Disclosure...87/113 (77%) EUPHAS-LIKE PATIENTS = 87/137 (64%) EUPHAS-LIKE patients Characteristic of EUPHAS - LIKE patients Age (years) 68.5 (66.5 -70.5) Sex (M / F) 56 …

Disclosure:

Member of the advisory board of EUPHAS 2

†National Center for Health Statistics, 2001. §American Cancer Society, 2001. *American Heart Association. 2000. ‡Angus DC et al. Crit Care Med. 2001;29:1303-10

Mortality of Severe Sepsis

AIDS* SEPSI SEVERA‡ IMA†

CANCRO mammella§

Mor

ti /

ann

o

SEPSI SEVERA

confronto con altre patologie maggiori (USA)

MORTALITA’

Proiezione della incidenza della Sepsi

Severa in USA: 2001-2050

2001 2025 2050 Anni

800

1,000

1,200

1,400

1,600

1,800 600

500

400

300

Casi di sepsi Severa Popolazione USA

Pop

olaz

ione

tot

ale

USA

(m

lioni

)

Cas

i di s

epsi

(x1

03)

Angus DC, et al. JAMA 2000;284:2762-70; Angus DC, et al. Crit Care Med 2001;29:1303-10 .

Invecchiamento Invasività

Immunosoppressione

Lo studio ha coinvolto 2950 pazienti* in 99 centri Italiani di

terapia intensiva

Mortalità nei pazienti con sepsi grave in Italia:

52,5%

The Italian Sepsis Study (1995)

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

* 1101 pazienti analizzabili alla prima interim analisis

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):364-366.

MICRORGANISMI

endotossina - esotossina

Macrofagi - cellule endoteliali

linfociti granulociti coagulazione permeabilità vasodilatazione

TNF, IL...

Role of endotoxin

Crit Care Med 2003 Jan;31(S1):S57-64.

J Infect Dis. 2004 Aug 1;190(3):527-34.

Endotoxemia in ICU

Gram negative infections

Gastro-intestinal translocation

Gastro-intestinal diseases

Ischemic shock

Traumas

Burns Liver diseases

Origin of endotoxins

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

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

LPS and Polymyxin-B

The structure of Toraymyxin

Enrolment Within 24h

1° treatment

2° treatment

After 24h

The most common treatment strategy with PMX

Blood Line

Femoral access

Blood pump 80-120 mL/min

The EUPHAS trial: groups

Clinical evidence of Toraymyxin therapy

Enrolment features: • Abdominal emergency surgery • Treatment within 24h • Two hemoperfusion sessions

JAMA. 2009;301(23):2445-2452

The EUPHAS trial: results

Clinical evidence of Toraymyxin therapy

Mor

talit

y

Effect on mortality in review

Crit Care. 2007;11(2):R47.

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

Abdomix

119 Polymixin

113 Control

Peritonitis+Septic Schok Random

<12 hrs

Primary end-point: survival

PMX Control p

Mortality @28 days 27,7% 19,5% 0.1391

SOFA Score @ 3 days (N. of pts with a reduction of 2 points)

18,3% 10% 0,009

D. Payen, Presented at ISICEM 2014 Brussels

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)

Is severity used to stratify patients?

Lancet Infect Dis. 2012 Dec;12(12):919-24

N Engl J Med. 2014 Mar 18

Enrollment window: 2 to 12 hours from lack of response to resuscitation regardless to vasopressors

Crit Care Res Pract. 2013;654708

Enrolment window: refractory septic shock norepinephrine > 0.25-0.5 μg/Kg/min

Mortality Range: 47-94%

Mortality Range: 18-34%

Mortality depends on staging of the disease

Different stage, different response

Septic shock showed a higher mortality rate and a different efficacy of the intervention

N Engl J Med. 2014 Apr 10;370(15):1412-21.

• Localization of septic source

• Presence of comorbidities

• Definition of the disease to stratify patients

• Severity at enrollment (vasopressor load?)

Summarizing influences on mortality in septic shock

www.euphas2.eu

• 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

What is the EUPHAS2 project The EUPHAS2 registry

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

Participating centers and patients

Hospitals N Italy 34 Switzerland 3 Spain 9 India 16 Japan 2

Oct 2010 – July 2013 64 hospitals 357 patients

Main origin N (%) Abdominal 157 (44) Pulmonary 63 (18) Cardiac 23 (7) Urinary 16 (4) Other 98(27)

Is EUPHAS still a reference?

Inclusion criteria to look for EUPHAS-LIKE patients: • Diagnosis of abdominal septic shock (CI>10) • PMX-DHP tretament between 24-48 hours

Characteristics of EUPHAS-LIKE patients Septic Shock 113/137 (82%) Timing to treatment 24-48 hours 87/113 (77%)

EUPHAS-LIKE PATIENTS = 87/137 (64%)

EUPHAS-LIKE patients Characteristic of EUPHAS-LIKE patients

Age (years) 68.5 (66.5-70.5)

Sex (M / F) 56 / 31 (64% M)

APACHEII score 20.6 (18.7-22.5)

SOFA score 11.2 (10.4-12.0)

MAP 69.6 (66.6-72.6)

Vasopressor Dependency Index 7.6 (6.1-9.1)

EUPHAS data

Clinical outcomes EUPHAS-LIKE Parameter Basal 72 hours p

MAP (mmHg) 69.6 (66.6-72.6) 85.4 (82.0-88.8) <.001

VDI (mmHg-1) 7.6 (6.1-9.0) 2.4 (1.4-3.5) <.001

P/F 211 (189-232) 238 (218-257) NS =

Creatinine (mg/dL) 2.21 (1.58-2.85) 1.31 (1.14-1.48) .033

Urinary output (L/die) 1.82 (1.45-2.19) 2.84 (2.36-3.3) NS

Platelets (103cells/mm3) 182.4 (153.1-211.7) 133.6 (106.9-160.4) NS

Bilirubin (mg/dL) 2.46 (1.73-3.20) 2.25 (1.37-3.14) NS =

Cardiovascular SOFA 3.82 (3.73-3.90) 2.05 (1.67-2.44) <.001

Renal SOFA 1.5 (1.18-2.68) 1.06 (0.75-1.81) 0.011

Coagulation SOFA 1.04 (0.77-1.81) 1.40 (1.09-2.48) <.001

Respiratory SOFA 2.38 (2.15-4.53) 2.12 (1.91-4.03) NS =

Hepatic SOFA 1.03 (0.76-1.79) 0.85 (0.59-1.44) NS =

EUPHAS2-EUPHAS comparison

Log rank P=0.03

Hospital Mortality EUPHAS

CTRL EUPHAS

PMX EUPHAS2

EUPHAS-LIKE 67 % 41 % 41 %

Esse sono, insieme, conseguenza e causa di eventi metabolici e danno tissutale

Le alterazioni circolatorie hanno un ruolo centrale nello SHOCK settico

L’evento emodinamico principale nello shock settico è la

MODS INSUFFICIENZA CARDIOCIRCOLATORIA

vasodilatazione arteriosa

Vasopressor load and mortality

submitted

All (n = 52)

Non Responders

(n = 22)

Responders (n = 30)

pa

30 day hospital mortality (%)

15 (29) 10 (45) 5 (17) 0.032

ICU length of

stay

16 (10-38) 15 (8-41) 17 (10-37) 0.68

Hospital length of stay

58 (26-112) 52 (19-102) 59 (27-116) 0.58

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

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.

submitted

MORTALITA’ NEI COMPLIANT E NON-COMPLIANT AL

SEPSIS CARE BUNDLE

Critical Care 2005, 9:R764-770.

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