Post on 14-Feb-2019
Giovanni B. Pertosa
Polimixina B in Emoperfusione: La terapia addizionale nello shock endotossino-mediato
SEMINARIO ANTE 2018 XXVI Corso Nazionale di Aggiornamento
Riccione 16-18 Aprile 2018
UNIVERSITA’ DEGLI STUDI DI BARI ALDO MORO DIPARTIMENTO DELL’EMERGENZA E DEI TRAPIANTI DI ORGANI
UNITÀ INTERDIPARTIMENTALE: “Gestione Tecniche Depurative Extracorporee in Area Critica ed Aferesi Terapeutica”.
Responsabile: Prof. Giovanni B. Pertosa
IL SALASSO ALLEGGERIVA LA PLETORA STAGNANTE NEI VASI
Le malattie febbrili richiedevano salassi abbondanti
Sepsis: is defined as the evidence of infection plus life-threatening organ dysfunction, clinically characterised by an acute change of 2 points or greater in the SOFA score. (Previously, suspected infection was enough for the diagnosis of sepsis, in the presence of at least two SIRS criteria).
Clinical definitions
Singer et al, JAMA 2016
Singer et al, JAMA 2016
EUROPE
700,000 cases every year 400 cases of sepsis per 100,000 habitants annually
ITALY In Italy there are around
60,000 deaths due to sepsis every year
Sepsis: a global burden
31,500,000 people per year develop sepsis
5,300,000 people die every year
Globally
Sepsis: new message from WHO
The resolution calls for governments and policy makers to improve policies and procedures related to sepsis, with particular focus on prevention of infection and limitation of further spread of antibiotic resistance. The WHA stresses the importance of raising public awareness of sepsis through proper communication of symptoms, causes and possible outcomes. Awareness also concerns healthcare workers, who should be trained to recognize the symptoms of sepsis fast and provide early treatment. The resolution requests that the WHO and the Director General develop guidelines for the diagnosis and clinical management of sepsis. Finally, a report on the global epidemiology and burden of sepsis should be published by the end of 2018 to draw attention to the public health impact of sepsis.
Reinhart et al, NEJM – May 2017
Sepsis, Septic Shock, Refractory Septic Shock (different severity = different outcomes)
Insult
Sepsis Septic Shock Healthy individual
Insult
Mort
alit
y
Refractory Septic Shock
NEP+EP requirement ≥ 0.25 μg/kg/min
Refractory Septic Shock
Sepsis Septic Shock Healthy individual
Mort
alit
y
Refractory Septic Shock
NEP+EP ≥ 0.25 mcg/kg/min
Clinical definitions
Septic Shock: is defined as sepsis with fluid-unresponsive hypotension REQUIRING VASOPRESSORS to maintain Mean Arterial Pressure of 65 mm Hg or greater and SERUM LACTATE LEVEL > 2 mmol/L (>18 mg/dL) after adequate fluid resuscitation.
Singer et al, JAMA 2016
“This condition is associated with hospital mortality rates greater than 40%.” (Vasopressor and Lactate as vital sign)
Quenot et al. , CC 2013
39.5%
42%
48.7%
• 106 patients with septic shock receiving high-dose-vasopressor therapy (dose > 1 μg/kg/min)
• 28-day mortality 60.4% • 90-day mortality 66.3% • 50% of patients died before day 10 • SOFA score > 10 and weight-based mean dose > 0.75 μg/kg/min were associated
with a mortality rate of 86.4% The weight-based mean dose (WMD) of vasopressor was the best
prognostic factor (WMD integrates each variation of vasopressor dose)
Auchet et al. 2017, Ann Int Care 7(1)
Vasopressor Load and Mortality
Literature suggests: the Higher Dosage and the Longer administration of vasopressors,
the HIGHER IS MORTALITY
(the degree of hypotension resistance influences survival)
Vasopressor Load and Mortality
ETIOLOGY
Organism
GRAM NEGATIVE BACTERIA:
p.e. E.coli/S.aureus
FUNGI
p.e. Candida albicans
Predisposing factors
Aging population
Invasive procedures
Immunocompromised patients (cancer, organ
transplantation, autoimmune diseases)
(CAUS
E)
ROLE OF ENDOTOXIN IN
SEPTIC SHOCK
Gram negative infections
Gastro-intestinal translocation
Gastro-intestinal
diseases
Ischemic
shock
Traumas
Burns Liver diseases
Origin of Endotoxins
THE GUT, an area very rich of endotoxins
PART VARIABLE IN LENGHT AND COMPOSITION
DEPENDENT OF BACTERIA
COMMON PART OF ALL GRAM NEGATIVE BACTERIA
and PART RECOGNISED BY IMMUNE SYSTEM THAT PLAYS A ROLE AS “TRIGGER” OF INFLAMMATORY
RESPONSE
ENDOTOXIN: molecular structure of LPS
(PAMP)
Triggers of the septic cascade
PAMPs Pathogen Associated Molecular Pathways
DAMPs Danger Associated Molecular Pathways or Damage Associated Molecular Pathways (and also known as alarmins)
• ENDOTOXIN • Lipoteichoic acid • Lipoproteins • Peptidoglycans • Bacterial DNA • Etc.
• HMGB-1 • Heat shock proteins • s100 protein • Serum amyloid A • Uric acid • ATP, DNA • Formyl peptides • IL-1α, IL-18, etc.
Endotoxin – a therapeutic target
Opal et al. 2003, Crit Care Med 31(1suppl)
IL-6
Cytokine Storm!
Central nervous system • Confusion
Lungs • ARDS
Cardiovascular system • Shock
Liver • Excretory failure
Pancreas • Hyperglycemia
Gastrointestinal tract • Loss of barrier function
Kidneys • Oliguria
Microcirculation • Microvascular thrombosis
Endotoxin – clinical impact
Septic shock
BP= Blood Purification
Devices to Remove Endotoxin and Inflammatory Molecules
Esteban E, Mediators of Inflammation, 2013
Contrib Nephrol. 2010;167:35-44.
Capacità adsorbente del Toraymyxin
Cruz D, Convegno SMART 2012
TORAYMYXIN rimuove l’endotossina dal sangue,
sfruttando le proprietà farmacologiche della
POLIMIXINA B vs. LPS: •Legame ionico
•Legame idrofobico
Toraymyxin (Polymyxin B-based Medical Device )
NEUTRALIZZAZIONE
-FLUSSO EMATICO: 80-120 ML/MIN -DURATA: 2 ORE -N° DI TRATTAMENTI: 2 EMOPERFUSIONI (il secondo dopo 24 ore) -ANTICOAGULAZIONE: EPARINA 3000 IU
come bolo + 20 IU /kg/h
Involucro in policarbonato
Legame covalente
Dosaggio attività endotossinica
C’è u a relazio e tra livelli circola ti di Endotossina e sopravvivenza?
Monti et al, Contrib Nephrol. 2010
High endotoxin activity is associated with HIGHER VASOPRESSORS NEED
Endotoxemia and Severity of Septic Shock
Acta Med Okayama. 2009 Feb;63(1):65-9. http://ccforum.com/supplements/14/S2
Rimozione non solo di Endotossine, ma anche di Cellule Infiammatorie (Monociti attivati)
Minerva Anestesiol 2010;76
Immunomodulazione
Endotoxin: a therapeutic target and Polymyxin B Action
Opal et al. 2003, Crit Care Med 31(1suppl)
Pazienti con sepsi severa e shock settico
dovuti ad infezioni della cavità addominale
che hanno richiesto chirurgia d'urgenza
Randomizzazione entro 6 ore
dall'intervento
Trattamento entro 24 ore dall'intervento
JAMA 2009 Jun 17;301(23):2445-52
Miglioramento emodinamico
Riduzione della mortalità e tempo di ospedalizzazione
JAMA 2009 Jun 17;301(23):2445-52
mortality
Int Care Med 2008 Sep;34(9):1638-45.
Miglioramento della funzione renale
0
2
4
6
8
10
T0 T72
Rif
le S
core
PMX CONTROL
*
Sixteen RCTs have been included to analyze the effectiveness of hemoperfusion, hemofiltration and plasma exchange treatment in sepsis Extracorporeal blood purification positively and significantly influences sepsis-related mortality
Department of Critical Care Medicine, The Clinical Research, Investigation, and Systems Modeling of Acute illness (CRISMA) Center, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA
Kellum et al, CCM 2013
Kellum et al, CCM 2013
16 publications considered: 2/16 reported Jadad score = 5 (EUPHAS one of this trial)
8/16 studies on Polymyxin B - HP Overall Mortality : 42.7%
Treated Group (Blood purification): 35.7% Control Group (NO Blood Purification): 50.1% Overall Analysis (considering all Blood Purifications) Mortality Rate Reduction = 30% (RR=0.69; p<0.001)
Overall Results
Among EC techniques, Polymyxin-B based hemoperfusion more significantly influences global mortality
Kellum et al, CCM 2013
Of 3.759 patients, 1.068 patients received PMX-HP, based on hospital data. Propensity score matching produced a matched cohort of 978 pairs, with and without PMX-HP.
The 28-day mortality was 40.2% (393/978) in the PMX-HP group and
46.8% (458/978) in the control group (p=0.003).
A subgroup analysis revealed that patients who received two sessions
of PMX-HP had a 28-day mortality of 35.7% while patients who received only one session of PMX-HP had a 28-day mortality of
42.6%. In the subgroup of patients with abdominal infection the 28-day
mortality was 35.8% in the PMX-HP group and 44.0% in the control group (OR 0,71; IC 0,55-0,92).
Potential survival benefit of Polymyxin B hemoperfusion in septic shock patients on continuous renal replacement therapy: a propensity-matched analysis Iwagami, M., Yasunaga, H., Noiri, E., Horiguchi, H., Fushimi, K., Matsubare, T., Yahagi, N., Nangaku, M. and Doi, K.
Iwagami et al, Blood Purif 2016
PMX-HP (n=978) Control (n=978)
0
20
40
602
8-d
ay
mo
rta
lity
(%)
40.2%
46.8%
p = 0.003
TAKE HOME MESSAGE: In patients with septic shock, requiring CRRT due to AKI, PMX-HP is associated with a significant increase in Survival.
Potential survival benefit of Polymyxin B hemoperfusion in septic shock patients on continuous renal replacement therapy: a propensity-matched analysis Iwagami, M., Yasunaga, H., Noiri, E., Horiguchi, H., Fushimi, K., Matsubare, T., Yahagi, N., Nangaku, M. and Doi, K.
Iwagami et al, Blood Purif 2016
BLOOD PURIFICATION THERAPIES CONSIDERED FOR THE FIRST TIME -Not reccomended in favour -Not reccomended against
Surviving Sepsis Campaign - 2016 International Guidelines
Rhodes et al, CCM 2017
Surviving Sepsis Campaign - 2016 International Guidelines
Rhodes et al, CCM 2017
FOR THE FIRST TIME BLOOD PURIFICATION THERAPIES ARE CONSIDERED IN INTERNATIONAL SEPSIS GUIDELINES
POLYMYXIN B HEMOPERFUSION THERAPY IS THE
ONLY THERAPY CONSIDERED BY SSC FOR ENDOTOXIN NEUTRALIZATION, REFLECTING THAT EVIDENCE IS ACCUMULATING FOR THIS THERAPY
AT THE MOMENT THE EVIDENCE IS NOT ENOUGH
FOR A RECOMMENDATION IN FAVOUR IN INTERNATIONAL SEPSIS GUIDELINES
Cutuli et al., Ann. Intensive Care (2016) 6:77
Data from phase 1 collected from January 2010 to December 2014
•35 hospitals inserted data
•Data from 357 patients were recorded (297 from European Centers and 60 from Asia)
•Main sources of infection were the abdomen (44%) and the lung (17.6%)
Sources of infection
Cutuli et al., Ann. Intensive Care (2016) 6:77
Patients n=357 T0 T 72 P (wilcoxon)
SOFA score 12.4 ± 4.2 10.5 ± 5.3 < 0.001
Cardiovascular
SOFA
3.32 ± 1.29 2.16 ± 1.77 < 0.001
Renal
SOFA
2.23 ± 1.62 1.84 ± 1.77 0.013
Hepatic
SOFA
1.22 ± 1.28 1.19 ± 1.30 0.80
Respiratory
SOFA
2.40 ± 1.06 1.95 ± 0.95 < 0.001
Coagulation
SOFA
1.33 ± 1.29 1.67 ± 1.38 0.004
Inotropic
Score
30(11.9-72.5) 6.0 (0.0-22) < 0.001
Lactates (mmol/l) 3.4 (1.9-6.0) 1.9 (1.3-
2.9)
< 0.001
Platelets (103 / microl) 117 (56-220) 86 (40-163) < 0.001
Variables Changes at 72 hours after PMX-HP Cutuli et al., Ann. Intensive Care (2016) 6:77
Survival Rate after PMX-HP
28 Days SURVIVAL Rate [%]
All Population [n=357] 54.5
Pulmonary Patients 47.5
Abdominal Patients 60.4
Abdominal Patients Treated within
24 Hours 64.5
Cardiovascular Responders 75
Patients with abdominal source of infection, who were treated within 24 h from diagnosis, had a survival rate of 64.5%, similar to the results obtained in the EUPHAS RCT, confirming the feasibility of using PMX-HP in the daily clinical practice.
Cutuli et al., Ann. Intensive Care (2016) 6:77
High-volume hemofiltration (HVHF) is not recommended for blood purification in sepsis. However, higher hemofiltration doses may be prescribed to match individual patient needs (Grade 1A). • Polymyxin B (PMX B) hemoperfusion is not recommended for the general population but it should be considered in patients post surgery for abdominal sepsis and septic shock (Grade C). • Plasma exchange, liver support, ECCOR and CRRT/ ECMO should be used only for specific indications based on center and physician expertise and results of ongoing trials (Grade D). • In order to maximize precision CRRT, equipment designed specifically for children should be used for patients below 15 kg of body weight and especially in neonates (Grade A).
Cerda et al, Blood Purification - 2016
ADQI INITIATIVE CONSENSUS GROUP PMX-HP THERAPY RECOMMENDED in FAVOUR
Acute Dialysis Quality Initiative (ADQI)
EUPHRATES trial
EUPHRATES trial - protocol design
Designed to evaluate the safety and efficacy of PMX-HP therapy Phase III, Double Blinded, Randomized, Controlled Study
STANDARD OF CARE + PMX-HP THERAPY VS
STANDARD OF CARE Adaptive with an Interim Analysis for sample size re-
assessment
EUPHRATES trial – selection criteria
ENDOTOXIN EAA ≥ 0.6
SEPTIC SHOCK
MODS > 9
EUPHRATES Patient
Centralized coordinating center confirmed patient eligibility prior to randomization
EUPHRATES – population
921 Screened for Septic shock + EAA ≥ 0.6
450 Randomized ITT
295 MODS > 9 ITT, MODS > 9
PMX = 147 SHAM = 148
PP
Screen fail EAA < 0.6 =342 EAA ≥ 0.6 =113 NO EAA=16
MODS < 9 n= 155
< 2 hemoperfusions completed
244
PMX = 115 SHAM = 129
28 D Mortality
244 EAA ≥ 0.6 - MODS > 9,
2 hemoperfusions completed
PP
PMX = 115 SHAM = 129
EUPHRATES – PP population – primary endpoint
Primary Endpoint was not met in PP polulation (n=244)
31.9%
36.9% p = 0.407
5% in favour of treatment but not statistically significant
Primary Endpoint was not met Was the study under-powered? Was the effect size overstimated? Were these confounding factors? EUPHRATES was a biomarker driven clinical trial Thus, the Biomarker was investigated as a potential confounding factor
Indeed, the patient population was selected based on a MINIMUM
endotoxin activity value (…and not MAXIMUM)
EUPHRATES trial
ENDOTOXIN EAA ≥ 0.6
SEPTIC SHOCK
EAA dose-response curve
The dose response curve is asymptotic at 0 and 1.0
At EA > 0.9 the concentration
can be any value above 4600 pg/mL
( > 50 μg) An EA value > 0.9 corresponds
to a high, but not accurately measureable endotoxin concentration
244 EAA ≥ 0.6 - MODS > 9 2 hemoperfusions completed
PP
PMX = 115 SHAM = 129
194 MODS > 9, 0.6 ≤ EAA < 0.9
mPP
PMX = 88 SHAM = 106
EAA > 0.9 (n=50)
EUPHRATES – mPP population
Time Absolute
reduction% P-value
14 days 14% 0.010*
28 days 10.7% 0.047*
90 days 11% 0.038*
Absolute Reduction of Mortality
Modified per protocol population (mPP) (n=194); Septic Shock – 0.6 ≤ EAA < 0.9 – MODS>9
EUPHRATES – mPP – Primary Endpoint
* Adjusted for baseline MAP and APACHE scores
Modified per protocol population (mPP) (n=194); Septic Shock – 0.6 ≤ EAA < 0.9 – MODS>9
EUPHRATES – mPP – Primary Endpoint
PMX-B
SHAM
p<0.038
• Increase in MAP* in favor of the PMX-HP group
+ 5.0 mmHg
• Mechanical ventilation free days** in favor of the PMX-HP group
+ 14
MV Free Days
* Average difference from day 0 to day 3 in patients treated with PMX-HP compared to the control group (SHAM) ** Median difference in 28 days in patients treated with PMX-HP compared to the control group (SHAM)
EUPHRATES TRIAL – Secondary Endpoint Modified per protocol population (mPP) (n=194); Septic Shock – 0.6 ≤ EAA < 0.9 - MODS>9
EUPHRATES – Conclusions
Although the primary endpoint was missed, a significant step forward has been made in demonstrating a benefit in a PERSONALIZED approach to the treatment of Septic Shock The mPP Population (Septic Shock - 0.6 ≤ EAA < 0.9 – MODS >9 showed 42% Mortality Risk Reduction at 28 Days
Towards a personalized therapy
• Endotoxin is recognized as the most potent trigger of the septic cascade
• Elevated levels of endotoxin correlates with increased
mortality risk
• Endotoxin levels can increase up to 1000-fold during the progression of sepsis
• It has been demonstrated that polymyxin B
hemoperfusion removes endotoxin effectively, both in vitro and in vivo
• Numerous clinical studies have demonstrated improvement in hemodynamics, organ function and Outcome
“Matching the cure with the disease”
La Polimixina B è il più efficace neutralizzatore di
endotossina (640.000 EU)
Adsorbimento selettivo dei monociti attivati.
Ripristino della risposta immunitaria
Shock settico e Polimixina B
Ripristi o rapido dell’e odi a ica e della fu zio e d’orga o
Riduzione rapida della dose di vasopressori
Ripristino della funzionalità del microcircolo
Azienda Ospedaliero-Universitaria Policlinico di Bari