic regression.2. Age-adjusted interaction statistic by logistic regressionRussell et al. Crit Care Med 2009;37:811 - 818

  24. Clinical Year in Review- Sepsis • Russell JA, et al and the VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-87. • Ferrer R, et al and Edusepsis Study Group. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA. 2008;299:2294-2303. • Moreno RP, et al and SAPS 3 Investigators. Sepsis mortality prediction based on predisposition, infection and response. Intensive Care Med 2008; 34:496–504. • Dulhunty JM, et al and for the ANZICS Clinical Trials Group. Does severe non-infectious SIRS differ from severe sepsis? Results from a multi-centre Australian and New Zealand intensive care unit study. Intensive Care Med. 2008;34:1654-61.

  25. Clinical Year in Review- Sepsis • Most studies of new therapeutic agents to decrease the high mortality of patients with severe sepsis have been negative. • Clinical study results and evidence-based guidelines are often not translated into clinical practice.

  26. JAMA 2008;299(19):2294-2303 Study Timeline PERCEPTION a before-and-after intervention study EDUCATIONAL PROGRAMME POST-EDUCATION DATA COLLECTION LONG-TERM FOLLOW-UP BASELINE DATA COLLECTION NOV-DEC 854 patients MAR-JUN 247 patients MAR-JUN 1465 patients JAN-FEB 2007 2006 2005

  27. THE SPANISH NETWORK 59 ICUs (21% of all Spanish ICUs) 1 3 2 2 1 General Coordination: Antonio Artigas Ricard Ferrer (Sabadell, Barcelona) SSC Coordination M. Levy 13 8 4 9 3 9 6 24 3 Area Coordinators:

  28. Educational Program General Coordination Design EP Sepsis Definitions Sepsis early recognition Sepsis treatments Educational Material Area Coordinators Area Coordinators + PI Homogenize the EP

  29. Educational Program: Homogeneity Interview Hospital Manager ICU ED Medical Ward Surgical Ward Physicians Clinical training PI Nurses Graphic material: distribution and display

  30. Inclusion Criteria All ICU admissions from the emergency department or from wards because of severe sepsis or septic shock. All ICU patients who develop severe sepsis or septic shock.

  31. Process-of-care variables SEPSIS RESUSCITATION BUNDLE 6H SEPSIS MANAGEMENT BUNDLE 24H

  32. Resuscitation Bundle (6H) 90 80 70 60 50 % Compliance 40 30 20 10 0 Lactate Blood Cultures Antibiotics Fluids + CVP>8 SvcO2>70 All Vasopresors Preintervention Intervention * p<0.05 68.9 62.4 66.5 * 54.4 50.1 46.7 40.9 * * 39.0 26.7 * 21.4 11.4 10.0 6.3 * 5.3 *

  33. Management Bundle (24h) 90 80 70 60 50 % Compliance 40 30 20 10 0 Steroids APC Glucose IPP All Preintervention Intervention * p<0.05 85.7 82.7 54.7 51.9 49.6 45.4 44.6 * * 44.3 * 15.7 * 10.9

  34. Educational Program and Mortality p= .036 p= .01 28d Mortality: Kaplan-Meier curve Absolute reduction: 4.3% Relative reduction 10% Absolute reduction: 4.3% Relative reduction 10% SSC objective was 25%!

  35. Impact of Baseline Compliance Management Bundle Resuscitation Bundle * * * * Mortality * * p<0.05 Cat 1: < 4 tasks (n= 20) Cat 2: 4-5 tasks (n= 19) Cat 3: > 5 tasks (n= 20)

  36. Resuscitation Bundle (6H) Long-term follow up (23 centers) * p<0.05 71.0 * * 69.6 * 65.4 65.2 60.5 61.1 59.1 56.7 53.5 53.0 44.7 42.8 * 39.3 30.0 25.2 * 14.6 13.7 12.9 10.0 7.3 6.3

  37. Management Bundle (24h) Long-term follow up (23 centers) * p<0.05 94.8 89.6 87.8 * 69.7 * 59.1 59.1 * 56.3 51.0 49.0 44.3 44.7 38.4 * 26.7 19.6 9.4

  38. Educational Program and Mortality Long-term follow up (23 centers) 38,5

  39. Clinical Year in Review- Sepsis • At baseline, process of care compliance rates were extremely low. • After the intervention, compliance improved in the sepsis resuscitation and management bundles and hospital mortality decreased from 44% to 40%. • Long-term follow-up revealed that compliance with sepsis resuscitation bundles returned to baseline but compliance with sepsis management and mortality remained stable in relation to the post-intervention period.

  40. Clinical Year in Review- Comments • This study demonstrated that a national educational program decreased hospital mortality in patients with severe sepsis. • The study suggests that quality improvement programs using bundles of care may be more effective in decreasing mortality in sepsis than new treatments. • Despite the fact that the interventions were rather simple, not institution specific and did not include more sophisticated, effective methods, mortality still decreased.

  41. Clinical Year in Review- Comments • Baseline compliance was rather poor and although compliance improved, the improvement rates were not dramatic nor sustained, especially for some bundles which would seem important in decreasing mortality such as antibiotic administration. • Recent studies of steroid therapy (Sprung CL. N Engl J Med. 2008;358:111-124) and glucose control (Brunkhorst FM. N Engl J Med 2008;358:125-39; Finfer S. N Engl J Med 2009;360:1283-97) showing a lack of benefit in decreasing mortality raise questions as to the benefit of these bundles used in this study in decreasing mortality. • The design without a control group makes it difficult to establish a causal connection between the intervention, improvement in process of care variables and outcome.

  42. Clinical Year in Review- Sepsis • Russell JA, et al and the VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-87. • Ferrer R, et al and Edusepsis Study Group. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA. 2008;299:2294-2303. • Moreno RP, et al and SAPS 3 Investigators. Sepsis mortality prediction based on predisposition, infection and response. Intensive Care Med 2008; 34:496–504. • Dulhunty JM, et al and for the ANZICS Clinical Trials Group. Does severe non-infectious SIRS differ from severe sepsis? Results from a multi-centre Australian and New Zealand intensive care unit study. Intensive Care Med. 2008;34:1654-61.

  43. The PIRO Concept • Predisposition: Premorbid illness with reduced probability of short term survival. Cultural or religious beliefs, age, gender. • Insult: Culture and sensitivity (infection) of infecting pathogens; detection of disease amenable to source control. • Response: SIRS, other signs of sepsis, shock, C-reactive protein. • Organ: Organ dysfunction as number dysfunction of failing organs or composite score (e.g., MODS; SOFA; LOD). Levy MM, Fink MP, Marshall JC, et al. (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med 29:530-538.

  44. Clinical Year in Review- Sepsis • PIRO (predisposition, infection, response, organ dysfunction/failure), a system for risk stratification, remains a concept that has not been tested clinically. • Using the SAPS 3 database, 2628 patients in the ICU for > 48 hours were evaluated to determine the usefulness of PIRO for predicting mortality in patients with infection and sepsis.

  45. SAPS 3 PIRO Score Predisposition Injury Response/Organdysfunction/failure • Age • Intra-hospital location • Co-Morbidities • Length of stay in the hospital • Reasons for ICU admission • Acquisition of infection • Extension of infection • Site of infection • Agent • Renal dysfunction • Coagulation dysfunction • Cardiovascular failure • Respiratory failure • Renal failure • Coagulation failure • CNS failure Moreno R. Intensive Care Med 2008;34:496-504

  46. Clinical Year in Review- Sepsis • Hospital mortality was 41%. • The SAPS 3 PIRO score had excellent predictive value for mortality and the PIRO components independently contributed to outcome prediction.

  47. SAPS 3 INFECTION MODEL SCORE SHEET Moreno R. Intensive Care Med 2008;34:496-504

  48. PROGNOSTIC PERFORMANCE: Discrimination SAPS 3 model: aROC: 0.735 (95% CI: 0.716-0.754) PIRO model: aROC: 0.772 (95% CI: 0.754-0.790)

  49. Clinical Year in Review- Comments • This is the first study addressing the question as to which factors affect the outcome of patients with sepsis in which the three levels of predisposition, injury and response were addressed together. • This study demonstrates the clinical validity of the PIRO concept whose components independently contributed to mortality prediction. • This PIRO system modeling the risk of mortality from sepsis attributes different weights to specific organ failures which is different than other scores which give all organ failures the same weight. • Although provocative, the proposed system should be prospectively validated in an independent cohort to demonstrate its specific usefulness and clinical utility.

  50. Does severe non-infectious SIRS differ from severe sepsis?Results from a multi-centre Australian and New Zealand intensive care unit study Dulhunty JM1,2, Lipman J1,2, Finfer S3-5, and the Sepsis Study Investigators for the ANZICS Clinical Trials Group Intensive Care Med. 2008;34:1654-1661

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