disclosure...87/113 (77%) euphas-like patients = 87/137 (64%) euphas-like patients characteristic of...
TRANSCRIPT
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