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

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

Endotossinemia e mortalità

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