Disclosure: Member of the advisory board of EUPHAS 2

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2 Disclosure: Member of the advisory board of EUPHAS 2

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4 SEPSI SEVERA confronto con altre patologie maggiori (USA) MORTALITA Mortality of Severe Sepsis Morti / anno AIDS* CANCRO mammella IMA SEPSI SEVERA National Center for Health Statistics, American Cancer Society, *American Heart Association Angus DC et al. Crit Care Med. 2001;29:

5 Proiezione della incidenza della Sepsi Severa in USA: Casi di sepsi (x10 3 ) 1,800 Casi di sepsi Severa 600 1,600 Popolazione USA 1,400 Invecchiamento Invasività 1, ,000 Immunosoppressione Anni 500 Popolazione totale USA (mlioni) Angus DC, et al. JAMA 2000;284: ; Angus DC, et al. Crit Care Med 2001;29:

6 The Italian Sepsis Study (1995) Mortalità nei pazienti con sepsi grave in Italia: 52,5% Lo studio ha coinvolto 2950 pazienti* in 99 centri Italiani di terapia intensiva * 1101 pazienti analizzabili alla prima interim analisis L.Salvo et al. The Italian sepsis study: preliminary results on the incidence and evolution of SIRS, sepsis, severe sepsis and septic shock. Intensive care medicine (1995) 21: S244-S249

7 MORTALITA :Studi multicentrici italiani N. Brienza et al. Gruppo Italiano Replay Epidemiologia della sepsi in Italia Minerva Anestesiol 2005, 71, (Suppl 1 al n 10):

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9 MICRORGANISMI endotossina - esotossina Macrofagi - cellule endoteliali TNF, IL... linfociti granulociti coagulazione permeabilità vasodilatazione

10 Role of endotoxin Crit Care Med 2003 Jan;31(S1):S57-64.

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12 Endotoxemia in ICU J Infect Dis Aug 1;190(3):

13 Origin of endotoxins Gram negative infections Gastro-intestinal diseases Traumas Gastro-intestinal translocation Ischemic shock Burns Liver diseases

14 WHICH endotoxemia is relevant? Circulating endotoxin active enough towards immune system Lack of ability of the host to respond to the endotoxic burden These lead to the need for a targeted intervention

15 LPS and Polymyxin-B The interaction between Polymyxin-B and LPS in driven by: 1. IONIC forces: long range interaction (weaker) 2. HYDROFOBIC forces: short range interaction (stronger) Lipide A of LPS PM-B

16 The structure of Toraymyxin

17 The most common treatment strategy with PMX Blood Line Enrolment Within 24h Blood pump ml/min Femoral access 1 treatment After 24h 2 treatment

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19 The EUPHAS trial: groups JAMA. 2009;301(23): Enrolment features: Abdominal emergency surgery Treatment within 24h Two hemoperfusion sessions Clinical evidence of Toraymyxin therapy

20 The EUPHAS trial: results Mortality Clinical evidence of Toraymyxin therapy

21 Effect on mortality in review Crit Care. 2007;11(2):R47.

22 Una meta-analisi più recente Crit Care Med 2013; 41

23 Abdomix Peritonitis+Septic Schok Random Primary end-point: survival 119 Polymixin 113 Control <12 hrs PMX Control p days 27,7% 19,5% SOFA 3 days (N. of pts with a reduction of 2 points) 18,3% 10% 0,009 D. Payen, Presented at ISICEM 2014 Brussels

24 Randomized clinical trials (RCTs) are considered the gold standard for examining the efficacy and safety Most published RCTs that aim to reduce mortality have produced negative results Many reasons: ineffective interventions difficulty recruiting adequate sample sizes post-randomization patient attrition heterogeneous patient populations or treatment-effect use of inappropriate outcomes unreasonable assumptions (e.g, predicted effect sizes)

25 Is severity used to stratify patients? Lancet Infect Dis Dec;12(12):919-24

26 Mortality depends on staging of the disease N Engl J Med Mar 18 Mortality Range: 18-34% Enrollment window: 2 to 12 hours from lack of response to resuscitation regardless to vasopressors Mortality Range: 47-94% Crit Care Res Pract. 2013; Enrolment window: refractory septic shock norepinephrine > μg/kg/min

27 Different stage, different response N Engl J Med Apr 10;370(15): Septic shock showed a higher mortality rate and a different efficacy of the intervention

28 Summarizing influences on mortality in septic shock Localization of septic source Presence of comorbidities Definition of the disease to stratify patients Severity at enrollment (vasopressor load?)

29 The EUPHAS2 registry What is the EUPHAS2 project Multi-center collaborative data collection reporting clinical experience with Toraymyxin device Phase 1 (closed): Observational, retrospective Phase 2 (opening): Observational, prospective Aim: To describe clinical efficacy of Polymyxin-B based hemoperfusion in current clinical practice To verify the reproducibility of published data To identify subgroup of patients which could potentially benefit of the treatment

30 EUPHAS2: a registry of treatments PHASE 1 WAS A RETROSPECTIVE DATA COLLECTION PRO: Description of every day practice Description of adherence to published published evidence New trends in application of the treatment CONS: No control group No enrolment/esclusion criteria (eterogeneity of patients) Possible lack of data due to retrospective nature Possible underpower in statistical analyses

31 Participating centers and patients Oct 2010 July hospitals 357 patients Hospitals N Italy 34 Switzerland 3 Spain 9 India 16 Japan 2 Main origin N (%) Abdominal 157 (44) Pulmonary 63 (18) Cardiac 23 (7) Urinary 16 (4) Other 98(27)

32 Is EUPHAS still a reference? Inclusion criteria to look for EUPHAS-LIKE patients: Diagnosis of abdominal septic shock (CI>10) PMX-DHP tretament between hours Characteristics of EUPHAS-LIKE patients Septic Shock 113/137 (82%) Timing to treatment hours 87/113 (77%) EUPHAS-LIKE PATIENTS = 87/137 (64%)

33 EUPHAS-LIKE patients Characteristic of EUPHAS-LIKE patients Age (years) 68.5 ( ) Sex (M / F) 56 / 31 (64% M) APACHEII score 20.6 ( ) SOFA score 11.2 ( ) MAP 69.6 ( ) Vasopressor Dependency Index 7.6 ( ) EUPHAS data

34 Clinical outcomes EUPHAS-LIKE Parameter Basal 72 hours p MAP (mmhg) 69.6 ( ) 85.4 ( ) <.001 VDI (mmhg -1 ) 7.6 ( ) 2.4 ( ) <.001 P/F 211 ( ) 238 ( ) NS = Creatinine (mg/dl) 2.21 ( ) 1.31 ( ).033 Urinary output (L/die) 1.82 ( ) 2.84 ( ) NS Platelets (10 3 cells/mm 3 ) ( ) ( ) NS Bilirubin (mg/dl) 2.46 ( ) 2.25 ( ) NS = Cardiovascular SOFA 3.82 ( ) 2.05 ( ) <.001 Renal SOFA 1.5 ( ) 1.06 ( ) Coagulation SOFA 1.04 ( ) 1.40 ( ) <.001 Respiratory SOFA 2.38 ( ) 2.12 ( ) NS = Hepatic SOFA 1.03 ( ) 0.85 ( ) NS =

35 EUPHAS2-EUPHAS comparison Log rank P=0.03 Hospital Mortality EUPHAS CTRL EUPHAS PMX EUPHAS2 EUPHAS-LIKE 67 % 41 % 41 %

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37 MODS INSUFFICIENZA CARDIOCIRCOLATORIA Le alterazioni circolatorie hanno un ruolo centrale nello SHOCK settico Esse sono, insieme, conseguenza e causa di eventi metabolici e danno tissutale L evento emodinamico principale nello shock settico è la vasodilatazione arteriosa

38 Vasopressor load and mortality

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41 Table III.-Outcome measures with regard to response Data are reported as median (Interquartile Range) for quantitative variables. a Mann Whitney U test or t-test, as appropriate. 30 day hospital mortality (%) ICU length of All (n = 52) Non Responders (n = 22) Responders (n = 30) 15 (29) 10 (45) 5 (17) (10-38) 15 (8-41) 17 (10-37) 0.68 p a stay Hospital length 58 (26-112) 52 (19-102) 59 (27-116) 0.58 of stay ICU free days 20 (0-45) 15 (0-51) 22 (4-46) 0.51 Mechanical Ventilation free days 1.5 (0-5) 0.5 (0-5) 2 (0-6) 0.41 submitted

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43 MORTALITA NEI COMPLIANT E NON-COMPLIANT AL SEPSIS CARE BUNDLE Critical Care 2005, 9:R

44 CONCLUSIONS Septic shock is still a severe burden in ICU pts Several studies have resulted in contrasting results Restoration of normal physiology is still a consistent end point The timing of intervention is mandatory The tools used to achieve these goals appears to be justified by actual data but need to be used properly according to specific protocols

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