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  Pharmaceutical Patents  

 

Title:  Process for metabolic control and high solute clearance and solutions for use therein
United States Patent: 
7,884,132
Issued: 
February 8, 2011

Inventors: 
Tolwani; Ashita (Birmingham, AL), Speer; Rajesh (Birmingham, AL), Stofan; Brenda (Homewood, AL)
Assignee: 
The UAB Research Foundation (Birmingham, AL)
Appl. No.: 
11/273,290
Filed:
 November 14, 2005


 

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Abstract

The present disclosure describes novel standardized citrate replacement fluid solutions and a standardized dialysate solution for use with CRRT methods. The standardized citrate replacement fluid solutions and standardized dialysate solutions do not require modification based on the clinical status of the individual patients. The use of the standardized solutions described herein offers significant advantages over the prior art solutions used in CRRT. The present disclosure describes superior metabolic and electrolyte control and significantly increased dialyzer patency in: (a) 24 intensive care unit (ICU) patients with ARF using a 0.67% trisodium citrate replacement fluid solution, and (b) 32 ICU patients with ARF using a 0.5% trisodium citrate replacement fluid solution. Both groups were treated with Bicarbonate-25 dialysate and achieved effluent rates of 35 mL/kg/hr.

Description of the Invention

FIELD OF THE DISCLOSURE

The present disclosure relates generally to the field of renal function and renal disease. The present disclosure relates specifically to the use of a defined dilute regional trisodium citrate solution during continuous renal replacement therapy for the treatment of renal disease.

BACKGROUND

Continuous renal replacement therapy (CRRT) is well established as a modality for the management of renal failure in the critically ill patient. When CRRT was first developed, the major indications for use were fluid and solute removal associated with renal failure, such as those patients developing acute renal failure (ARF). Acute renal failure (ARF) is rarely an isolated process but is often a complication of underlying conditions such as sepsis, trauma, and multiple-organ failure in critically ill patients. As such, concomitant clinical conditions significantly affect patient outcome. CRRT applications have developed over time to include use for patients with chronic renal failure (CRF) and for other indications. Continuous renal replacement therapy (CRRT) has recently emerged as the dialysis technique of choice for critically ill patients with acute renal failure (ARF). There are several types of CRRT therapy, including but not limited to, continuous venovenous hemofiltration (CVVH). CRRT is generally recognized as offering significant advantages to intermittent dialysis for fluid and metabolic control (1). Additionally, high ultrafiltration rates (greater than or equal to 35 ml/kg/hr) using CRRT, such as CVVH, have been associated with improved patient survival (2).

During CRRT procedures, solutions must be added to keep the blood flowing through the CRRT device from clotting. Heparin sodium is the most common anticoagulant used for CRRT. Systems are frequently flushed with dilute heparin through the system during the priming procedure (5,000-10,000 U/L normal saline) followed by a constant delivery of heparin for the duration of therapy. For many years, it was the anticoagulant of choice for all forms of dialysis that used a blood path. However, as CRRT was applied to the more profoundly ill patients, heparin was found to be associated with complications caused by coagulation disorders seen in the critically ill. Side effects that may be observed include, but are not limited to, systemic anticoagulation, thrombocytopenia and suppressed aldosterone secretion. The effects on systemic coagulation make heparin administration very problematic in patients with gastrointestinal bleeding or traumatic injury in which hemostasis is impaired due to coagulation factor consumption or occult bleeding from wounds or vascular puncture sites. Frequent monitoring of coagulation studies and platelet counts as well as continual monitoring for bleeding complications is essential for any patient undergoing heparin anticoagulation of the CRRT system. Patients do not require bolusing with heparin before initiation of therapy, because the goal is not to anticoagulate patients but rather to provide regional anticoagulation for the system. If the heparin used for priming is not thoroughly flushed from the system, patients will still receive a small heparin bolus from the priming volume.

Trisodium citrate has been used for many years as an anticoagulant for blood products. It was introduced to CRRT as a regional anticoagulant in the early 1990s. Relatively normal hepatic function is required to metabolize sodium citrate.

Therefore, trisodium citrate has been used to provide anticoagulation of blood in the extracorporeal circuit during CRRT. Citrate affects anticoagulation by binding with calcium and rendering calcium unavailable to the clotting cascade. Since several steps of the clotting cascade are dependent on calcium, the absence of calcium prevents clotting. Once the blood from the extracorporeal circuit is returned to the patient it mixes with the central venous blood which contains calcium and the anticoagulant effect is neutralized. In other words, citrate when returned to the patient from the extracorporeal circuit is no longer an anticoagulant. Generally, calcium is administered to the patient on a continuous basis to prevent any depletion of calcium stores which may occur as a result of citrate binding with calcium and loss of calcium through the extracorporeal circuit.

The prior art has recognized that complications may arise when using trisodium citrate as a regional anticoagulant. The toxicities of this approach include metabolic alkalosis due to citrate accumulation and its subsequent metabolism to bicarbonate, and the effects of reduced systemic ionized calcium. Subjectively the patient may experience palpitations, perioral tingling and stomach cramps. Objective features of citrate toxicity include myocardial depression, arrhythmias and systemic alkalosis which may or may not include an anion gap. Proper surveillance of the rate of citrate administration and monitoring and correction of systemic ionized calcium may obviate these effects. Since normal liver function is required for the metabolism of trisodium citrate, patients with liver disease may be prone to developing citrate toxicity and caution must be exercised in treating these patients with citrate.

Although the use of citrate for regional anticoagulation has been shown to be superior to heparin (4), it often complicates CRRT. A small number of regional citrate anticoagulation protocols offer high solute clearance but also require several customized solutions (5,6,7,8,9,10). Customization of solutions, with subsequent adjustments based on or determined by patient clinical status, expends pharmacy resources in preparing the solutions and increases the risk of error in the preparation of the solutions and their administration (11). This customization of solutions can vary not only between individual patients, but can vary as to the same patient based on that patient's changing clinical status. In addition, if a patient's clinical status changes over the course of treatment, previously prepared solutions may have to be discarded, thereby increasing the costs of treatment. In 2004, two patients receiving CRRT died after potassium chloride, rather than sodium chloride, was mistakenly added to a custom-made dialysate (12,13). As the FDA does not presently require batch testing for quality control, potentially hazardous CRRT solution errors may be unrecognized. In a recent international survey on the management of critically ill ARF patients, the greatest concerns with CRRT included anticoagulation, dialyzer clotting, nursing workload, lack of standards, and cost (3).

The ideal CRRT protocol should provide volume control, metabolic (acid-base and electrolyte) control, and adequate solute clearance, without significant complications related to bleeding or clotting and should be versatile to allow for independent adjustment of the above parameters. Furthermore, the CRRT protocol should use standardized solutions and should not require more than two or three different types of solutions in order to minimize the strain on the compounding pharmacy and healthcare providers. Finally, the CRRT should ideally run with little or no interruption.

The present disclosure provides novel solutions for use with CRRT. In one embodiment, the CRRT protocol is a continuous venovenous hemodiafiltration (CVVHDF) method. CVVHDF provides both diffusive and convective solute clearance and easily maintains a filtration fraction <20% at low blood flow rates and high effluent rates, thereby decreasing the likelihood of filter clotting (14). The present disclosure also provides a simplified set of CRRT solutions for use in CRRT.

Altering the composition of CRRT solutions for each patient proved to be costly, labor-intensive, and error-prone. As a result, we first devised a simplified citrate protocol using 2% trisodium citrate delivered as replacement fluid at 250 ml/hr (citrate 17.5 mmol/hr), with a standardized normal saline dialysate delivered at 1000 ml/hr (15). However, this method could not provide higher effluent rates without also causing severe metabolic complications.

In one embodiment, a bicarbonate-based dialysate and a dilute citrate solution used for both anticoagulation and replacement fluid are disclosed. The citrate solution provides adequate metabolic control, a high ultrafiltration rate, and effective regional anticoagulation without requiring customization based on the clinical status of an individual patient.

DETAILED DESCRIPTION

The present disclosure provides standardized solutions of dilute citrate as replacement fluid solution for use in CRRT protocols and further provides methods of using the citrate solution in CRRT protocols. The present disclosure describes a 0.67% trisodium citrate (TSC) solution and a 0.5% TSC solution as the citrate replacement fluid solution. The present disclosure also provides standardized solutions of dialysate and calcium for use in CRRT protocols and further provides methods of using the dialysate and calcium solutions in combination with the citrate replacement fluid solutions. The standardized solutions and methods of the preset disclosure are a practical and economical improvement over currently published CRRT protocols incorporating citrate solutions.

The prior art has recognized that citrate solutions could be used in CRRT methods. Prior art CRRT protocols utilizing citrate solutions required solutions customized to meet the needs of the individual patient in order to address metabolic and electrolyte requirements and often required further alterations during use as a result of the changing clinical status of the patient. Table 1 (see Original Patent) describes the most recent CVVHDF CRRT protocols using citrate for regional anticoagulation. As can be seen, the protocols described by Mehta (10), Kutsogiannis (9), Tobe (8) and Cointault (5) require the use of 4 or more solutions during CRRT. The protocols described by Gabutti (6) and Dorval (7) disclose the use of 3 solutions; however, it should be noted that the citrate solutions require customization of the potassium (Gabutti) or potassium and phosphate levels (Dorval) depending on the clinical status of the individual patients.

The citrate replacement fluid solution, the dialysate solution and the calcium solution described herein are standardized solutions which do not require modification or customization on a per patient basis or during use based on the clinical status of the patient. Furthermore, the standardized replacement fluid, dialysate and calcium solutions are the only three solutions required in order to implement CRRT methods. This is a distinct advantage over many prior art methods which required up to 5 distinct solutions (and which were customized based on individual patient needs). The use of these standardized solutions in CRRT, such as but not limited to CVVHDF, allow for high solute clearance and superior regional anticoagulation properties. Therefore, the novel standardized solutions disclosed herein do not require customization based on the needs of an individual patient. Furthermore, the standardized solutions disclosed herein do not require alterations during use. The standardized solutions achieve metabolic and electrolyte control, as well as a constant effluent rate, by altering solution flow rates rather than by changing the composition of the solutions.

Preparation of Standardized Solutions

The present disclosure provides a novel, standardized citrate replacement fluid solution, a standardized dialysate solution and a standardized calcium solution for use in a variety of CRRT protocols. The solutions are described below.

The present disclosure describes a standardized citrate replacement fluid solution and the use of the citrate replacement fluid solution in CRRT methods. The citrate replacement fluid solution comprises from about 15 to about 25 mmol/L citrate and from about 130-150 mmol/L sodium (Na+). In one embodiment, the sodium is isotonic (about 140 mmol/L). Two embodiments of the citrate replacement fluid solution are described: (i) a 0.67% trisodium citrate (TSC) solution; and (ii) a 0.5% TSC solution. In the first embodiment, the 0.67% TSC replacement fluid solution comprises 23 mmol/L citrate and 140 mmol/L sodium. The 0.67% TSC solution was prepared by pooling the following into an empty 3 L bag: 2500 mL of 0.45% NaCl, 500 mL of 4% citrate (4% TSC Solution; Baxter, McGraw Park, Ill., U.S.A.), and 6 mL of concentrated NaCl (4 mmol/mL). As would be obvious to one of ordinary skill in the art, alternate methods of formulation providing alternate volumes may be used. In the second embodiment, the 0.5% TSC solution comprises 18 mmol/L citrate and 140 mmol/L sodium. The 0.5% citrate solution was prepared by pooling the following into an empty 3 L bag: 2250 mL of 0.45% NaCl, 325 mL of 4% citrate (4% TSC Solution; Baxter, McGraw Park, Ill., U.S.A.), and 15 mL of concentrated NaCl (4 mmol/mL). As would be obvious to one of ordinary skill in the art, alternate methods of formulation providing alternate volumes may be used.

The dialysate solution comprises from about 120 to about 145 mmol/L sodium, from about 110 to about 130 mmol/L chloride (CL.sup.-), from about 20 to about 35 mmol bicarbonate (HCO.sub.3), from about 2 to about 4 mmol/L potassium (K+) and magnesium from about 0.5 to about 0.7 mmol/L. In one embodiment the dialysate solution comprises 140 mmol/L sodium, 118.5 mmol/L chloride, 25 mmol/L bicarbonate, 4.0 mmol/L potassium and 0.58 mmol/L magnesium (referred to as Bicarbonate-25). The dialysate solution was prepared by pooling the following into an empty 4 L bag: 4000 mL of Sterile Water for injection, 240 mL of Normocarb.RTM. (Dialysis Solutions Inc, Toronto, Canada), 36 mL of concentrated NaCl (4 mmol/ml), and 9 mL of concentrated KCl (2 mmol/mL). Normocarb.RTM. contains 140 mmol/L, chloride 106.5 mmol/L, bicarbonate 35 mmol/L, and Magnesium 0.75 mmol/L. The calcium solution comprises from about 20 to about 50 mmol/L calcium. In one embodiment, the calcium solution is a calcium gluconate solution of 38.75 mmol/L prepared by adding 200 mL of 10% calcium gluconate solution to 1000 mL of 0.9% NaCl. A bicarbonate-based dialysate was used to offset the citrate removed in the effluent [16,17].

Many methods may be used to formulate solutions described herein. The foregoing is provided as exemplary only and is not meant to exclude other methods of preparation of the solutions.

Description of CRRT Technique

In the embodiment described herein, the CRRT technique was CVVHDF. In one embodiment, CVVHDF was performed using a COBE Prisma pre-pump M100 set with an AN69 dialyzer (effective surface area of 0.9 m.sup.2) through a double lumen 12 French catheter inserted into either the internal jugular, subclavian, or femoral vein. FIGS. 1A and 1B (see Original Patent) illustrate schematically the CRRT protocol using a 0.67% citrate replacement fluid solution (FIG. 1A) and a 0.5% citrate replacement fluid solution (FIG. 1B). The prepump M100 infusion set is commercially available and consists of a simple stopcock and extension line that allows a greater portion of the access line to be diluted by redirecting the citrate replacement fluid solution close to the blood access site and before the blood pump. Such a placement permits anticoagulation of virtually the entire extracorporeal circuit when the citrate replacement solution is delivered pre-filter. Such a placement also maintains filter patency, extending filter life. The calcium solution was administered through a separate central venous line (or through the accessory infusion port of a large bore multi-lumen central venous catheter) Post-filter ionized calcium levels were measured from the post-filter blood sample port (blue in color) located on the return line of the Prisma device to guide the regional citrate dose.

Since the infusion set is routed through the pre-filter replacement fluid port of the Prisma, the citrate replacement fluid solution infusion rate is accounted for by the Prisma device in calculations of net fluid removal. In the embodiment described, hemodiafiltration was accomplished using a blood flow rate of 90-180 mL/min. Other blood flow rates may also be used as is known in the art. In an alternate embodiment, blood flow rates from 50-250 ml/min may be used. The dose of dialysis obtained using the methods described herein may be calculated as is know to one of ordinary skill in the art. In one embodiment, a weight based scheme is used to determine the dose of dialysis. Using the Prisma machine, the total effluent rate in mL/hr is equal to the sum of the replacement fluid rate (mL/hr), dialysate rate (mL/hr), and fluid removal rate (mL/hr). In the embodiment described herein, effluent rates of 35 mL/kg/hr were used and determined by the patient's bodyweight in kilograms at initiation of CVVHDF. Other effluent rates may also be used as would be obvious to one of ordinary skill in the art. In an alternate embodiment, the effluent rates may be from about 20 to about 50 ml/kg/hr. The rate of delivery of the citrate replacement fluid solution and the dialysate solution may be independently varied from about 500 to about 3500 ml/hr. In one embodiment, the rate of delivery of the citrate replacement fluid solution and the dialysate solution are 1000 mL/hr. The rate of delivery may be determined by the healthcare provider based on patient requirements or treatment objectives. The rate of delivery of the calcium solution may be varied from about 10 to about 150 mL/hr. In one embodiment, the rate of delivery of the calcium solution is about 60 mL/hr. The rate of delivery may be determined by the healthcare provider based on patient requirements or treatment objectives.

The rate of delivery of the citrate replacement fluid solution, the dialysate solution and the calcium solution may be titrated from the initial delivery rate as determined by the healthcare provider based on patient requirements or treatment objectives. For example, the citrate replacement fluid solution and the dialysate solution may be titrated from the initial rate in predetermined increments to maintain post-filter ionized calcium levels between 0.25-0.5 mmol/L In one embodiment, the predetermined increments are from about 25 to 200 mL/hr.

The calcium solution may be titrated by in predetermined increments to maintain systemic ionized calcium levels between 0.9-1.3 mmol/L. In one embodiment, the predetermined increments are from about 10 to about 30 mL/hr. For example, if systemic ionized calcium levels in the range of about 0.8 to 0.9 mmol/L, the rate of delivery of the calcium solution may be increased by 10 ml/hr and if the systemic ionized calcium levels are less than about 0.8 mmol/L, the rate of delivery of the calcium solution may be increased by 20 mL/hr. If the systemic ionized calcium were greater than about 1.3 mmol/L, the rate of delivery of the calcium solution may be decreased by 10 ml/hr increments until a therapeutic level was obtained.

In the embodiment described above, the effluent rate (mL/kg/hr) was used as a surrogate for the dose of dialysis and calculated as follows: Effluent Rate=(Dialysate flow rate (mL/hr)+Replacement fluid flow rate (mL/hr)+Fluid removal rate (mL/hr))/Patient weight (kg)

For example, a 70 kg patient would require a total effluent rate of 2450 mL/hr (70 kg.times.35 mL/kg/hr). Rates for the replacement fluid solution, dialysate solution, and fluid removal would then be adjusted to achieve an effluent rate of 2,450 mL/hr. In one embodiment, the replacement fluid solution and dialysate solution rates were set equally at initiation of CRRT (for example at >1000 ml/hr) and titrated according to the metabolic, anticoagulation, and fluid balance requirements of the patient. The replacement fluid solution and dialysate solution rates may also be set to differ from one another. However, the total effluent rate remained constant.

In an alternate embodiment, a non-weight based scheme may be used to determine the dose of dialysis. In one example of such a scheme, the delivery rate of replacement fluid solution and dialysate solution may be set at a constant rate, with changes made to the fluid removal rate. For example, the rates of delivery of the replacement fluid solution and the dialysate solution may be set as desired (such as from 500 to 3500 ml/hr) and, depending on desired volume status to be achieved, the fluid removal rate may be adjusted.

Monitoring of CRRT Therapy

Serum and post-filter ionized calcium levels are measured to ensure that post-filter ionized calcium levels are in the range of 0.25 to 0.5 mmol/L and serum ionized calcium levels are in the range of about 0.9 to 1.3 mmol/L. Measurements may be taken as determined by the healthcare providers. In one embodiment, serum and post-filter ionized calcium levels were measured 1 hour after initiation of CRRT and then every six hours thereafter. Arterial blood gases (ABGs), serum electrolytes (including but not limited to, magnesium, calcium, and phosphorous), coagulation parameters, and complete blood count are also measured as determined by the healthcare providers. In one embodiment, these components were measured at least daily. Healthcare providers were instructed to call for serum pH <7.20 or >7.45, bicarbonate <15 or >35 mmol/L, or systemic ionized calcium <0.9 or >1.3 mmol/L. Any changes to the fluid removal flow rate, citrate replacement fluid solution flow rate, or dialysate solution flow rate resulted in reciprocal adjustments to ensure a constant effluent rate of 35 mL/kg/hr. Dialyzer filters were changed routinely every 72 hours per the manufacturer's recommendations. Monitoring for citrate toxicity was performed as previously described (18).

Statistical Analysis

Results are presented as means, medians, and interquartile ranges. Baseline characteristics and outcome measures were compared using the Student's t-test or the Wilcoxon rank-sum test for quantitative variables, and the Pearson Chi-square test or Fisher's Exact test for proportions. Filter survival was compared using Kaplan-Meier survival statistics and the log-rank test. A p value <0.05 was considered statistically significant.

Methods of Treatment

The present disclosure also describes a method of treating an individual having a disease or condition treatable using CRRT and the standardized solutions described herein. In one embodiment, the disease or condition is a renal disease. The renal disease may be, but is not limited to, ARF and CRF. There are a variety of causes that contribute to and/or cause ARF or CRF; such causes include, but are not limited to, nephritis, drug use/overdose, surgical intervention, complications arising in premature infants and neonatal environments, transplant procedures, burns, trauma, sepsis, shock and multi-organ failure (25). In an alternate embodiment, the disease or condition is not a renal disease and may include, but not be limited to, drug use/overdose, correction of severe acid base abnormalities, solute/fluid balance control, congestive heart failure, removal of sepsis mediators or cytokines, cerebral edema states, ARDS, liver support, pancreatitis, and burn management (26). The methods of treatment comprise identifying an individual in need of such treatment and administering to such individual the standardized citrate replacement fluid solution and the standardized dialysate solution using a CRRT protocol. In one embodiment, citrate replacement fluid solution is the 0.67% TSC solution or the 0.5% TSC solution described herein, the dialysate solution is the Bicarbonate-25 solution and the CRRT protocol is a CVVHDF protocol as described herein where the citrate replacement fluid solution is introduced via the extracorporeal circuit. The citrate replacement fluid solution and the dialysate solution are administered at rates of about 500 to 3500 mL/hr and the effluent rate is between 20 and 45 mL/kg/hr. In one embodiment, the citrate is delivered at a rate of about 10-40 mM/hr.

The present disclosure also provides a method of providing regional anti-coagulation during a CRRT procedure using the standardized solutions described herein. The method of providing anti-coagulation comprises identifying an individual in need of such anti-coagulation and administering to such individual the standardized citrate replacement fluid solution and the standardized dialysate solution using a CRRT protocol. In one embodiment, citrate replacement fluid solution is the 0.67% TSC solution or the 0.5% TSC solution described herein, the dialysate solution is the Bicarbonate-25 solution described herein and the CRRT protocol is a CVVHDF protocol as described herein where the citrate replacement fluid solution is introduced via the extracorporeal circuit for the prevention of coagulation. The citrate replacement fluid solution and the dialysate solution are administered at rates of about 500 to 3500 mL/hr and the effluent rate is between 20 and 45 mL/kg/hr. In one embodiment, the citrate is delivered at a rate of about 10-40 mM/hr.

The present disclosure also provides methods for extending the patency of a dialysate filter used during a CRRT procedure using the standardized solutions described herein. The method of extending the patency of a dialysate filter comprises identifying an individual in need of CRRT and administering to such individual the standardized citrate replacement fluid solution and the standardized dialysate solution using a CRRT protocol. In one embodiment, citrate replacement fluid solution is the 0.67% TSC solution or the 0.5% TSC solution described herein, the dialysate solution is the Bicarbonate-25 solution described herein and the CRRT protocol is a CVVHDF protocol as described herein where the citrate replacement fluid solution is introduced via the extracorporeal circuit for the prevention of coagulation. By preventing coagulation of the blood in the extracorporeal circuit, the life of the dialysate filter is extended. In one embodiment, filter patency was greater than 70% after 72 hours of CRRT. The citrate replacement fluid solution and the dialysate solution are administered at rates of about 500 to 3500 mL/hr and the effluent rate is between 20 and 45 mL/kg/hr. In one embodiment, the citrate is delivered at a rate of about 10-40 mM/hr.
 

Claim 1 of 3 Claims

1. A citrate containing replacement fluid solution, said replacement fluid solution consisting essentially of about 15 to about 25 mmol/L citrate and from about 130-150 mmol/L sodium.

 

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If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.
 

 

     
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