SUBSTITUTION INFUSION FLUID AND CITRATE ANTICOAGULATION

Abstract: The invention relates to a substitution infusion fluid for hemofiltration of a specific composition. The use of said substitution infusion fluid significantly reduces the risk of the occurrence of abnormalities in a patient undergoing hemofiltration. The invention also relates to a process for hemofiltration of blood wherein said substitution infusion fluid is used. The invention also relates to a citrate anticoagulation fluid of a specific composition. The invention also relates to a process for hemofiltration of blood wherein said substitution infusion fluid is used in combination with said citrate anticoagulation fluid. The use of said substitution infusion fluid in combination with said citrate anticoagulation fluid significantly further reduces the risk of the occurrence of abnormalities in a patient undergoing hemofiltration.

Description: Title Substitution infusion fluid and citrate anticoagulation Description Technical Field The invention relates to a substitution infusion fluid, particularly for use in hemofiltration of blood and to a citrate anticoagulation solution. Background Art Pure hemofiltration is a renal-replacement therapy that is widely used in Intensive Care Units (ICU's) and to a lesser extent for patients with chronic renal insufficiency. In ICU's, hemofiltration therapy is mostly employed as so-called continuous-veno-venous hemofiltration (CWH) or continuous- arterio-venous-hemofiltration (CAVH) . Hemofiltration as a renal-replacement therapy in an ICU can also be combined with hemodialysis as so-called continuous-veno- venous-hemodiafiltration or continuous-arterio-venous- hemodiafiltration. The addition of hemodialysis to a hemofiltration therapy implies the addition of a hemodialysis fluid (a so-called 'dialysate' ) flow, making such combined therapy forms more complex than pure hemofiltration. Typically, in both CWH and CAVH, an artificial kidney is used. This kidney may be formed of hollow-fibers or of plates, and is connected to a patient ' s bloodstream by an extracorporeal circuit. In CWH the supply from and return to the blood of the patient is made via two venous accesses, using a blood pump to provide the driving force for the transport of blood from the patient into the artificial kidney and back to the patient. In CAVH, the access which provides the supply of blood to the artificial kidney is made via an artery and the return of the blood to the patient is made via a venous access. In this set-up, the arterial blood pressure provides the driving force for the transport of blood, which implies that the blood flow rate directly varies with the blood pressure. Because of better control of blood flow and treatment efficiency, CWH often is the preferred form of renal replacement therapy in ICU's. In CWH the patient's blood is passed through the artificial kidney, over a semipermeable membrane. The semipermeable membrane selectively allows matter in the blood to cross the membrane from the blood compartment into the filtrate compartment, mimicking the natural filtering function of a kidney. This leads to a considerable loss of fluid from the blood, which is removed as the filtrate in the artificial kidney. In order to keep the blood volume of the patient at a desired (constant) level, a substitution infusion fluid is added to the blood stream in the extracorporeal circuit, after is has passed through the artificial kidney and before it re-enters the patient's vein. In a normal CWH procedure, approximately 50 litres of filtrate are removed per 24 hours, and approximately the same amount of substitution infusion fluid is added into the return of blood side of the extracorporeal circuit. The substitution infusion fluid commonly used is conventional infusion fluid consisting of a physiological saline solution generally only containing about 140 mmol/L of sodium ions, 1,6 mmol/L of calcium ions, 0.75 mmol/L of magnesium ions, 36 mmol/L of bicarbonate ions, and 110 mmol/L of chloride ions. In order to prevent coagulation of the blood during hemofiltration, usually an anticoagulant is added to the blood in the extracorporeal circuit before it enters the artificial kidney. In the past, heparin or fractionated heparin was often used for this purpose. A drawback of the use of heparin, however, is that this use leads to systemic anticoagulation (i.e. anticoagulation of all blood including that within the patient), giving rise to the risk of the occurrence of serious bleeding complications, particularly in seriously ill patients. Instead of heparin, citrate ions can be used as anticoagulant, as has been proposed for the first time by Pinnick et al., New England Journal of Medicine 1983, 308, 258-263. Citrate ions, usually added in the form of trisodium citrate, are believed to bind free calcium ions in the blood, which have a pivotal role in the coagulation cascade. Citrate ions, added to the blood into the extracorporeal circuit before it enters the artificial kidney, are only active as an anticoagulant in the extracorporeal circuit, whereby the risk of bleeding complications due to systemic anticoagulation is avoided. Citrate ions are metabolised in skeletal muscle and liver tissue. Only in cases of severe hepatic failure combined with severe shock, or of certain (rare) metabolic diseases, the metabolism of citrate may run short, leading to too high citrate concentrations in the systemic blood circulation, which on its turn may endanger the patient. Accordingly, trisodium citrate, is an attractive anticoagulant for use in hemofiltration procedures, especially for use in CWH treatment in ICU patients. During hemofiltration, part of the citrate ions is removed from the blood in the artificial kidney. The citrate ions that flows over into the systemic circulation of the patient, are rapidly metabolised to bicarbonate ions in skeletal muscle and liver tissue (about 2.8 molecules bicarbonate are made from 1 citrate molecule). Because trisodium citrate contains on a molar basis three times as many sodium ions as citrate ions, the sodium ions that flow over into the systemic circulation of the patient significantly increases the blood sodium concentration. As a result hypernatremia and/or an abnormal increase in bicarbonate ions (metabolic alkalosis) may occur. Therefore, replacement of a part of the trisodium citrate by citric acid may reduce the sodium load and, by its acid component, neutralizes part of the bicarbonate generated. Accordingly, a mixture of trisodium citrate with citric acid, is a more attractive anticoagulant for use in hemofiltration procedures than trisodium citrate alone, especially for use in CWH treatment in ICU patients. Because citrate ions bind to positively charged metal ions like calcium, magnesium, iron, zinc, copper, and manganese, these ions are also partly removed in the artificial kidney, leading to a net removal of calcium and magnesium ions and other metal ions from the patient's blood. As a result, hypocalcemia and/or hypomagnesemia and/or shortages of other metal ions may be induced in the patient. Especially the hypocalcemia, hypomagnesemia, and/or metabolic alkalosis, may induce life- threatening complications in the patient. Further, a net removal of phosphate and potassium ions, trace elements, water-soluble vitamins, amino acids and of glucose occurs in the artificial kidney during hemofiltration. This may lead to significant degrees of hypophosphatemia, hypokalemia, and shortages of trace elements, water-soluble vitamins, amino acids, and/or glucose, with the risk of deteriorating the patient's condition. Especially the hypophosphatemia may also induce life- threatening complications in the patient. Disclosure of the Invention The present invention aims at providing a means of preventing the occurrence of the above described abnormalities, and thereby to overcome the problems encountered during hemofiltration in the past. It is especially an object of the invention to obviate the shortcomings of the hemofiltration procedure followed in ICU's up to now, particularly when trisodium citrate is used as anticoagulant. Surprisingly, it has been found that these goals may be reached by making use of a substitution infusion fluid of a specific composition. Accordingly, the invention relates to an aqueous substitution infusion fluid for hemofiltration comprising - between 0.2 and 1, preferably between 0.4 and 0.8 mmol/L of dihydrogen phosphate ions; - between 70 and 130, preferably between 90 and 110 mmol/L of sodium ions; - between 1.6 and 2.6, preferably between 1.9 and 2.3 mmol/L of calcium ions; - between 0.25 and 1.25, preferably between 0.5 and 1.0 mmol/L of magnesium ions; - between 1 and 4, preferably between 1.8 and 3.5 mmol/L of potassium ions; - between 3 and 11.5, preferably between 5.5. and 7.5 mmol/L of glucose; - below 5.5 mmol/L, preferably between 0 and 3.1 mmol/L of acetate ions; and - below 5.5. mmol/L, preferably between 0 and 3.1 mmol/L of bicarbonate ions. The substitution infusion fluid is usually supplemented with chloride ions to achieve a neutral electrochemical balance. By using the specific substitution infusion fluid according to the invention in a hemofiltration procedure, the concentrations of potassium, phosphate, calcium, magnesium and bicarbonate ions and of glucose remain substantially within ranges of which it is accepted that they lead not to unacceptable risk of complications within the patient. In most cases, the concentrations of these ions and glucose remain more or less constant in the systemic blood of the patient undergoing hemofiltration. Consequently, the chances of the occurrence of" the problems encountered in hemofiltration to date are significantly reduced, if not eliminated altogether. Particularly, the chances of the above indicated abnormalities, such as electrolyte or acid-base abnormalities are significantly reduced. The substitution infusion fluid according to the invention may conveniently be prepared by dissolving salts in water in such amounts that the desired concentrations are reached, as is well within the expertise of the normal person skilled in the art. During the preparation, it is desired that a sterile environment is maintained. Accordingly, the substitution infusion fluid preferably is sterile, according to the European pharmacopeia, thereby avoiding the risk of infections in a patient when the fluid is used during hemofiltration. Typically, the substitution infusion fluid is hypotonic. Exemplary values are between 200 and 270 mOsm/L. Nevertheless, it has been found that the fluid is well tolerated by patients when it is used in a hemofiltration procedure. It has been found that the hypotonicity is in fact beneficial by compensating for the hypertonicity induced at the arterial side of the extracorporeal circuit by the anticoagulant. The result is that the blood that is returned into the patient's blood stream has substantially normal (physiological) osmolarity. Surprisingly, it has also been found that the prevention of the occurrence of the above described abnormalities may further be improved by making use of a citrate anticoagulation fluid of a specific composition. Accordingly, the invention also relates to an aqueous citrate anticoagulation fluid for hemofiltration comprising - between 5 and 135 mmol/L of citric acid, preferably between 15 and 60 mmol/L of citric acid; and - between 80 and 550 mmol/L of trisodium citrate, preferably between 125 and 300 mmol/L of trisodium citrate. By using the specific citrate anticoagulation infusion fluid according to the invention in a hemofiltration procedure, the blood is effectively anticoagulated within the extracorporeal circuit and not within the systemic circulation of the patient and the concentrations of sodium, calcium, magnesium and bicarbonate ions remain substantially within ranges of which it is accepted that they lead not to unacceptable risk of complications within the patient. In most cases, the concentrations of these ions remain more or less constant in the systemic blood of the patient undergoing hemofiltration. Consequently, the chances of the occurrence of the problems encountered in hemofiltration to date are significantly reduced, if not eliminated altogether. Particularly, the chances of the above indicated abnormalities, such as electrolyte or acid-base abnormalities, and/or severe bleeding complications are significantly reduced. The specific citrate anticoagulation infusion fluid according to the invention may conveniently be prepared by dissolving trisodium citrate and citric acid in water in such amounts that the desired concentrations are reached, as is well within the expertise of the normal person skilled in the art. During the preparation, it is desired that a sterile environment is maintained. Accordingly, the citrate anticoagulation infusion fluid preferably is sterile, according to the European pharmacopeia, thereby avoiding the risk of infections in a patient when the fluid is used during hemofiltration. This citrate anticoagulant solution is preferably used during hemofiltration in combination with a substitution infusion fluid out of the above mentioned ranges, comprising about 118 mmol/L of sodium ions, about 2.6 mmol/L of potassium ions, about 0.8 mmol/L of phosphate ions, about 0.9 mmol/L of magnesium ions, about 6.5 mmol/L of glucose, less than 5.5 mmol/L of acetic acid, and chloride ions to keep electrochemical balance. The addition of acetic acid may help to prevent the formation of calciumphosphate sedimentation in said solutions. Best Mode for Carrying Out the Invention In a preferred embodiment, the present substitution infusion fluid is an aqueous solution meeting the above requirements, preferably comprising about 100 mmol/L of sodium ions, about 2.2 mmol/L of potassium ions, about 0.6 mmol/L of phosphate ions, about 2.1 mmol/L of calcium ions, about 0.8 mmol/L of magnesium ions, about 7.0 mmol/L of glucose, and less than 3.1 mmol/L of acetate ions, in the absence of bicarbonate ions, and supplemented with chloride ions to keep electrochemical balance. It has been found that when a substitution infusion fluid of this type is used, the concentrations of the indicated ions in the patient's blood remains substantially within the physiological range throughout the hemofiltration procedure. In a preferred embodiment, the present citrate anticoagulation solution for hemofiltration treatment is an aqueous solution meeting the above requirements, comprising about 38 mmol/L of citric acid and about 212 mmol/L of trisodium citrate. This citrate anticoagulation solution is preferably used during hemofiltration in combination with a substitution infusion fluid comprising about 118 mmol/L of sodium ions, about 2.6 mmol/L of potassium ions, about 0.8 mmol/L of phosphate ions, about 0.9 mmol/L of magnesium ions, about 6.5 mmol/L of glucose, less than 5.5 mmol/L of acetic acid, and chloride ions to keep electrochemical balance. Brief Description of Drawing By way of example, the invention will now be described in more detail while referring to the enclosed Figure, which illustrates the process of hemofiltration by CWH. Blood is extracted from a vein of a patient and transported to an artificial kidney (4, 5, 6) via the arterial side (1) of an extracorporeal circuit (1, 2) by the driving force of a blood pump (14). Anticoagulant, trisodium citrate, is added to the blood between the blood pump and the artificial kidney (10). In the artificial kidney, the blood is filtered over a semipermeable membrane ( 5 ) . The filtrate is removed from the fitrate compartment of the artificial kidney (6) via connecting tubing ( 7 ) . A pump ( 8 ) takes care of the transport of filtrate into a collection reservoir (9) . The retentate blood is transported back from the retentate compartment of the artificial kidney (4) to the patient's blood stream via the venous side of the extracorporeal circuit (2), after passage of an airtrap (3). The airtrap serves to remove all air bubbles from the blood before it is returned into the patient's blood stream. Preferably, the blood is returned into the patient ' s blood stream at the same place as at which it was extracted, e.g. by way of a double-lumen venous catheter. Before the hemofiltered blood is returned to the patient, the substitution infusion fluid is added from a reservoir (11), via a pump (12) and a heater (13). The heater ensures that the fluid ultimately entering the patient' s body is substantially equal to the patient's body temperature, thus making the entire procedure substantially less uncomfortable. During the procedure, the amount of filtrate collected in the reservoir (9) is determined accurately, e.g. by weighing (device not shown) . The amount of substitution infusion fluid added to the blood is adapted to this amount. This makes it possible to make sure that exactly the same volume of fluid is returned to the patient ' s body ( 2 ) , as was originally extracted therefrom (1). The flow through pumps (8) and (12) are accordingly precisely adjusted to one another. Typically, the substitution infusion fluid is administered (infused) into the blood at a rate of between 8 and 80 L per 200 mL blood. In practice, means, such as an audible alarm, are often provided for alarming nursing personnel should an interruption of the blood, filtrate, or substitution flow occur. Typically, said specific anticoagulation fluid of trisodium citrate and citric acid is infused into the blood at a rate of between 1.3 and 4 mL per 200 mL blood.

Claims: Claims 1. Aqueous substitution infusion fluid for hemofiltration comprising - between 0.2 and 1 mmol/L of dihydrogen phosphate ions; - between 70 and 130 mmol/L of sodium ions; - between 1.6 and 2.6 mmol/L of calcium ions; - between 0.25 and 1.25 mmol/L of magnesium ions; - between 1 and 4 mmol/L of potassium ions; - between 3 and 11.5 mmol/L of glucose; - below 5.5 mmol/L of acetate ions; and - below 5.5 mmol/L of bicarbonate ions. 2. Substitution infusion fluid according to claim 1, comprising between 0.4 and 0.8 mmol/L of dihydrogen phosphate ions. 3. Substitution infusion fluid according to any of the preceding claims, comprising between 90 and 110 mmol/L of sodium ions. 4. Substitution infusion fluid according to any of the preceding claims, comprising between 1.9 and 2.3 mmol/L of calcium ions. 5. Substitution infusion fluid according to any of the preceding claims, comprising between 0.5 and 1 mmol/L of magnesium ions. 6. Substitution infusion fluid according to any of the preceding claims, comprising between 1.8 and 3.5 mmol/L of potassium ions. 7. Substitution infusion fluid according to any of the preceding claims, comprising between 5.5 and 7.5 mmol/L of glucose. 8. Substitution infusion fluid according to any of the preceding claims, comprising between 0 and 3.1 mmol/L of acetate ions. 9. Substitution infusion fluid according to any of the preceding claims, comprising between 0 and 3.1 mmol/L of bicarbonate ions. 10. Substitution infusion fluid according to any of the preceding claims, further comprising amino acids and/or trace elements . 11. Substitution infusion fluid according to any of the preceding claims, being an aqueous solution comprising about 100 mmol/L of sodium ions, about 2.2 mmol/L of potassium ions, about 0.6 mmol/L of phosphate ions, about 0.8 mmol/L of magnesium ions, about 7.0 mmol/L of glucose, less than 3.1 mmol/L of acetate ions, and chloride ions to keep electrochemical balance. 12. Process for hemofiltration of blood, wherein a substitution infusion fluid according to any of the preceding claims is used. 13. Substitution infusion fluid for hemofiltration according to any of the preceding claims, being an aqueous solution comprising about 107 mmol/L of sodium ions, about 2.5 mmol/L of potassium ions, about 0.8 mmol/L of phosphate ions, about 0.9 mmol/L of magnesium ions, about 6.4 mmol/L of glucose, less than 5.5 mmol/L of acetic acid, and chloride ions to keep electrochemical balance. 14. Substitution infusion fluid for hemofiltration according to any of the preceding claims, being an aqueous solution comprising about 118 mmol/L of sodium ions, about 2.6 mmol/L of potassium ions, about 0.8 mmol/L of phosphate ions, about 0.9 mmol/L of magnesium ions, about 6.5 mmol/L of glucose, less than 5.5 mmol/L of acetic acid, and chloride ions to keep electrochemical balance. 15. Substitution infusion fluid for hemofiltration according to any of the preceding claims, further comprising iron ions, and/or zinc ions, and/or copper ions, and/or manganese ions, and/or water-soluble vitamins. 16. Substitution infusion fluid for hemofiltration according to any of the preceding claims, further comprising between 0.5 and 5.5 mmol/L of acetic acid. 17. Substitution infusion fluid for hemofiltration according to any of the preceding claims, that is being used in combination with a citrate anticoagulation solution comprising between 0 and 135 mmol/L of citric acid and between 80 and 550 mmol/L of trisodium citrate. 18. Citrate anticoagulation solution for hemofiltration treatment, comprising between 15 and 135 mmol/L of citric acid and between 80 and 550 mmol/L of trisodium citrate. 19. Citrate anticoagulation solution for hemofiltration treatment, being an aqueous solution comprising about 38 mmol/L of citric acid and about 212 mmol/L of trisodium citrate. 20. Process for hemofiltration of blood, wherein a substitution infusion fluid and/or a citrate anticoagulation solution according to any of the preceding claims is used.

Inventors: CHANG PE CHOU, CHANG, PE, CHOU
Applicants: CHANG PE CHOU, CHANG, PE, CHOU
Application year: 2000
Main classification: A61K33
IPC codes: A61K33, A61K38, A61M1