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2. PROBLEM EXTENT SEVERE SEPSIS AND SEPTIC SHOCK MORTALITY IS UNDER CONTROL…..!!! MISSION 1) Increase awareness, understanding and knowledge 2) Define standards of care in severe sepsis 3) Reduce the mortality associated with sepsis by 25% over the next 5 years

3. PROBLEM EXTENT Italian ICU REGISTRY: (margherita, prosafe projects, GIVITI group): (margherita, prosafe projects, GIVITI group): SEPTIC SHOCK patients 2006: 158 ICUs, n 2160, H MORTALITY 62,1% 2007: 157 ICUs, n 2347, H MORTALITY 61,2 % 2008: 174 ICUs, n 3067, H MORTALITY 60,9% 2009: 180 ICUs, n 3229, H MORTALITY 59,0% 2010: 181 ICUs, n 3312, H MORTALITY 57,4% 2011: 121 ICUs, n 2896, H MORTALITY 57,5% 2012: 147 ICUS, n 3596, H MORTALITY 57,4%

4. Steroid Glyce mia rh APC CPFA Seleni um CVVH high volume EGDT Albumi ne Erito ran (anti- LPS) HES NEGATIVE TRIALS SINCE… CEMETERY SECTION 2010-2014 PROBLEM EXTENT

5. GUIDELINES The majority of STRONG recommendations ‘DO NOT USE’ EBM and SEPSIS

6. PROBLEM EXTENT Arise Impress Promise ?

7. EARLY GOAL DIRECTED THERAPY

8. Rivers 01Process 14Arise 14 Usual Care Pre-RND NA2,1 ± 1,42,6 ± 1,4 EGDT Pre-RNDNA2,2 ± 1,42,5 ± 1,3 Usual Care 0-6 h3,5 ± 2,52,3 ± 1,91,7 ± 1,4 EGDT 0-6 h5,0 ± 3,0 2,8 ± 2,0, 2,0 ± 1,4 Usual Care 72 H13,3 ± 7,76,6 ± 4,55,1 ± 3,1 EGDT 72 H13,4 ± 6,47,2 ± 4,66,3 ± 3,1 FLUID INTAKE IN EARLY RESUSCITATION: A CHANGE ?

9. BUNDLES EFFECTIVENESS Favors SSPFavors controls

10. Clinical Evolution All the severe sepsis are equal ? Patient Identification

11. All the severe sepsis are equal ? Patient Identification 72 ICUs (Australia-New Zealand) from 2000-2013: 1,1 x 10 6 patients, 10,9 x 10 5 infection and organ failure < 24 h admission 87,9% SIRS 12,1% no SIRS (19,8%: 0 sign; 80,2%: 1 sign)

12. ARE ALL THE PATIENTS WITH SEPTIC SHOCK SIMILAR ? PREDISPOSITION: Pre-existing illness, genetic polymorphisms INSULT: Site of infection, type of infection, virulence and sensitivity of infecting pathogens; RESPONSE SIRS, other signs of sepsis, activated inflammation (PCT or IL-6) or impaired host responsiveness (HLA-DR); ORGAN DYSFUNCTION time and number of failing organs

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16. - IMMUNE DYSFUNCTION

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18. MDR infections and IgM MODENA ICU 2008-2013: 94 SEPTIC SHOCK patients with documented MDR/XDR infections Factors influencing mortality ORIC 95%p Pre-existing condition Cancer2,9651,14-7,710.026 Infection by Acinetobacter B.3,1971,01-10,210.045 IgM preparation0,2830.14-0.590.001 Multivariate analysis of risk factors for 30 days mortality. Multivariate logistic model including all the variables resulted to be significant or with an alfa level ≤ 0.10 at univariate analysis (i.e. Pre-exisiting conditions, Gram stain, resistance to carbapenems, type of bacteria, SAPS II, Mechanical ventilation, therapy with rhAPC and IgM preparation). Hosmer-Lemeshow test P =0.55 p <0,02

19. Days of septic shock Monocyte HLA-DR expression in patients with septic shock by MDR infections 5 patients PATIENT WITH MDR INFECTIONS Which differences ? Courtesy by Prof Cossarizza, Department of Immunology, University of Modena

20. MODENA ICU 2014: 10 SEPTIC SHOCK 5 MDR (1 death), SOFA score 8 (7-10); 5 No MDR (0 death), SOFA score 9 (8-12) PATIENT WITH MDR INFECTIONS Which differences ? Lymphocyte count and immunoglobulin concentration at shock appearance No MDR MDR

21. TAKE HOME PICTURE Clinical Research Pathophysiology Experience

22. TAKE HOME PICTURE

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25. - IMMUNOTHERAPYFACTS

26. - IMMUNOTHERAPYGM-CSF

27. - IMMUNOTHERAPYG-CSF

28. - IMMUNOTHERAPYG-CSF

29. Study Population: Retrospective cohort study, septic shock, January 2008 -December 2011. Excluded patients with end of life decisions and end-stage liver disease Methods: Standard of care (6-hour bundle + 24-hour bundle) + IgM therapy within 24 hour after shock at the discretion of the attending physician. 168 patients: 92 (55%) received IgM therapy Sepsis Bundles: The compliance to interventions included in the sepsis bundles were high and similar between the 2 groups but blood cultures before antibiotic and protective ventilation were provided more frequently in IgM patients. MODENA EXPERIENCE: early IgM-enriched immunoglobulin in septic shock

30. No IgM (N=76) IgM (N=92) P value 30 days mortality35 (46,1)23 (25,0)0,004 ARR = 21% NNT = 5 No IgM (N=59) IgM (N=59) P value 30 days mortality27 (45,8)15 (25,4)0,021 Multivariate logistic regression OR 0,35; CI 95% 0,14–0,85 Propensity Score Matching age, year of admission, type of admission, primary site of infection, pre- existing diseases, SOFA and SAPS II score, 6-hour and 24 hour bundles compliance. Results (2008-2011) Early IgM-enriched immunoglobulin in septic shock

31. PREDISPOSITION: Pre-existing illness, genetic polymorphisms INSULT: Site of infection, type of infection, virulence and sensitivity of infecting pathogens; RESPONSE SIRS, other signs of sepsis, activated inflammation (PCT or IL-6) or impaired host responsiveness (HLA-DR); ORGAN DYSFUNCTION time and number of failing organs PATIENTS WITH SEPTIC SHOCK ARE REALLY HETEROGENEOUS Which patients benefit the most of Ig therapy?

32. MDR infections and IgM MODENA ICU 2008-2013: 94 SEPTIC SHOCK patients with documented MDR/XDR infections All patients (N=94) 30 days Survivors (N=54;57%) 30 days Non-Survivors (N=40;43%) P value Age, years; mean (SD) 70.9 (12.2)69.6 (13.4)72.6 (10.2) 0.44 Surgical admission; N (%) 42 (44.7)26 (48.1)16 (40.0) 0.43 Pre-existing condition; N (%) 0.006 None 29 (30.9)19 (36.5)10 (23.8) Cancer 23 (24.5)7 (13.5)16 (38.1) Site of infection; N (%) 0,31 Pneumonia 51 (54,3)25 (46,3)26 (65,0) Intra-abdominal 39 (41,5)23 (36,2)16 (40,0) Blood 24 (25,5)11 (20,4)13 (32,5) Hospital acquired infection N (%) 60 (63,8)31 (57,4)29 (72,5) 0.132 Gram negative; N (%) 75 (79.8)47 (87.0)28 (70.0) 0.042 resistant to carbapenems; N (%) 27 (28.7)13 (24.1)14 (35.0) 0.051 Microorganisms; N (%) 0.028 Pseudomonas Aeruginosa 24 (25.5)14 (25.9)10(25,0) Escherichia Coli 21 (22.3)15 (27.8)6 (15.0) Acinetobacter baumannii 16 (17,0)6 (11.1)10 (25.0) MRSA 12 (12.8)3 (5.6)9 (22.5) Klebsiella Pneumonia 10 (10.6)8 (14.8)2 (5.0) Others 11 (11.7)8 (14.8)3 (7.5) SOFA; mean (SD) 9,7 (3,5)9.4 (3.4)10.1 (3.6) 0.243 SAPS II; mean (SD) 58,9 (17.4)56.1 (15.3)62.7 (19.6) 0.104

33. MDR infections and IgM MODENA ICU 2008-2013: 94 SEPTIC SHOCK patients with documented MDR/XDR infections # patients until December 2011, (N = 75) TREATMENTS p 0,044 p 0,024

34. IgM and MDR microrganisms Antibody titers vs ‘Italian 2013-2014 MDR’ bacteria IgM - Pentaglobin © Courtesy by by Prof. Gian Maria Rossolini, Dpt. of Medical Biotechnologies - University of Siena and University of Florence (Italy)

35. Why IgM preparation ? IgG (Mw 150) IgA (Mw 160) IgM (Mw 970) Plasma73% (1320 mg/dl) 19% (350 mg/dl) 8% (150 mg/dl) IgG polyvalent> 98%< 2%Nn IgM enriched76%12% KEY NOTES →Natural IgM is the first to appear during ontogeny, the oldest and the only class of antibody present in all vertebrates →Immune IgM is the first antibody to be produced during immune response →IgM has low affinity but high reactivity to common components of invading microorganisms such as nucleic acids, phospholipids and carbohydrates. →The pentameric structure provides an high binding affinity (x 1000 respect to IgG) for the complement protein C1q that promotes the elimination of the pathogen/apoptotic cells by phagocytic cells. →IgM participates in diverse pathophysiologies including infection, B cell homeostasis, inflammation, autoimmunity and atherosclerosis.

36. Anti Bacterial Anti Toxin Anti Inflammatory Anti-apoptotic effect on immune cells Ig Therapy: HOW MAY IT WORK ? Pleiotropic effects Inflammasome Modulation

37. Modena On Going Research Host immune response in patients with septic shock by multidrug resistant bacteria before and after the administration of IgM- enriched immunoglobulins. A single-centre pilot study. Study participants and design. A total of 15 patients with septic shock by MDR bacteria and treated with IgM preparation will be included in a prospective, observational, proof of concept, single-centre pilot study. The study will be performed in an academic post-operative and medical ICU in Modena’s Policlinico, Italy, from September 2014 to September 2015. Immunological Measurements LPS and cytokine quantification Analysis of activated caspase-1 RNA Isolation and Real Time PCR for expression of 84 key genes involved in the function of inflammasomes, Monocyte immunophenotype Quantification of circulating mtDNA immunoglobulins and lymphocyte immunophenotyping

38. Clinical Evolution All the severe sepsis are equal ? Patient Identification

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40. Less fluids (30%) More Inotropes (24%) No accordance vasopressor Pressures or Echo ? SEPSIS IN ABDOMINAL SURGICAL PATIENTS FLUID INTAKE IN EARLY RESUSCITATION: A CHANGE ?

41. CONCLUSIONS Clinical Decision making -Patients with septic shock by MDR Infections have still an high risk of mortality despite the application of treatments included in the traditional sepsis bundles. -New strategies should be considered for the management of this high risk population -Patients with septic shock and MDR infection seems to have a severe impairment of innate and adaptive immune-system (immune-paralysis phase) -IgM may have some benefit in this population by Providing direct bacterial inactivation and clearance Supporting the immune-system (anti-apoptotic mechanisms ?)

42. FLUID THERAPY SEPSIS IN ABDOMINAL SURGICAL PATIENTS PIRO Fluid resuscitation

43. TRADITIONAL APPROACH Aggressive Resuscitation with fluids to restore ASAP optimal organ perfusion Low-volume fluid resuscitation Dilution of clotting factors Hypothermia Increase of hydrostatic pressure Intra-abdominal hypertension HAEMORRAGIC SHOCK

44. © Copyright Showeet.com - Courtesy by A. Cossarizza IMMUNE DYSFUNCTION & INFLAMMASOME