oxiris - smart medical solutions · shock (n = 40)6 oxiris membrane-high volume hdf 4 4 prospective...

oXirisA single CRRT set with multiple benefits for managing critically ill patients with AKI

P O W E R E D B Y

Adsorption of inflammatory mediators

Heparin-grafted for reduced

thrombogenicity

Supports renal function

57042F oXiris Sales Brochure_v1o.indd 1 29/04/2016 11:49

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A single CRRT set combining three functionalities

Permanent heparin graft on the inner membrane surface1,2

AN 69 membrane technology – a copolymer of acrylonitrile and sodium methallyl sulfonate2

Polyethylenelmine surface treatment1–3

What is oXiris?

A single-use set for continuous renal replacement therapy

• Part of a dedicated range of products to support continuous renal replacement therapy (CRRT), oXiris is a single-use set comprised of a hollow fiber membrane and tubing lines.1

• The oXiris set is designed to be used exclusively with the Prismaflex system, for the provision of CRRT and fluid management in patients with acute kidney injury (AKI), fluid overload, or both.1

Designed to provide multiple functionalities in a single set

• The oXiris membrane is characterized by three features:1–3

• The features of the oXiris set are designed to combine three functionalities in a single device, with multiple potential benefits for managing critically ill patients with AKI.1–8

The oXiris membrane is permanently heparin grafted and is designed to have capacity for the adsorption of endotoxin in addition to cytokines.


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A single CRRT set combining three functionalities

Managing critically ill patients with AKI requiring CRRT – what potential benefits does the oXiris set offer?

oXiris membrane composition and microstructure1,2

Adsorption of inflammatory mediators3–6

Potential for improvedorgan function5–7 and

hemodynamic stability5,6

Combines three functionalities in a

single set

Designed to simplifymultiple treatment

challengesPermanent heparingraft1,2

Local inhibition of coagulation2

Designed to reduce membranethrombogenicity2

AN-69-based membrane with

diffusive, convective and adsorptive properties2

Delivery of hemodialysisand hemofiltration2

Supports renal function and fluid management1

The oXiris set – three functionalities in a single device:

• Renal function support via a choice of CRRT modalities1

• Capacity to remove cytokines and endotoxin,5–7,9 without the need for additional equipment 1

• Support CRRT efficiency by offering clinically acceptable filter life when used with anticoagulation therapy,8 with potential to minimize treatment interruptions and reduce workload for care providers.

A single set for all CRRT modalities using the familiar Prismaflex system


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Elevated levels of specific inflammatory mediators may be associated with poor outcomes in patients with AKI

• Critically ill patients are a heterogenous population likely to require multiple therapeutic interventions10 – a characteristic that complicates assessment of treatment outcomes in the AKI setting.

• Consequently, confirmation of an association between removal of inflammatory mediators during CRRT and improved clinical outcomes for patients with AKI, in a randomized controlled trial setting, may be challenging.

• However, some observational studies have found elevated levels of specific cytokines or endotoxin in patients with AKI to be associated with:





Should we target removal of inflammatory mediators during CRRT in critically ill patients with AKI?

Increased mortality11,12 Poorer renal recovery13

Findings from such observational studies suggest that removal of inflammatory mediators is a potential therapeutic target in the management of critically ill patients with AKI.


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What evidence is there to support the adsorption of inflammatory mediators by the oXiris membrane?

Note: Findings from preclinical, single-arm, and observational studies have not been confirmed in randomized controlled trials. Some data are preliminary and have not been peer reviewed.

Findings from in-vitro and observational studies suggest that the oXiris membrane has capacity to adsorb inflammatory mediators from the circulation4–7,14

In-vitro filtration experiments have shown the oXiris membrane to:

• Have capacity to remove spiked endotoxin from the plasma of healthy volunteers14

• Significantly reduce levels of high mobility group box 1 (HMGB1) – a DNA-binding protein involved in activation of the systemic inflammatory responsea – from bovine serum by membrane adsorption.4

aElevated levels of HMGB1 have been observed in patients with AKI.15

Findings from published observational studies suggest that:

• CRRT with the oXiris membrane may reduce plasma levels of specific cytokines in patients with AKI or renal failure, plus sepsis or septic shock5,6

• While the capacity of the oXiris membrane to remove endotoxin has not been demonstrated in patients with AKI, reduced endotoxin activity has been demonstrated in patients with endotoxemiab who required CRRT.9

bThe oXiris membrane is indicated for the provision of CRRT and fluid management in patients with renal failure, fluid overload, or both.1 Please refer to the product instructions for use for a comprehensive overview of correct usage.


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In vitro study: Reduced levels of bovine serum HMGB1 with the oXiris membrane4

Single-arm, observational study: Reduced blood cytokine levels following CRRT with the oXiris membrane in patients with sepsis and renal failure6

Mea

n (S

D) H

MGB

1 co

ncen

tratio

n,ng

/mL

Time after starting blood filtration, minutes

oXiris set

*

PAES set20

15

10

5

00 15 0 15

Mea

n (S

D), p

g/m

L

IL-6

* *

Procalcitonin800

600

400

200

0

Mean (SD), ng/m

L

50

40

30

20

10

0Before

treatmentAfter

24 hoursBefore

treatmentAfter

24 hours

The efficacy of two membranes for the removal of HMGB1 from bovine serum was compared over 120 minutes. After 15 minutes, serum concentration of HMGB1 was significantly reduced with the oXiris membrane but not with a polyarylether sulfone hemofiltration set. Electron microscopy confirmed HMGB1 adsorption on the membrane.4 *p = statistically significant. HMGB1, high mobility group box 1; PAES, polyarylether sulfone; SD, standard deviation.

Adult patients with sepsis/septic shock and renal failure (n = 40) underwent high-volume HDF using the oXiris membrane. After 24 hours of treatment, blood levels of IL-6 and procalcitonin were significantly decreased from baseline.6

*p < 0.05. HDF, hemodiafiltration; IL, interleukin; SD, standard deviation.Note: Limited data are available to support the removal of cytokines with the oXiris membrane and available studies lack control groups. The findings of this study are not necessarily in line with all published literature.


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Summary of single-arm, observational studies: Significantly reduced levels of IL-6, procalcitonin, and endotoxin following CRRT with the oXiris membrane

Summary of published observational studies that have reported statistically significant (p < 0.05) reductions in levels of inflammatory mediators following CRRT with the oXiris membrane.aThe oXiris membrane is indicated for the provision of CRRT and fluid management in patients with AKI, fluid overload, or both. Please refer to the product instructions for use for a comprehensive overview of correct usage. AKI, acute kidney injury; CRRT, continuous renal replacement therapy; CVVHDF, continuous veno-venous hemodiafiltration; ET, endotoxin; HDF, hemodiafiltration; IL-6, interleukin-6; PC, procalcitonin; RRT, renal replacement therapy.

Inflammatory mediator

Study CRRT modality IL-6 PC ET

Prospective observational pilot study in adults with AKI caused by sepsis or septic shock (n = 34)5

oXiris membrane-CV VHDF

4 4

Prospective observational study in patients with renal failure and sepsis/septic shock (n = 40)6

oXiris membrane-high volume HDF

4 4

Prospective observational study in adults with septic shock requiring RRT (n = not reported)a9

oXiris membrane-CRRT

4 4

• The oXiris membrane has been shown to have capacity for the adsorption of endotoxin and the pro-inflammatory protein, HMGB1, in vitro.4,14

• In some observational studies, CRRT with the oXiris membrane has been reported to: – Reduce levels of the pro-inflammatory cytokines, IL-6 and procalcitonin, in

patients with AKI or renal failure5–7

– Reduce endotoxin activity level in patients with endotoxemia who required CRRT.9


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Potential for improved organ function and hemodynamic stability

Is the removal of inflammatory mediators during CRRT with the oXiris membrane associated with improved clinical outcomes for patients with AKI?

Some observational studies have reported improvements in clinical outcomes following CRRT with the oXiris membrane in patients with AKI5–8

oXiris membraneused to reduce levels of circulating inflammatory

mediators5–7

Improved organ function5,7 and

hemodynamic stability5–7 observed in same studies


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Potential for improved organ function and

hemodynamic stability


Single-arm, observational study: Increased arterial pressure following CRRT with the oXiris membrane in patients with AKI5

Adult patients with AKI caused by sepsis or septic shock (n = 34) underwent CVVHDF using the oXiris membrane (40 mL/kg/hour). Mean (SD) treatment duration was 79 (25) hours. Following treatment, a significant increase in mean arterial pressure was observed.5

***p < 0.001. AKI, acute kidney injury; CVVHDF, continuous veno-venous hemodiafiltration; SD, standard deviation.

Mea

n (S

D) a

rteria

l pre

ssur

e,m

mHg

***100

80

60

40

20

0Before treatment After treatment

Observational study: Improved SOFA scores following CRRT with the oXiris membrane in patients with AKI8

Adult patients (n = 6) with AKI due to infection with Gram-negative bacteria underwent CVVH with the oXiris membrane. Clinical outcomes were compared with historic matched controls who had been treated with post-dilutional CVVH using a polysulfone high-flux hemofilter. Organ function, as assessed by SOFA score, was significantly improved at 48 hours post-initiation of treatment in the oXiris membrane group but not in the control group.8

*p = 0.013. AKI, acute kidney injury; CVVH, continuous veno-venous hemofiltration; SOFA, Sequential Organ Failure Assessment.

Med

ian

SOFA

sco

re,

inte

rqua

rtile

rang

e

37% reduction*

oXiris set (n = 6) Controls (n = 24)25

20

15

10

5

0

Time post-initiation of CVVH, hours

0 24 48 0 24 48


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Potential for improved organ function and hemodynamic stability


Summary of single-arm, observational studies: Improved organ function and hemodynamic stability following CRRT with the oXiris membrane

Summary of observational studies that have reported statistically improvements in organ function (SOFA score) and hemodynamic stability following CRRT with the oXiris membrane. *p < 0.05; **p < 0.01; ***p < 0.001 versus baseline.AKI, acute kidney injury; CRRT, continuous renal replacement therapy; CVVHDF, continuous veno-venous hemodiafiltration; CVVH, continuous veno-venous hemofiltration; HDF, hemodiafiltration; SOFA, Sequential Organ Failure Assessment.

Findings from observational studies suggest that, for some patients with AKI, CRRT using the oXiris membrane may have a positive effect on clinical outcomes – organ function and hemodynamic stability.5–8 The association between these outcomes and inflammatory mediator removal is uncertain.5–7

Outcomes improved

StudyCRRT

modalityDecreased SOFA score

Increased arterial

pressure

Reduced norepinephrine

dose

Prospective observational study in adults with AKI due to infection with Gram-negative bacteria (n = 6), compared with historical controls (n = 24)8

oXiris membrane-

CVVH

4

After 48 hours*

Prospective observational study in postoperative cardiac patients with renal failure and sepsis/septic shock (n = 25)7

oXiris membrane-high volume

HDF

4

After 72 hours***

4

After 72 hours**

4

After 72 hours**

Prospective observational pilot study in adults with AKI caused by sepsis or septic shock (n = 34)5

oXiris membrane-

CVVHDF

4

After treatment***

(average duration 79 hours)

4

After treatment***

(average duration 79 hours)

4

After treatment***(average duration

79 hours)

Prospective observational study in patients with renal failure and sepsis/septic shock (n = 40)6

oXiris membrane-high volume

HDF

4

After 24 hours*


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Designed to reduce thrombogenicity

Clotting and clogging are potential reasons for loss of filter patency, reduced CRRT circuit life, and treatment interruptions

• Filter clogging is thought to occur when proteins and cells are deposited on the membrane, leading to:16

– Blockage of hollow fibers

– Reduced membrane permeability leading to reduced filter efficacy

– Increased transmembrane pressure.

• Filter clotting is a common complication encountered during traditional CRRT with heparin anticoagulation.17 Filter clotting results in:

– Patient blood loss18

– Reduced dialysis dose delivery19

– Treatment interruptions for filter changes17 and increased workload for care providers.18

Permanent heparingraft1,2

Local inhibitionof coagulation2

Designed to reducemembrane

thrombogenicity2

What is the benefit of reduced membrane thrombogenicity for CRRT in patients with AKI?


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Survey: Frequency of clinical and technical complications encountered during renal replacement therapy in patients with AKI20

A survey of practice patterns among clinicians dedicated to critical care nephrology and renal replacement therapy in patients with acute renal failure was conducted at an international nephrology meeting. Results from 560 completed questionnaires suggested that filter clotting was the most common technical complication encountered during CRRT, while bleeding was a common clinical complication.20

CRRT, continuous renal replacement therapy; IHD, intermittent hemodialysis.Ricci Z, et al. Practice patterns in the management of acute renal failure in the critically ill patient: an international survey. Nephrol Dial Transplant 2006;21(3):690–96. By permission of Oxford University Press.

Hematoma

Thrombosis

Infection-related

Low efficiency

Hemorrhage/bleeding

Hypotension

Need to change treatment

0 10 20

IHD CRRT

%

Clinical complications

Technical complications

30 40

Line disconnection

Low ultrafiltration

Nurse availability

Fluid balance errors

Machine malfunction

Access dysfunction

Filter clotting

0 25 50

%

75 100


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Designed to inhibit coagulation locally by adsorbing and enhancing the anticoagulatory potency of antithrombin III

The inner surface of the oXiris membrane is grafted with heparin – how may this distinctive feature reduce thrombogenicity?

• During CRRT, contact between blood and the foreign surface of the extracorporeal circuit initiates a coagulatory response that can lead to filter clotting.18

• The permanent grafting of heparin onto the inner surface of the oXiris membrane is designed to reduce thrombogenicity by adsorbing antithrombin III (ATIII) from the blood and facilitating formation of a stable complex with thrombin.2

• With release of the stable ATIII-thrombin complex into the bloodstream, it has been proposed that the heparin graft catalyzes the conversion of ATIII from a weak to a potent anticoagulant.2

• This proposed mechanism of action has been investigated in vitro.2


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In vitro study: The oXiris membrane has affinity for ATIII2

In vitro study: The oXiris membrane promotes formation of ATIII-thrombin complex in vitro2

In an adsorption experiment, affinity for biotinylated ATIII was found to be greater with the heparin-grafted oXiris membrane than the non-heparin-grafted AN 69 ST membrane.2

ATIII, antithrombin III.

The formation of ATIII-thrombin complex after incubation of the oXiris and AN 69 ST membranes with ATIII followed by thrombin has been investigated in vitro. Stable ATIII-thrombin complex formation was found to be greater with the heparin-grafted oXiris membrane than the non-heparin-grafted AN 69 ST membrane.2

0.0

0.5

1.0

1.5

2.0

2.5

Adso

rptio

n, re

lativ

e va

lue

1 2 4

oXiris membrane

ATIII concentration, µg/mL6 8

AN 69 ST membrane

0

100

150

200

250

300

Conc

entra

tion

of s

tabl

e AT

III-t

hom

bin

com

plex

form

ed, n

g/m

L

2 4

oXiris membrane

Thrombin concentration, units/mL5

AN 69 ST membrane

50

The heparin graft on the inner surface of the oXiris membrane is intended to reduce thrombogenicity by adsorbing ATIII from the blood and enhancing its anticoagulatory potency at a local level.2

Evidence from in-vitro investigations supports this proposed mechanism of action.2


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• Administration of systemic or regional anticoagulation is generally required in CRRT to achieve effective treatment by preventing filter clotting and/or reduced membrane permeability.18

• However, many critically ill patients with AKI have impaired blood clotting capabilities and are at increased risk for serious bleeding.20–22

• The clinical practice guideline from KDIGO (Kidney Disease: Improving Global Outcomes) suggests that:18

– Systemic anticoagulation with heparin is avoided during CRRT in patients with increased bleeding risk

– Regional citrate anticoagulation is used during CRRT in patients with increased bleeding risk, and for patients without impaired coagulation or increased bleeding risk (where there is no contraindication to citrate).

Used in combination with regional citrate anticoagulation, the oXiris membrane may support CRRT efficiency by reducing membrane thrombogenicity2 and offering clinically acceptable filter life,8 potentially minimizing treatment interruptions.17,20

The oXiris set used with anticoagulation therapy may provide clinically acceptable filter life span for CRRT

In a very small, prospective case series of six patients with sepsis-induced AKI undergoing CVVH using the oXiris membrane with regional citrate anticoagulation, the life-span of the hemofilter was 61 hours.a,8

61 h

Anticoagulation during CRRT

aNo conclusions on the relative anticoagulant effects of the heparin graft on oXiris versus the regional citrate anticoagulation regimen can be drawn based on this study.


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Supports renal function and fluid management


diffusive, convective andadsorptive properties2


Supports renal functionand fluid management1

• The oXiris set is indicated for use with the Prismaflex system to provide CRRT and fluid management in patients with AKI, fluid overload, or both.1

• This single set can be used in a choice of four CRRT modalities,1 and with either heparin or regional citrate anticoagulation.

• For critically ill patients with AKI, potential advantages of slow, continuous removal of toxins and excess fluid during CRRT compared with more rapid treatment with intermittent renal replacement therapy may include:18

– Greater hemodynamic stability

– Easy control of fluid balance

– User-friendly systems.

What treatments can be delivered via the oXiris set?

“We suggest using CRRT, rather than standard intermittent RRT, for hemodynamically unstable patients (2B).”

KDIGO clinical practice guideline18


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Choice of CRRT modalities

A single set offering a choice of CRRT modalities for managing critically ill patients with AKI

The oXiris set has diffusive, convective and adsorptive properties, allowing it to clear both small- and medium-to-larger-sized molecular weight solutes from the blood via continuous hemodialysis and continuous hemofiltration modalities.2,23

Slow continuous ultrafiltration (SCUF)

Continuous veno-venoushemofiltration (CVVH)

Continuous veno-venoushemodialysis (CVVHD)

Continuous veno-venoushemodiafiltration (CVVHDF)

• The oXiris set offers flexibility in the treatment of AKI – a single set that can be used to support renal function and fluid management via a choice of CRRT modalities, and choice of anticoagulation therapy,1 to suit patient requirements.

• Since 2009, more than 15,000 patients globally have been treated using the oXiris set.24


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User experience

Combines threefunctionalities in a

single set


challenges

By combining multiple features and functions in a single device, CRRT using the oXiris set may help to improve treatment efficiency and clinical outcomes for critically ill patients with AKI.1,2,4–8

CRRT using the oXiris set may offer potential handling benefits for care providers

How might the oXiris set help ease CRRT delivery for your critically ill patients with AKI?

No changeto practice

Treatmentflexibility

Ease of delivery

Potential to reduce workload

• Simple incorporation into the familiar Prismaflex system with same set up as traditional CRRT1

• Should require no change in clinical practice or requirement for staff training

• Can be used in a choice of CRRT modalities1

• Can be used with either heparin or regional citrate anticoagulation

• No additional equipment required for removal of inflammatory mediators1,25,26

• May help to provide clinically acceptable filter life,8 with potential to minimize treatment interruptions17,20 and support adequate dialysis dose delivery18,19


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References

1. Gambro Lundia. oXiris. Instructions for use, 2015.

2. Gambro Industries. oXiris preclinical data and clinical evaluation. Data on file, 2007.

3. Thomas M, et al. Contrib Nephrol 2011;173:119–29.

4. Imahase H, et al. Abstract presented at Sepsis 2012, Paris, France, November 7–9, 2012: P10.

5. Caravetta P, et al. Abstract presented at the 18th International Conference on Continuous Renal Replacement Therapies, San Diego, CA, United States, February 12–15, 2013: 53.

6. Turani F, et al. Abstract presented at the 33rd International Symposium on Intensive Care and Emergency Medicine, Brussels, Belgium, March 19–22, 2013: P63.

7. Candidi F, et al. Abstract presented at the 27th Annual Meeting of the European Association of Cardiothoracic Anaesthesiologists, Amsterdam, The Netherlands, May 23–25, 2012: O-56.

8. Shum HP, et al. Hong Kong Med J 2013;19:491–7.

9. Adamik BA, et al. Abstract presented at the 33rd International Symposium on Intensive Care and Emergency Medicine, Brussels, Belgium, March 19–22, 2013: P66.

10. Hébert PC, et al. Chest 2002;121:1290–300.

11. Simmons EM, et al. Kidney Int 2004;65:1357–65.

12. Payen D, et al. PLoS One 2012;7:e35838.

13. Murugan R, et al. Nephrol Dial Transplant 2014;29:1854–64.

14. Gambro Industries. oXiris. In vitro study comparison with Toraymyxin®, 2011.

15. Zakiyanov O, et al. BMC Nephrol 2013;14:245.

16. Joannidis M, Oudemans-van Straaten HM. Critical Care 2007;11:218.

17. Beitland S, et al. Critical Care Research and Practice 2012. Article ID: 869237.

18. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. Kidney Int, Suppl 2012;2:1–138.

19. Claure-Del Granado R, et al. Clin J Am Soc Nephrol 2011;6:467–75.

20. Ricci Z, et al. Nephrol Dial Transplant 2006;21:690–6.

21. Hetzel GR, et al. Nephrol Dial Transplant 2011;26:232–9.

22. Venkata C, et al. Journal of Intensive Care 2013;1:9.

23. Friedrich JO, et al. Critical Care 2012;16:R146–R.

24. Baxter Healthcare. oXiris manufacturing information, 2015.

25. CytoSorbents Inc. CytoSorb 300 mL device. Instructions for use, 2012.

26. Toray Industries Inc. Toraymyxin PMX-20R. Extracorporeal hemoperfusion cartridge. Instructions for use, 2013.


Making possible personal.

Baxter, AN 69, AN 69 ST, oXiris, and Prismaflex are trademarks

of Baxter International Inc., or its subsidiaries.

EUMP/MG146/15-004 April 2016





Combines three functionalities in a

single set


challengesPermanent heparingraft1,2

Local inhibition of coagulation2

Designed to reduce membranethrombogenicity2


diffusive, convective and adsorptive properties2


Supports renal function and fluid management1


oxiris - smart medical solutions · shock (n = 40)6 oxiris membrane-high volume hdf 4 4 prospective...

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