EXTRACORPOREAL BLOOD CIRCUIT

Abstract

The present disclosure relates to extracorporeal blood circuits used for gas exchange in blood, in particular circuits for cardiopulmonary bypass.

Claims

1. An extracorporeal blood circuit comprising a) a gas exchange device; and b) a capillary dialyzer comprising a plurality of semipermeable hollow fiber membranes, wherein the membranes comprise i) a copolymer of acrylonitrile and sodium methallyl sulfonate, ii) a polyethyleneimine, and iii) heparin, and wherein the blood compartment of the dialyzer comprising the lumen of the semipermeable hollow fiber membranes is connected to the extracorporeal blood circuit.

2. The extracorporeal blood circuit of claim 1, wherein the gas exchange device is a membrane oxygenator.

3. The extracorporeal blood circuit of claim 1, wherein the extracorporeal blood circuit is a cardiopulmonary bypass (CPB).

4. The extracorporeal blood circuit of claim 3, wherein the blood circuit comprises a heart-lung machine (HLM).

5. The extracorporeal blood circuit of claim 1, wherein the extracorporeal blood circuit is configured for extracorporeal membrane oxygenation (ECMO).

6. The extracorporeal blood circuit of claim 3, wherein the cardiopulmonary bypass is a veno-arterial bypass.

7. The extracorporeal blood circuit of claim 3, wherein the cardiopulmonary bypass is a veno-venous bypass.

8.-11. (canceled)

12. A method of treating a subject via an extracorporeal blood circuit, said method comprising the step of administering a diffusion device to the subject, wherein the diffusion device comprises semipermeable membranes comprising i) a copolymer of acrylonitrile and sodium methallyl sulfonate; ii) a polyethyleneimine; and iii) heparin, in a cardiopulmonary bypass.

13. The method of claim 12, wherein the diffusion device is a capillary dialyzer.

14. The method of claim 12, wherein the cardiopulmonary bypass comprises a membrane oxygenator.

15. The method of claim 12, wherein the cardiopulmonary bypass comprises a heart-lung machine.

16. The method of claim 12, wherein the cardiopulmonary bypass is a veno-arterial bypass.

17. The method of claim 12, wherein the cardiopulmonary bypass is a veno-venous bypass.

18. A method of treating a subject via an extracorporeal blood circuit, said method comprising the step of administering a filtration device to the subject, wherein the filtration device comprises semipermeable membranes comprising i) a copolymer of acrylonitrile and sodium methallyl sulfonate; ii) a polyethyleneimine; and iii) heparin, in a cardiopulmonary bypass.

19. The method of claim 12, wherein the filtration device is a capillary dialyzer.

20. The method of claim 12, wherein the cardiopulmonary bypass comprises a membrane oxygenator.

21. The method of claim 12, wherein the cardiopulmonary bypass comprises a heart-lung machine.

22. The method of claim 12, wherein the cardiopulmonary bypass is a veno-arterial bypass.

23. The method of claim 12, wherein the cardiopulmonary bypass is a veno-venous bypass.

Description

EXAMPLES

[0024] Removal of inflammatory mediators and endotoxins by a capillary dialyzer having an effective surface area of 1.5 m.sup.2 (oXiris, Gambro Lundia AB) was tested. The dialyzer comprises hollow fiber membranes comprising a copolymer of acrylonitrile and sodium methallyl sulfonate. The surface of the fibers comprises 30 mg/m.sup.2 of high MW polyethyleneimine (PEI) and is grafted with 4,5001,500 UI/m.sup.2 of heparin. The fibers have an inner diameter of 240 m and a wall strength of 40 m.

[0025] Interleukin-10 (IL-10; MW=18 kDa), Interleukin 6 (IL-6; MW=26 kDa), High-mobility group box 1 (HMGB-1; MW=30 kDa) and Tumor necrosis factor alpha (TNF-a; MW=51 kDa) were used as cytokines. Lipopolysaccharide (LPS; MW>100 kDa) was used as endotoxin.

[0026] The in vitro experiments were conducted using a pool of 500 ml of frozen human plasma with a protein content of 605 g/l from healthy volunteers stabilized with a LPS theoretical concentration of [25-75] EU/mL. Spiking of IL-10, IL-6, HMGB-1 and TNF-a cytokines at a respective concentration of 500 pg/mL, 1,500 pg/mL, 30 ng/mL and 250 pg/mL was performed prior to the start of circulation.

[0027] A number of n=3 samples was selected (including n=3 multiple batches), which has been found adequate to demonstrate a systematic removal mechanism and considering that clinical outcomes related to endotoxin/cytokine removal may significantly differ depending on the patient pathological conditions (no direct clinical correlation between the foreseen cytokine adsorbed quantity and the plasma final circulating cytokine level). The circulation conditions are representative of standard CRRT practices.

[0028] Prior to circulation of the plasma pool, the blood compartment of the dialyzer was washed with 1.5 L of heparinized (5 UI/mL) saline solution at 150 ml/min. Additional 500 ml of the solution were used to rinse the dialysate compartment by ultrafiltration.

[0029] The plasma pool was circulated in a closed loop for 120 min at 150 ml/min. Sampling was performed during the circulation at baseline and after t=5, t=10, t=30, t=60 and t=120 min directly from the plasma pool.

[0030] Concentration of cytokines was measured in duplicate by enzyme-linked immunosorbent assay (ELISA) utilizing matched antibody pairs and recombinant (Quantikine R&D system, France; and IBL international, Germany for human HMGB-1). LPS concentration was measured in duplicate by limulus amoebocyte lysate (LAL) chromogenic method (K-QCL Lonza assay).

[0031] Removal Rate specifications at the end of the circulation (t=120 min) are calculated for each mediator using:

[0032] RR.sub.(t=120 min)=[1C.sub.(t=120 min)/C.sub.(t=0 min)]100

[0033] with

[0034] C.sub.(t=0 min): initial concentration in the plasma pool (baseline sample)

[0035] C.sub.(t=120 min): final concentration in the plasma pool at t=120 min

[0036] The results are summarized in Table 1.

TABLE-US-00001 TABLE 1 Mean calculated removal rate at t = 120 min for IL-10, IL-6, HMGB-1, TNF-a cytokines and LPS Cytokine adsorption RR (%) LPS adsorption IL-10 IL-6 HMGB-1 TNF- RR (%) Batch 1 94.1 82.9 93.0 84.5 73.6 Batch 2 97.9 82.0 92.7 77.4 77.8 Batch 3 97.0 82.8 99.3 60.2 82.0 Mean (n = 3) 96.3 82.6 95.0 74.0 77.8 SD 2.0 0.5 3.7 12.5 4.2 CV (%) 2.1 0.6 3.9 16.9 5.4 *calculated at t = 120 min

[0037] The in vitro experiments confirm the high affinity of the oXiris membrane to the different cytokines challenged (IL-10/IL-6/HMGB-1 and TNF-a) as well as to the endotoxin LPS. Those observations appear consistent with available clinical evidence, suggesting the capability of the device for selective elimination of inflammatory mediators and associated improved patient condition (improved SOFA score and cardiovascular function).