CA2189416A1 - Sterile biocarbonate concentrate - Google Patents

Abstract

A sterile bicarbonate concentrate for use in a dialysis solution, a process for preparing the concentrate and dialysis solution, and uses of the concentrate and solution.

Description

BP File No. 8385-003/LMK

Title: STERILE BICARBONATE CONCENTRATE
FIELD OF THE INVENTION
The present invention relates to a sterile bicarbonate concentrate, a dialysis solution prepared using the concentrate, a process for preparing the concentrate and solution, and uses of concentrate and solution.
BACKGROUND OF THE INVENTION
The purification and separation of fluids using dialysis can be advantageously used in many medical applications, particularly conditions where renal function has significantly declined. Two principal dialysis methods are used to support patients requiring renal replacement therapy. In hemodialysis, a dialysis machine removes waste products such as urea, creatinine and uric acid from the blood. A patient's blood is introduced by the dialysis machine and flows past a semipermeable membrane (artificial kidney) which is typically made of cellulose. Blood solutes containing the waste permeate through the membrane and into a dialysis solution or dialysate formulated to control solute net movement through the membrane.
Hemodialysis can be either continuous or intermittent.
Intermittent hemodialysis involves short intensive periods of treatment on alternate days, while continuous hemodialysis involves continuous fluid removal and continuous blood purification. Some slow continuous hemodialysis procedures use a veno-venous (CVVHD) access and others use an arterio-venous (CAVHD) access.
Peritoneal dialysis which also uses reverse osmosis principles, is another procedure which is used to remove waste products from a patient. This type of dialysis uses the peritoneal lining of the patient's abdomen as a semipermeable membrane to filter blood. In peritoneal dialysis, peritoneal dialysate is infused into the patient's peritoneum through a catheter. Fluid and waste removal is achieved by an osmotic '- 2189416 gradient from the blood to the dialysate, generated by a high glucose concentration, permitting water to flow out from the blood. Fluids and waste products pass from the many blood vessels and capillaries in the peritoneal membrane into the dialysate, and after a sufficient period of 5 time the dialysate containing the fluids and waste products is drained from the abdomen.
Continuous ambulatory peritoneal dialysis (CAPD), which does not require a specialized machine is the most common type of peritoneal dialysis. Generally, dialysate passes from a plastic bag through a catheter to the peritoneum, and after about 4 to 6 hours the dialysate containing fluids and waste products is drained into the bag. Continuous Cyclic Peritoneal Dialysis (CCPD) is similar to CAPD except that a machine connected to a catheter automatically fills and drains the dialysate from the abdomen. Intermittent Peritoneal Dialysis (IPD) uses a similar type of machine as CCPD to add and drain the dialysate for intensive periods several times each week.
Hemofiltration and hemodiafiltration are modifications of hemodialysis. Hemodialysis involves the removal of solutes and fluid from blood across a dialysis membrane by exposure to a dialysate.
Movement of solute is by diffusion and by convection as it follows water through the membrane. Fluid removal is brought about by a hydrostatic pressure gradient generated by the dialysis machine. In hemofiltration, blood is treated using ultrafiltration only (convection, not diffusion) and simultaneous reinfusion of a physiologic parenteral solution.
Hemodiafiltration is hemodialysis with the addition of hemofiltration to increase convective clearance to improve the clearance of fluids and waste products. It also involves the infusion of a parenteral solution to replace the ultrafiltered volume.
Continuous renal replacement therapy (CRRT) is any of the above methods of dialysis continued 24 hours a day. CRRT usually takes place in an intensive care setting. To simplify the equipment necessary, CRRT

does not produce dialysate from concentrate, but uses premade dialysate, usually peritoneal dialysis solution which comes in 2 or 5 liter bags. This solution is sterile and is buffered by lactate.
The dialysis solutions used in all forms of dialysis contain buffers in an attempt to correct metabolic acidosis. Common buffers used in dialysis solutions include bicarbonate, lactate and acetate buffers. During chronic hemodialysis, hemofiltration and hemodiafiltration the hemodialysis machine makes dialysate from concentrate and treated water. More modern machines can make bicarbonate dialysate, using dual proportioning systems. Calcium and bicarbonate present after proportioning and dilution begin to precipitate, but not to a clinically significant extent. Because of this precipitation bicarbonate dialysis machines must have acid rinses on a regular basis.
Bicarbonate buffer is a preferred buffer for dialysis since bicarbonate is the physiological buffer of the body. However, preparing pre-made mixtures of bicarbonate dialysate and oral or intravenous replacement solutions, which may contain various mixtures of bicarbonate, calcium, magnesium and glucose, are difficult to prepare, sterilize and store. During heat sterilization and storage of dialysis solutions containing both calcium and bicarbonate, precipitation as carbonate salts will occur unless a stabilizing agent such as glycylglycine is added. In glucose containing peritoneal dialysis solution, glucose caramelizes at high pH and therefore the bags are kept at low pH (5.4).
During preparation and storage of a bicarbonate buffered solution, CO2 is released from the solution, changing the bicarbonate concentration and pH of the solution. Attempts have been made to address these problems.
Acids such as acetic acid, lactic acid, hydrochloric acid, or carbon dioxide have been added to bicarbonate dialysis solutions to prevent caramelization of the glucose and to avoid precipitation (U.S. Patent No.
5,211,643 to Reinhardt et al). Separate batches of concentrates have also been used which contain calcium/magnesium on the one hand, and the bicarbonate on the other hand to prevent precipitation (U.S. Patent No.
4,630,727 to Feriani et al).
In bicarbonate dialysis solutions, the bicarbonate is in equilibrium with CO2 which readily escapes from solution leading to loss of 5 bicarbonate and a change in pH. The following solutions have been proposed to control the CO2 content of the bicarbonate solution: storage in a powder form until use; use of an impermeable barrier; and addition of buffers such as histidine, or glycylglycine (H. Yatzidis, Nephron 64:27-31, 1993).
Kaye et al. have proposed a dialysate for hemodialysis that is bicarbonate based. (M. Kaye et al., Clinical Nephrology 31:132-138, 1989; M.
Kaye and D. Fisher, Clinical Nephrology 34:84-87, 1990; and M. Kaye, Clinical Nephrology 40:221-224, 1993). Calcium is infused distal to the dialyzer into the drip chamber using an infusion pump and is a component of the dialysate. In Kaye's studies, the patient's are not critically ill and his system is set up for chronic hemodialysis, not for acute hemodialysis. The concentrate used by Kaye is not sterile.
Furthermore, Kaye's system is used for intermittent, but not for continuous dialysis.
Acute renal failure in critically ill patients which is generally accompanied by metabolic derangements and high overall mortality poises significant challenges for renal replacement therapy. Acute intermittent hemodialysis has been the conventional therapy.
Bicarbonate dialysate which is typically used in acute intermittent hemodialysis is not sterile but only clean.
Problems with the rapid removal of fluid and changes in electrolytes which occur during intermittent hemodialysis have led to the development and use of continuous renal replacement therapies (CRRT) for critically ill patients (P.Y.W. Tam et al., Clinical Nephrology 30:79-85, 1988 and E.F.H. Van Bommel et al, Am. J. Nephrol. 15:192-200, 1995).
Solute and volume removal are continuous during CRRT eliminating the large shifts occurring between body compartments during intermittent hemodialysis, which may lead to hypotension and interfere with renal recovery (E.F.H. Van Bommel, Nephrol. Dial. Transplant. 1995 Editorial Comments, p. 311). CRRT techniques include peritoneal dialysis, continuous arterio-venous and veno-venous ultrafiltration, hemofiltration, hemodialysis and hemodiafiltration. Traditionally CRRT
has used peritoneal dialysis solution as the dialysate.
Lactate and acetate, which are converted by normally functioning livers into bicarbonate, have also been used as buffers in dialysis solutions. Prior to the development of dual proportioning machines, lactate was typically used in dialysate for peritoneal dialysis, and acetate for hemodialysis. Lactate containing peritoneal dialysis solution has been used in CRRT dialysate with some success. However, in intensive care patients, such as patients who have developed hypotension and lactic acidosis, lactate from the dialysis solution may not be metabolized to bicarbonate because of liver dysfunction, and when the dialysate lacks bicarbonate, acidosis may be worsened due to bicarbonate removal during dialysis. (A. Davenport et al., Nephron 1991:59:461-465, 1991 and M.
Leblanc et al., Am. J. Kid. Dis. 26:910-917, 1995). Lactate buffered solutions are still used for peritoneal dialysis. Acetate hemodialysis has been shown to cause hypotension in patients with heart disease (F. H. Leenen, Artificial Organs 8:411-417, Nov. 1994).
For acute hemodialysis in the intensive care unit CRRT typically uses lactate based sterile solutions (peritoneal dialysis solution). Research into methods to provide bicarbonate dialysate have been ongoing.
Recently, a method was reported for providing non-sterile bicarbonate dialysate for patients in the intensive care undergoing CRRT (M. Leblanc, AJKD 26(6):910-917, 1995).
It is important to use a sterile dialysis solution in CRRT in order to avoid pyrogenic reactions caused by bacteria and endotoxin contamination of the dialysate solution. It is also important to have a solution which is readily available for use. While sterile lactate or acetate-based dialysis solutions may be used in CRRT they suffer from the disadvantages discussed above. It has been suggested that bicarbonate dialysate may be preferable to lactate or acetate-based solutions (M.
Leblanc et al., Am. J. Kid. Dis. 26:910-917, 1995). However, it has not been possible to provide a sterile and readily available bicarbonate solution for CRRT due to the problems discussed above with bicarbonate solutions.
SUMMARY OF THE INVENTION
Broadly stated, the present invention provides a bicarbonate concentrate for use in a dialysis solution for continuous renal replacement therapy (CRRT) in a critically ill patient consisting of the following composition in grams per litre: NaCl 86.87 + 8.6 g/l, MgCl2 2.05 + 0.2 g/l, and NaHCO3 39.69+ 3.9 g/l, and wherein the concentrate is sterile and can be stored at room temperature for up to 24 months.
The invention also relates to a dialysis solution comprising the bicarbonate concentrate of the invention and a pharmaceutically acceptable diluent. The invention also relates to a replacement solution for hemofiltration comprising the bicarbonate concentrate of the invention and a pharmaceutically acceptable diluent.
Still further the invention contemplates a method for treating acute renal failure in a critically ill patient comprising dialyzing blood from the patient using a dialysis solution comprising a sterile diluent and a bicarbonate concentrate consisting essentially of the following composition in grams per litre: NaCl 86.87 + 8.6 g/l, MgCl2 2.05 + 0.2 g/l, and NaHCO3 39.69+ 3.9 g/l.
The invention still further relates to the use of a dialysis solution of the invention (a) in CRRT in a critically ill patient; (b) as an intravenous replacement solution in hemofiltration methods, including hemodiafiltration; (c) as a dialysis solution during cardiac bypass surgery;
and (d) as an oral electrolyte replacement solution.
DETAILED DESCRIPTION OF THE INVENTION

The present inventors have developed a sterile bicarbonate concentrate containing magnesium, sodium, chloride and bicarbonate which provides a more physiological and superior dialysis solution when compared to known dialysis solutions containing glucose and lactate 5 and/or calcium. The bicarbonate concentrate of the present invention provides a dialysis solution that avoids the problems of prior art bicarbonate dialysis solutions in that it is highly stable i.e. calcium does not precipitate, and the concentrate can be stored for about up to 24 months. Preferably the dialysis solution is used for acute hemodialysis in intensive care patients.
The bicarbonate concentrate and dialysis solution of the invention are cost effective because they simplify patient management reducing nursing and medical staff time. They reduce or eliminate the need for corrective measures due to lactate or dextrose contained in other dialysates, lowering costs of extra syringes, needles, insulin, bicarbonate, etc. They also replace problematic lactate based peritoneal dialysis solutions used for dialysate in continuous hemodialysis.
It has been found that the bicarbonate concentrate of the present invention and dialysis solutions prepared from the concentrate are very suitable for CRRT, and in particular in CRRT adapted for acute renal replacement therapy of critically ill patients in particular, patients in intensive care units. The stability and sterility of the dialysis concentrate of the invention necessarily results in reduced renal replacement therapy costs.
The present invention therefore provides a bicarbonate concentrate for use in a dialysis solution for CRRT in critically ill patients consisting of the following composition in grams per litre: NaCl 86.87 +
8.6 g/l, MgCl2 2.05 + 0.2 g/l, and NaHCO3 39.69+ 3.9 g/l. The concentrate is sterile and can be prepared aseptically using USP standards and cold filtration for sterility. The concentrate can be stored at room temperature (55 to 85~ F) for up to 24 months. In an embodiment of the invention the concentrate consists of the following in grams per litre: NaCl 86.87, MgCl2 2.05, and NaHCO3 39.69.
The bicarbonate concentrate of the invention may be prepared by mixing the various components of the concentrate using conventional methods. In particular, the various components of the concentrate of the invention may be mixed in a litre of sterile water to produce the overall composition. The bicarbonate concentrate of the invention may be prepared according to the constituent ranges, or according to the preferred amounts set forth herein to prepare a unit dose i.e. a dose amount that can be mixed with a sterile pharmaceutically acceptable diluent (e.g. 1, 3 or 5 litres of sterile water) to prepare a dialysis solution for use in CRRT as described herein. The bicarbonate concentrate (or unit dose) of the invention may be sterilized by cold filtration and prepared in an asceptic fashion according to USP standards with an asceptic fill. It may subsequently be sterilized by further methods, such as gamma irradiation.
The bicarbonate concentrate may be used to produce a dialysis solution by mixing a sterile pharmaceutically acceptable diluent with the concentrate. Accordingly, the invention relates to a dialysis solution comprising the bicarbonate concentrate of the invention and a pharmaceutically acceptable diluent. Pharmaceutically acceptable diluents which may be used in the dialysis solution of the invention include sterile water and dextrose 5% in sterile water, if a high osmotic gradient is desired for ultrafiltration, or if the patient requires a caloric boost.
The bicarbonate solution is generally prepared by mixing 80 + 1 ml, preferably 80 ml of concentrate, with 1 litre of a sterile pharmaceutically acceptable diluent. In an embodiment of the invention the dialysis solution consists of the following in mMol per litre: Na 140 +
14 mmol/l, Mg 0.75 + 0.07 mmol/l, Cl 106.5 + 10 mmol/l, and HCO3 35.0 +

3.5 mmol/l. Preferably, the dialysis solution consists of the following in mMol per litre: Na 140, Mg 0.75, Cl 106.5, and HCO3 35Ø If the dialysis solution is made in a PVC (polyvinyl chloride type) plastic container, it is advisable to use it within about 24 hours in order to avoid loss of bicarbonate through the plastic. The dialysis solution may be stored at room temperature (55 to 85~ F) or refrigerated.
The invention also relates to enhanced embodiments of the dialysis solution of the invention which include the composition described above containing other additives. Examples of such additives are glucose, potassium, and amino acids. The additives may also be administered to a patient using other routes of administration.
Calcium may be added to the diluent for CRRT, just prior to administration (M Leblanc et al, AJKD, 1995). However, it is more cost effective to administer calcium intravenously, rather than by injecting it into the diluent.
The dialysis solution of the invention may be used in CRRT
and is preferably used to treat acute renal failure in critically ill patients.
In contrast to prior art dialysis methods, the treatment typically does not involve incorporating calcium into the blood using the dialysis procedure. Therefore, the invention also contemplates a method for treating acute renal failure in a critically ill patient comprising dialyzing blood from the patient without introducing calcium into the blood removed from the patient during dialysis, and using a sterile dialysis solution prepared by mixing a sterile diluent with a sterile bicarbonate concentrate consisting essentially of the following composition in grams per litre: NaCl 86.87 + 8.6 g/l, MgCl2 2.05 + 0.2 g/l, and NaHCO3 39.69+
3.9 g/l. The invention also relates to the use of a dialysis solution of the invention in CRRT of a critically ill patient.
Continuous renal replacement therapies (CRRT) include peritoneal dialysis, continuous arterio-venous and veno-venous ultrafiltration, hemofiltration, hemodialysis and hemofiltration.
The term "critically ill patient" or "critically ill patients" refers to patients that have a high mortality rate, acute renal failure, multiple organ failure, and multiple metabolic derangements. Critically ill patients 2189~16 which can be treated using the dialysis solution of the invention typically have acute renal failure and a high APACHE II score (Knaus W.A. Et al., Crit. Care Med. 13:818-827, 1985). An assessment of the number of failing organs may be performed using the procedure described in Jordan, D.A. Et al., Crit Care Med 15:897-904, 1987.
The bicarbonate concentrate and dialysis solution of the invention are preferably administered to patients in intensive care who require dialysis and are hemodynamically unstable, or whose liver function is either impaired or at risk of impairment. Liver transplantation patients especially are difficult to manage and very often cannot handle any dialysate which contains lactate. Unable to transform the lactate in lactate buffered dialysis solutions to bicarbonate, they may go into acidosis if such solutions are used, and they require large doses of bicarbonate to correct pH imbalance. Many of these patients are also unable to handle the dextrose delivered by usual dialysates and may therefore require insulin to correct hyperglycemia.
The dialysis solution of the invention is compatible with all systems used for CRRT including the commercially available systems such as the COBE Prisma Denver, Colorado, Baxter CRRT System, Chicago, Ill., Hospal BSM22, Medolla, Italy, IMED Pump System, San Diego, California, Fresenius CRRT system, Dusseldorf, Germany or any other CRRT machine that uses peritoneal dialysate or other lactate-containing fluid as CRRT hemodialysate. When the dialysis solution is used with conventional systems for CRRT the consumption rate will typically be a unit dose of concentrate per hour assuming a dialysate flow of 1 litre per hour.
The bicarbonate concentrate and dialysis solution of the invention may also be used in patients undergoing cardiopulmonary bypass surgery.
Cardiac surgery requires a still, bloodless operating field which is generally achieved by inducing electromechanical arrest of the heart. A
chemical solution (cardioplegia) is administered to the heart to produce cardiac arrest. Cardioplegia contains a number of components including potassium, and glucose. The administration of potassium cardioplegia produces unwanted problems in two clinical scenarios. In patients with oliguric renal failure the kidneys are not able to excrete the potassium 5 load resulting in significant hyperkalemia. Continuous cardioplegia where the patient receives large volumes of cardioplegia, also produces significant hyperkalemia, hyperglycemia and dilutional hyponatremia. In these clinical scenarios hemodialysis with the dialysis concentrate and dialysis solution of the invention can be used to more effectively clear potassium from the circulation and reduce excess volume.
The bicarbonate concentrate and dialysis solution of the invention may be used to prepare a dialysate for peritoneal dialysis. The ability to make sterile bicarbonate buffered peritoneal dialysate at the bedside is particularly advantageous in third world settings. The bicarbonate concentrate and dialysis solution of the invention may also be used for slow nocturnal hemodialysis. This is a form of dialysis where patients dialyse themselves at home overnight. In another embodiment, the dialysis concentrate may be used as, or in, an oral electrolyte solution for treating dysentary.
The amounts and components of the bicarbonate concentrate and dialysis solution of the invention may be modified to adapt to their use in cardiovascular surgery, peritoneal dialysis, hemodiafiltration, hemofiltration, and as an electrolyte solution.
The dialysis solution of the invention may be preferably contained in a plastic container (bag) for use at the bedside. In a preferred embodiment, the solution will be prepared to a desired concentration for dialysis. In this embodiment, sterile water and all electrolytes, except calcium, are mixed, and if desired diluted, and placed in a carbon dioxide impermeable bag. At the time of dialysis, calcium may be added from, for example, a pre-filled syringe. The pre-filled syringe is preferably injected directly into the bag, or alternatively may be injected into the patient.

In one embodiment of the invention, the pre-filled syringe with calcium is sold in a kit form with the bag. In another, a section of the bag will be sealed off and filled with a calcium solution. When required, the separating membranes within the bags will be broken, and calcium will be 5 released into the portion bag containing the sterile water and the other electrolytes.
Containers, in particular bags which are impermeable to carbon dioxide, are preferably selected for use in the present invention. For example, a bag may be made with three layers of plastic material, sandwiched together (see for example, bag produced by Bieffe Medital, 20157 Milano, 41100 Modena, Italy.) The following non-limiting examples are illustrative of the present invention:
Example 1 Patients dialysed with the solution of the invention during bypass surgery.
During bypass surgery, six patients were dialysed using the dialysis solution of the invention. After dilution, the dialysate solution contained approximately 140 mMol/l of Na, 0.75 mMol/l of Mg, 106.5 mMol/l of Cl, 35 mMol/l of HCO3. Thirty other patients were dialysed using 1.5% dianeal, a commercially available dialysate. The study found a 49% difference in glucose levels. In the six patients dialysed with the dialysate of the invention, there was a glucose level of 20.4 mMol/l whereas in the thirty patients dialysed using the dianeal dialysate there was a 13.7 mMol/l glucose level.
Example 2 Patients dialysed with a dialysis solution of the invention a) A 65 year old man, was treated in an intensive care unit with multiorgan system failure involving liver impairment with elevated bilirubin, low albumin, elevated PT, ascites and a lactic acidosis. The patient developed high lactate levels on standard, lactate based dialysate 2 1 8 9 g 1 ~

solutions for CRRT. A dialysis solution as described in Example 1 was used as a dialysate at 1 L/hr. Lactate levels rapidly declined and the patient's condition began to stabilize. The dialysis system used was a Gambro AK10 (Gambro Inc., Lund, Sweden). This system resulted in ultrafiltration of approximately one half litre per hour, requiring the use of intravenous replacement solution. The patient's bicarb level rose to normal and the patient tolerated this infusion over a 36 hour period, at which time dialysis could be safely discontinued.
b! A 46 year old male, a known ethanol abuser with a history of peptic ulcer disease and upper GI bleeding was admitted with a diagnosis of cirrhosis, hepatic encephalopathy and pneumonia as well as acute renal failure. Blood pressure was 130/70 His laboratory exam revealed sodium 125, potassium 6.1, chloride 91, bicarb 25. His urea was 57.4 creatinine 696, glucose 4.3. His hemoglobin was 125, white count 39 and platelets 83. Over a 12 hour period his potassium increased to 6.5 and his creatinine climbed to 706. He was treated aggressively and then started on dialysis. He was initially treated with peritoneal dialysis via an acute peritoneal dialysis catheter but there was no significant benefit. He was then transferred to CVVHD. The dialysate as described in Example 1 was used at a flow of 1 liter per hour and as a replacement IV solution at 1 liter per hour. Ultrafiltration was set at net 300 cc per hour. Over the course of four days the patient remained on this form of dialysis with no complications. His creatinine fell quickly on dialysis and by the fourth day of dialysis was down to 259. His bicarb remained between 21 and 24 throughout, and his lactate level, which had been 1.6, fell to 0.9. The patient's condition improved dramatically and dialysis was stopped. He continued to improve and was able to be discharged home on day 18.
c) A 24-year old male with a history of morbid obesity and non-insulin dependent diabetes was admitted after a motor vehicle accident.
He had fractures, and his admission was complicated by gram-positive septicemia requiring inotropic support and IV antibiotics. He developed ARDS requiring intubation. He developed metabolic acidosis requiring IV bicarb administration, eight amps per day. By day 16 his creatinine had begun to increase, and was 113 umol/L, urea 14.7. His renal function returned towards normal with volume expansion, and his creatinine dipped below 100 umol/L. He was found to have a paralysis of the lower extremity. He had a CT with contrast on day 28, showing a fracture at T2.
On day 32 he developed sepsis, with E. coli in his urine and his blood, requiring antibiotics. By day 40 he had developed oliguria and was volume overloaded. Because of obligate food requirements and hypotension, it was decided to start him on CWHD on day 54. His urea was 35 and his creatinine was 500. Ultrafiltration was set at 300 cc/hr. He was dialysed using the dialysate as described in Example 1 at lL/hr, and he was given separate intravenous calcium as needed. At initation of dialysis his pH was 7.29, his PCO2 76, PO2 67 and his bicarb was 36. He had this chronic respiratory acidosis for most of his admission. His urea decreased to 24, his creatinine decreased to 180 umol/L, and his blood gases were 7.36, PCO2 50, PO2 96 by day 12 and bicarbonate 28. On day 44 the CVVHD was discontinued, as his urine output had increased to 40 cc/hr. On day 51 his urine output again decreased, and this was thought to be due to an episode of asystole. He was started back on CVVHD on day 51 with the dialysate as described in Example 1 at lL/hr, and remained on for 5 more days, when his urine output returned. One week later his urine output again dropped off, with no obvious etiology, and he was started on intermittent hemodialysis to allow him to be transferred from the intensive care. He remained on intermittent hemodialysis for three weeks, and then was switched to peritoneal dialysis to give 24 hour dialysis for better volume control. He tolerated peritoneal dialysis well, and was rehabilitated.
d) A 78 year old woman with a history of non-insulin dependent diabetes mellitus who had a two week history of a bladder infection, frequent voiding, dysuria and fever was admitted. She had nausea and vomiting two days prior to admission and collapsed at home prior to being brought to hospital. Her medications include amlodipine 5 mg daily, multivitamins daily and glucazide as well as metformin 500 mg three times daily. In emergency she was found to be volume overloaded.
Her urea was 28.5, creatinine 564, potassium 6.6, bicarb 10, anion gap was 28. Her glucose was 5.6. Her pH was 7.19, PCO2 19, PO2 113, and her bicarb 9. Her hemoglobin was 109 and white count was 16.8. Her creatinine had been 117 two months earlier. She was admitted and taken to the intensive care unit for urgent continuous venovenous haemodialysis and hemofiltration via an internal jugular catheter. She was initially started on Hemosol (Hospal Gambro Lundia, Sweden) as dialysate running at one litre per hour. Ultrafiltration replacement with Hemosol was set at one liter per hour. For hours after starting this regimen the bicarb dipped to 5, the blood gases deteriorated to pH 6.99, PO2 136, PO2 8, bicarb was 2 on blood gasses. A bicarb drip was started with three amps of bicarb in normal saline at 200 cc per hour. The lactate level was found to be 21.2 and it had been 12.9 on admission. The patient was taken off the lactate containing dialysate and infusate and switched over to the dialysate as described in Example 1 and bicarbonate infusate. Over the course of four hours, her bicarb rose to 19 then to 27 after 12 hours. Her lactate dropped to 6 then to 0.9 within 12 hours. Over the course of 12 hours her urine output, which had been less than 30 cc per hour, increased to 100 cc per hour. She did not require further dialysis after this point. Her condition improved on antibiotic therapy and she was able to be discharged home on day 8.
e) A 54 year old man with a history of non insulin dependent diabetes for 11 years, was admitted for cellulitis and sepsis. He required multiple operative procedures for debridement of his foot and over the course of his admission developed acute renal failure. This was felt to be due to sepsis. The patient was hypotensive, with blood pressure 90/60. At that time his creatinine had increased to 538 and his urea was 11.4. His ~- 218~116 creatinine had been 53 on admission. His bicarb had fallen to 13 and his potassium was 5.5. He was initially started on Hemosol dialysate at 1 liter per hour as an infusate at 1 liter per hour. Net UF was set at 200 cc per hour. He became hypotensive on the following day. By the evening of day 3 he remained hypotensive and was on large doses of inotropes and at that time his lactose was found to be 8. He had large infusions of sodium bicarb, 2 amps in 1 liter of normal saline. On this aggressive bicarb replacement his bicarb increased to 25 and his sodium remained at 140.
Despite aggressive therapy and continuing CVVHD using hemosol as dialysate and replacement solution and despite maximum inotrope therapy the patient's blood pressure continued to drop and he succumbed after 6 days of dialysis therapy.
f) A 68 year old man with acute renal failure due to multifactorial causes as well as, sepsis, aminoglycoside use and hypertension was admitted. He became volume overload and acidemic. His bicarb dropped to 19. His urea was 40 and his creatine 524. On day 1 he was started on continuous venovenous hemodialysis using the dialysate as described in Example 1 at 1 liter per hour. His bicarb began to increase and the following day was 21. His urea dropped to 32 and his creatinine to 405. On the third day his bicarb increased to 22, then to 23 by day 4. On day 7 his bicarb was 24, his urea 18 and creatinine 264. He remained on CVVHD
and his bicarb remained stable at 25. After 12 days despite adequate metabolic control (bicarb was 24, urea 21, creatinine 188, potassium 3.9, calcium 2.2 and phosphate 1.5), all therapy CVVHD was discontinued as the patient's overall condition deteriorated with new ventricular arhythmias and asystolies and the patient was made "No CPR". On day 13 he passed away.
g) A 71 year old woman, developed acute renal failure following presentation with an incarcerated hernia. Post-op she developed oliguria and a rise in creatinine. She was found to have hemegranular casts. The next day CWHD was started. Her bicarb had dropped to 17, her urea was 2189gl~
-20, her creatinine 479. CVVHD was commenced with the dialysate as described in Example 1 at 1 liter per hour and net ultrafiltration at 200 cc per hour. The patient tolerated dialysis well and had an elevation in her blood pressure upon starting dialysis. Her bicarb increased to 22, her creatinine decreased to 421 and her urea 19.2. On day 5 her bicarb had dropped to 20. She remained on heparin for the CVVHD. On day 9 she was found to have intracerebral bleeding. CVVHD was discontinued and she was continued on intermittent hemodiaylsis with no heparin. Her bicarb fluctuated on intermittent hemodialysis, dropping as low as 14 prior to treatment. Her urea increased to 51, her creatinine to 404. On day 15, her pH was 7.30, bicarb 18 and CO2 36.
On alternate-day dialysis there was difficulty controlling volume status and the patient fluctuated between hyper and hypo volemia. Her condition began deteriorating by day 24 and she required ainatropic support. Shortly after this, progressive care was withdrawn and the patient passed away.
h) A patient was admitted for acute renal failure complicated by trauma. He was treated with CVVHD and the dialysate as described in Example 1 for 8 days. Following treatment, his renal function returned.
Unfortunately the patient succumbed to sepsis 6 weeks later.
i) A patient was admitted for treatment of Hodgkin's disease.
Following tumor lysis, the patient was dialysed with CVVHD and the dialysate as described in Example 1 for one day. There was an overwhelming tumor burden on the liver, and the patient died.
j) A male ethanol abuser who was found to have acute renal failure, sepsis and hepatic failure was dialysed with the dialysate as described in Example 1 for five days. Subsequently, therapy was withdrawn and he passed away.
k) A patient was diagnosed with renal failure and dialysed with the solution as described in Example 1 for 8 days. To allow for transfer of the patient, the patient was switched to peritoneal dialysis.

218991~

1) A patient was admitted with acute renal failure, overwhelming sepsis, and hepatic failure. He was dialysed with the dialysate of the invention for 6 days, but succumbed.
m) A patient was admitted with acute renal failure and hepatic 5 failure. He was dialysed with the dialysate as described in Example 1 for one day, and renal function returned. However, the patient later succumbed to hepatic failure.
Having illustrated and described the principles of the invention in a preferred embodiment, it should be appreciated to those skilled in the art that the invention can be modified in arrangement and detail without departure from such principles. We claim all modifications coming within the scope of the following claims.
All publications, patents and patent applications referred to herein are incorporated by reference in their entirety to the same extent as if each 15 individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

Claims (6)

1. A dialysis concentrate for use in a dialysis solution for CRRT in critically ill patients consisting of the following composition in grams per litre: NaCl 86.87 ~ 8.6 g/l, MgCl2 2.05 ~ 0.2 g/l, and NaHCO3 39.69~3.9 g/l and wherein the concentrate is sterile and can be stored at room temperature for up to 24 months.

2. A dialysis solution comprising the dialysis concentrate as claimed in claim 1 and a pharmaceutically acceptable diluent.

3. A replacement solution comprising the dialysis concentrate as claimed in claim 1 and a pharmaceutically acceptable diluent.

4. A method for treating acute renal failure in a critically ill patient comprising dialyzing blood from the patient using a sterile dialysis solution comprising a sterile diluent and a dialysis concentrate consisting essentially of the following composition in grams per litre: NaCl 86.87 ~
8.6 g/l, MgCl2 2.05 ~ 0.2 g/l, and NaHCO3 39.69~3.9 g/l.

5. Use of a dialysis solution as claimed in claim 2 for treatment of a critically ill patient.

6. Oral or intravenous use of a replacement solution as claimed in claim 3 for treatment of a critically ill patient.