View
4
Download
0
Category
Preview:
Citation preview
CytoSorbents TM
Proceedings6th International User’s Meeting
Brussels, Belgium, March 18th 2019
CytoSorb Therapy – REGAIN CONTROL
20.000 Patienten weltweit
alle Präsentation finden Sie .....SEE PRESENTATIONS AS WEBCASTSThe individual presentations can be found as a webcast on our website at cytosorb.com/IUM_brussels_2019
Or simply scan the QR code
cytosorb.com/IUM_brussels_2019
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
5
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
77
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
8
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
B ARF Sepsis CytoSorb
60
50
40
30
20
10
0
% A
POPT
OSI
S
B ARF Sepsis CytoSorb
60
50
40
30
20
10
0
% P
hago
cyto
sis
9
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
BASE 10 60 120
100
90
80
70
60
50
40
30
20
10
0
% A
popt
osis
& C
aspa
se 3
Apoptosis
Caspase 3
40
30
20
10
0
MFI
3 day CVVH
2 day CVVH
1 day CVVH
12h CVVH + CytSorb
24h CVVH + CytoSorb
100
80
60
40
20
0
% m
ono
DR
+
MFI
MFI CPFA
% mono DR +
CPFA MARS Prometheus CytoSorb
2500
2000
1500
1000
500
0
billi
rubi
n [m
g] /
trea
tmen
t
Reduction of bilirubin per treatment
CPFA MARS Prometheus CytoSorb
3500
3000
2500
2000
1500
1000
500
0
bile
aci
ds [m
cmol
] / tr
eatm
ent
Reduction of bilde acids per treatment
10
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.)
FROM EXPERIMENTS TO EVIDENCE
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
Control Adsorber
15
10
5
0
Scor
e po
ints
Radiologic lung injury scoring
Control Adsorber
6
4
2
0
Scor
e po
ints
*
Microscopic lung injury scoring
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
Pump IPump II
Cytokine Filter
Ventilator
EVLP Dome
Reservoir
Gas mixture
Heat exchanger
Deoxygenator
Leukocyte filter
PA
LA
Fig. 1. EVLP circuit
1111
Control Adsorber
Control Adsorber
12
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
1 2 3 4 5 6 7 8 9 10 11 12
100
80
60
40
20
0
pg/m
L
IL-1α
*
hours
A
1 2 3 4 5 6 7 8 9 10 11 12
15
10
5
0
ng/m
L
IL-6
* *
hours
D
1 2 3 4 5 6 7 8 9 10 11 12
600
400
200
0
pg/m
L
IL-12
* *
hours
G
1 2 3 4 5 6 7 8 9 10 11 12
6
4
2
0
ng/m
L
IL-1β
* *
hours
B
1 2 3 4 5 6 7 8 9 10 11 12
6
4
2
0
ng/m
L
IL-1ra
*
hours
C
1 2 3 4 5 6 7 8 9 10 11 12
20
15
10
5
0
ng/m
L
IL-8
* * *
hours
E
1 2 3 4 5 6 7 8 9 10 11 12
800
600
400
200
0
pg/m
L
IL-10
* *
hours
F
1 2 3 4 5 6 7 8 9 10 11 12
1.5
1.0
0.5
0.0
ng/m
L
TNF-α
*
hours
I
1 2 3 4 5 6 7 8 9 10 11 12
12
8
4
0
ng/m
L
IL-18
* * *
hours
H
Fig. 4. Perfusate cytokine levels of controls and CytoSorb-treated lungs throughout the 12 hours perfusion period
12
FROM EXPERIMENTS TO EVIDENCE
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
FROM EXPERIMENTS TO EVIDENCE
14
Continuation: Safety Aspects and Drug Removal
FROM EXPERIMENTS TO EVIDENCE
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
Pre-CPB
Post- CPB
6h 24h
300
200
100
0
Act
ivity
(%)
vWF
Pre-CPB
Post- CPB
6h 24h
300
200
100
0
Act
ivity
(%)
FVII
Pre-CPB
Post- CPB
6h 24h
300
200
100
0
Act
ivity
(%)
FV
Pre-CPB
Post- CPB
6h 24h
300
200
100
0
Act
ivity
(%)
FIX
Pre-CPB
Post- CPB
6h 24h
300
200
100
0
Act
ivity
(%)
FII
Pre-CPB
Post- CPB
6h 24h
300
200
100
0
Act
ivity
(%)
AT
Pre-CPB
Post- CPB
6h 24h
300
200
100
0
Act
ivity
(%)
FXI
Pre-CPB
Post- CPB
6h 24h
300
200
100
0
Act
ivity
(%)
FXII
**
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
FROM EXPERIMENTS TO EVIDENCE
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
FROM EXPERIMENTS TO EVIDENCE
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
FROM EXPERIMENTS TO EVIDENCE
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
Pre CytoSorb Post CytoSorb
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
Pre CytoSorb Post CytoSorb
15.215.0528.2627.61
APACHE Score* SOFA Score*
Non Survival Group (n = 60)
Pre CytoSorb Post CytoSorb
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
Pre CytoSorb Post CytoSorb
4,15
p value - 0.04
5.01
Survival Group
Pre CytoSorb Post CytoSorb
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
CYTOSORB IN VARIOUS FIELDS OF APPLICATION
○ 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
CYTOSORB IN VARIOUS FIELDS OF APPLICATION
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
CYTOSORB IN VARIOUS FIELDS OF APPLICATION
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
CYTOSORB IN VARIOUS FIELDS OF APPLICATION
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
CYTOSORB IN VARIOUS FIELDS OF APPLICATION
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
CYTOSORB IN VARIOUS FIELDS OF APPLICATION
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
CYTOSORB IN VARIOUS FIELDS OF APPLICATION
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 support@cytosorbents.com
CytoSorbents Switzerland GmbH
c/o MGM GmbH Wielandstrasse 5 | 4153 Reinach BL | Switzerland T +41 61 713 73 78F +41 61 713 73 79 support@cytosorbents.com 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
Recommended