cytosorbents · past, present and future of cytosorb - c ronco, vicenza, italy 7 from experiments...

CytoSorbents TM

Proceedings6th International User’s Meeting

Brussels, Belgium, March 18th 2019

CytoSorb Therapy – REGAIN CONTROL

20.000 Patienten weltweit

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Table of contents

Key findings of the symposium 4

Welcome lecture - JL Vincent, Brussels, Belgium 6

Opening lecture Past, present and future of CytoSorb - C Ronco, Vicenza, Italy 7

From experiments to evidence

Hemoadsorption modulates pulmonary metabolism and edema formation 10 - I Iskender, Zurich, Switzerland

Influence of CytoSorb on microcirculation and hemodynamics 12 - C Ince, Rotterdam, The Netherlands

Safety aspects and drug removal - A Schneider, Lausanne, Switzerland 13

The International CytoSorb Registry – Latest update 16 - F Brunkhorst, Jena, Germany

Shock reversal

My clinical experiences after 100 patients - Y Mehta, Delhi, India 18

CytoSorb in cardiac arrest - D Dürschmied, Freiburg, Germany 22

CytoScore helps me to find the right starting point 24 - K Kogelmann, Emden, Germany

What do we know and what do we have to do? CytoSorb in various fields of application

Liver failure - D Tomescu, Bucharest, Romania 26

Rhabdomyolysis - J Duranteau, Paris, France 28

ECMO - F Pappalardo, Milan, Italy 30

Necrotizing fasciitis - D Payen, Paris, France 31

PICU - A Rybalko, Moscow, Russia 32

Special case lecture

My very special CytoSorb case - A Nierhaus, Hamburg, Germany 34

4

6th International CytoSorb users meeting emphazises that CytoSorb is more than just a cytokine adsorber

Numbers• 850* active users worldwide• More than 56,000* CytoSorb human treatments in

more than 30,000* individual patients and in various indications (septic shock, cardiac surgery both intraoperative & postoperative, myoglobinemia, liver dysfunction/failure, severe acute pancreatitis, viral sepsis, intoxications)

• Growing Registry database – more than 680* patients have already been included in the Registry and 599* in the current interim analysis

• Number of peer-reviewed publications rises to more than 70*

Confirmation of primary effects• Once more hemodynamic stabilization and

reduction in vasopressor needs were confirmed as the central therapeutic effect of CytoSorb therapy in a large case series of 100 patients from India, especially when the therapy is started within the first 24 hours after diagnosis

Promising novel stratification approach• A stratification method based on a newly defined

score (CytoScore) might help to better identify the right patient for CytoSorb therapy

One day before the 39th International Symposium of Intensive Care and Emergency Medicine (ISICEM), CytoSorbents held its 6th International CytoSorb Users Meeting at the Square Meeting Center in Brussels, Belgium. More than 150 participants from 24 countries including physicians, partners, and distributors joined the meeting to share and discuss their experiences with the CytoSorb therapy.Following a welcome speech by Professor Jean-Louis Vincent and an opening lecture on the past, present and future of CytoSorb therapy by Professor Claudio Ronco, an excellent panel of speakers presented the most recent data and findings on the following topics: • From experiments to evidence - including the latest update on the International CytoSorb Registry• Application of CytoSorb for shock reversal in different indications• Use of CytoSorb in various other fields of application

Given the constantly growing evidence base it was once again emphazised that the early start of CytoSorb therapy is key to successful treatment and that the primary therapeutic goal of CytoSorb treatment is hemodynamic stabilization with a reduction in catecholamine dosages. Moreover, CytoSorb should be seen as being more than purely a cytokine adsorber, providing removal of a broad spectrum of inflammatory mediators and toxins. This precisely addresses the complexity of the immune system and might also explain some of the clinical effects observed in treated patients. Besides this, there are increasing indications that CytoSorb might have a direct impact on the cellular immune function, barrier integrity and organ functions. To help better identify the right patient for CytoSorb therapy a promising novel stratification approach based on a newly defined scoring system (CytoScore) was presented, which still need to be validated on a broader scale. We thank all contributors and participants who have joined this platform that has enabled users, partners and distributors to exchange their experiences with CytoSorb. The lessons learned will support how best to design large-scale pivotal trials that will help to definitely answer still outstanding topics of interest. This will ensure uniformity of treatment so that all users worldwide benefit from the latest information.

Key findings from the Symposium include

*Status March 2019

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Safety• CytoSorb hemoadsorption appears to be a very

safe procedure in various extracorporeal circuits and does not seem to be associated with any significant impairment in coagulation factors

Potential impact on mortality• The latest interim analysis of the CytoSorb Registry

continues to show a decrease in observed mortality vs. expected mortality, with the most profound effect in the sickest patients

New fields of application• CytoSorb in eCPR (extracorporeal cardiopulmonary

resuscitation) was associated with no severe complications, a decrease in surrogate parameters and improvement of clinical course in several cases

• Cytokine removal (with CytoSorb) was shown to improve lung function in an ex vivo lung perfusion model and might therefore have a place in the setting of organ transplant

CytoSorb is more than a cytokine adsorber• Data show that besides the removal of a broad

spectrum of inflammatory mediators and toxins, the effects of CytoSorbs also include the direct impact on the cellular immune function, barrier functions and organ functions

Broad agreement on the following aspects by the vast majority of present users:• The decision regarding CytoSorb should be made

independent of the indication and start of CRRT or other extracorporeal therapies

• Primary therapeutic goal of CytoSorb treatment is hemodynamic stabilization with a reduction in catecholamine dosages.

• In septic/vasoplegic shock patients, start of CytoSorb should be considered as soon as possible or after a maximum of 6 hours of inadequate or non-response to standard therapies

Consensus on the strategy to confirm effecti-veness of CytoSorb therapy• Broad support for CytoSorbents’ approach to

conduct smaller, but targeted studies in well-defined patient populations, further building the Registry database and enable direct communication of all stakeholders through Users Meetings

• Consent on the increasing significance of personalized medicine and thus reliance not only on large RCTs is of growing importance for the generation of evidence

• Any statement on the efficiency of CytoSorb should not include mortality (JL Vincent & F Brunkhorst)

• The intervention strategy in sepsis should be an integrated and sequential approach including immunomodulation via extracorporeal therapies and represents very personalized therapy

On the following pages, you will have the opportunity to go through all the important information from a large part of the presentations, at a glance.

Enjoy your reading.

6

Welcome Lecture JL Vincent, Brussels, Belgium

In his welcome lecture Professor Vincent shared his view on the potential role of extracorporeal organ support in critical care medicine.

There is a true place for extracorporeal organ systems in critical care• Professor Vincent underscored that the ECOS

concept (Extracorporeal Organ Support) including renal replacement therapy, extracorporeal membrane oxygenation, liver support, and metabolic support will be further developed in the years to come

• He is also convinced that elimination of excess toxic substances/mediators will be routinely performed in critically ill patients in the future

Revisiting the strategy • Despite the call for large randomized trials (RCTs)

in the field of critical care, there are barely any valid RCTs available that show any really positive effects of new interventions for the treatment of this relatively hetereogenous patient population

• The question was raised, whether survival/mortality is a reasonable endpoint of studies in such patient populations

• Based on the failed trials in the past he emphasized caution in taking “too large a step at a time”

• He further pointed out the problem that rando-mized-controlled trials may potentially not be the right tool to assess the efficacy and viability of extracorporeal blood purification therapies and that perhaps Users Meetings (with interactive discussions, sharing of experiences etc.) and registries would probably be the right approach to refine application for those technologies

• Professor Vincent proactively supports CytoSorbents‘ strategy of conducting smaller, but targeted studies in well-defined patient populations

WELCOME LECTURE

CONCLUSIONS*• According to Professor Vincent, the way to go for introducing new technologies into the field

of critical care medicine is to change the way of thinking away from conducting large RCT with mortality as an endpoint and rather to learn from the past

• The community should not be too ambitious about producing “hard evidence” on new therapy options for critically ill patients jeopardizing the commercialization of potentially promising treatments by using the wrong endpoints

• Registries, big data and interactive discussions in various platforms will help to make progress in establishing new therapeutic concepts in critical care medicine

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Setting the stage, Professor Ronco gave a compre-hensive introduction on blood purification in general and on the CytoSorb therapy in particular, the underlying operating principle and its potential benefit in the treatment of critically ill patients.

Patterns of molecules during different phases of uremia and sepsis• Uremic and septic syndromes are complex disorders

and share common patterns including peaks of retention molecules in blood i.e.

○ Urea and related small molecules ○ Middle molecular weight toxins ○ Large molecules or protein bound solutes

• High plasma levels of these molecules may represent the causative factor for multiple organ dysfunction

• Molecules may present in different concentration levels at different phases of the syndrome (e.g. during bacterial invasion, pathologic immune response, organ failure)

Different types of separation processes• Separation processes require energy• Most used processes are:

○ Separation by barrier (e.g. dialysis, ultrafiltration)

○ Separation by solid agent (e.g. adsorption)

Rationale for the use of sorbents in blood purification• Limited efficiency of membrane separation

processes such as hemodialysis• Possible selectivity or size exclusion of adsorptive

processes• Possibility of placing the sorbent in direct contact

with blood

Limitations for the use of sorbents in blood purification• The sorbent must be hemocompatible or

adequately coated• Size dependent non-selective adsorption may

cause unwanted losses of important substances (e.g. antibiotics)

• Sorbents might alter the requirement for heparin in the circuit

Hemoperfusion-adsorption• Hemoperfusion is a technique in which the patient’s

blood is circulated through a unit containing a sorbent material

• Blood purification is obtained by adsorption of molecules onto the sorbent particles, which can be synthetic or natural

• In the past, problems related to hemoperfusion were mostly due to the incompatibility of the biomaterial used as a sorbent e.g. early hemoperfusion treatments used charcoal sorbent resulting in symptoms of systemic inflammation

Requirements for an effective sorbent therapy• Effective and safe sorbent material• Adequately designed sorbent cartridge• Optimal utilization of the available surface of the

sorbent

Requirements for a suitable adsorbent material• High selectivity/affinity to enable precise separation• High capacity to minimize the amount of sorbent

needed• Favorable kinetics and transport properties for

rapid sorption• Chemical and thermal stability; low solubility in the

fluid contact phase• Hardness and mechanical strength to prevent

crushing and erosion• Free flowing tendency for ease of filling and

emptying of the packed bed• High resistance to fouling for long life and low

solute interference• No tendency to promote undesirable chemical

reactions or side effects• Possibility of regeneration desireable• Relatively low cost

Properties of CytoSorb• Biocompatible divinylbenzene copolymer beads • Surface area of ~800 m2/g• Pore size adsorbs proteins up to 55 kDa (restricts

larger proteins such as albumin to enter the inner surface)

• Binding by hydrophobic interactions

Opening Lecture Past, Present and Future of CytoSorbC Ronco, Vicenza, Italy

WELCOME LECTURE

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Continuation: Opening Lecture Past, Present and Future of CytoSorb

OPENING LECTURE

Surface coating, biocompatibility and performance• Coating can be obtained by adsorption, chemical

grafting or crosslinking of a hemocompatible film on the surface of a polymeric material

Reduction of cytokines with the CytoSorb resin• Effective removal of various cytokines with CytoSorb

both in vitro and in vivo (Kellum JA et al., Crit Care Med 2004;32:801-805)

• CytoSorb reduces substances, including Nuclear Factor Kappa B (NFƘB), which initiate and maintain the production of cytokines

• In the clinical setting (septic patients with ARDS), a significant reduction in IL-6 (5 to 18% per pass of blood through the device) vs. no reduction in the standard of care group was found (Schädler D et al., PLoS One. 2017 Oct 30;12(10):e0187015)

Application of CytoSorb• Indicated for clinical conditions with elevated

cytokines (sepsis & cardiac surgery patients)• Biocompatible, highly porous polymer beads

adsorbing molecules of middle molecular weight (~10–55 kDa range) including cytokines

Recent unpublished in vitro data• Reduction in pro-apoptotic tendency of septic

plasma following CytoSorb treatment (Fig. 1.)• Improvement in the phagocytic capacity of

monocytes after treatment with CytoSorb (Fig. 1.)• Apoptosis correlated inversely with cell phagocytic

function (Fig.1.)• Level of apoptosis and Caspase 3 activation in

plasma of septic patients was significantly reduced already at 2 hours of CytoSorb treatment (Fig. 2.)

• Improved capacity to restore immune homeostasis in septic patients in a way that monocytes have a re-established function to expose the antigen via a preserved HLA-DR receptor (Fig. 3.)

Summary of CytoSorb effects based on current evidence and available clinical data • Easy to use and safe • Attenuated inflammatory response (IL-6) and

potentially increased immunohomeostasis• Improvement in hemodynamics • Reduction of vasopressor requirements• First indication towards protection of capillary

integrity and reduction of mortality

Comparison with various liver support technologies • Comparison data show a significant advantage of

CytoSorb over various other liver support therapies in terms of reduction in bilirubin and bile acids (Riva S et al., I° Workshop ‘Purification Therapies-L’evoluzione della cura’ 27-28 January 2017, Milan)

Proposed interventional strategy in sepsis• An integrated and sequential approach with

○ Pharmacological approach ○ Timely Endotoxin removal (EAA) ○ Immunomodulation using extracorporeal

therapies ○ Provide adequate organ support ○ Promote conditions that favor organ recovery

• Aim is personalized therapy using precision sequential extracorporeal therapy

• However, the right patient for the right therapy has to be identified

Fig. 1. Apoptotic tendency and monocyte phagocytic capacity in the plasma of patients with acute renal failure (ARF), patients with sepsis and plasma of septic patients treated with CytoSorb

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CONCLUSIONS*• CytoSorb represents a promising therapeutic approach with an increasing evidence base

• Clinical effects include attenuation of the inflammatory response, improvement in hemodynamics with a concomitant reduction of vasopressor requirements as well as protection of capillary integrity and reduction of mortality

• Moreover, there is first evidence towards a potentially improved capacity to restore immune homeostasis through a re-established function of monocytes to expose the antigen via a preserved HLA-DR receptor and an mprovement in the phagocytic capacity

• Finally, a reduction in pro-apoptotic tendency in septic plasma following CytoSorb treatment was shown ex vivo

9

OPENING LECTURE

Fig. 2. Level of apoptosis and Caspase 3 activation in plasma of patients treated with CytoSorb

Fig. 3. Preservation of HLA-DR receptor activity in a patient undergoing renal replacement therapy (CRRT) and subsequently CRRT+CytoSorb treatment

Fig. 4. Reduction of bilirubin (left) and bile acids (right) with various liver support techniques including CytoSorb

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Hemoadsorption modulates pulmonary metabolism and edema formation I Iskender, Zurich, Switzerland

FROM EXPERIMENTS TO EVIDENCE

Dr. Iskender shared his experiences with CytoSorb in an ex vivo lung perfusion (EVLP) setting.

Role of ex vivo perfusion in solid organ trans-plantation• Ex vivo lung perfusion (EVLP) has emerged as

a modern preservation technique and is now a widely expanding technology allowing for more accurate lung assessment and also improvement of function in lungs who are considered marginal for transplantation

• Growing application in solid organ transplantations, also being applied for heart, liver and kidney transplantation

• According to the International Registry there is an increasing number of lung transplantations worldwide with 4554 in 2016

• However, transplant donor shortage remains a huge problem, only 30% of the donor lungs available can be used

• Moreover, primary graft dysfunction is also a major issue and further contributes to transplant shortage

• Any strategies that can increase donor transplant availability will have a positive impact for patients waiting for an organ

Novel strategies have been implemented to overcome donor shortage• Extension of donor criteria• Size-reduced lung transplantation• Transplantation of lungs from non-heart-beating

donors• Living-donor lobar lung transplantation• AB0-incompatible lung transplantation• Normothermic ex vivo lung perfusion

Association of inflammation and donor graft function • A recent study examined the impact of ex vivo lung

perfusion on cytokines, chemokines, and growth factors and their correlation with graft performance in high-risk brain death donors and donors after cardiac death (Machuca TN et al. Protein expression profiling predicts graft performance in clinical ex vivo lung perfusion. Ann Surg. 2015;261(3):591-7)

• Primary graft dysfunction was paralleled by a very high inflammatory response and release of various cytokines, chemokines, and growth factors which continue to accumulate in perfusate over time during EVLP

• Perfusate protein expression during EVLP could therefore differentiate lungs with good outcome from lungs with primary graft dysfunction after transplantation

Presentation of data from a previous pig EVLP model• Hypothesis

○ Cytokine adsorption improves lung function via clearance of inflammatory mediators during prolonged EVLP

• Objective ○ To examine safety and efficacy of continuous

cytokine removal in a pig EVLP model• Methods

○ Pig EVLP model ○ Groups (n=5/each): control and adsorber ○ Lung retrieval followed by 24 h preservation

under cold ischemia (4°C) and subsequent EVLP for 12 hours

○ Usage of a dedicated EVLP circuit• Measurements

○ EVLP lung physiology: Peak airway pressure, dynamic compliance, pulmonary vascular resistance, PaO2

○ Electrolyte imbalance: pH, potassium, calcium, sodium

○ Pulmonary metabolism: glucose, lactate, lactate/pyruvate ratio (oxidation marker), albumin

○ Radiologic assessment of lung injury at the end of EVLP (12 h)

○ Microscopic assessment of lung injury ○ Perfusate cytokine levels (IL-1α, IL-1β, IL-1ra,

IL-6, IL-8, IL-10, IL-12, IL-18, TNFα)• Results

○ Significantly improved peak airway pressure and dynamic compliance in the CytoSorb –treated lungs, also trend towards an improved pulmonary vascular resistance and PaO2 in the CytoSorb group

○ Electrolyte balance was markedly better in the CytoSorb group

○ Significantly less glucose consumption, decreased lactate production and better lactate/pyruvate ratio in the CytoSorb group–treated lungs

○ Less infiltration of inflammatory cells in the CytoSorb–treated lungs (Fig. 2.)

○ Lower radiologic lung injury scoring and less edema in the CytoSorb group (Fig. 3.)

○ Perfusate cytokine levels were significantly reduced in the adsorber group (Fig. 4.)


Presentation of new data from a pig EVLP model with subsequent lung transplantation• Methods

○ Pig EVLP model + lung transplant model ○ Groups (n=5/each) - 1. Control, 2. Adsorber ○ Lung retrieval followed by 24 h preservation

under cold ischemia (4°C), subsequent EVLP for 6 hours, retransplantation only of the left lung and observation of these animals for the next 4 hours

• Results ○ Operation characteristics (donor) i.e. donor

body weight, donor PaO2/FiO2 ratio, cold ischemic time and donor static compliance were comparable between groups

○ Significantly improved peak airway pressure and oxygenation function in the CytoSorb group

○ Electrolyte balance was markedly better in the CytoSorb group

○ Significantly less glucose consumption and lactate production in the CytoSorb group–treated lungs

○ Lower radiologic lung injury scoring and less edema in the CytoSorb group

○ Perfusate cytokine levels were significantly reduced in the adsorber group

○ Post-transplant pulmonary physiology: decreased peak airway pressure, improved pulmonary dynamic compliance and oxygenation function in the CytoSorb group

○ Isolated allograft function: superior gas exchange: PO2 and PCO2 and lung compliances in the CytoSorb group

○ Local inflammatory response: decreased IL-1β, IL-6 and IL-8 in CytoSorb-treated lungs

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Fig. 2. Microscopic assessment of lung injury in controls and CytoSorb-treated lungs after the 12 hours perfusion period

Fig. 3. Radiologic assessment of lung injury in controls and CytoSorb-treated lungs after the 12 hours perfusion period

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CONCLUSIONS*• Continuous perfusate filtration through sorbent beads is effective and safe during prolonged EVLP

• Cytokine removal decreased the development of pulmonary edema and suppressed anaerobic glycolysis (less glucose consumption, decreased lactate production and better lactate/pyruvate ratio) in this setting

• Perfusate cytokine levels were significantly reduced in the CytoSorb group resulting in less infiltration of inflammatory cells and lower radiologic lung injury

• Significantly improved peak airway pressure, oxygenation function and dynamic compliance as well as a trend towards an improved pulmonary vascular resistance and PaO2 in the CytoSorb–treated lungs

• Further studies are needed to test the beneficial effect of cytokine filtration during EVLP on post-transplant lung function

Continuation: Hemoadsorption modulates pulmonary metabolism and edema formation

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Safety Aspects and Drug Removal

A Schneider, Lausanne, Switzerland

In his presentation, Dr. Schneider gave a comprehensive overview on the currently available evidence supporting the safety of CytoSorb therapy and shared data on the impact of CytoSorb on drug removal.

What is the clinically available data on CytoSorb – can we use it safely?• Post marketing surveillance suggests no major

adverse effects after >50,000 treatments administered around the world

• A randomized controlled trial by Bernardi et al. (Critical Care 2016; 20:96) in 37 patients undergoing elective cardiac surgery in whom 19 were treated with CytoSorb during cardiopulmonary bypass, reported no device-related adverse events and technical feasibility

• The randomized controlled trial by Schädler et al., (PLOS One 2017; 30(12): e0187015) in 100 mechanically ventilated patients with severe sepsis or septic shock and acute lung injury using CytoSorb in hemoperfusion mode or with CRRT for 6 hours per day up to 7 days, reported one serious adverse, potentially device-related event in form of a reduction in platelet count in 1 CytoSorb-treated patient

• Available case series (n=6) in the field of sepsis and cardiac surgery reported no device-related adverse events (Table 1.)

• Single center, pilot, randomized controlled trial (Poli EC et al., Critical Care 2019; epub) with 30 patients undergoing elective cardiac surgery deemed at risk of complications were included and randomly allocated to either standard of care (n=15) or CytoSorb (n=15) during cardiopulmonary bypass (CPB)

○ The study showed similar rates of adverse events between hemoadsorption and control groups and no obvious adverse events appeared to be directly attributable to the CytoSorb device

○ Coagulation factors cross-adsorber clearance tests (measurement before and after the adsorber at one hour of cardiopulmonary bypass treatment) showed no difference in coagulation factors between pre- and post-adsorber measurements (Fig. 1.). However, there was a statistically significant difference in pre- and post-adsorber levels for antithrombin and Factor II

○ Therefore, there is no significant coagulation factor adsorption by CytoSorb and only mild coagulation activation and heparin adsorption (Fig. 2.)

Available data on antibiotic clearance by CytoSorb • In vitro data:

○ Marginal removal of aminoglycosides ○ Almost complete removal of vancomycin and

teicoplanin ○ However, in vivo properties might vary from in

vitro in terms of protein level/protein binding, dilution volume, impact of continuous renal replacement therapy when used

• In vivo data (mostly case reports): ○ Relevant removal for vancomycin and

aminoglycosides ○ Minor removal for linezolid and meropenem ○ Low removal of piperacillin and imipenem

Case presentation (Poli EC et al., Clindamycin clearance during CytoSorb® hemoadsorption: A case report and pharmacokinetic study. Int J Artif Organs 2019; epub)• 14-year-old boy with refractory septic shock • Panton-Valentine leucocidin producing MRSA

pneumonia was diagnosed• Installation of veno-arterial (VA) extracorporeal

membrane oxygenation (ECMO)• Despite ECMO he developed refractory vasoplegic

shock• CytoSorb insertion into the ECMO system on day 4

after admission • Marked decrease of vasocative substances

(epinephrine, norepinephrine, vasopressin, dobutamine) from the time CytoSorb was installed into the system

• Since clindamycin, a key component of Panton-Valentine leucocidin producing methicillin-resistant Staphylococcus aureus treatment, might be removed by CytoSorb hemoadsorption, serial plasma concentration measurements of the drug were performed culminating in the development of a pharmacokinetic model incorporating variable plasma clearance. According to this model, CytoSorb did not seem to result in significant clindamycin removal and therefore CytoSorb hemoadsorption during Panton-Valentine leucocidin producing methicillin-resistant Staphylococcus aureus infection appears safe and feasible and adaptation of clindamycin dosage seems unnecessary

1313


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Continuation: Safety Aspects and Drug Removal


Presentation of data on potential drug removal in a pig model• Aim

○ To ensure patient safety through animal testing of CytoSorb in combination with antibiotics, antimycotics and virostatics in pigs

• Methods ○ Animal study, 12 pigs: treated with CytoSorb

for 6.5 hours, 12 pigs: controls ○ Antimicrobials administered (17 drugs in total)

in four groups and serial blood measurements taken

• Results ○ No difference between CytoSorb and control

for clindamycin and piperacillin ○ Very moderate increase in removal of linezolid,

fluconazole and meropenem in the CytoSorb group and all measurements were much higher than the mean inhibitory concentration

Medication removal can be beneficial in situations of intoxications• Venlafaxine• Dabigatran• Ticagralor• Rivaroxoban

Context Study type Sample Size Modality Adverse Events / Safety Issues

Nemeth 2018 Cardiac Transplantation Case series 16

(vs 16 controls)Within CPB

Mean = 203 minNo difference in adverse

events observed

Friesecke 2017 Sepsis / Cardiac surgery / Others Observational 198

With CRRT / Within CPB or hemoperfusion Range

from 8 to 60.8 hrs

No device-associated side effect

Träger 2016 Cardiac Sx (Endocarditis) Case series 39

(28 hist. controls)During CPB

Median = 132 min.No mention of adverse

events

Träger 2017 Post-CPB SIRS Case series 16 With CRRTRange: 5-88 h

No mention of adverse events

Kogelmann 2017 Septic shock Case series 26 With CRRTNo device-related adverse events during or after the

treatment sessions

Friesecke 2017 Septic shock Case series 20 With CRRTNo serious adverse effects

of the therapy were observed

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Fig. 2. Coagulation factors trans-adsorber clearance tests in the peri-operative treatment periodControl CytoSorb * p < 0.05

CONCLUSIONS*• No adverse events noted in clinical trials/case series, and therefore CytoSorb hemoadsorption

appears to be a safe procedure during o CPB for cardiac surgery o ECMO o Continuous renal replacement therapy

• It does not seem to be associated with a significant impairment of coagulation factors

• CytoSorb’s effect on antibiotic levels seems minimal, however therapeutic drug monitoring is strongly recommended particularly in septic shock and reliable data are needed

• Removal of certain molecules can be salutary in some situations

15


Fig. 1. Coagulation factors cross-adsorber clearance tests measured before and after the adsorber at one hour of CPB treatment

Act

ivity

[%]

250

200

150

100

50

0

AT FII FIX FV FVIII FXI FXII vWF

Coagulation factors

pre Adsorber

post Adsorber

**

D1 D2 D3 D4 D5 D6 D7 D8

Time (days)

24h24h24h9h

CytoSorb hemoadsorption

Ul/k

g/h

0.05

0.04

0.03

0.02

0.01

0.00

μg/k

g/m

in

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.0

Adrenalin

Noradrenalin

Vasopressin

Dopamine

Fig. 3. Time course of vasoactive substances before and during CytoSorb treatment

* p < 0.05

16

Professor Brunkhorst reported on the results of the 7th interim analysis of the Registry.

Why should we conduct Registries?• Randomized controlled trials (RCT) deliver only part

of the information which patients and physicians need for decision making

• Other study types must be included and may be more important for individual decisions rather than quantifying efficacy by RCTs

• They are one part (besides RCTs etc.) for helping clinical decision making

Characteristics of Registries• No given intervention (non-interventional study)• No randomization• Precise defined target population• Representative or total inclusion of the target

population (no exclusion criteria) • Active, standardized data assessment

Priorities for future sepsis clinical trials• In the future, more intelligent studies have to be

designed, in which mortality is not the primary endpoint and not every patient is enrolled, but rather well-defined subgroups of patients who might respond to treatment

• Suggestion to perform predictive enrichment trials to a priori defined patients that might respond to certain therapies

• Until this point, robust registries represent a good tool for documenting real life clinical data and to test external validity of the results of trials in broader patient populations

Latest (7th) update on the International CytoSorb RegistryStudy population and indications• Sepsis/septic shock• Cardiac surgery with CPB (cardio-pulmonary

bypass) ○ preemptive CytoSorb use in OR ○ postoperative CytoSorb use in ICU

• Other indications ○ Liver failure, acute pancreatitis, trauma, burns,

ARDS with ECMO, other indications with ECLS

In-/Exclusion Criteria• Inclusion Criteria

○ Use of CytoSorb®

○ Age >= 18 years ○ Signed informed consent

• Exclusion Criteria ○ none

Current status • Status March 2019: 240 registered sites from

31 countries, 75 in process, 57 sites ready for recruitment, 35 sites recruiting

• N=684 of registered and documented patients from May 2015 to February 2019

• Results from the 7th Interim analysis

Example data from the sepsis cohort• Patient characteristics

○ Low median age of 60.5 years in patients with septic shock

• Inflammatory mediators ○ Lower IL-6 and CRP values after treatment

compared to pre-treatment levels• Disease severity

○ APACHE II score of 30.1 on average and SAPS II score of 68.6 points significantly higher than those known from former sepsis studies (SISPCT, VISEP, MAXSEP) worldwide

• Length of stay ○ Very long ICU stay on average for 30.5 days ○ Predicted mortality ○ APACHE II predicted mortality is 70.8% ○ Observed ICU mortality equaled 64.1% and

hospital mortality 66.7% ○ Of note, this signal towards lower than

predicted mortality could also be found in the cardiac surgery with CPB and postoperative CytoSorb use in the ICU as well as in the other indications

○ The difference between predicted and observed mortality is particularly pronounced amongst the most seriously ill patients (APACHE II score >35)

○ Accordingly, the most severely ill patients may benefit most from CytoSorb therapy (APACHE II Score> 35)

Survival rate of patients with septic shock dependent on treatment start• Clear trend towards a survival benefit in patients

with septic shock that are treated earlier

Subjective, semiquantitative assessment of the treatment – “Did the condition of your patient improve?”• None of the attending physicians stated that

a septic patient had deteriorated after using CytoSorb, the majority however had the perception that the patients’ status improved during treatment

• This was also similar in other indications• There were no adverse device-related events

reported

The International CytoSorb Registry – Latest Update F Brunkhorst, Jena, Deutschland


CONCLUSION*• This is the first time a company dealing with blood purification techniques is pushing combined

generation of evidence through investigator-initiated and sponsored randomized controlled trials and a treatment Registry in a systematic manner, which is a valid way to generate more evidence

• There will be sufficient data available in 2019 to provide further insights into the efficacy of the CytoSorb treatment, predominantly also on the dependence on the time point of use

• Preliminary data from the current registry evaluation suggest a positive influence of CytoSorb therapy on mortality (lower than expected), especially in the most severely ill patients (APACHE II score> 35), and further indicate survival benefit in patients with early initiation of therapy

• Therefore, CytoSorb therapy looks very promising in the light of the current study update


17

Indication Severe Sepsis /

septic shock N=348 (58.1 %)

Indication Other

N=149 (24.9%)

Indication Cardiac surgery with CPB,

postoperative CytoSorb use in ICU

N=43 (7.2%)

Indication Cardiac surgery with CPB, preemptive CytoSorb use

in OR N=59 (9.8 %)

Data base status 19 Nov 2018: Patients with „completed“ visits

N=599

Figure 2. Kaplan-Meier curve of patients with septic shock. Patients treated within 12 hours after onset of septic shock (blue solid line) show better long-term (84-day) survival compared to patients treated after more than 12 hours

following septic shock diagnosis (green dashed line)

Surv

ival

Pro

pabi

lity

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 7 14 21 28 35 42 49 56 63 70 77 84

Length of stay (hospital days

> 12h ≤ 12h

Onset of CytoSorb / APACHE II score

Figure 1: Mortality in patients with septic shock as a function of disease severity grouped by APACHE II Score Level

APACHE II: scoure grouped

Num

ber o

f pat

ient

s100

80

60

40

20

0

Pred

icte

d an

d ob

serv

ed m

orta

lity

[%]

APACHE II Score: Mortality by outcome, grouped by APACHE II Score levels - ITT except preemptive use, only

patients with APACHE II and outcome known

0 - <5 5 - <10 10 - <15 15 - <20 20 - <25 25 - <30 30 - <35 >=35

125

100

75

50

25

0

46,951,4

60,5

65,867,9

90,4

77,3

47,1

29,6

64,7

FrequencyAPACHE II: predicted mortality (%), 95% Confidence LimitsHospital mortality, 95% Confidence Limits

3 8 22 64 74 79 81 134Number of patients

Note: Because of low patient numbers, no statistics for APACHE II Score <15 are displayed

18

SHOCK REVERSAL

My clinical experiences after 100 patients

Y Mehta, Delhi, India

Professor Metha presented data from a large set of 100 septic patients treated with CytoSorb and also shared latest results from a small study conducted in CytoSorb-treated patients undergoing major aortic surgery.

State of sepsis in developing countries• Sepsis is a major cause of morbidity and mortality

and the second leading cause of death worldwide• This is even more pronounced in the developing

countries as has been shown in a multicenter, prospective cohort surveillance of device-associated infections studied in 21,069 patients from 55 intensive care units (ICU) from 8 developing countries during 2002-2005, underlining the association with a considerable increase in mortality (Rosenthal VD et al., Am J Infect Control 2014;42(9):942-56)

• Data from India are sparse and only available via numbers on epidemiology of infection (both community and hospital acquired)

• In an indian study cohort in septic patients, ICU mortality was 56.1%, 28-day mortality 62.8% and hospital mortality 63.6%

• Sepsis in Indian ICUs is predominantly due to gram-negative pathogens (73.4%)

CytoSorb experience in 100 septic patients• Study Title

○ Retrospective single center cross-sectional registry to evaluate clinical outcomes following extracorporeal cytokine adsorption device use (CytoSorb) in patients with sepsis and septic shock

• Methodology ○ Records of all patients who received CytoSorb

therapy following diagnosis of sepsis or septic shock (as per the Surviving Sepsis Guidelines) and hospitalized in the intensive care unit from August 2016 to August 2018 were included

○ Institutional Ethics Committee approval was given

○ A protocol-trained registry coordinator collected and transcribed the data onto a case record form. Following cross-verification and approval of the transcribed data by the investigator, data were analyzed for primary and secondary outcome measures

• Objective ○ To analyse the differences (before and after

CytoSorb treatment) in the following aspects between survivors and non–survivors (group comparisons): - Baseline characteristics - Mean arterial pressure (MAP) and vasopressor need

- SOFA and APACHE scores - Laboratory parameters and cytokine levels - Impact of time of CytoSorb initiation on outcome

• Results ○ Baseline characteristics were comparable

between groups ○ In the survivor group, there was an

improvement in MAP accompanied by a decrease in requirements for all vasopressors post CytoSorb therapy (Fig. 1.), whereas in the non-survivor group, there was no improvement in vasopressor needs (or even an increase) accompanied by a decrease in MAP (Fig. 2.)

○ In the survivor group, sepsis scores such as APACHE II and SOFA (pre vs. post CytoSorb therapy) showed improvement, while this was not the case in non-survivors (Fig. 3.)

○ Survivors showed a significant improvement in lactate levels after CytoSorb therapy, whereas lactate levels tended to increase in non-survivors (Fig. 4.)

○ Significant decrease in cytokine levels in the survivor group for IL-6, IL-10 and TNFa comparing pre- and post-treatment concentrations (Fig. 5.)

○ Survival based on CytoSorb therapy initiation in the ICU showed that a high proportion of patients survived when therapy was started within 48 hours after sepsis diagnosis (Fig. 6.)

○ A reduction in ICU stay was seen in patients where CytoSorb was initiated within 48 h after sepsis diagnosis (Fig. 7.)

A pilot comparative study on CytoSorb vs. Control in patients undergoing on–pump cardiac surgery• Study Design

○ Prospective, non-randomized, observational study

• Study group ○ Patients undergoing major aortic surgery

(Bentall, ascending aortic replacement, arch repair) under hypothermia with or without circulatory arrest

○ Control group – On pump surgery without CytoSorb

○ CytoSorb group - On pump surgery with CytoSorb

• No of Patients ○ Control group : 7 ○ CytoSorb group : 7

SHOCK REVERSAL

• Measurements ○ Cytokine levels (IL-6), PCT, leucocytes, MAP,

inotrope requirement assessed at 4 pre-defined time points T0 - pre CPB, T1 – post CPB, T2 - post-operative day 1, T3 - post-operative day 2

• Results ○ Comparable demographic data between

groups ○ CytoSorb group showed significantly lower

IL-6 levels at all time points as compared to controls

○ PCT levels were higher in the control group compared to the study group at all time points

○ MAP values were higher in the study group compared to control group at T2 and T3

○ Post operative ventilation duration was also reduced in the CytoSorb group as compared to controls

○ Significantly shorter ICU and hospital stay in the CytoSorb group

MAP and Vasopressor Dose

Vasopressors Pre (mean) Post (mean) p value

MAP [mmHg] 62.8 68.2 0.023

Epinephrine 19.38 12.77 0.040

Norepinephrine 17.68 14.04 0.030

Vasopression 2.01 1.34 0.040

*p value <0.05Epinephrine Norepinephrine Vasopressin MAP

Pre CytoSorb Post CytoSorb

* *

*

*

MAP and Vasopressor Dose

Vasopressors Pre (mean) Post (mean)

MAP [mmHg] 66.13 64.31

Epinephrine 14.67 16.50

Norepinephrine 14.97 18.30

Vasopression 3.73 3.35

*p value <0.05Epinephrine Norepinephrine Vasopressin MAP


Fig. 1. Vasopressor requirements pre and post treatment in the survivors group

Fig. 2. Vasopressor requirements pre and post treatment in the non-survivors group


15.215.0528.2627.61

APACHE Score* SOFA Score*

Non Survival Group (n = 60)


10.3212.314.0824.6

APACHE Score* SOFA Score*

Survival Group(n=40)

Fig. 3. Sepsis scores (APACHE II and SOFA) pre and post treatment in the survivor (left) and non-survivors group (right)

1919

20

SHOCK REVERSAL

Continuation: My clinical experiences after 100 patients

Cytokine levels (Survival group)

Interleukins Pre (mean, pg/ml) Post (mean, pg/ml)

IL-2 18.36 12.21

IL-4 11.4 9.73

IL-6* 274,107.2 156,423.2

IL-10* 293.76 124.34

TNF* 20.83 15.86

IFNG 20.28 19.82

IL-17a 36.28 29.86

IL-2 IL-4 TNF INFG IL17A

Pre (mean) Post (mean)

* p value < 0.05

18,36

12,21 11,49,73

20,83

15,86

20,2819,82

29,86

36,28

IL-6* IL-10*

254

1962

124.34

293,76

Fig. 5. Cytokine levels pre and post treatment in the survivors group


4,15

p value - 0.04

5.01

Survival Group


5,18

p value > 0.053.72

Non-Survival group

Fig. 4. Serum lactate levels pre and post treatment in the survivor (left) and non-survivors group (right)

CONCLUSION*• In the study with 100 septic patients, the following outcomes with CytoSorb therapy could be

observed: o Hemodynamic stabilization with reduction in vasopressor requirements o Improvement in sepsis scores i.e. SOFA and APACHE II o Improvement in laboratory parameters o Additionally, data show that survival outcome was better in patients where CytoSorb was used within 48 hours of septic shock o However, larger studies need to re-confirm the potential benefits of this treatment option in septic patients

• In patients undergoing major aortic surgery on CPB, CytoSorb use leads to: o Decreased cytokine and PCT levels o Better hemodynamic stability o Reduced duration of mechanical ventilation o Decreased ICU & hospital length of stay

21

SHOCK REVERSAL

CytoSorb initiated Mean Hospital stay

< 2 Days 13.24

3 to 7 Days 31.08

> 7 Days 20.00

Fig. 7. Hospital stay among survivors based on CytoSorb therapy initiation

Time when CytoSorb Therapy started after admission among non-survivors

Frequency Percent Cumulative %

< 2 days after admission 17 28.33 28.33

3-7 days after admission 32 53.33 81.67

> 7 days after admission 11 18.33 100

Total 60 100

Time when CytoSorb Therapy started after admission among survivors

Frequency Percent Cumulative %

< 2 days after admission 28 70 70

3-7 days after admission 7 17.5 87.5

> 7 days after admission 5 12.5 100

Total 40 100

Fig. 6. Impact of time of CytoSorb initiation on outcome

22

In his talk Dr. Dürschmied spoke about the application of extracorporeal cardiopulmonary resuscitation and presented results from a case series in 25 refractory cardiac arrest patients treated with CytoSorb therapy.

Extracorporeal cardiopulmonary resuscitation• Very promising data from a retrospective registry

with a propensity score-matched analysis comparing patients undergoing conventional cardiopulmonary resuscitation (cCPR, n=523) and extracorporeal cardiopulmonary resuscitation (eCPR, n=112) (Patricio D et al., Crit Care 2019;23(1):27)

• Survival was higher in the eCPR group and neurological outcome was favourable with a higher proportion of patients being in cerebral performance category (CPC) 1-2 (i.e. able to work at 3 months)

• eCPR may be the ultima ratio after refractory cardiac arrest for longer than 60 min

• Predictors of survival: low-flow time, rhythm, witnessed collapse, age

Current status at the University Hospital Freiburg• 30-bed medical Intensive Care Unit• 150 ECMOs per year• 20-30 eCPRs per year• Survival rate of 36% for patients treated with eCPR

with very promising long-term survival rates (6-year data)

• Interdisciplinary approach with cardiologists, anesthesiologists, cardiac surgeons, perfusionists

Case presentation• 18-year-old male patient with ongoing CPR due to

ventricular fibrillation after collapsing while playing soccer

• Despite 60 min of CPR (persisting VFib) no return of spontaneous circulation could be achieved

• Implantation of a veno-arterial (VA) ECMO system• Additionally, an Impella heartpump was implanted

upon arrival at University Hospital Freiburg• The patient developed post-cardiac arrest

syndrome with massive hyperinflammation (IL-6 18,000 pg/ml, PCT 175 ng/ml) and hyperlactatemia (15 mmol/l)

• CytoSorb was introduced into the system resulting in a decrease in plasma lactate levels and IL-6, however the patient went into multiple organ failure (heart, kidney, liver, lung, hemostasis)

• After 4 days it was found that the patient had suffered anoxic brain injury

Case series of 25 patients undergoing eCPR in combination with CytoSorb• 30 day survival in these patients was 24% compared

to an expected survival (by SOFA score) of 10%, this was a similar survival compared to the entire cohort of eCPR patients (n=212) treated in Freiburg until current date (Fig. 1)

• Values of lactate and bilirubin before and after CytoSorb treatment were comparable with an already published study by Pappalardo et al. (Artificial Organs 2018)

• Best predictor of survival was the decrease in lactate (Fig. 2.), i.e. patients showing no decrease of lactate during the treatment had a low probability of survival

• Moreover, interleukin-6 and procalcitonin plasma concentrations could be markedly reduced when analyzing pre- and post-treatment levels (Fig. 3)

Initiation of a pilot trial at University Hospital Freiburg• CYTokine adsorption in post-cardiac arrest

syndrome for patients requiring Extracorporeal cardiopulmonary Resuscitation (CYTER)

• Single center randomized controlled trial in 30 patients with refractory cardiac arrest and ongoing CPR followed 1:1 randomization for institution of eCPR with VA ECMO plus CytoSorb (3x24 hours) or without CytoSorb

• Primary endpoint: IL-6 removal• Secondary endpoints: 30-day survival, lactate,

vasopressor use, renal function, IL-1b, IL-10, IL-8, TNFa, fluid balance, PK/PD (72h) of sulbactam/ampicillin, platelet function testing

• Ultimate goal is to conduct a randomized multi-center trial (2020-2021) with n>100 patients in 10 eCPR centers in Europe powered for 30-day survival

CytoSorb in Cardiac Arrest

D Dürschmied, Freiburg, Germany

SHOCK REVERSAL

CONCLUSION*• Application of CytoSorb is feasible in patients with refractory cardiac arrest

• Combined application of CytoSorb in eCPR was associated with o No severe complications o A decrease in surrogate parameters (IL-6, lactate) o An improvement in the clinical course in several cases

23

SHOCK REVERSAL

Fig. 2. Decrease of lactate as best predictor of survival

Fig. 3. Lactate and bilirubin concentration pre- and post-treatment levels with CytoSorb in eCPR

Fig. 1. 30-day-survival with CytoSorb in eCPR

CytoSorb

(n=25)

Expected

(SOFA)

Total

(n=212)

30 day survival (%)30

25

20

15

10

5

0

100

50

0

-50

-100

% d

ecre

ase

Survival (days)

Correlation survival - parameter decrease

10 20 30

Lactate (%) r = 0.46, p < 0.01

PCT (%) r = 0.03, p = 0.89

Bili (%) r = 0.02, p = 0.90

LAC pre

LAC post

Lactate

LAC pre

LAC post

25

20

15

10

5

0

Papppalardo 2018 Duerschmied unpublished

Lact

ate

[mm

ol/l]

Bili pre

Bili post

Bilirubin22 20 18 16 14

Bili pre

Bili post

10

5

0

Papppalardo 2018 Duerschmied unpublished

Bili

[mg/

dl]

days

24

In his presentation Dr. Kogelmann explained how the decision to use CytoSorb therapy in patients with septic shock is made in his department and introduced a new decision algorithm (CytoScore).

Indication for the application of CytoSorb• Changes in SOFA score represent an indicator of

failure of conventional therapy • The focus is therefore mainly on SOFA score

changes and vasopressor requirements• The use of CytoSorb is indicated in patients whose

clinical condition worsens, including ongoing organ failure despite fully exhausted standard sepsis therapy

Developing a new dynamic score (CytoScore)• Defined parameters:

○ Blood lactate and changes within the first 6 hours

○ Catecholamine demand and changes within the first 6 hrs

○ Initial volume demand and requirement for additional boluses within the first 6 hrs

○ Need for 2nd catecholamine and/or hydrocortisone use

• Set thresholds: ○ Lactate 2 mmol ○ Vasopressor 0.1µg/kg/min ○ 30 ml/kg initial volume (defined according to

Sepsis-3, SSC-Guidelines, SOFA) ○ Each parameter with this value is counted with

1 point

○ Dynamic increases lead to an additional point, decreases are counted with 0

○ In this scoring system, septic shock is typically represented within the range of 7-10 points

First validation results of the CytoScore• Retrospective analysis in 385 patients treated

between 2014-2018 who fulfilled the Sepsis-3 criteria

• Inclusion criteria: ○ Patients with septic shock meeting Sepsis-3

criteria • Exclusion criteria:

○ Patient not ICU treated or not documented ○ ICU treatment but no vasopressor administered

or no lactate documented• 207 patients were included in the analysis (178

were excluded)• Of those 207 patients, 138 received no and 69

received CytoSorb treatment• Results

○ Patients with a score between 6-8 points seemed to benefit most from CytoSorb treatment in terms of survival

○ The analysis impressively shows that patients with a start of CytoSorb therapy within 24 hours after diagnosis of septic shock, pneumonia and a mean score between 6-8 (n=16) have a survival probability of 62.5% (APACHE II was 38.1, predicted mortality of 88%) compared to survival of 25.9% in patients with no CytoSorb treatment

CytoScore Helps Me To Find The Right Starting Point K Kogelmann, Emden, Germany

SHOCK REVERSAL

CONCLUSION*• Timing and indication are of utmost importance - the best results were seen with early use

(<24 hours) in pneumonia patients

• CytoScore might be helpful for identifying the right patient who would benefit most from CytoSorb therapy

• However, the score needs to be sufficiently validated with external data

25

SHOCK REVERSAL

Parameters

Lactate [mmol/l] < 2 - ≥ 2

Lactate change within 6 h decreased increased increased > 50 %Norepinephrine demand [μg/kg/min] to achieve a MAP of 65 mmHg < 0.1 - ≥ 0.1

Norepinephrine demand change within 6 h decreased increased increased > 50 %

2nd catecholamine required - yes -

Hydrocortisone administration - yes -

Initial volume bolus - < 60 ml/kg ≥ 60 ml/kg

0 1 2APACHE II CytoSorb treatment Score

YES NOSpecial indications: no score required

Fig. 1. Association of the CytoScore, delay of therapy start and survival rate in pneumonia patients

Surv

ival

(%)

70

60

50

40

30

20

10

0

25,9

62,5

36,537,8

54,5

Fig. 1. Representation of the new CytoScore

pneumonia (63)

pneumonia & CytoSorb (37)

pneumonia and CytoSorb

< 24 hrs (22)

pneumonia & Score 6-8

(27)

pneumonia & CytoSorb < 24hrs & Score 6-8 (16)

26

Professor Tomescu provided an overview on the types of acute liver failure with special focus on acute-on-chronic liver failure and the underlying inflammatory response. She further presented data from a retrospective analysis of acute-on-chronic liver failure patients treated with CytoSorb as well as 2 case reports.

Types of liver disease in the intensive care unit (ICU)• Decompensated cirrhosis• Acute liver failure• Acute-on-chronic liver failure (AoCLF)• Drug-induced liver injury• Septic shock with multiple organ failure• Postoperative liver failure

Acute-on-chronic liver failure• High mortality in patients with AoCLF depending on

the number of organ dysfunctions (most frequent is acute renal failure)

• Acute renal failure and/or hepatic encephalopathy are major risk factors for mortality

• Most common precipitating events are bacterial infections before active alcoholism and gastrointestinal bleeding

• Patients with AoCLF due to bacterial infections have systemic hyperinflammation with high levels of plasma pro-inflammatory cytokines, persistently high levels of these mediators throughout the course are associated with poor outcome (i.e. TNFa, IL-6, IL-8) (Claria J et al., Hepatology 2016;64:1249)

• Leucocyte count is positively correlated with 28-day mortality (Moreau et al., Gastroenterology 2013, 144:1426)

• There is a modified systemic inflammatory response during AoCLF with a lot of apoptosis leading to the generation of damage-associated molecular patterns (DAMPs) plus bacterial components (pathogen-associated molecular patterns; PAMPs)

Inflammation in liver failure• In normal individuals there are only low levels of

translocation of bacteria into the circulation• In compensated cirrhosis however, there is:

○ An increase in paracellular translocation of bacterial products

○ Stimulation of an augmented pro-inflammatory cytokine response and release of reactive oxygen species (ROS) and nitric oxide species (NOx) within the gut-associated lymphoid tissue (GALT)

○ Initiation of the vicious circle: mediators impact on the mechanical and secretory barrier and on the flora

• Decompensated cirrhosis is: ○ Characterized by overgrowth of intestinal

bacterial and epithelial tolerance ○ Enhanced transcytosis of viable bacteria

leading to immune paralysis in the GALT ○ 2nd vicious circle: perpetuating loop by a

relative lack of bacterial killing

Management of AoCLF in the ICU• Requires a multidisciplinary approach: intensivist,

gastroenterologist, surgeon• Advanced monitoring during standard therapy• 24/7 specialized care• Communication between key players • Main goal is sustaining organ functions

(cardiovascular, respiratory, neurological, renal)• Provide time for organ recovery/bridge to

transplantation

Results from application of CytoSorb in AoCLF patients • Patients with AoCLF admitted to the ICU• Inclusion criteria: fulfilling >2 SIRS criteria, need

for renal replacement therapy (RRT), severe inflammation (CRP, leucocytes, temperature)

• Exclusion criteria: age <18 years, severe thrombocytopenia (<25,000/µl) or active bleeding

• Included in the study were n=24 patients treated with 3 consecutive sessions of continuous veno-venous hemodiafiltration (CVVHDF) plus CytoSorb

• Results ○ 24 patients were included in the final analysis

(mean age 43±16 years) ○ Median number of SIRS criteria was 2.5 [2,4] ○ Median number of organ dysfunctions was 3 [1,6] ○ Mean duration of a single RRT therapy was

19±7 hours ○ Mean Clif-SOFA score at ICU admission was

12.8±2.1 and the mean Clif-C ACLF score was 55.2±10.9

○ Five patients (20.8%) had a grade 2 AoCLF and 19 patients (79.2%) had grade 3 AoCLF

○ The median ICU length of stay was 10 [2, 58] days

○ Overall survival was 54.2% (n=13/24) ○ Ten patients (41.7%) had a decrease in Clif-

SOFA ○ Survival was significantly higher (70%) in

patients with a decrease in Clif-SOFA score (Fig. 1.)

Liver Failure

D Tomescu, Bucharest, Romania

CYTOSORB IN VARIOUS FIELDS OF APPLICATION

CONCLUSION*• From the preliminary data it can be assumed that CytoSorb might be beneficial in liver failure

• Treatment is feasible and safe in these patients

• If AoCLF patients are well assessed preoperatively, they can be safely (i.e. without severe bleeding risk etc.) treated with CytoSorb

27


○ All patients (n=5) with AoCLF grade 2 had a decrease in Clif-SOFA score with 100% survival

○ Survival in patients with AoCLF grade 3 was 42.1% (8/19)

Case presentation 1 - Primary graft non-function• Published case report (Tomescu DR et al., Int J Artif

Organs 2016; 39(3):136-40)• Intraoperative use of CytoSorb in a liver transplant

patient after developing signs of primary graft non-function requiring emergency transplantation with a AB0 incompatible graft

• During and after each treatment a significant and rapid decrease of pro- and anti-inflammatory cytokines was observed, especially for interleukin-6 (IL-6), IL-10 and monocyte chemotactic protein 1 (MCP-1)

• Reduction of cytokines was associated with a normalization of cardiac output and systemic vascular resistance, and improved liver function

Case presentation 2 - ALF due to Wilson’s Disease• 17-year-old patient who was admitted to ICU for

hepatic encephalopathy (grade II-III, ammonia 137 µmol/l) and respiratory distress

• She had a history of Wilson‘disease (for 4 years) but had neglected treatment ever since

• Upon arrival, her MELD score was 45• Laboratory results on admission: total bilirubin 65

mg/dl, direct bilirubin 54 mg/dl, INR 2.5, PT 33 sec, fibrinogen 204 mg/dl, thrombocytes 125,000/µl, hemoglobin 6.1 g/dl, leucocytes 9130/µl

• ARDS was confirmed by chest X-ray showing bilateral infiltrates, SpO2 of 75% while breathing room air, requiring intermittent non-invasive ventilation (CPAP)

• Procalcitonin level was 2.49 ng/ml and CRP level 36.2 mg/l

• A rapid deterioration within hours occurred, requiring intubation and mechanical ventilation

• Treatment with therapeutic plasma exchange (TPE) was performed in the ICU on day 1 for severe coagulopathy and cholestasis

• The patient was listed for liver transplantation and the mother was rapidly investigated as a potential living donor

• As bridging to liver transplantation, to decrease the elevated bilirubin levels and in order to diminish the inflammatory response present in the acute liver failure, continuous veno-venous hemofiltration with a CytoSorb adsorber was performed prior to surgery and continued throughout the liver transplantation procedure

• Living relative liver transplantation was performed (less than 48 hours after admission) with a duration of surgery of 380 mins, an anhepatic phase of 30 minutes, a blood loss of 3.5 liters requiring transfusion of 4 red blood cell concentrates as well as intraoperative atrial fibrillation followed by sinus bradycardia and hemodynamic instability

• The patient was extubated within 12 hours after surgery and the chest X-ray was clear with no signs of ARDS, however she had hepatic encephalopathy grade II

• Initial poor function of the graft was diagnosed with increased hepatic cytolysis, increased bilirubin levels, decreased synthesis of coagulation factors (requiring administration of fibrinogen 1g/day), persistent elevated lactate levels (2-4 mmol/l), repeated episodes of supraventricular tachycardia and grade 1-2 hepatic encephalopathy

• Despite this she had a full recovery and was discharged to the ward on postoperative day 11

Fig. 1. Survival of patients with an increase or a decrease in Clif-SOFA score

Cum

ulat

ive

Surv

ival

1.0

0.8

0.6

0.4

0.2

0.0

0 5 10 15 20 25 30

ICU stay (days)

Clif-SOFA score increase

Clif-SOFA score decrease

28

Professor Duranteau shared his ideas on how CytoSorb could be useful in treating rhabdomyolysis and to prevent acute renal failure.

Definition of rhabdomyolysis • Acute muscle weakness, myalgia, and muscle

swelling• Creatine kinase (CK) cut-off value of >1000 IU/l/ or

CK >5x upper limit of normal• CK >5000-10,000 IU/l is defined as severe

rhabdomyolysis • Causes are hypoxic, physical, chemicobiological

Pathogenesis of rhabdomyolysis• Direct sarcolemmic injury• Impairment of production of ATP or inability of the

myocyte to increase metabolic demands• Dysfunction of Na+-K+ ATPase pumps and Ca++-

Na+ exchangers• Free ionized calcium enters the intracellular space

and activates proteases and apoptosis pathways• Production of reactive oxygen species leads to

mitochondrial dysfunction• Persistent contraction and energy depletion • Hypoperfusion of injured tissue due to hypovolemia

and muscle fluid sequestration (compartment syndrome)

• High concentrations of muscle cell contents are released into the blood stream such as electrolytes, enzymes (creatine kinase [CK], lactate dehydrogenase), proteins (myoglobin), and purine metabolites (uric acid)

Complication of rhabdomyolysis• Electrolyte imbalances (resulting in metabolic

acidosis, arrhythmias or cardiac arrest)• Compartment syndrome (edema, inflammation,

and fluid sequestration)• Hypovolemia (results from fluid sequestration within

damaged muscle)• Acute kidney injury (incidence ranges from 10% to

50%)• DIC (disseminated intravascular coagulation)

Prevention of acute kidney injury • Fluid resuscitation• Alkalinization • Diuretics• Renal replacement therapy (RRT)

Rhabdomyolysis promotes acute renal failure• Myoglobin precipitates when it interacts with the

Tamm-Horsfall protein (uromodulin) (produced by the thick ascending limb of the loop of Henle) – this process is favored by acidic urine

• Distal tubule obstruction, renal vasoconstriction, proximal tubule injury

• Myoglobin can promote oxidative stress

Presentation of 2 published case reports using CytoSorb in rhabdomyolysis• CytoSorb™ in a patient with legionella-pneumonia

associated rhabdomyolysis: a case report (Wiegele M and Krenn CG, ASAIO Journal 2015; 61 :e14)

○ Severe rhabdomyolysis reported in the context of Legionella pneumonia

○ Despite administration of antibiotics, liver enzymes and parameters of renal function deteriorated, indicating a trend toward multiple organ failure

○ Creatine kinase and myoglobin levels increased in combination with reduced urine excretion

○ CytoSorb was run in stand-alone mode on day 6 after admission and within 8 hours, myoglobin levels decreased from 18,390 to 10,020 ng/ml and with a second cycle it again declined from 13,400 to 8,359 ng/ml

○ Renal function completely recovered and hemodialysis was not necessary at any time of hospitalization

• Hemoadsorption in a Case of Severe Septic Shock and Necrotizing Fasciitis Caused by Nontraumatic Renal Rupture due to Pyelonephritis with Obstructive Uropathy (Kousoulas L et al., Case Reports in Critical Care 2018; 5248901)

○ A 25-year-old female with nontraumatic renal rupture with retroperitoneal abscess, perforation of the colon, and severe necrotizing fasciitis of the right lower limb

○ She underwent a right nephrectomy, a right hemicolectomy, surgical debridement of the retroperitoneum, and an upper thigh amputation

○ Severe septic shock and rhabdomyolysis with acute renal failure: combined treatment of hemoadsorption using a CytoSorb hemoadsorber and continuous venovenous hemodialysis (CVVHD)

○ Treatment was associated with rapid hemodynamic stabilization and decrease in IL-6 as well as myoglobin and creatine kinase (CK) levels

○ Subsequently the patient recovered and was discharged home with no signs of infection and with normal renal function

Rhabdomyolysis J Duranteau, Paris, France


CONCLUSION*• CytoSorb is a promising tool in the treatment of rhabdomyolysis, however the device has to be

studied more extensively in this field of application

• CytoSorb should be used in a patient collective which is at high risk of developing acute renal failure, best selected by the CK level

• A preliminary study investigating CytoSorb in trauma patients has been set up by Prof. Duranteau and is waiting ethical approval

29

Causes of Rhabdomyolysis

Prevention of acute kidney injury

Hypoxic Physical Chemical Biological

External

• Alcohol• Lipid-lowering drugs

(fibrates, statins)• Over-the-counter

medications• Illicit drugs

Internal

• Hypokalemia• Hypophosphatemia• Hypocalcemia• Hypo-/hypernatremia

External

• Bacterial, viral, and parasitic myositis

• Organic toxins (snake venom, spider bites)

Internal

• Dermatomyositis, polymyositis

• Endocrinopathies• Adrenal insufficiency• Hypothyroidism• Hyperaldosteronism• Diabetic ketoacidosis• Hyperosmolar state

External

• Crush injury• Trauma• Burns• Electrocution• Hypothermia• Hyperthermia

(heat stroke)

Internal

• Prolonged seizures• Severe agitation

(delirium tremens, psychosis)

• Neuroleptic malignant syndrome

• Malignant hyperthermia

External

• Carbon monoxide exposure

• Cyanide exposure

Internal

• Compartment syndrome

• Vascular compression• Immobilization• Prolonged surgery• Vascular thrombosis• Vasculitis

Fluid resuscitation

Alkalinization

Diuretics

Renal replacement therapy

• Extracorporeal removal of myoglobin by RRTs has been proposed as an effective preventive therapy for rhabdomyolysis-induced AKI

• Several studies have reported on myoglobin removal by different dialysis modalities, filters, and flow types, but effect on mortality or end-stage renal disease is uncertain

• Until randomized studies are performed, the routine use of RRT as preventive therapy in rhabdomyolysis-induced AKI cannot be recommended


SPECIAL ATTENTIONS SHOULD BE PAID TO*• The fact that this therapy could save dying patients not responding to conventional treatment

• Drug dosage and pharmacokinetics have to be acknowledged in clinical practice

• Initiation of CytoSorb should not be triggered by laboratory markers but rather by clinical parameters (e.g. vasopressor requirements)

• Do not use CytoSorb in patients with established full blown multiple organ failure as treatment might be too late and therefore futile

Professor Pappalardo gave a presentation on what we know and what we have to do using CytoSorb in combination with extracorporeal membrane oxygen-ation (ECMO) in various fields of application.

Extracorporeal support in Intensive Care Units (ICU)• The upcoming years will be the years of

extracorporeal and mechanical circulatory support techniques in the ICU

• Organ failure failure will be treated with a variety of life saving devices such as extracorporeal membrane oxygenation and heart pumps such as Impella to resuscitate patients

• However, these techniques do not represent causal treatments but rather supportive therapies to bridge the patients to definative therapies (i.e. heart replacement, recovery of the heart or lungs)

• All of these techniques are accompanied by iatrogenic side effects that are in addition to the primary disorder. For ECMO these include bleeding, thromboembolism, kidney and liver injury, infective risk of the vascular access, hyperinflammation, hemolysis and rhabdomyolysis

Key issues that might improve the application of CytoSorb in the ECMO setting• General indications

○ ECMO represents the ‘ideal model’ as CytoSorb is the primary adjunct to ECMO therapy (CytoSorb=therapy for ECMO side effects)

○ According to Professor Pappalardo, in the future CytoSorb should be implemented per se into every ECMO therapy circuit

• Differences when CytoSorb is applied in veno-arterial (VA) or veno-venous (VV) ECMO

○ Given that VA ECMO is a more traumatic or non-physiological procedure (e.g. very high shear forces, laminar flow) compared to VV ECMO, the resulting hyperinflammation is more severe in VA patients

• Principles of application ○ When and for how long should CytoSorb be

used? ○ Sustainability (contemporary duration of ECMO

run)• Therapy goals

○ Underlying disease plus ECMO burden results in a toxic milieu which can be treated using CytoSorb therapy

• Technical integration in the circuit ○ Easy and safe application already possible

today• Start/stop of therapy

○ Recommendation is to simultaneously start and stop together with the ECMO therapy

• Special clinical scenarios ○ More and more complex scenarios that require

application of CytoSorb ○ Organ donation (donation after circulatory

death- donation after brainstem death) ○ Extracorporeal cardiopulmonary resuscitation

(eCPR) ○ VA-ECMO + Impella (ECPella)

ECMOF Pappalardo, Milan, Italy

30


31

CONCLUSION*• Necrotizing fasciitis with organ failure is a rare disease

• Pathophysiology is poorly understood, however superantigens appear to play a significant role

• The disease is characterized by a dramatic increase in inflammatory mediators (e.g. IL-6)

• Blood purification strategies seem to be effective but need to be adapted (dosing and timing)

• CytoSorb appears to be a suitable technique to reduce the systemic levels of mediators, however more clinical data are still needed

Professor Payen presented the pathophysiological background and the published experience with the use of CytoSorb in necrotizing fasciitis.

Necrotizing fasciitis• Is a relatively rare disease with 3 cases/100,000

inhabitants/year • Results from a combination of the effect of

streptococcal toxins (enterotoxins with superantigen activity) and the host response to streptococcal infection with a complex interplay

• Necrotizing fasciitis is mainly related to toxic shock syndrome (TSS) due to Streptococcus (STSS) or Staphylococcus infection

• STSS represents a severe complication of (mainly invasive) group A streptococcal infections

• 13 - 15% of patients with invasive Group A streptococcus infections develop STSS with a mortality rate ranging from 23 to 44%

• STSS therefore remains a severe, and frequently life-threatening condition in the Intensive Care Unit

• The morbidity associated with STSS can be very significant, particularly when extensive surgical debridement is required

• STSS mortality is influenced by medical history, the site of infection, comorbidities, extremes of age, and the delay of diagnosis

• Symptoms are closely related to cytokines and vasodilating mediators, resembling or superior to those observed in “classic” septic shock

• Although rare, the severe forms have a high mortality (40-60%)

• Early recognition is crucial• A pan-specialty approach is the cornerstone for

good outcomes i.e. surgeons; infectious disease specialists, ICU specialists

Clinical criteria for streptococcal toxic shock syndrome based on CDC definitions• Clinical criteria: hypotension, 2 or more organ

failures, generalized erythematous macula rash, soft tissue necrosis

• Laboratory criteria: isolation of group A streptococcus

The 3 clinical steps: • Phase 1: influenza like syndrome• Phase 2: Systemic manifestations and necrotizing

fasciitis• Phase 3: Circulatory shock with very high mortality

Background of the inflammatory response• Concept of Pathogen-Associated Molecular

patterns (PAMPs) and Damaged-Associated Molecular patterns (DAMPs)

• Categorization and function of cell signaling molecules involved in the inflammatory process (interleukins, chemokines, interferons, tumor necrosis factors, growth factors)

• Conventional antigen and superantigen presentation

Presentation of 2 published case reports on CytoSorb application in necrotizing fasciitis• Hetz H et al., Int J Artif Organs 2014;37(5):422-6

○ 60-year-old female with radial fracture developing surgical wound infection (after osteosynthesis) progressing to necrotizing fasciitis (proven infection β-hemolytic streptococcus) with septic shock and multiple organ failure

○ She was treated with CytoSorb therapy over a period of four days, resulting in a significant reduction of IL-6 and an overall improvement of the patient’s condition

• Eid M et al., IJAO 2018; 41(3): 178 – 82 ○ 41-year-old patient with necrotizing fasciitis and

multiple organ failure ○ Extracorporeal life support (ECLS – veno-

arterial) was implemented due to heart failure requiring high doses of catecholamines

○ As a result of acute renal failure, continuous renal replacement therapy (CRRT) was started

○ Despite these treatments the patient continued to deteriorate, so a CytoSorb adsorber was added to the CRRT circuit, in parallel to the ECLS resulting in hemodynamic stabilization along with normalization of lactic acidosis and other blood parameters.

Necrotizing Fasciitis D Payen, Paris, France

31


32

In his talk Dr. Rybalko discussed the application of CytoSorb in pediatric patients and presented different anecdotal cases.

Indications for CytoSorb use on a pediatric intensive care unit• Acute Respiratory Distress Syndrome• Systemic Inflammatory Response Syndrome• Sepsis and septic shock• Multiple organ failure• Ischemic-reperfusion injury• Hyperbilirubinemia• Mechanical hemolysis during extracorporeal

membrane oxygenation (ECMO)

Yet the CytoSorb literature database lists only 16 cases of using CytoSorb in children, which is very little in compari-son to the data for adults

Quality factors when working with pediatric patients• Patient category, i.e. newborns, infants, adolescents• Smaller circulatory volume

○ Hemodilution risk ○ Unstable hemodynamics at the start and during

procedure• There is an additional roller pump and circuit to

provide for recommended flow to perform the procedure

• Unstable work of extracorporeal system with side-stream

CytoSorb therapy in adolescents during cardi-opulmonary bypass cardiac surgery• Treatment of hyperinflammation• Vasoplegia prevention and treatment• Plasma free hemoglobin reduction• Protection from reperfusion injury

CytoSorb therapy in adolescents during ECMO therapy• Treatment of hyperinflammation• Free hemoglobin reduction• Treatment of capillary leak • MOF treatment• Reduction of cardiotonic support requirement

Case presentation 1 - Application of CytoSorb in a pediatric with Wolman’s disease• Female pediatric patient (age 3 months) with a

weight of 4.9 kg and Wolman’s disease (lipid storage disease), acute liver failure (total bilirubin 1136.7 µmol/l), encephalopathy, but stable hemodynamics

• CytoSorb therapy was applied in hemoperfusion mode in order to ameliorate acute liver failure

• Technical application details (also applied in pediatric patients <10 kg with ECMO support)

○ Standard continuous renal replacement therapy (CRRT) machine

○ Standard dialysis catheter 6.5 Fr in the right jugular vein

○ Pediatric set – 54 ml priming volume ○ CytoSorb - 120 ml priming volume ○ 1 unit of fresh frozen plasma ○ 1 unit of filtered washed erythrocytes ○ Circuit and CytoSorb were prefilled as

described above in 1:1 proportion ○ Dopamine infusion 5 µg/kg/min to stabilize

hemodynamics during the procedure• As a result, bilirubin levels decreased from 1137

µmol/l to 177 µmol/l during 15 hours of CytoSorb therapy (Fig. 1.)

Case presentation 2 – Application of CytoSorb together with ECMO and CRRT in a pediatric patient• 7 month old child, weight 5 kilos, congenital

heart disorder (ALCAPA), mitral valve insufficiency, post-ischemic cardiofibrosis (class III by Ross HF classification)

• The child has been operated on, but could not be weaned from the heart-lung machine, so ECMO was started directly in the operation theatre

• When transferred to the ICU, she had massive hemolysis, acidosis and anuria, and required full flow ECMO for life support

• In the ICU multi-organ failure progressed accompanied by an increase in laboratory parameters (urea 40 µmol/l, creatinine to 246 µmol/l, CRP to 260 mg/l, PCT to 150 ng/ml)

• Increasing dosages of vasopressors were required with the ECMO still running and CRRT was started on day 5 due to a non-improving situation

• Despite ECMO ongoing for 10 days (low cardiac output, very small systolic-diastolic difference, high pressure in the left atrium) and CRRT running for 5 days, she had anuria throughout the procedure. Norepinephrine requirement was 0.3 µg/kg/min, Glasgow scale 10-13. According to Pediatric Critical Care textbooks, her predicted mortality was 100%

• Echocardiography revealed progressive aortic insufficiency, pointing to myocardial dysfunction

• Despite the progress of the disease, the decision

PICUA Rybalko, Moscow, Russia


CONCLUSION*• CytoSorb can be easily and safely used in children of more than 10 kg in any mode

(hemoperfusion, CRRT, ECMO and any combination of those)

• To use CytoSorb in children <10 kg, more equipment and very well trained personnel are needed

• A CytoSorb cartridge with smaller volume would be helpful in pediatric patients, but even with the current CytoSorb significant clinical improvements can be achieved

33

was made to initiate CytoSorb therapy, despite the following problems:

○ big priming volume for a 7 months old child, large volume of donor blood components, expected hemodilution and hemodynamic instability

• After only one CytoSorb therapy session doses of norepinephrine and dopamine could be reduced, systolic-diastolic pressure difference increased and she became hemodynamically stable (Fig. 2.). This was paralleled by a marked reduction of CRP (from 118 mg/l to 53 mg/l) and PCT (from 17.31 ng/ml to 0.9 ng/ml) levels (Fig. 3.)

• The patient began to move, and became more alert

• ECMO flow could already be reduced by 50% after the 1st CytoSorb treatment and completely stopped after the 2nd CytoSorb treatment

• Diuresis subsequently increased and was restored 5 days after the last CytoSorb session while and on day 13 she was successfully weaned from both ECMO and CRRT

• Extubation on day 24 after surgery and eventually discharge home in a stable condition

Fig.2. Course of catecholamines in a pediatric patient with combined CytoSorb, ECMO and CRRT therapy

Dop

amin

e [g

/kg/

min

]N

orep

inep

hrin

e [μ

g/kg

/min

]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Cardiotonics & Vasopressors

CRRT

Dopamine

Norepinephrine

Days

0 0

3

55 5 5 5 5 5

4

3

6 6 6

8

9 9

6

000000000000,040,040,050,100,080,05

Bilir

ubin

con

cent

ratio

n [μ

mol

/l]before CS 15 HRS of CS 1 day after 2 days after 3 days after 5 days after 7 days after

Bilirubin concentration

time

360

177

501550

1137

477456

Fig 1. Course of bilirubin in a child with Wolman’s disease treated with CytoSorb


SPECIAL CASE LECTURE

Dr Nierhaus presented his experiences in a special case session.

Patient Data and Medical History • Female patient, 36 years, 168 cm, 48 kg• Medical history of systemic lupus erythematodes

(SLE) diagnosed in 2012 and since then she had various associated complications including chronic renal failure (lupus nephritis class III/IV, proliferative), polyserositis, pancytopenia, chronic hypertension, secondary antiphospholipid syndrome with pulmonary embolism 2013

• Medication in previous years therefore comprised of cyclophosphamide, azathioprine, mycophenolate mofetil, steroids, rituximab and other biologicals

Epicrisis• Referral from community hospital to University

Hospital Hamburg Eppendorf with septic shock of unknown origin and acute-on-chronic renal failure following kidney biopsy

• On admission she had a temperature of 39.8°C, blood pressure of 78/45 mmHg with tachycardia (128 bpm), lactate 7.8 mmol/l, procalcitonin (PCT) level 129 ng/l and IL-6 19,600 pg/ml. Furthermore, she exhibited signs of disseminated intravascular coagulopathy as well as acute liver dysfunction/failure

• Gram-negative septic shock due to soft tissue infection (E. coli) of the left thigh and groin (positive blood culture and tissue biopsy)

• HSV-/CMV reactivation was confirmed as signs of immune incompetence as well as vitamin B12 deficiency

• Given the hyperinflammatory response with excess inflammatory mediators, CytoSorb treatment was initiated in combination with continuous veno-

venous hemodialysis (CVVHD) using 2 adsorbers in the first 24 hours and another adsorber for the next 24 hours

• During the course of the treatments, PCT and IL-6 levels decreased markedly paralleled by a decrease in vasopressor requirements (Fig. 1.) and lactate plasma levels (<2 mmol/l) with further improvements between day 5-8 followed by weaning from dialysis

• On day 8 her clinical condition deteriorated (second hit) including profound hemodynamic instability requiring high dosages of norepinephrine, which was due to septic shock (Klebsiella pneumonia) followed by reinitiation of CytoSorb plus CVVHD (3 adsorbers over 3 days) resulting in shock resolution and decrease in inflammatory mediators (Fig. 1.)

• Day 11-20 was characterized by further consolidation, weaning and mobilisation

• On day 27 the patient could be discharged with normal inflammatory mediator values (IL-6 <5 pg/ml), CRP <15 mg/dl)

My Very Special CytoSorb Case A Nierhaus, Hamburg, Germany

3434

CONCLUSIONS*• There is often a second hit in patients who are immunologically compromised either by their

medical history or from the first hit

• In this special patient, innate immune response was well preserved, as evidenced by the excessive release of IL-6, while adaptive immune response was severely compromised

• Application of CytoSorb should be considered early in sufficiently sick patients

• Prepare to re-install therapy if a 2nd septic hit occurs

• When high levels of inflammation and shock severity are present, consider adsorber change after less than 24 hours (12 hours in this case)

SPECIAL CASE LECTURE

35

Fig. 1. Course of IL-6, PCT and norepinephrine during the critical phase

1 2 3 4 5 6 7 8 9 10 11 12 13

25,000

20,000

15,000

10,000

5,000

0

120

100

80

60

40

20

0PC

T [m

g/l]

IL-6

[pg/

ml]

1st hit: blood stream

infection (E. coli)

2nd hit: Pneumonia(Klebsiella)

Norepinephrine

IL-6

PCT

Norepinephrine

days

CytoSorbents TM

CytoSorb Therapy –REGAIN CONTROL

CytoSorbents Europe GmbH

Müggelseedamm 13112587 Berlin | Germany T +49 30 654 99 145 F +49 30 654 99 146 [email protected]

CytoSorbents Switzerland GmbH

c/o MGM GmbH Wielandstrasse 5 | 4153 Reinach BL | Switzerland T +41 61 713 73 78F +41 61 713 73 79 [email protected] www.cytosorb.com

*The statements here represents the personal opinions and views of the speaker only and do not necessarily reflect accepted medical knowledge in general. The clinical and preclinical data and results obtained with the CytoSorb adsorber are not transferable to other products.CytoSorb should only be administered by personnel who have been properly trained in administration of extracorporeal therapies. CytoSorb is not available for commercial sale in USA.CytoSorb and CytoSorbents are trademarks of the CytoSorbents Corporation, USA. © Copyright 2019, CytoSorbents Europe GmbH. All rights reserved. B1039R04EN2019

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