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360° vitality
Latest news from Gambro research relating to hyperinflammation
The PrismafleX eXeed™ systemand the septeX® set
Beyond continuous renal replacement therapy: Cutting-edge technology to remove middle-sized molecules
Sepsis is characterized by the release of an excessive amount of pro- and anti-inflammatory cytokines into the blood circulation.
Cytokines are soluble, low molecular weight glycoproteins acting as inflammatory mediators regulating both intrinsic and specific immune responses. Cytokines have local effects at low con-centrations but endocrine and systemic effects at higher concentrations. Elevated circulating con-centrations in several cytokines such as TNF alpha, IL6 and IL10, have been associated with morbidity and mortality in patients with sepsis. Removal of such cytokines may decrease their blood levels and attenuate organ injury.
The specific septeX membrane enables the non-selective removal of all molecules of molecular weight up to 45 kDa, such as some humoral mediators of the inflammatory response to sepsis. Elimination of such molecules leads to significant reductions in the plasma concentration of these mediators.
The septeX therapy is not intended to replace standard CRRT* but to allow a targeted therapy when the removal of large molecules is required.
* Continuous renal replacement therapy
• A unique therapy option only available for the PrismafleX system
• Proprietary Gambro technology confers this PAES-based membrane a so-called “high cut-off” capability for the non-selective removal of molecular weights up to 45 kDa (e.g. cytokines)
• Controlled trials have demonstrated the effective elimination and significant reduction of plasma levels in septic mediators
For selected patients with hyperinflammation, the septeX® set could provide a valuable therapeutic alternative.
Membrane structure of the septeX® set
septeX fiber cross section 2000x septeX fiber cross section 30000x
The septeX® set is operated on the PrismafleX® system in “CVVHD” and “CVVHD + post” modality
The septeX membrane effectively removes mediators in diffusive modality. A non-convective therapy allows limited albumin losses due to the large pore size of the septeX membrane. PrismafleX eXeed software features a specific therapy setting—“CRRT septeX”—with relevant preset parameters for patient safety.
Rel
ativ
e nu
mbe
r of
por
es
Pore size (µm)
1
0
0.001 0.01 0.1
= High-flux= High cut-off
The septeX membrane pore size is 2 to 3 times bigger than standard high-flux membranes
septeX fiber Standard high-flux fiber
Figure 1: Ex vivo sieving coefficients for cytokines and albumin
Siev
ing
coef
ficie
nt
100000 Molecular weight [Da]
1
0.8
0.6
0.4
0.2
0
1000 10000 IL-1IL-6
ß2mIL-10
TNF-αAlbumin
High-flux
High cut-off membrane
Median (25th–75th percentiles)
How to use the septeX® therapy
The septeX therapy is operated in CVVHD modality
• Blood flow rate: 80 to 400 ml/min• Dialysate flow rate: 500 to 8000 ml/h to achieve
35 ml/kg/h Note: An increased dialysate flow will increase the cytokines clearance
• Pre-blood pump infusion: 50 to 500 ml/h in case dilution of blood is necessary
To avoid a blood-air interface in the PrismafleX deaeration chamber, a small amount of post-dilu-tion fluid can be added (saline/replacement fluid). Then the user can choose the modality “CVVHD + post” and add 50 to 500 ml/h post replacement flow, if required.
Dialysate EffluentReplacement post dilution
Pre-blood pump infusion
septeX® membrane
Blood pump
Prismaflex modality: CVVHD + post
Patient
Clinical experience—the septeX® set
Increased dialysate flow yields higher cytokine clearance 1, 5
Blood flow rate (QB) = 150 ml/min, * QD = Dialysate flow rate
Blood flow rate (QB) = 250 ml/min
Results from Morgera et al. clinical study (Am J Kidney Dis., 2004)
Clearance (ml/min)
IL-6 (after 30 min)
IL-6 (after 24 h)
10
7
QD* 1 l/h
27
16
QD 2.5 l/h
Clearance (ml/min)
IL-1
IL-6
TNF-alpha (trimer)
18–23
13–18
2–9
QD 1 l/h
22–33
18–20
6–11
QD 8 l/h
Results from Uchino et al. ex vivo study (ASAIO, 2002)
An albumin loss is observed when using this type of membrane with a maximum loss occurring during the first 12 hours.
Data from Morgera et al. (Am J Kidney Dis., 43 [3]: 444-453, 2004, Table 3).The calculated data in the figures above show total (cumulated), median and maximum albumin loss data at different treatment times (0.5, 4 and 24 hours) at a dialysate flow rate of 1.0 and 2.5 l/h using a single device.
Limited albumin loss during treatment with the septeX® set
Albumin loss at QD = 1.0 I/h and 2.5 I/h
Treatment time (h)
Tota
l alb
umin
loss
(g)
16
14
12
10
8
6
4
2
00 5 10 15 20 25
Dialysate flow: 1.0 I/h = Albumin loss
(Maximal)= Albumin loss
(Median)
Treatment time (h)
Tota
l alb
umin
loss
(g)
Dialysate flow: 2.5 I/h = Albumin loss
(Maximal)= Albumin loss
(Median)
0 5 10 15 20 25
16
14
12
10
8
6
4
2
0
Clearances for the septeX® set: convincing results from in vitro and ex vivo measurements 3
Clearance (ml/min)
QB 80 ml/min
QB 200 ml/min
QB 400 ml/min
QD 1 l/h
17
17
17
Urea clearance in buffer solution
QD 2.5 l/h
41
42
41
QD 4 l/h
63
67
66
QD 8 l/h
80
124
131
Clearance (ml/min)
QD 1 l/h
Myoglobin clearance in bovine plasma
QD 2.5 l/h QD 4 l/h QD 8 l/h
QB 80 ml/min
QB 200 ml/min
QB 400 ml/min
13
18
19
22
30
32
25
36
45
23
36
42
Clearance (ml/min)
QD = 2.5 l/h
45 ± 1.5
28 ± 4.4
Cytokine clearance in human plasma, QB = 200 ml/min
QD = 8 l/h
46 ± 16
28 ± 6
IL-1
IL-6
Effect of decreased cytokine plasma levels 4
The high cut-off membrane allows the achievement of a significantly greater decrease in serum IL-6 in HD mode than a standard hemofiltration membrane in HD mode. The comparison of a high cut-off membrane to a standard hemofiltration membrane has shown*: • A trend to an improvement in blood pressure
with the high cut-off membrane in HD mode (not significantly different, however)
• A trend to a decrease in norepinephrine require-ments with the high cut-off membrane in HD mode (not significantly different, however)
* All comparisons done in HD modality for both membranes; average albumin loss was observed as 7.7 g (septeX technology HCO membrane group) versus 1.0 g (standard HFHD membrane group).
Cytokine levels and interleukin concentrations: clinical results
In septic patients with acute renal failure, the high cut-off membrane used in HD mode achieved simultaneous uremic control and diffusive cytokine clearance as well as a greater relative decrease in plasma cytokine concentrations than with a standard hemo-filtration membrane used in HD mode.
Plasma cytokine
IL-8
IL-6
IL-10
–13.5 (–22.1–0.7)
–7.2 (–10.9–1.8)
–17.5 (–24.3–7.6)
0.9 (–5.6–12.9)
2.2 (–1.1–7.9)
0.8 (–8.8–6.5)
HCO-IHD HF-IHD P
0.02
0.01
‹ 0.01
IL-18 –17.1 (–25.0–8.2) 1.8 (–8.3–6.2) 0.2
Relative changes from pre-filter to post-filter plasma cytokine levels during high cut-off and high-flux intermittent hemodialysis
Relative changes presented as median percent (25th to 75th percentiles).
Abbreviations: IL-6: interleukin 6; HCO-IHD: high cut-off intermittent hemodialysis; HF-IHD: standard high-flux intermittent hemodialysis.
Relative changes in plasma IL-6 levels during HCO-IHD, –30.3% (25th to 75th percentiles, –53.4 to –8.3) versus HF-IHD, 1.1% (25th to 75th percentiles, –14.3 to 32.8; P = 0.05).
Relative changes in plasma interleukin 6 (IL-6) concentrations during high cut-off (HCO) intermittent hemodialysis (IHD) and high-flux (HF)-IHD from baseline to end of treatment.
Cha
nge
in p
lasm
a IL
-6 (%
)
High cut-off IHD(from baseline to end)
High-flux IHD(from baseline to end)
50
25
0
-25
-50
-75
P = 0.05
Antit
hrom
bin
III [m
g/dI
]
Time (h) Time (h) Time (h)
72
Fact
or II
[%]
120
100
80
60
40
20
0
120
100
80
60
40
20
0
120
100
80
60
40
20
072
Pro
tein
C [m
g/dI
]
72
Coagulation factors are not affected during CRRT with the septeX® membrane2
An important aspect of high cut-off membrane technology is its potential impact on coagulation factor levels.
Clinical data show that coagulation factors are not affected by septeX membrane usage.
The figure shows plasma values for antithrombin III (mw 60 kDa), factor II (mw 69 kDa), and protein C (mw 62 kDa) before, after 12 h and after 72 h of hemofiltration. Stable values were also found for protein S (mw 69 kDa) and factor VIII (mw 265 kDa).
Baseline and follow-up values for antithrombin III (60 kDa), coagulation factor II (69 kDa) and protein C (62 kDa) represented as box and whisker plots. Boxes represent median values and the 25th and 75th percentiles while whiskers represent extreme values.
All coagulation factors remained stable throughout the observation period.
0 12 0 120 12
Coagulation factors are not affected during CRRT with the septeX® membrane
Bibliography
1. S. Morgera, et al. Renal replacement therapy with high-cut-off haemofilters: Impact of convection and diffusion on cytokine clearances and protein status. American Journal of Kidney Diseases 2004, 43(3): 444-4536 patients per modality CVVHD 1 & 2.5l/h // CVVH 1 & 2.5l/h 2. Morgera, et al. Intermittent high permeability haemofiltration in septic patients with acute renal failure. Intensive Care Med, 2003 3. Gambro Internal data – 2572 – septeX clearances 4. Haase et al; Haemodialysis Membrane With a High-Molecular-Weight Cutoff and Cytokine Levels in Sepsis Complicated by Acute Renal Failure: A Phase 1 Randomized Trial. AJKD 2007 Vol 50;pp 296-304Phase I pilot study – involving 10 patients. Cross-over study, 4 hrs of High cut-off HD (HCO HD) followed by 4 hrs of standard high-flux HD (HFHD). 5. S. Uchino, et al. Cytokine Dialysis: an ex-vivo study. ASAIO Journal, 2002; 48: 650–3.
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Gambro® is a registered trademark of Gambro Lundia AB.
PrismafleX eXeed™ is a trademark of Gambro Lundia AB.
Prismaflex® is a trademark of Gambro Lundia AB, registered in the United States and in other countries.
septeX® is a trademark of Gambro Lundia AB, registered in the European Union.
Not for use in the USA.
