Multipart fluid system and a system for regional citrate anticoagulation with a phosphate comprising anticoagulation fluid

Abstract

The present invention concerns a multipart fluid system for dialysis therapy, wherein the multipart fluid system comprises an anticoagulation fluid and at least one treatment fluid from the group consisting of dialysis fluid and infusion fluids. According to the invention the anticoagulation fluid comprises 10-40 mM citrate, and 0.1-2.0 mM phosphate; and the at least one treatment fluid comprises 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2.0 mM phosphate; with provisos that the at least one treatment fluid comprises citrate when total calcium concentration is 0 mM; and the at least one treatment fluid comprises calcium when the citrate concentration is 0 mM. The present invention further concerns a system for regional citrate anticoagulation in an extracorporeal blood circuit.

Claims

1. A multipart fluid system for dialysis therapy, said multipart fluid system comprising: an anticoagulation fluid; and at least one treatment fluid from the group consisting of dialysis fluid and infusion fluids, wherein the anticoagulation fluid comprises 10-40 mM citrate, and 0.1-2.0 mM phosphate, wherein the at least one treatment fluid comprises 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2.0 mM phosphate, and wherein a concentration of the phosphate in the anticoagulation fluid is equivalent to the concentration of the phosphate in the at least one treatment fluid, with provisos that the at least one treatment fluid comprises citrate when total calcium concentration is 0 mM; and the at least one treatment fluid comprises calcium when the citrate concentration is 0 mM.

2. The multipart fluid system according to claim 1, wherein said anticoagulation fluid comprises 0.5-2.0 mM phosphate.

3. The multipart fluid system according to claim 1, wherein said at least one treatment fluid comprises 0.5-2.0 mM phosphate.

4. The multipart fluid system according to claim 1, wherein said anticoagulation fluid comprises 10-40 mM citrate.

5. The multipart fluid system according to claim 1, wherein said anticoagulation fluid comprises 1.5-4 mM total calcium.

6. The multipart fluid system according to claim 1, wherein said anticoagulation fluid further comprises 0-1.5 mM magnesium, 0-5.0 mM potassium, 0-11 mM glucose, and 130-150 mM sodium.

7. The multipart fluid system according to claim 1, wherein said at least one treatment fluid comprises 2.0-8.0 mM citrate.

8. The multipart fluid system according to claim 1, wherein said at least one treatment fluid comprises 2.0-7.0 mM citrate and 1.8-2.4 mM total calcium.

9. The multipart fluid system according to claim 1, wherein said at least one treatment fluid comprises 3.5-5.5 mM citrate and 1.5-2.4 mM total calcium.

10. The multipart fluid system according to claim 1, wherein said at least one treatment fluid further comprises 0-1.5 mM magnesium, 0-5.0 mM potassium, 0-11 mM glucose, and 130-150 mM sodium.

11. The multipart fluid system according to claim 1, wherein said at least one treatment fluid further comprises a physiological buffer.

12. The multipart fluid system according to claim 11, wherein said physiological buffer is bicarbonate.

13. The multipart fluid system according to claim 12, wherein said at least one treatment fluid comprises <40 mM bicarbonate.

14. A system for regional citrate anticoagulation in an extracorporeal blood circuit comprising an arterial blood line configured to be connected to a vascular access for withdrawing blood from a patient and a venous blood line configured to be connected to the vascular access for returning blood to the patient, the system comprising: a filter with a dialysate side and a blood side, which blood side is in fluid communication with the arterial and venous blood lines, wherein the blood side is in fluid communication with an anticoagulation fluid source comprising 10-40 mM citrate and 0.1-2 mM phosphate, wherein the dialysate side is in fluid communication with a treatment fluid source comprising 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2 mM phosphate, and wherein a concentration of the phosphate in the anticoagulation fluid source is equivalent to the concentration of the phosphate in the treatment fluid source, with provisos that the at least one treatment fluid comprises citrate when total calcium concentration is 0 mM; and the at least one treatment fluid comprises calcium when the citrate concentration is 0 mM.

15. A system according to claim 14, the system comprising: a pre-filter infusion line connected to the arterial blood line upstream the filter and connected to an anticoagulation fluid source containing 10-40 mM citrate and 0.1-2 mM phosphate to be infused into the blood stream in the arterial blood line; and a post-filter infusion line connected to the venous blood line downstream the filter and connected to a treatment fluid source comprising 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2 mM phosphate to be infused into the blood stream in the venous blood line.

16. A system according to claim 14, the system comprising: a pre-filter infusion line connected to the arterial blood line upstream the filter and connected to an anticoagulation fluid source containing 10-40 mM citrate and 0.1-2.0 mM phosphate to be infused into the blood stream in the arterial blood line.

17. A system according to claim 14, the system comprising: a first pre-filter infusion line connected to the arterial blood line upstream the filter and connected to an anticoagulation fluid source containing 10-40 mM citrate and 0.1-2.0 mM phosphate to be infused into the blood stream in the arterial blood line; and a second pre-filter infusion line connected to the arterial blood line upstream the filter and connected to a treatment (infusion) fluid source comprising 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2 mM phosphate to be infused into the blood stream in the arterial blood line.

18. A system for regional citrate anticoagulation in an extracorporeal blood circuit according to claim 17, which further comprises a post-filter infusion line connected to the venous blood line downstream the filter and connected to an treatment (infusion) fluid source comprising 0.1-2.0 mM phosphate to be infused into the blood stream in the venous blood line.

19. A system for regional citrate anticoagulation in an extracorporeal blood circuit according to claim 15, wherein the dialysate side of the filter is in fluid communication with a dialysis fluid source comprising 0.1-2.0 mM phosphate.

20. A system for regional citrate anticoagulation in an extracorporeal blood circuit according to claim 14, wherein said anticoagulation fluid comprises 0.5-2.0 mM phosphate.

21. A system for regional citrate anticoagulation in an extracorporeal blood circuit according to claim 14, wherein said system further comprises a control unit adapted to control the anticoagulation fluid flow rate in relation to the blood flow rate.

22. A system according to claim 14, wherein the system comprises the multipart fluid system as is defined in claim 1.

23. A system for regional citrate anticoagulation in an extracorporeal blood circuit according to claim 17, wherein the dialysate side of the filter is in fluid communication with a dialysis fluid source comprising 0.1-2.0 mM phosphate.

24. A system for regional citrate anticoagulation in an extracorporeal blood circuit according to claim 18, wherein the dialysate side of the filter is in fluid communication with a dialysis fluid source comprising 0.1-2.0 mM phosphate.

25. A system for regional citrate anticoagulation in an extracorporeal blood circuit, the system comprising: an arterial blood line configured to be connected to a vascular access for withdrawing blood from a patient; a venous blood line configured to be connected to the vascular access for returning blood to the patient; a filter with a dialysate side and a blood side, wherein the blood side is in fluid communication with the arterial and venous blood lines; an anticoagulation fluid source comprising 10-40 mM citrate and 0.1-2 mM phosphate, the anticoagulation fluid source connected to the arterial blood line upstream the filter; and a treatment fluid source comprising 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2 mM phosphate, wherein a concentration of the phosphate in the anticoagulation fluid source is equivalent to the concentration of the phosphate in the treatment fluid source, and wherein the treatment fluid source is connected to at least one blood line selected from the group consisting of the arterial and the venous blood line, the treatment fluid source connected downstream of the anticoagulation fluid source.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1-8 shows different embodiments of the system for regional citrate anticoagulation in an extracorporeal blood circuit.

(2) FIG. 9. Shows the level of bicarbonate required when changing the concentration of citrate.

(3) FIG. 10 illustrates the change of bicarbonate equivalents in the treated blood.

DEFINITIONS

(4) The term dialysis therapy means all types of dialysis treatments both for chronic renal insufficiency and acute renal insufficiency.

(5) The term CRRT means a continuous renal replacement therapy and this type of treatment mode is used in case of acute renal insufficiency or in case of chronic renal insufficiency when using a wearable artificial kidney system.

(6) The term filter means a unit comprising semipermeable membranes. This unit may also be called a semipermeable membrane, a dialyzer, a dialysis filter or a dialysis membrane.

(7) The term anticoagulation fluid means a fluid which is intended to provide for the anticoagulation effect within the extracorporeal blood circuit and which is intended to be infused within the extracorporeal blood circuit.

(8) The term anticoagulation fluid source means the source of anticoagulation fluid. The source may be provided as fluid concentrate or in form of dry powder concentrate.

(9) The term treatment fluid means a dialysis fluid for perfusion of a filter or an infusion fluid, i.e. a fluid for pre- or postinfusion. Thus, treatments fluid includes dialysis fluid, infusion fluid, replacement fluid, and substitution fluid.

(10) The term source of treatment fluid means the source of treatment fluid, which may be provided as fluid concentrate or in form of dry powder concentrate.

(11) The term dialysis fluid means a fluid for perfusion of a filter, on the dialysate side of such a filter, opposite the blood side.

(12) The term infusion fluid means a fluid which is infused into the extracorporeal blood circuit either for predilution, i.e. infused into the extracorporeal blood flow before the blood enters the filter or for postdilution, i.e. infused into the extracorporeal blood flow after the blood has exited the filter and before the blood is returned to the patient. Infusion fluids are normally also named as replacement fluids, substitution fluids or hemofiltration fluids.

(13) The term total calcium concentration means the total amount of calcium present in a fluid, thus representing the sum of calcium present as ionized, complex bound and protein bound calcium.

(14) The term citrate means citric acid or any salt thereof. The salt may be formed with sodium, magnesium or potassium. The sodium citrate may be present as trisodium citrate, disodium hydrogencitrate, or monosodium dihydrogencitrate. The citrate may be added to the anticoagulation fluid and/or the treatment fluid.

(15) The term phosphate means phosphoric acid or any salt thereof. The salt may be formed with sodium, magnesium, or potassium, The component may be added as phosphate (PO.sub.4.sup.3), hydrogenphosphate (HPO.sub.4.sup.2) or dihydrogen phosphate (H.sub.2PO.sub.4.sup.). Examples of salts are trisodium phosphate, disodium hydrogenphosphate, monosodium dihydrogenphosphate. The phosphate may be added to the anticoagulation fluid and/or the at least one treatment fluid.

DETAILED DESCRIPTION OF THE INVENTION

(16) When patients receive continuous dialysis therapy, phosphate will be lost over the semipermeable membrane and administration of phosphate by intravenous routes must be carried out with great caution, as it is difficult to decide the correct amount of phosphate to be administered to the patient. If too much phosphate is administered hyperphosphatemia might develop, having serious consequences for the patient, for example hypocalcaemia, metastatic calcification and hypotension, and if too little phosphate is administered the hypophosphatemia is not corrected.

(17) The regional anticoagulation systems of today with citrate as anticoagulant added in large volumes of anticoagulation fluids limits the amounts of available volume of the treatment fluids. In order to safeguard a proper phosphate balancing throughout the renal replacement treatment, the amount of phosphate needs to be balanced within as many of the used fluids as possible. By adding a balancing concentration of phosphate to at least one of the fluids, especially within the anticoagulation fluid, the phosphate level within the patient is better balanced throughout the treatment, and intravenous administration of phosphate may thereby be omitted.

(18) In the multipart fluid system and the system for regional citrate anticoagulation according to the invention, the following combinations may be provided, wherein the term anticoagulation fluid apart from the anticoagulation fluid within the multipart fluid system, also includes the anticoagulation fluid source within the system for regional citrate anticoagulation, the term treatment fluid apart from the treatment fluid within the multipart fluid system also includes the treatment fluid source, the term infusion fluid apart from the infusion fluid within the multipart fluid system also includes the infusion fluid source within the system for regional citrate anticoagulation, the term dialysis fluid apart from the dialysis fluid in the multipart fluid system also includes the dialysis fluid source within the system for regional citrate anticoagulation.

(19) In one embodiment of the invention is a multipart fluid system for dialysis therapy provided. This multipart fluid system comprises an anticoagulation fluid and at least one treatment fluid from the group consisting of dialysis fluid and infusion fluids, wherein the anticoagulation fluid comprises 10-40 mM citrate, and 0-2.0 mM phosphate; and the at least one treatment fluid comprises 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2.0 mM phosphate; with provisos that the at least one treatment fluid comprises citrate when total calcium concentration is 0 mM; and the at least one treatment fluid comprises calcium when the citrate concentration is 0 mM.

(20) In one embodiment of the multipart fluid system the anticoagulation fluid comprises 10-40 mM citrate and 0.1-2.0 mM phosphate.

(21) Said anticoagulation fluid may, according one embodiment of the invention be used together with at least one infusion fluid comprising 0-5 mM total calcium, 0-8 mM citrate and 0.1-2.0 mM phosphate, with the provision that the infusion fluid comprises citrate when the total calcium concentration is 0 mM, or comprises calcium when the citrate concentration is 0 mM.

(22) Said anticoagulation fluid may, according to another embodiment of the invention be used together with a dialysis fluid comprising 0-5 mM total calcium, 0-8 mM citrate and 0.1-2.0 mM phosphate, with the provision that the infusion fluid comprises citrate when the total calcium concentration is 0 mM, or comprises calcium when the citrate concentration is 0 mM.

(23) Said anticoagulation fluid may according to another embodiment of the invention be used together with two infusion fluids, a first infusion fluid comprising 0-5 mM total calcium, 0-8 mM citrate and 0.1-2.0 mM phosphate, with the provision that the infusion fluid comprises citrate when the total calcium concentration is 0 mM, or comprises calcium when the citrate concentration is 0 mM; and a second infusion fluid comprising 0.1-2.0 mM phosphate. In one embodiment said second infusion fluid further comprises 0-5 mM total calcium, 0-8 mM citrate, with the provision that the second infusion fluid comprises citrate when the total calcium concentration is 0 mM, or comprises calcium when the citrate concentration is 0 mM.

(24) Said anticoagulation fluid may according to even another embodiment of the invention be used together with at least one infusion fluid comprising 0-5 mM total calcium, 0-8 mM citrate and 0.1-2.0 mM phosphate, with the provision that the infusion fluid comprises citrate when the total calcium concentration is 0 mM, or comprises calcium when the citrate concentration is 0 mM; and a dialysis fluid comprising 0.1-2.0 mM phosphate. In one embodiment said dialysis fluid further comprises 0-5 mM total calcium, 0-8 mM citrate, with the provision that the dialysis fluid comprises citrate when the total calcium concentration is 0 mM, or comprises calcium when the citrate concentration is 0 mM.

(25) Said anticoagulation fluid may according to a further embodiment of the invention be used together with a first infusion fluid comprising 0-5 mM total calcium, 0-8 mM citrate and 0.1-2.0 mM phosphate, with the provision that the infusion fluid comprises citrate when the total calcium concentration is 0 mM, or comprises calcium when the citrate concentration is 0 mM; and a second infusion fluid comprising 0.1-2.0 mM phosphate, and a dialysis fluid comprising 0.1-2.0 mM phosphate. In one embodiment said second infusion fluid further comprises 0-5 mM total calcium, 0-8 mM citrate, with the provision that the second infusion fluid comprises citrate when the total calcium concentration is 0 mM, or comprises calcium when the citrate concentration is 0 mM. In another embodiment said dialysis fluid further comprises 0-5 mM total calcium, 0-8 mM citrate, with the provision that the dialysis fluid comprises citrate when the total calcium concentration is 0 mM, or comprises calcium when the citrate concentration is 0 mM. In even another embodiment said second infusion fluid and said dialysis fluid comprises 0-5 mM total calcium, 0-8 mM citrate, with the provision that said second infusion fluid and said dialysis fluid comprises citrate when the total calcium concentration is 0 mM, or comprises calcium when the citrate concentration is 0 mM.

(26) Said anticoagulation fluid may according to one embodiment of the invention be used together with at least one infusion fluid comprising 2-8 mM citrate.

(27) Said anticoagulation fluid may according to another embodiment of the invention be used together with a dialysis fluid comprising 2-8 mM citrate.

(28) Said anticoagulation fluid may according to another embodiment of the invention be used together with at least one infusion fluid comprising 2-8 mM citrate and 0.1-2.0 mM phosphate.

(29) Said anticoagulation fluid may according to a further embodiment of the invention be used together with a dialysis fluid comprising 2-8 mM citrate and 0.1-2.0 mM phosphate.

(30) Said anticoagulation fluid may according to one embodiment of the invention be used together with at least one infusion fluid comprising 2-8 mM citrate and 0.1-2.0 mM phosphate; and a dialysis fluid comprising 2-8 mM citrate and 0.1-2.0 mM phosphate.

(31) Said anticoagulation fluid may according to one embodiment of the invention be used together with at least one infusion fluid comprising 1-5 mM total calcium.

(32) Said anticoagulation fluid may according to another aspect of the invention be used together with a dialysis fluid comprising 1-5 mM total calcium.

(33) Said anticoagulation fluid may also be used together with at least one infusion fluid comprising 2-8 mM citrate and 1-5 mM total calcium.

(34) Said anticoagulation fluid may also be used together with a dialysis fluid comprising 2-8 mM citrate and 1-5 mM total calcium.

(35) Said anticoagulation fluid may also be used together with at least one infusion fluid comprising 2-8 mM citrate and 1-5 mM total calcium; and a dialysis fluid comprising 2-8 mM citrate and 1-5 mM total calcium.

(36) Said anticoagulation fluid may in one embodiment comprise 0.5-2.0 mM phosphate, preferably 0.6-1.5 mM phosphate, and more preferably 0.8-1.2 mM.

(37) Said anticoagulation fluid may in one embodiment comprise 10-40 mM citrate, preferably 15-40 mM citrate, more preferably 20-30 mM citrate. Said anticoagulation fluid may in one embodiment comprise 1.5-4 mM total calcium, preferably 2-3 mM total calcium, and most preferably 2.2-2.6 mM mM calcium.

(38) Said anticoagulation fluid may in one embodiment further comprise 0-1.5 mM magnesium, 0-5.0 mM potassium, 0-11 mM glucose, and 130-150 mM sodium. Also 0-140 mM chloride may be included in the anticoagulation fluid.

(39) Said at least one infusion fluid may in one embodiment comprise 0.5-2.0 mM phosphate, preferably 0.6-1.5 mM phosphate, and more preferably 0.8-1.2 mM.

(40) Said at least one infusion fluid may in another embodiment further comprise 2.0-8.0 mM citrate. In one embodiment said at least one infusion fluid may comprise 2.0-7.0 mM citrate and 1.5-2.4 mM total calcium. In even another embodiment said at least one infusion fluid may comprise 3.0-5.0 mM citrate and 1.8-2.4 mM total calcium. In a further embodiment said at least one infusion fluid further comprises 0-1.5 mM magnesium, 0-5.0 mM potassium, 0-11 mM glucose, 130-150 mM sodium and 0-140 mM chloride. Said at least one infusion fluid may further comprise a buffer, preferably bicarbonate, and preferably in a concentration of <40 mM bicarbonate. For example, the concentration of bicarbonate is 10-40 mM, such as about 10, 15, 20, 25, 30, 35 and 40 mM bicarbonate.

(41) Said dialysis fluid may in another embodiment comprise 0.5-2.0 mM phosphate, preferably 0.6-1.5 mM phosphate, and more preferably 0.8-1.2 mM phosphate.

(42) Said dialysis fluid may in another embodiment further comprise 2.0-8.0 mM citrate. In one embodiment said dialysis fluid may comprise 2.0-7.0 mM citrate and 1.8-2.4 mM total calcium. In even another embodiment said dialysis fluid may comprise 3.0-5.0 mM citrate and 1.8-2.4 mM total calcium. In a further embodiment said dialysis fluid further comprises 0-1.5 mM magnesium, 0-5.0 mM potassium, 0-11 mM glucose, 130-150 mM sodium and 0-140 mM chloride. Said dialysis fluid may further comprise a buffer, preferably bicarbonate, and preferably in a concentration of <40 mM bicarbonate. For example, the concentration of bicarbonate is 10-40 mM, such as about 10, 15, 20, 25, 30, 35 and 40 mM bicarbonate.

(43) In one embodiment of the present invention the multipart fluid system according to the invention or the system for regional citrate anticoagulation according to the invention comprises an anticoagulation fluid or an anticoagulation fluid source comprising 10-40 mM citrate, and at least one infusion fluid or at least one infusion fluid source comprising 2-8 mM citrate and 0.1-2.0 mM phosphate.

(44) In another embodiment of the present invention the multipart fluid system according to the invention or the system for regional citrate anticoagulation according to the invention comprises an anticoagulation fluid or an anticoagulation fluid source comprising 10-40 mM citrate, and a dialysis fluid or a dialysis fluid source comprising 2-8 mM citrate and 0.1-2.0 mM phosphate.

(45) In even another embodiment of the present invention the multipart fluid system according to the invention or the system for regional citrate anticoagulation according to the invention comprises an anticoagulation fluid or an anticoagulation fluid source comprising 10-40 mM citrate, at least one infusion fluid or an infusion fluid source and a dialysis fluid or a dialysis fluid source comprising 2-8 mM citrate and 0.1-2.0 mM phosphate.

(46) In one embodiment of the present invention the multipart fluid system according to the invention or the system for regional citrate anticoagulation according to the invention comprises an anticoagulation fluid or an anticoagulation fluid source comprising 10-40 mM citrate, and at least one infusion fluid or at least one infusion fluid source comprising 1-5 mM total calcium and 0.1-2.0 mM phosphate.

(47) In another embodiment of the present invention the multipart fluid system according to the invention or the system for regional citrate anticoagulation according to the invention comprises an anticoagulation fluid or an anticoagulation fluid source comprising 10-40 mM citrate, and a dialysis fluid or a dialysis fluid source comprising 1-5 mM total calcium and 0.1-2.0 mM phosphate.

(48) In even another embodiment of the present invention the multipart fluid system according to the invention or the system for regional citrate anticoagulation according to the invention comprises an anticoagulation fluid or an anticoagulation fluid source comprising 10-40 mM citrate, at least one infusion fluid or an infusion fluid source and a dialysis fluid or a dialysis fluid source comprising 1-5 mM total calcium and 0.1-2.0 mM phosphate.

(49) An embodiment of the invention is a multipart fluid system for dialysis therapy, comprising an anticoagulation fluid and at least one treatment fluid from the group consisting of dialysis fluid and infusion fluids. The anticoagulation fluid comprises 10-40 mM citrate, and 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 mM phosphate; and the at least one treatment fluid comprises 0-5 mM total calcium, 0-8 mM citrate, and 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 mM phosphate.

(50) The concentration of phosphate may be selected to be the same in the anticoagulation fluid and the at least one treatment fluid; or the concentration of phosphate may be selected to be different.

(51) The systems for regional citrate anticoagulation as are herein described may comprise any of the multipart fluid systems defined herein.

DETAILED DESCRIPTION OF THE DRAWINGS

(52) In FIG. 1 is shown a first system for regional citrate anticoagulation in an extracorporeal blood circuit comprising an arterial blood line 1 configured to be connected to a vascular access (not shown) for withdrawing blood from a patient and a venous blood line 2 configured to be connected to the vascular access (not shown) for returning blood to the patient. This system comprises a filter 3 with a dialysate side and a blood side, which blood side is in fluid communication with the arterial blood line 1 and venous blood line 2; a pre-filter infusion line 4 connected to the arterial blood line 1 upstream the filter 3 for infusing an anticoagulation fluid 5 containing 10-40 mM citrate and 0.1-2.0 mM phosphate into blood in the arterial blood line 1; and a post-filter infusion line 6 connected to the venous blood line 2 downstream the filter 3 for infusing a treatment fluid being an infusion fluid 7 comprising 0-5 mM total calcium, 0-8 mM citrate and 0.1-2.0 mM phosphate into blood in the venous blood line 2. An effluent bag 8 is provided in fluid communication with the dialysate side of the filter 3, to collect the plasma water (ultrafiltrate) withdrawn from the blood passing the filter 3.

(53) In FIG. 2 is shown another embodiment of the system in FIG. 1 with the addition that the dialysate side of the filter 3 is in fluid communication with a dialysis fluid source 9 comprising 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2.0 mM phosphate.

(54) In FIG. 3 is shown a second system for regional citrate anticoagulation in an extracorporeal blood circuit. This system includes an arterial blood line 1 configured to be connected to a vascular access for withdrawing blood from a patient and a venous blood line 2 configured to be connected to the vascular access for returning blood to the patient. This system also comprises a filter 3 with a dialysate side and a blood side, which blood side is in fluid communication with the arterial and venous blood lines, and which dialysate side is in fluid communication with a dialysis fluid source 9 comprising 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2.0 mM phosphate and an effluent bag 8 for the spent dialysis fluid and the plasma water (ultrafiltrate) withdrawn from the blood passing the filter 3. The system further comprises a pre-filter infusion line 4 connected to the arterial blood line 1 upstream the filter 3 for infusing an anticoagulation fluid 5 containing 10-40 mM citrate and 0.1-2.0 mM phosphate into the blood in the arterial blood line.

(55) In FIG. 4 is shown a third embodiment of the system for regional citrate anticoagulation in an extracorporeal blood circuit according to the present invention. This third system includes an arterial blood line 1 configured to be connected to a vascular access for withdrawing blood from a patient and a venous blood line 2 configured to be connected to the vascular access for returning blood to the patient. This system further comprises a filter 3 with a dialysate side and a blood side, which blood side is configured in fluid communication with the arterial and venous blood lines. A pre-filter infusion line 4 is connected to the arterial blood line 1 upstream the filter 3 for infusing an anticoagulation fluid 5 containing 10-40 mM citrate and 0.1-2.0 mM phosphate into blood in the arterial blood line 1. A second pre-filter infusion line 10 is connected to the arterial blood line 1 upstream the filter 3 for infusing an infusion fluid 11 comprising 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2.0 mM phosphate into blood in the arterial blood line 1. Also here an effluent bag 8 is provided in fluid communication with the dialysate side of the filter 3, for receiving the plasma water (ultrafiltrate) withdrawn from the blood passing the filter 3.

(56) In FIG. 5 is another embodiment of the third system in FIG. 4 shown, which further comprises a post-filter infusion line 6 connected to the venous blood line 2 downstream the filter 3 for infusing an infusion fluid 7 comprising 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2.0 mM phosphate into blood in the venous blood line 2.

(57) In FIG. 6 is yet another embodiment of the third system in FIG. 4 shown, wherein the dialysate side of the filter 3 is in fluid communication with a dialysis fluid source 9 comprising 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2.0 mM phosphate.

(58) In FIG. 7 is another embodiment of the system in FIG. 6 shown. This system further comprises a post-filter infusion line 6 connected to the venous blood line 2 downstream the filter 3 for infusing an infusion fluid 7 comprising 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2.0 mM phosphate into the blood in the venous blood line 2.

(59) In FIG. 8 is another embodiment of the systems above shown, which further comprises a control unit 12 adapted to control the anticoagulation fluid flow rate in relation to the blood flow rate. Such a control unit may be provided in all the systems shown in the different embodiments of FIG. 1-FIG. 7. By having such a control unit 12, the system is monitoring and securing that the amount of citrate within the blood is enough to maintain anticoagulation within the extracorporeal blood circuit.

(60) In the systems according to the invention, pumps are configured to pump blood (pump 13) through the extracorporeal blood circuit, anticoagulation fluid (pump 14) into the extracorporeal blood circuit, infusion fluid (pumps 15a and 15b) into the extracorporeal blood circuit, dialysis fluid (pump 16) into the dialysate side of the filter 3, and plasma liquid (ultrafiltrate) and optional spent dialysis fluid (pump 17) out from the dialysate side of the filter 3 and into the effluent bag 8.

EXAMPLES

(61) By way of example, and not limitation, the following examples identify a variety of multipart fluid systems and systems for regional citrate anticoagulation pursuant to embodiments of the present invention.

Example 1

(62) TABLE-US-00001 TABLE 1 Anticoagulation Infusion fluid for Dialysis Component fluid preinfusion fluid Citrate, (mM) 30 4 4 Phosphate, (mM) 0.8 0.8 0.8 Calcium, (mM) 2.5 2.3 2.3 Magnesium, (mM) 0.5 0.5 0.5 Potassium, (mM) 3 3 3 Glucose, (mM) 0 0 5.5 Sodium, (mM) 140 140 140

(63) The multipart fluid system of table 1 was used in a system for regional citrate anticoagulation according to FIG. 5.

Example 2

(64) TABLE-US-00002 TABLE 2 Anticoagulation Infusion fluid for Dialysis Component fluid postinfusion fluid Citrate, (mM) 35 3 4 Phosphate, (mM) 1.0 0 1.0 Calcium, (mM) 2.3 2.4 2.4 Magnesium, (mM) 0.75 0.75 0.75 Potassium, (mM) 2 2 2 Glucose, (mM) 0 0 5.5 Sodium, (mM) 140 140 140

(65) The multipart fluid system of table 2 was used in a system for regional citrate anticoagulation according to FIG. 2.

EVALUATIONS

(66) The new multipart fluid system and the system for regional citrate anticoagulation have been evaluated by use of simulation program developed in-house by Gambro. It computes equilibrium concentrations of species present in plasma and fluids used for dialysis by use of equilibrium constants (SCD base 2001.sup.1). The species (electrolytes, albumin and formed complexes) taken into account are shown in Table 1.

(67) TABLE-US-00003 TABLE 1 Normal plasma concentration of electrolytes and albumin together with the complexes taken into account formed with Ca.sup.2+ and Mg.sup.2+ Normal plasma total Complex formation Specie conc (mM) (Kratz 1998.sup.2) with Ca.sup.2+ and Mg.sup.2+ Ca.sup.2+ 2.1-2.6 (1.1-1.3 ionized) Mg.sup.2+ 0.7-1.0 Na.sup.+ 135-145 Cl.sup. 100-108 HCO.sub.3.sup., bicarbonate, 22-26 CaHCO.sub.3.sup.+, MgHCO.sub.3.sup.+ bic Phosphate, HPO.sub.4.sup.2; 0.7-1.0 CaHPO.sub.4, MgHPO.sub.4 H.sub.2PO.sub.4.sup. C.sub.6H.sub.5O.sub.7.sup.3, citrate, cit 0.1-0.3 (infants, Ca-cit.sup., Ca-cit.sub.2.sup.4, Ames1950.sup.3) Mg-cit.sup.. Mg-cit.sub.2.sup.4 Albumin, alb 0.5-0.6 Alb-Ca.sub.n, alb-Mg.sub.n, n = 1-10
The transport of each species is governed by its mobility and the flow rates of plasma and dialysis fluid. Values for the mobility of different species are found in literature. The transport of ions is also affected by the demand for electroneutrality, which is expressed as the development of a membrane potential. In order to handle the effects of complex formations and albumin binding, the dialyzer is split up into a number of segments and the transport calculations are performed in an iterative manner. The transport across the dialyzer membrane in one segment leads to a new equilibrium for the complex formation and albumin binding, which forms the input to the next segment for the next iteration. About 30 iterations are needed to find the equilibrium concentrations along the entire dialyzer.

(68) The requirements of the treatments are: 1. An adequate dialysis treatment 2. A sufficient anticoagulant effect, i.e. the ionized calcium through the blood side of the filter (dialyzer) must be 0.2-0.5 mM, preferably 0.3-0.4 (according to literature) 3. The plasma concentration of phosphate when returned to the patient has to be at normal level, i.e. about 0.7-1.0 mM. 4. The total plasma concentration of calcium when returned to the patient has to be at normal level, i.e. about 2.5 mM. Other electrolyte concentration levels must also be satisfactory.

(69) In the following examples different multipart systems are presented. These have been evaluated in accordance with the above. The flow rates used at the evaluation is presented, they are denoted and explained as follows:

(70) Qbblood flow rate from patient;

(71) Qpbppre blood pump flow rate;

(72) Qprepre-filter treatment fluid rate;

(73) Qpostpost filter treatment fluid flow rate; and

(74) Qdflow rate of dialysis fluid.

Example A

(75) TABLE-US-00004 Anticoagulation Infusion fluid for Dialysis Component fluid postinfusion fluid Citrate, (mM) 30 0 4 Phosphate, (mM) 1.0 0.6 1.0 Calcium, (mM) 2.4 2.3 2.3 Magnesium, (mM) 0.5 0.5 0.5 Potassium, (mM) 3 3 3 Glucose, (mM) 0 0 5.5 Sodium, (mM) 140 140 140 Bicarbonate 0 15 15

(76) TABLE-US-00005 TABLE A The result with multipart system according to Example A, with Qb 120 ml/min, Qpbp 16.0 ml/min, Qpre 0.0 ml/min, Qpost 4.8 ml/min, Qd 20.0 ml/min. Concentration of plasma returning to patient (mmol/l) Citrate, total 4.29 Phosphate, total 1.06 Calcium, total 2.26 Calcium, ionized 0.43 Bicarbonate (total CO.sub.2) 18.49 Bicarbonate + citrate 31.37 pH 7.60

Example B

(77) TABLE-US-00006 Anticoagulation Infusion fluid for Dialysis Component fluid preinfusion fluid Citrate, (mM) 30 4 4 Phosphate, (mM) 1.0 0.6 1.0 Calcium, (mM) 2.4 0 2.3 Magnesium, (mM) 0.5 0.5 0.5 Potassium, (mM) 3 3 3 Glucose, (mM) 0 0 5.5 Sodium, (mM) 140 140 140 Bicarbonate 0 15 15

(78) TABLE-US-00007 TABLE B The result of Example B, with Qb 120 ml/min, Qpbp 16.0 ml/min, Qpre 0.0 ml/min, Qpost 4.8 ml/min, Qdi 20.0 ml/min. Concentration of plasma returning to patient (mmol/l) Citrate, total 4.54 Phosphate, total 1.06 Calcium, total 2.12 Calcium, ionized 0.38 Bicarbonate (total CO.sub.2) 18.49 Bicarbonate + citrate 32.11 pH 7.62

Example C

(79) TABLE-US-00008 Anticoagulation Infusion fluid for Component fluid postinfusion Dialysis fluid Citrate, (mM) 10 4 4 Phosphate, (mM) 0.8 0.8 0.8 Calcium, (mM) 2.4 2.2 2.2 Magnesium, 0.5 0.5 0.5 (mM) Potassium, (mM) 3 3 3 Glucose, (mM) 0 0 5.5 Sodium, (mM) 140 140 140 Bicarbonate 0 35

(80) TABLE-US-00009 TABLE C The result of Example C, with Qb 120 ml/min, Qpbp 48.0 ml/min, Qpre 0.0 ml/min, Qpost 27.2 ml/min, Qd 20.0 ml/min. Concentration of plasma returning to patient (mmol/l) Citrate, total 3.70 Phosphate, total 1.03 Calcium, total 2.30 Calcium, ionized 0.52 Bicarbonate (total CO.sub.2) 13.83 Bicarbonate + citrate 24.94 pH 7.59

Example D

(81) TABLE-US-00010 Anticoagulation Infusion fluid for Component fluid postinfusion Dialysis fluid Citrate, (mM) 12 4 4 Phosphate, (mM) 0.8 0.8 0.8 Calcium, (mM) 2.2 2.2 2.2 Magnesium, 0.5 0.5 0.5 (mM) Potassium, (mM) 2 2 2 Glucose, (mM) 0 0 5.5 Sodium, (mM) 140 140 140 Bicarbonate 0 30 30

(82) TABLE-US-00011 TABLE D The result of Example D, with Qb 120 ml/min, Qpbp 40.0 ml/min, Qpre 0.0 ml/min, Qpost 19.2 ml/min, Qd 20.0 ml/min. Concentration of plasma returning to patient (mmol/l) Citrate, total 3.96 Phosphate, total 1.02 Calcium, total 2.21 Calcium, ionized 0.46 Bicarbonate (total CO.sub.2) 16.72 Bicarbonate + citrate 28.58 pH 7.62

Example E

(83) TABLE-US-00012 Anticoagulation Infusion fluid for Component fluid postinfusion Dialysis fluid Citrate, (mM) 18 4 4 Phosphate, (mM) 0.8 0.8 0.8 Calcium, (mM) 2.2 2.2 2.2 Magnesium, 0.5 0.5 0.5 (mM) Potassium, (mM) 3 3 3 Glucose, (mM) 0 0 5.5 Sodium, (mM) 140 140 140 Bicarbonate 0 30 30

(84) TABLE-US-00013 TABLE E The result of Example E Qb 120 ml/min, Qpbp 26.7 ml/min, Qpre 0.0 ml/min, Qpost 5.8 ml/min, Qd 20.0 ml/min. Concentration of plasma returning to patient (mmol/l) Citrate, total 4.32 Phosphate, total 1.01 Calcium, total 2.21 Calcium, ionized 0.42 Bicarbonate (total CO.sub.2) 20.56 Bicarbonate + citrate 33.53 pH 7.63

Example F

(85) TABLE-US-00014 Anticoagulation Infusion fluid for Component fluid postinfusion Dialysis fluid Citrate, (mM) 25 4 4 Phosphate, (mM) 0.8 0.8 0.8 Calcium, (mM) 2.5 2.3 2.3 Magnesium, 0.5 0.5 0.5 (mM) Potassium, (mM) 3 3 3 Glucose, (mM) 0 0 5.5 Sodium, (mM) 140 140 140 Bicarbonate 0 25 25

(86) TABLE-US-00015 TABLE F The result of Example F, with Qb 120 ml/min, Qpbp 26.7 ml/min, Qpre 0.0 ml/min, Qpost Concentration of plasma returning 5.8 ml/min, Qd 20.0 ml/min. to patient (mmol/l) Citrate, total 4.49 Phosphate, total 1.00 Calcium, total 2.28 Calcium, ionized 0.42 Bicarbonate (total CO.sub.2) 21.13 Bicarbonate + citrate 34.60 pH 7.62

Example G

(87) TABLE-US-00016 Anticoagulation Infusion fluid for Component fluid postinfusion Dialysis fluid Citrate, (mM) 25 3 4 Phosphate, (mM) 1.25 0.6 1.25 Calcium, (mM) 2.5 2.3 2.3 Magnesium, 0.5 0.5 0.5 (mM) Potassium, (mM) 3 3 3 Glucose, (mM) 0 0 5.5 Sodium, (mM) 140 140 140 Bicarbonate 0 15 15

(88) TABLE-US-00017 TABLE G The result of Example G, with Qb 120 ml/min, Qpbp 19.2 ml/min, Qpre 0.0 ml/min, Qpost 1.6 ml/min, Qd 20.0 ml/min Concentration of plasma returning to patient (mmol/l) Citrate, total 4.46 Phosphate, total 1.17 Calcium, total 2.28 Calcium, ionized 0.42 Bicarbonate (total CO.sub.2) 18.31 Bicarbonate + citrate 31.69 pH 7.62

Example H

(89) TABLE-US-00018 Anticoagulation Infusion fluid for Component fluid postinfusion Dialysis fluid Citrate, (mM) 30 4 4 Phosphate, (mM) 1.25 0.6 1.25 Calcium, (mM) 2.5 2.3 2.3 Magnesium, 0.5 0.5 0.5 (mM) Potassium, (mM) 3 3 3 Glucose, (mM) 0 0 5.5 Sodium, (mM) 140 140 140 Bicarbonate 0 15 15

(90) TABLE-US-00019 TABLE H The result of Example H, with Qb 120 ml/min, Qpbp 16.0 ml/min, Qpre 0.0 ml/min, Qpost 4.8 ml/min, Qd 20.0 ml/min Concentration of plasma returning to patient (mmol/l) Citrate, total 4.54 Phosphate, total 1.15 Calcium, total 2.28 Calcium, ionized 0.41 Bicarbonate (total CO.sub.2) 18.49 Bicarbonate + citrate 32.12 pH 7.61

Example I

(91) TABLE-US-00020 Anticoagulation Infusion fluid for Component fluid postinfusion Dialysis fluid Citrate, (mM) 40 4 4 Phosphate, (mM) 1.0 1.0 1.0 Calcium, (mM) 2.3 2.3 2.3 Magnesium, 0.5 0.5 0.5 (mM) Potassium, (mM) 2 2 2 Glucose, (mM) 0 0 5.5 Sodium, (mM) 140 140 140 Bicarbonate 0 15 15

(92) TABLE-US-00021 TABLE I The result of Example I, with Qb 120 ml/min, Qpbp 12.0 ml/min, Qpre 0.0 ml/min, Qpost 8.8 ml/min, Qd 20.0 ml/min. Concentration of plasma Result returning to patient (mmol/l) Citrate, total 4.60 Phosphate, total 1.08 Calcium, total 2.25 Calcium, ionized 0.40 Bicarbonate (total CO.sub.2) 18.67 Bicarbonate + citrate 32.48 pH 7.60

Example J

(93) TABLE-US-00022 Anticoagulation Infusion fluid for Component fluid postinfusion Dialysis fluid Citrate, (mM) 35 5 5 Phosphate, (mM) 0.8 0.8 0.8 Calcium, (mM) 2.2 2.0 2.0 Magnesium, 0.7 0.7 0.7 (mM) Potassium, (mM) 3 3 3 Glucose, (mM) 0 5.5 5.5 Sodium, (mM) 140 140 140 Bicarbonate 0 15 15

(94) TABLE-US-00023 TABLE J The result of Example J, with Qb 120 ml/min, Qpbp 13.7 ml/min, Qpre 0.0 ml/min, Qpost 7.1 ml/min, Qd 20.0 ml/min. Concentration of plasma returning to patient (mmol/l) Citrate, total 4.90 Phosphate, total 0.99 Calcium, total 2.14 Calcium, ionized 0.36 Bicarbonate (total CO.sub.2) 18.61 Bicarbonate + citrate 33.62 pH 7.61

Example K

(95) TABLE-US-00024 Anticoagulation Infusion fluid for Dialysis Component fluid postinfusion fluid Citrate, (mM) 25 4 4 Phosphate, (mM) 0.6 0.6 0.6 Calcium, (mM) 2.2 2.0 2.0 Magnesium, (mM) 0.7 0.7 0.7 Potassium, (mM) 4 4 4 Glucose, (mM) 0 5.5 5.5 Sodium, (mM) 140 140 140 Bicarbonate 0 15 15

(96) TABLE-US-00025 TABLE K The result of Example K, with Qb 120 ml/min, Qpbp 19.2 ml/min, Qpre 0.0 ml/min, Qpost 1.6 ml/min, Qd 20.0 ml/min Concentration of plasma returning to patient (mmol/l) Citrate, total 4.48 Phosphate, total 0.92 Calcium, total 2.16 Calcium, ionized 0.40 Bicarbonate (total CO.sub.2) 18.30 Bicarbonate + citrate 31.75 pH 7.61

Example L

(97) TABLE-US-00026 Anticoagulation Infusion fluid for Dialysis Component fluid postinfusion fluid Citrate, (mM) 30 5 5 Phosphate, (mM) 0.8 0.8 0.8 Calcium, (mM) 2.2 2.0 2.0 Magnesium, (mM) 0.8 0.8 0.8 Potassium, (mM) 3 3 3 Glucose, (mM) 0 0 5.5 Sodium, (mM) 140 140 140 Bicarbonate 0 15 15

(98) TABLE-US-00027 TABLE L The result of Example L, with Qb 120 ml/min, Qpbp 16.0 ml/min, Qpre 0.0 ml/min, Qpost 4.8 ml/min, Qd 20.0 ml/min. Concentration of plasma returning to patient (mmol/l) Citrate, total 4.84 Phosphate, total 1.00 Calcium, total 2.15 Calcium, ionized 0.37 Bicarbonate (total CO.sub.2) 18.50 Bicarbonate + citrate 33.00 pH 7.61

Example M

(99) TABLE-US-00028 Anticoagulation Infusion fluid for Dialysis Component fluid postinfusion fluid Citrate, (mM) 30 4 4 Phosphate, (mM) 1.0 0.6 1.0 Calcium, (mM) 2.4 2.3 2.3 Magnesium, (mM) 0.5 0.5 0.5 Potassium, (mM) 3 3 3 Glucose, (mM) 0 0 5.5 Sodium, (mM) 140 140 140 Bicarbonate 0 15 15

(100) TABLE-US-00029 TABLE M The result of Example M, with Qb 120 ml/min, Qpbp 16.0 ml/min, Qpre 0.0 ml/min, Qpost 4.8 ml/min, Qd 20.0 ml/min. Concentration of plasma returning to patient (mmol/l) Citrate, total 4.54 Phosphate, total 1.06 Calcium, total 2.26 Calcium, ionized 0.41 Bicarbonate (total CO.sub.2) 18.49 Bicarbonate + citrate 32.11 pH 7.61

Example N

(101) TABLE-US-00030 Anticoagulation Infusion fluid for Dialysis Component fluid postinfusion fluid Citrate, (mM) 35 5 5 Phosphate, (mM) 0.8 0.8 0.8 Calcium, (mM) 2.2 2.0 2.0 Magnesium, (mM) 0.8 0.8 0.8 Potassium, (mM) 3 3 3 Glucose, (mM) 0 0 5.5 Sodium, (mM) 140 140 140 Bicarbonate 0 15 15

(102) TABLE-US-00031 TABLE N The result of Example N, with Qb 120 ml/min, Qpbp 13.7 ml/min, Qpre 0.0 ml/min, Qpost 7.1 ml/min, Qd 20.0 ml/min. Concentration of plasma Result returning to patient (mmol/l) Citrate, total 4.90 Phosphate, total 0.99 Calcium, total 2.14 Calcium, ionized 0.36 Bicarbonate (total CO.sub.2) 18.61 Bicarbonate + citrate 33.31 pH 7.61

Example O

(103) TABLE-US-00032 Anticoagulation Infusion fluid for Dialysis Component fluid preinfusion fluid Citrate, (mM) 30 4 4 Phosphate, (mM) 1.0 0.6 1.0 Calcium, (mM) 2.4 0 0 Magnesium, (mM) 0.5 0.5 0.5 Potassium, (mM) 3 3 3 Glucose, (mM) 0 0 5.5 Sodium, (mM) 140 140 140 Bicarbonate 0 15 15

(104) TABLE-US-00033 TABLE O The result of Example O, Qb 120 ml/min, Qpbp 16.0 ml/min, Qpre 4.8 ml/min, Qpost 0.0 ml/min, Qd 20.0 ml/min. Concentration of plasma returning to patient (mmol/l) Citrate, total 4.60 Phosphate, total 1.07 Calcium, total 1.63 Calcium, ionized 0.26 Bicarbonate (total CO.sub.2) 18.72 Bicarbonate + citrate 32.51 pH 7.66

(105) An aspect of the invention relates to a multipart fluid system for dialysis therapy, said multipart fluid system comprising an anticoagulation fluid and at least one treatment fluid from the group consisting of dialysis fluid and infusion fluids, wherein said anticoagulation fluid comprises 10-40 mM citrate, and 0.1-2.0 mM phosphate; and said at least one treatment fluid comprises 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2.0 mM phosphate; with provisos that the at least one treatment fluid comprises citrate when total calcium concentration is 0 mM; and the at least one treatment fluid comprises calcium when the citrate concentration is 0 mM.

(106) A second aspect of the invention relates to a multipart fluid system according to the aspect above, wherein said anticoagulation fluid comprises 0.5-2.0 mM phosphate, preferably 0.6-1.5 mM phosphate, and more preferably 0.8-1.2 mM phosphate.

(107) A third aspect of the invention relates to a multipart fluid system according to any of the aspects above, wherein said at least one treatment fluid comprises 0.5-2.0 mM phosphate, preferably 0.6-1.5 mM phosphate, and more preferably 0.8-1.2 mM phosphate.

(108) A fourth aspect of the invention relates to a multipart fluid system according to anyone of the preceding aspects above, wherein said anticoagulation fluid comprises 10-40 mM citrate, preferably 15-40 mM citrate, and more preferably 20-30 mM citrate.

(109) A fifth aspect of the invention relates to a multipart fluid system according to anyone of the preceding aspects, wherein said anticoagulation fluid comprises 1.5-4 mM total calcium, preferably 2-3 mM total calcium, and more preferably 2.2-2.4 mM total calcium.

(110) A sixth aspect of the invention relates to a multipart fluid system according to anyone of the preceding aspects, wherein said anticoagulation fluid further comprises 0-1.5 mM magnesium, 0-5.0 mM potassium, 0-11 mM glucose, 130-150 mM sodium and 0-140 mM chloride.

(111) A seventh aspect of the invention relates to a multipart fluid system according to anyone of the preceding aspects, wherein said at least one treatment fluid comprises 2.0-8.0 mM citrate.

(112) An eighth aspect of the invention relates to a multipart fluid system according to anyone of the preceding aspects, wherein said at least one treatment fluid comprises 2.0-7.0 mM citrate and 1.8-2.4 mM total calcium.

(113) A ninth aspect of the invention relates to a multipart fluid system according to anyone of the preceding aspects, wherein said at least one treatment fluid comprises 3.5-5.5 mM citrate and 1.5-2.4 mM total calcium.

(114) A tenth aspect of the invention relates to a multipart fluid system according to anyone of the preceding aspects, wherein said at least one treatment fluid further comprises 0-1.5 mM magnesium, 0-5.0 mM potassium, 0-11 mM glucose, and 130-150 mM sodium.

(115) An eleventh aspect of the present invention relates to a multipart fluid system according to anyone of the preceding aspects, wherein said at least one treatment fluid further comprises a physiological buffer.

(116) A twelfth aspect relates to a multipart fluid system according to the aspect above, wherein said physiological buffer is bicarbonate.

(117) A thirteenth aspect of the invention relates to a multipart fluid system according to the twelfth aspect, wherein said at least one treatment fluid comprises <40 mM bicarbonate.

(118) A fourteenth aspect of the invention relates to a system for regional citrate anticoagulation in an extracorporeal blood circuit comprising an arterial blood line configured to be connected to a vascular access for withdrawing blood from a patient and a venous blood line configured to be connected to the vascular access for returning blood to the patient, the system comprising:

(119) a filter with a dialysate side and a blood side, which blood side is in fluid communication with the arterial and venous blood lines;

(120) which blood side is in fluid communication with the arterial and venous blood lines;

(121) which blood side is in fluid communication with an anticoagulation fluid source comprising 10-40 mM citrate and 0.1-2 mM phosphate;

(122) which dialysate side is in fluid communication with a treatment fluid source comprising 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2 mM phosphate;

(123) with provisos that the at least one treatment fluid comprises citrate when total calcium concentration is 0 mM; and the at least one treatment fluid comprises calcium when the citrate concentration is 0 mM.

(124) A fifteenth aspect of the invention relates to a system according to the aspect above, wherein the system comprises:

(125) a filter with a dialysate side and a blood side, which blood side is in fluid communication with the arterial and venous blood lines;

(126) a pre-filter infusion line connected to the arterial blood line upstream the filter and connected to an anticoagulation fluid source containing 10-40 mM citrate and 0.1-2 mM phosphate to be infused into the blood stream in the arterial blood line; and

(127) a post-filter infusion line connected to the venous blood line downstream the filter and connected to an treatment fluid source comprising 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2 mM phosphate to be infused into the blood stream in the venous blood line;

(128) with provisos that the treatment fluid source comprises citrate when total calcium concentration is 0 mM; and the treatment fluid source comprises calcium when citrate concentration is 0 mM citrate.

(129) A sixteenth aspect of the invention relates to a system according to the fourteenth aspect wherein the system comprises:

(130) a filter with a dialysate side and a blood side, which blood side is in fluid communication with the arterial and venous blood lines, and which dialysate side is in fluid communication with a treatment fluid source comprising 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2 mM phosphate;

(131) with provisos that the treatment fluid source comprises citrate when total calcium is 0 mM; and the treatment fluid source comprises calcium when 0 mM citrate; and a pre-filter infusion line connected to the arterial blood line upstream the filter and connected to an anticoagulation fluid source containing 10-40 mM citrate and 0.1-2.0 mM phosphate to be infused into the blood stream in the arterial blood line.

(132) A seventeenth aspect of the invention relates to a system according to the fourteenth aspect wherein system comprises:

(133) a filter with a dialysate side and a blood side, which blood side is in fluid communication with the arterial and venous blood lines;

(134) a first pre-filter infusion line connected to the arterial blood line upstream the filter and connected to an anticoagulation fluid source containing 10-40 mM citrate and 0.1-2.0 mM phosphate to be infused into the blood stream in the arterial blood line; and

(135) a second pre-filter infusion line connected to the arterial blood line upstream the filter and connected to an treatment (infusion) fluid source comprising 0-5 mM total calcium, 0-8 mM citrate, and 0.1-2 mM phosphate to be infused into the blood stream in the arterial blood line;

(136) with provisos that the treatment (infusion) fluid source comprises citrate when total calcium concentration is 0 mM; and the treatment (infusion) fluid source comprises calcium when the citrate concentration is 0 mM.

(137) An eighteenth aspect of the invention relates to a system for regional citrate anticoagulation in an extracorporeal blood circuit according to the seventeenth aspect, which further comprises a post-filter infusion line connected to the venous blood line downstream the filter and connected to an treatment (infusion) fluid source comprising 0.1-2.0 mM phosphate to be infused into the blood stream in the venous blood line.

(138) A nineteenth aspect of the invention relates to a system for regional citrate anticoagulation in an extracorporeal blood circuit according to the fifteenth, seventeenth or eighteenth aspect wherein the dialysate side of the filter is in fluid communication with a dialysis fluid source comprising 0.1-2.0 mM phosphate.

(139) A twentieth aspect of the invention relates to a system for regional citrate anticoagulation in an extracorporeal blood circuit according to anyone of aspect fourteenth to nineteenth as above, wherein said anticoagulation fluid comprises 0.5-2.0 mM phosphate, preferably 0.6-1.5 mM phosphate, and more preferably 0.8-1.2 mM phosphate.

(140) A twenty-first aspect of the present invention relates to a system for regional citrate anticoagulation in an extracorporeal blood circuit according to anyone of the fourteenth to twentieth aspect, wherein said system further comprises a control unit adapted to control the anticoagulation fluid flow rate in relation to the blood flow rate.

(141) Calculations and Optimizations

(142) Citrate is metabolised in the body, and theoretically each citrate ion is converted into three bicarbonate ions. Citrate will therefore contribute to the acid base balance, and it is important to consider the contribution from citrate when citrate is included in the treatment fluids. In citrate anticoagulation rather high concentrations of citrate is needed in the anticoagulation fluid in order to get sufficient anticoagulative effect. This is even more pronounced with the multipart fluid system for dialysis therapy and the system for citrate anticoagulation in an extracorporeal blood circuit according to the present invention, especially in the embodiments wherein citrate also is present in the treatment fluids, like the dialysis fluid and/or the replacement fluids. We will now illustrate how the bicarbonate levels should be adjusted when citrate is used in order to get the best acid base balance in the patient.

(143) In these calculations and optimizations it is assumed that each citrate ion is converted into three bicarbonate ions in the body, and the term bicarbonate equivalents is used for the sum of the bicarbonate concentration and three times the citrate concentration. Since most intensive care patients are catabolic, more acid than normal will be produced, and the treatment fluids need to be alkalotic. The treatment efficiency is usually rather low, thus the contents of bicarbonate equivalents in the treatment fluids need to be rather high. In non-citrate therapies the bicarbonate concentration is often about 35 mM. Depending on the bicarbonate level in the untreated blood, the bicarbonate level in the blood that is returned to the patient is then around or slightly above 30 mM. It seems to be reasonable to attempt to achieve the same level of bicarbonate equivalents also when citrate is used, but since the conversion of citrate to bicarbonate may take some time the level of bicarbonate equivalents in the returning blood actually need to be slightly higher (see below). The goal is to find the best level of bicarbonate equivalents in the dialysis and replacement fluids for a given level of citrate in the anticoagulant.

(144) Below, all flow rates are denoted with Q and the concentrations with C, both with an index to indicate which flow is referred to. Index pre denotes the flow of anticoagulant (pre), index d is dialysate, r is replacement (only postdilution considered), e is effluent, b is whole blood, p is plasma, o is plasma out (returned to patient). WL denotes the weight loss rate, x is the dose of citrate for anticoagulation in mM citrate per liter blood, and a is the fraction of plasma in whole blood. Thus the variables are as follows:

(145) Qbflow rate of whole blood in to the system (L/h)

(146) Qpflow rate of plasma in to the system (L/h)

(147) Qpreflow rate of anticoagulation fluid (L/h)

(148) Qdflow rate of dialysis fluid (L/h)

(149) Qrflow rate of replacement fluid (postdilution) (L/h)

(150) Qeflow rate of effluent fluid (used treatment fluid) (L/h)

(151) WLweight loss rate (L/h)

(152) Cbbicarbonate equivalents in untreated whole blood (mM)

(153) Cpbicarbonate equivalents in untreated plasma (mM)

(154) Cobicarbonate equivalents in treated plasma (mM)

(155) Cprebicarbonate equivalents in anticoagulation fluid (mM)

(156) Cdbicarbonate equivalents in dialysis fluid (mM)

(157) Crbicarbonate equivalents in replacement fluid (mM)

(158) xdose of citrate (mM per liter of blood)

(159) fraction of plasma in whole blood

(160) There are some immediate relations
Qp=.Math.Qb(1)
Qpre.Math.Cpre=x.Math.Qb(2)

(161) The flow rate of effluent must match the flow rate of treatment fluids together with the weight loss rate so that
Qe=Qpre+Qd+Qr+WL(3)

(162) The treatment efficiency is low in intensive care, which means that the concentration in the effluent flow can be assumed to be equilibrated with the untreated plasma entering the dialyzer. This implies
Ce.Math.(Qpre+Qp)=Cpre.Math.Qpre+Cp.Math.Qp(4)

(163) Everything going into the dialyzer must equal everything that comes out. Thus
Cpre.Math.Qpre+Cp.Math.Qp+Cd.Math.Qd+Cr.Math.Qr=Ce.Math.Qe+Co.Math.(QpWL)(5)

(164) It will be assumed that the dialysis and replacement fluids have the same composition, so that Cd=Cr. By rearranging (5) we then get
Cd.Math.(Qd+Qr)=Ce.Math.Qe.Math.Cpre.Math.Qpre.Math.Cp.Math.Qp+Co.Math.(QpWL)(6)

(165) The first 3 terms on the right hand side of (6) can be simplified using first (4), then (3), and finally (4) again. We have

(166) $\begin{array}{cc}\mathrm{Ce}.Math.\mathrm{Qe}-\mathrm{Cpre}.Math.\mathrm{Qpre}-\mathrm{Cp}.Math.\mathrm{Qp}=\mathrm{Ce}.Math.\left(\mathrm{Qe}-\mathrm{Qpre}-\mathrm{Qp}\right)=\mathrm{Ce}.Math.\left(\mathrm{Qd}+\mathrm{Qr}+\mathrm{WL}-\mathrm{Qp}\right)==\frac{\mathrm{Cpre}.Math.\mathrm{Qpre}+\mathrm{Cp}.Math.\mathrm{Qp}}{\mathrm{Qpre}+\mathrm{Qp}}.Math.\left(\mathrm{Qd}+\mathrm{Qr}+\mathrm{WL}-\mathrm{Qp}\right)& \left(7\right)\end{array}$

(167) Qb is eliminated by inserting (1) into (2), Qpre is eliminated by inserting (2) into (7), and then insert (7) into (6) to get

(168) $\begin{array}{cc}\mathrm{Cd}.Math.\left(\mathrm{Qd}+\mathrm{Qr}\right)=\frac{x.Math.\mathrm{Qp}/+\mathrm{Cp}.Math.\mathrm{Qp}}{x.Math.\mathrm{Qp}//\mathrm{Cpre}+\mathrm{Qp}}.Math.\left(\mathrm{Qd}+\mathrm{Qr}+\mathrm{WL}-\mathrm{Qp}\right)+\mathrm{Co}.Math.\left(\mathrm{Qp}-\mathrm{WL}\right)==\frac{\mathrm{Cpre}}{x/+\mathrm{Cpre}}.Math.\left(x/+\mathrm{Cp}\right).Math.\left(\mathrm{Qd}+\mathrm{Qr}+\mathrm{WL}-\mathrm{Qp}\right)+\mathrm{Co}.Math.\left(\mathrm{Qp}-\mathrm{WL}\right)& \left(8\right)\end{array}$

(169) With the help of (8) we can study how the dialysis fluid concentration should be changed depending on the anticoagulation concentration if we want to keep the same concentration in the returning blood (which is the last term). For this purpose we can assume that the weight loss rate WL is zero, and that , x, Qp, Cp and Co are fixed. Since Qp is always (in intensive care) greater than Qd+Qr we see that Cd should be decreased when Cpre is increased. This change is nonlinear with Cpre, and when Cpre is much larger than x/ there will be no further decrease in Cd. With x in the range 3-5 mM and =0.7 there will thus not be much further decrease in Cd when Cpre is above about 50 mM.

(170) It is also advantageous if the blood outlet concentration of bicarbonate equivalents does not vary too much when the flow rate of dialysis or replacement fluid is changed, since it is then possible to adjust the treatment dose by changing these flow rates without disturbing the acid base balance. We can see from (8) that the influence from Qd and Qr will disappear totally if

(171) $\begin{array}{cc}\mathrm{Cd}=\frac{\mathrm{Cpre}}{x/+\mathrm{Cpre}}.Math.\left(x/+\mathrm{Cp}\right)& \left(9\right)\end{array}$

(172) This value for Cd might lead to a too low value for Co, and it could also be valuable to have a nonzero, but small influence on acid base from the flow rates. So a slightly higher Cd than given by (9) is preferable.

(173) In order to verify the results from these equations a number of simulations have been performed according to common principles for simulations. With the fluid concentrations and flow rates specified, the program calculates the resulting concentrations in the blood returned to the patient. The goal for the simulations was to find a suitable level of bicarbonate equivalents in the dialysis and replacement fluids for each specified level in the anticoagulation fluid. This was done by adjusting the level in the treatment fluids until the plasma level in the returned blood was as desired (chosen as 32.5 mM).

(174) The simulation program is developed in-house by Gambro. It computes equilibrium concentrations of species present in plasma and fluids used for dialysis by use of equilibrium constants (SCD base 2001.sup.1). The species (electrolytes, albumin and formed complexes) taken into account are shown in Table A.

(175) TABLE-US-00034 TABLE A Normal plasma concentration of electrolytes and albumin together with the complexes taken into account formed with Ca.sup.2+ and Mg.sup.2+ Normal plasma total conc (mM) Complex formation with Specie (Kratz 1998.sup.2) Ca.sup.2+ and Mg.sup.2+ Ca.sup.2+ 2.1-2.6 (1.1-1.3 ionized) Mg.sup.2+ 0.7-1.0 Na.sup.+ 135-145 Cl.sup. 100-108 HCO3.sub.3.sup., bicarbonate, 22-26 CaHCO.sub.3.sup.+, MgHCO.sub.3.sup.+ bic C.sub.6H.sub.5O.sub.7.sup.3, citrate, cit 0.1-0.3 (infants, Ca-cit.sup., Ca-cit.sub.2.sup.4, Mg-cit.sup.. Ames1950.sup.3) Mg-cit.sub.2.sup.4 Albumin, alb 0.5-0.6 Alb-Ca.sub.n, alb-Mg.sub.n, n = 1-10
The transport of each species is governed by its mobility and the flow rates of plasma and dialysis fluid. Values for the mobility of different species are found in literature. The transport of ions is also affected by the demand for electroneutrality, which is expressed as the development of a membrane potential. In order to handle the effects of complex formations and albumin binding, the dialyzer is split up into a number of segments and the transport calculations are performed in an iterative manner. The transport across the dialyzer membrane in one segment leads to a new equilibrium for the complex formation and albumin binding, which forms the input to the next segment for the next iteration. About 30 iterations are needed to find the equilibrium concentrations along the entire dialyzer.
The requirements of the treatments are: 1. An adequate dialysis treatment A sufficient anticoagulant effect, i.e. the ionized calcium through the blood side of the filter (dialyzer) must be 0.2-0.5 mM, preferably 0.3-0.4 (according to literature) 2. The total plasma concentration of calcium when returned to the patient has to be at normal level, i.e. about 2.2-2.4 mM. Other electrolyte concentration levels must also be satisfactory.

(176) The simulations were performed with a blood flow rate of 100 ml/min, a hematocrit of 30%, an albumin level of 30 g/L and no patient weight loss. The plasma concentrations in the incoming blood were 25 mM of bicarbonate, 0.85 mM of magnesium, 2.2 mM of calcium and no citrate. The dialysis and replacement fluids contained 5 mM of citrate, 2.1 mM of calcium and 0.85 mM of magnesium. These levels reflect the content in the plasma in the dialyzer, which is fairly independent of the other variables and are chosen in order to keep the balance. The anticoagulation fluid contained 2.2 mM of calcium, 0.85 mM of magnesium and no bicarbonate. The citrate level in the anticoagulation fluid was varied from 12 to 400 mM, and its flow rate was adjusted so that the level of ionized calcium after the dialyzer was always 0.3 mM, which is considered to be an adequate level for anticoagulation. The bicarbonate level in the dialysis and replacement fluids was varied as needed to keep the bicarbonate equivalents in the returned blood unchanged at 32.5 mM. The dialysis and replacement fluid flow rates (equally large) were chosen in each simulation so that the clearance (treatment dose) was the same (=2700 L/h) in all cases. Since the amount of anticoagulation fluid, which is delivered as a predilution addition, contributes to the clearance, but also decreases it due to dilution, it was necessary to have different flow rates of replacement fluid and dialysis fluid for each case.

(177) FIG. 9 shows the bicarbonate level needed in the treatment fluids for varying citrate levels in the anticoagulation fluid. As expected from the theoretical formula (8) the bicarbonate level needed in the treatment fluids decreases with increasing citrate level in the anticoagulation fluid.

(178) A second set of simulations were performed in order to evaluate the sensitivity of the level of bicarbonate equivalents in the returned blood to changes in treatment dose. The dose was in for all the cases increased to 3500 L/h by appropriate adjustments of the dialysis and replacement flow rates (still equal to each other), but all other parameters were kept unchanged. FIG. 10 shows the change in bicarbonate equivalents in the returning blood as a function of the citrate level in the anticoagulation fluid. It can be seen that the lowest sensitivity is for an anticoagulation fluid with about 16 mM of citrate. The change in bicarbonate equivalents is less than 1.3 mM for citrate levels between 13 and 40 mM, and is below 1 mM for citrate levels between 14 and 27 mM. The exact values for these ranges will depend slightly on all the other parameters, and these simulations should therefore only be used as a rough guideline.

(179) Pilot Study

(180) A non-randomized pilot study including five patients has been performed. All patients included in the study showed acute renal failure and CRRT was started at the general intensive care unit at Skane University Hospital in Lund, Sweden by using the dialysis fluid Phoxilium (Gambro) and the infusion fluid Hemosol B0 (Gambro) according to the standards at the unit and the extracorporeal circuit was anticoagulated with heparin. The treatment mode was Continuous Venous Venous Hemodiafiltration (CVVHDF). After onset of CRRT, the patients were monitored the first treatment day to assure stability in vital physiological parameters and a well functioning central dialysis catheter. Then the treatment scheme was changed to the multipart fluid system for citrate anticoagulation according to the present invention for a period of five hours. A new CRRT machine with a fresh filter was primed with the study fluids and at initiation of the study period this machine was connected to the patient.

(181) During the study period the patients were subjected to intense monitoring, regular blood sampling and were supervised by a physician present bedside. After completed CRRT regime with multipart fluid system according to the present invention, the patient continued the CRRT treatment using the standard fluids.

(182) In all patients the Gambro Prismaflex machine and a Hospal M100 AN 69 filter was used during the study period.

(183) The compositions of the fluids for the study were as described below in table B. The system was set up according to FIG. 2.

(184) TABLE-US-00035 TABLE B Compositions of anticoagulation fluid, dialysis fluid and infusion fluid used in the study: Anticoagulation Dialysis fluid (9) Infusion fluid (7) Component: fluid (5) mM mM mM Citrate.sub.tot 40 4.4 4.4 Ca.sub.tot 2.4 2.2 2.2 Mg.sub.tot 0.9 0.9 0.9 K.sup.+ 4 4 4 Cl.sup. 31.2 123.3 123.3 Na.sup.+ 140 140 140 bicarbonate.sub.tot 15 15

(185) Blood flow (Q.sub.B) was set to 100 ml/min. Anticoagulation fluid flow (Q.sub.PBP) was set to 730 ml/h, and dialysis fluid flow as well as infusion fluid flow (Q.sub.d and Q.sub.inf) was set to 1000 ml/h.

(186) Results

(187) Acid-base variables and serum electrolytes at the beginning and at the end of the treatment using the compositions of Table B are shown in Table C. Serum ionized calcium (Ca.sup.2+) and phosphate concentrations decrease significantly at the start of the citrate treatment, but remained thereafter stable during the study period. Serum concentrations of sodium (Na.sup.+), potassium (K.sup.+), magnesium (Mg.sup.2+) and chloride (Cl.sup.) remained also stable. No alkalosis or acidosis occurred during the citrate treatment, as the acid-base balance with the pH, carbon dioxide partial pressure (pCO.sub.2) and bicarbonate (HCO.sub.3.sup.) concentrations, as well as the calculated acid-base variables, all remained stable (see Table C). Also included are ions which are routinely not measured, thus unidentified strong anions (UA) are included. Examples of such ions are lactate, keto-acids and sulphate. UA.sup. may be calculated by (Na.sup.++K++Ca.sup.2++Mg.sup.2+)((Cl.sup.).sub.corrected+SID)).

(188) TABLE-US-00036 TABLE C Acid-base variables and the concentrations of serum electrolytes Normal values.sup.a Start End p =.sup.b Na.sup.+, mM 137-145 137 3 136 3 0.667 K.sup.+, mM 3.5-4.4 4.3 0.5 4.6 0.5 0.358 Ca.sup.2+, mM 1.16-1.35 1.2 0.05 1.1 0.04 0.008 Mg.sup.2+, mM 0.70-0.95 0.9 0.1 0.9 0.1 0.421 Cl.sup., mM 98-110 107 3 106 2 0.379 phosphate, mM 0.7-1.5 0.9 0.03 0.7 0.1 0.008 Alb, g/l 36-48 27 5 27 3 0.874 pH 7.35-7.45 7.42 0.04 7.43 0.05 0.709 pCO.sub.2, kPa 4.6-6.0 4.9 0.4 4.8 0.4 0.646 HCO.sub.3.sup., mM 22-27 24.1 2.6 24.6 1.8 0.773 AG.sub.measured, mM 16 2 10 4 10 2 0.813 AG.sub.corrected,.sup.c mM 16 2 14 3 15 1 0.794 BE, mM 3.0-+3.0 0.3 3 0.2 2 0.980 SID, mM 39 1 35 4 36 2 0.607 Cl.sup..sub.corrected,.sup.c mM 98-110 111 4 110 2 0.665 UA.sup., mM 8 2 3 3 3 1 0.702 UA.sup..sub.corrected,.sup.c mM 8 2 1 5 1 3 0.991 A.sup..sub.tot, mM 15 9 1 9 1 0.841 .sup.aNormal values from healthy controls (Fencl, 2000.sup.4) and reference values at Clinical Chemistry Laboratory, Skane University Hospital, Lund, Sweden. .sup.bDifferences between values at the beginning and at the end of the treatment .sup.cCorrected for water excess/deficit

(189) A high lactate level (>5 mM) in patients with liver failure or septic patients, may act as a useful marker of greater risk for citrate accumulation. The lactate levels were low in our patients before the treatment with the fluids according to the study, and remained stable during the treatment. Serum citrate levels were increased at the beginning of the treatment, but remained constant during the study and reached a peak value of 0.61 mM after two hours of treatment. Post-filter ionized calcium values remained statistically stable around 0.37 mM (Table D). The patients were initially low in total calcium concentration, and remained below normal total calcium value (2.1-2.6 mM) throughout the study period (Table D). An initial drop in ionized calcium was observed in the total to ionized calcium ratio, but the ratio remained stable below 2.25, with no clinical signs of citrate accumulation. No problem with the filter or with the CRRT circuit arose during the treatment period, and all values on the CRRT machine remained inside the normal intervals.

(190) TABLE-US-00037 TABLE D Calcium homeostasis Time (h) 0 2 5 p.sup.b = Ca.sup.2+ extracorporeal.sup.a, 0.37 0.04 0.37 0.03 0.38 0.04 0.409 mM Ca.sub.tot, mM 2.15 0.15 2.22 0.11 2.28 0.09 0.171 Ca.sup.2+, mM 1.24 0.05 1.12 0.04 1.14 0.04 0.008 Ca.sub.tot/Ca.sup.2+ ratio 1.74 0.13 1.97 0.11 1.96 0.06 0.017 .sup.aMeasured post-filter .sup.bDifferences between values at the beginning and at the end of the treatment

(191) Since the first report in the early 90ies, citrate anticoagulation in CRRT patients has gained interest. Citrate has been associated with longer circuit life, less bleeding, and possibly better patient and kidney survival compared to heparin. Despite these findings, citrate anticoagulation is often perceived as complex and associated with high risk for metabolic derangements. These concerns are based on cumbersome protocols and the more labour intensive monitoring. We have now designed new fluids for citrate anticoagulation where calcium and citrate are balanced with electrolytes at physiological concentrations in order to maintain the extracorporeal anticoagulation, keep patient calcium homeostasis, minimize metabolic complications and especially restore and maintain acid-base balance within the patient. The citrate and calcium-containing dialysis fluids kept the calcium concentrations below the recommended 0.40 mM in the extracorporeal circuit and no clotting occurred during this study.

(192) Metabolic derangements during citrate anticoagulation include alkalosis and acidosis, hypernatremia and hyponatremia, and hypocalcemia. The incidence of these complications depends on citrate concentration and the design of the protocol. Acid-base data in critically ill patients are often interpreted on the basis of either plasma bicarbonate concentration (HCO.sub.3.sup.) and anion gap (AG), or on the base excess/deficit (BE). However, hypoalbuminemia and hyper/hypophosphatemia regularly found in critically ill patients are not taken into account in these parameters. Therefore we used the Stewart concept.sup.5 of acid-base to calculate the metabolic effect of citrate and analysed the strong ion difference during conditions of abnormal albumin concentrations and water excess/deficit found in critically ill patients. The citrate and calcium-containing dialysis fluids and infusion fluids did not have metabolic effects on the patients. As no substitution of phosphate was done during this study, serum phosphate levels were significantly affected. Systemic ionized calcium levels stabilized after initial decline and ranged from 1.12 to 1.25 mM after five hours of citrate treatment. There were no instances of clinically significant hypocalcemia, and no adjustments of the infusion rate were needed.

(193) Accumulation of citrate can occur if its metabolism is insufficient. As citrate accumulation decreases the ionized calcium, and increases the total calcium concentration, the total to ionized calcium ratio is a useful test to detect citrate accumulation. The total to ionized calcium ration stabilised at 1.97 mM after two hours of treatment, well below 2.25 mM that would trigger consideration of probable citrate accumulation. Citrate accumulation can also increase the anion gap, although this variable is not sensitive in critically ill patients. In this study we used a fixed dose of citrate (5 mM per liter blood) in relation to blood flow to target optimal anticoagulation. This citrate dose is higher than the previously recommended target at 3 mM, albeit no significant systemic effect was noticed. Serum citrate reached a stable concentration of 0.4-0.7 mM with infusion fluid rates ranging from 1 to 2 l/h, suggesting that citrate was not accumulated in our patients. These results are comparable with previously published serum citrate concentration of 1.040.46 mM in 23 patients treated with 2.2% ACD CVVHDF (ACD, Anticoagulant Citrate Dextrose.sup.6). As a readily available substrate for the cellular citric acid cycle, low concentrations of systemic citrate may also have anti-inflammatory benefits. Intermediates from metabolized citrate were shown to protect proximal tubules against injury and promote recovery from sustained mitochondrial energetic deficit. Recently, an in vitro study showed that citrate at a concentration of 0.8 mM reduces endothelial inflammation and dysfunction during hypoglycemic state.

(194) In this pilot study, the novel concept for citrate anticoagulation was investigated, with the aim of eliminating the need for the final replacement of lost calcium and particularly with the aim to safeguard a proper acid-base balance within the patient. Not properly done, calcium infusion represents an increased risk for the patient, but also an increased complexity and cost of the treatment. Previous attempts to eliminate calcium replacement have failed, either because of filter clotting due to ineffective anticoagulation, or to the need of calcium infusions due to inadequate calcium substitution. The basic principle for the novel method is to keep the concentration of total calcium unchanged in the whole extracorporeal circuit by an appropriate amount of calcium in all treatment fluids. Furthermore, concentration of citrate in the anticoagulation fluids is sufficient to complex excess calcium, and even though the total calcium level is within physiological limits, the level of ionized calcium in the extracorporeal circuit is kept low. To succeed with this context, citrate was included in the dialysis and infusion fluids. Thus, the use of the multipart fluid system according to the present invention significantly contributed to simplification of citrate anticoagulation by omitting the continuous infusion of calcium.

(195) Furthermore, these dialysis fluids and/or infusion fluids in particular attained patients' acid-base balance and no circuit problems occurred during the treatment. With the balanced anticoagulation fluids together with the dialysis fluids and/or infusion fluids of the present invention the possibility to vary the flow rates of the different fluids within the multipart fluid system in a large interval without causing any acid-base imbalance within the patient is also provided.

(196) While the invention has been described in connection with what is presently considered to be the most practical embodiments, it is to be understood that the invention is not to be limited to the disclosed embodiments, but on the contrary, is intended to cover various modifications and equivalents included within the spirit and the scope of the appended claims.

REFERENCES

(197) .sup.1 SCDbase, Stability Constants Database IUPAC, Academic Software, 2001 .sup.2 Kratz A et al.; New Engl J Med 339:1063-1067, 1998 .sup.3 Ames R et. al.; Pediatrics 6:361-370, 1950 .sup.4 Fencl V., Jabor A., Kazda A., Figge J., (2000), Diagnosis of metabolic acid-base disturbances in critically ill patients. Am. J. Respir. Crit. Care Med 162: 2246-2251. .sup.5 Stewart P A, (1983) Modern quantitative acid-base chemistry. Can J Physiol Pharmacol 61: 1444-1461 .sup.6 Ronco C., Critical Care Nephrology, (2009), p 1296