Abstract:
The invention provides intradialytic parenteral nutrition (IDPN) solutions with low carbohydrate for the treatment of malnutrition in dialysis patients. The IDPN solutions of the invention are particularly advantageous for the treatment of malnutrition in patients who are diabetic or suffer from other glucose management related pathologies or patients who require strict fluid management.

Description:
RELATED APPLICATIONS 
       [0001]    This application claims the benefit of U.S. Provisional Application Nos. 61/078,636, filed on Jul. 7, 2007, and 61/080,567, filed on Jul. 14, 2008, the entire contents of each are incorporated herein by reference in their entireties. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The invention pertains to nutrition supplement compositions for patients receiving dialysis treatment and methods of using the nutrition supplement compositions. The nutrition supplement compositions include reduced levels of carbohydrates and lower volume to reduce complications in patients who are diabetic or suffer from other glucose management related pathologies, or patients who require strict fluid management. 
       BACKGROUND OF THE INVENTION 
       [0003]    Severe malnutrition remains a problem for patients receiving maintenance hemodialysis (MHD). Dialysis patients often have poor appetites and low energy. This malnutrition is reflected in low serum albumin concentrations, a strong predictor of increased morbidity and mortality. (Moore and Lindenfield,  Support Line  29(5):7-16 (October 2007)). Patients are often treated using diet liberalization, oral supplements and enteral feeding. When these methods are not effective intradialytic parenteral nutrition (IDPN) may be utilized for more aggressive nutrition repletion efforts. 
         [0004]    IDPN is infused during the hemodialysis procedure. IDPN has been used for decades and has resulted in weight gain and improved protein levels in patients. (U.S. Publication No. 2005/0148647). The typical IDPN treatment delivers 4-6 mg/kg/minute of glucose for patients in need of carbohydrate control and 6-8 mg/kg/minute for patients who do not need carbohydrate control. Blood glucose must be monitored to avoid problems associated with insulin resistance, hyperglycemia and hypoglycemia. In some cases, insulin is also administered either in the IDPN solution or more typically separately administered subcutaneously to modulate blood glucose levels. IDPN generally contains 1.2-1.4 g/kg of amino acids. However, these amounts can be lowered for patients who do not tolerate protein well. Monitoring of serum bicarbonate and carbon dioxide levels must be monitored to check for acidosis caused by administration of amino acids. Lipids are provided in IDPN at a rate between 4 mg/kg/minute and 12-12.5 g/hour depending on tolerance of the lipids by the patient. Generally, these lipids are emulsions of purified vegetable oil from soybean (Intraliipid® from Kabi Vitrum or Travamulsion® from Travenol) or safflower oil (Liposyn® from Abbott). (Powers,  Contemporary Dialysis and Nephrology: 29-31 (February 1990). 
         [0005]    IDPN is usually administered in one liter of solution, and occasionally micronutrients, like vitamins and minerals are co-administered in or with IDPN. IDPN has proved effective in decreasing morbidity and mortality in MHD patients, leads to increased levels of serum albumin and creatine levels, and increased body weight. (Moore and Celano,  Nutrition in Clinical Practice,  20(2):202-212 (2005)). Hypoglycemia is another potential dangerous result of the administration of insulin during IDPN with symptoms of nervousness, sweating, intense hunger, trembling, weakness, palpitations, and trouble speaking. 
         [0006]    Problems associated with IDPN include hyperglycemia, complications in patients with insulin resistance or other problems associated with glucose management, as well as complications in patients who require strict fluid management. The glucose concentrations administered with IDPN can cause hyperglycemia and hypoglycemia in some patients. The administration of insulin can sometimes successfully treat this hyperglycemia, but some patients demonstrate insulin resistance, and may not respond to insulin treatment. (Goldstein and Strom,  Journal of Renal Nutrition  1(1):9-22 (January 1991)). Hyperglycemia is a major barrier to effective nutrition support even outside the context of hemodialysis. Many studies report associations between hyperglycemia and increased morbidity and mortality. (McCowen and Bistrian,  Nutrition in Clinical Practice,  19(3):235-244 (June 2004)). Moreover, the amount of fluid in typical IDPN treatment is a barrier to use in patients with strict fluid management. Thus, a need exists for an improved IDPN composition for administration to patients that diminishes hyperglycemia associated with IDPN administration and decreases the need for the administration of insulin with IDPN. Moreover, a need exists for a lower volume IDPN dosage form. 
       SUMMARY OF THE INVENTION 
       [0007]    The invention provides intradialytic parenteral nutrition (IDPN) solutions with low carbohydrate content and low volume. The IDPN solutions of the invention are effective in the treatment of malnutrition in patients receiving dialysis treatment. These solutions also reduce the need for insulin administration when administered to patients undergoing maintenance hemodialysis (MHD) patients. Moreover, patients with metabolic conditions that impair their glucose tolerance and metabolism would also benefit from the IDPN solutions of the invention. Also, patients with strict fluid management would benefit from the IDPN solutions of the invention. The IDPN solutions of the invention also include amino acids and, optionally, lipids and/or micronutrients such as vitamins, trace elements and/or minerals. In certain preferred embodiments the IDPN solutions are lipid free. In other preferred embodiments, the IDPN solutions of the invention are kept in containers for administration to patients, such as bags appropriate for parenteral administration. In one embodiment, each bag contains one dose of IDPN for a patient. In other embodiments, these doses are supplemented with pharmaceuticals, such as insulin. These doses are often administered subcutaneously using a separate administration system. 
     
    
     DETAILED DESCRIPTION 
       [0008]    The invention provides intradialytic parenteral nutrition (IDPN) solutions with low carbohydrate and low volume. The IDPN solutions of the invention allow medical personnel to engage in reduced carbohydrate management for MHD patients when they receive IDPN. Moreover, the IDPN solutions of the invention are particularly effective for treating malnutrition in MHD patients who have glucose management difficulties including patients that are insulin resistant, who have type I diabetes or pancreatitis. Also, the reduction of carbohydrate in the IDPN solutions of the invention favors anabolism over catabolism, thus effectively treating malnutrition. In preferred embodiments, the IDPN solutions of the invention have reduced volume, so as to reduce side effects associated with high infusion volumes including dyspnea, increased respiratory rate, rhonchi edema, hypertension, and anxiety. The IDPN solutions of the invention are especially appropriate for patients that have adequate caloric intake but not protein intake. Further, the IDPN solutions of the invention can be administered to normal weight or obese patients. 
         [0009]    Preferably, the IDPN solutions of the invention contain carbohydrate and amino acids. In some embodiments of the IDPN solution of the invention, the solution also contains lipids. In other embodiments of the IDPN solution of the invention, the solution also contains micronutrients such as vitamins, trace elements and/or minerals. In other embodiments of the IDPN solution of the invention, the solution also contains pharmaceuticals such as insulin. In preferred embodiments, of the IDPN solution of the invention, pharmaceuticals are coadministered with the IDPN, but are not part of the IDPN solution. For example, insulin can be administered subcutaneously in a separate injection. Preferably, the carbohydrate contained in the IDPN solutions of the invention dextrose (D-glucose). The amino acids contained in the IDPN solutions of the invention include combinations of two or more of the standard 20 amino acids. Preferably, all 20 of the amino acids are administered in the IDPN solutions of the invention. More preferably, 17 amino acids are used. Preferably, the solution of amino acids used to make the IDPN solution of the invention is a concentrated solution and is used in the invention due to the benefits of low volume. Preferably the concentrated solution contains 15 g/mL of amino acids. More preferably, the concentrated solution contains 20 g/mL of amino acids. 
         [0010]    Preferably, the IDPN solutions of the invention contain between 0.02 and 0.10 g/mL of dextrose in solution. Preferably, the IDPN solutions of the invention contain between 0.04 and 0.08 g/mL of dextrose in solution. More preferably, the IDPN solutions of the invention contain between 0.05 and 0.07 g/mL of dextrose in solution. More preferably the IDPN solutions of the invention contains between 0.055 and 0.065 g/mL of dextrose in solution. In various embodiments of the IDPN solutions of the invention, the solutions contain 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09 or 0.10 g/mL of dextrose in solution. In other embodiments of the IDPN solutions of the invention, the solutions contain 0.055, 0.056, 0.057, 0.058, 0.059, 0.060, 0.061, 0.062, 0.063, 0.064 or 0.065 g/mL of dextrose in solution. 
         [0011]    Preferably, the IDPN solutions of the invention are packaged in sterile containers for administration to patients. Preferably, the sterile containers are bags used for parenteral administration of IDPN solutions to a patient. Preferably the bags hold between 100 mL of IDPN solution and 2 liters of IDPN solution. More preferably, the bags hold between 300 mL or 1 liter of IDPN solution. More preferably, the bags hold between 419 mL of IDPN solution and 809 mL of IDPN solution. More preferably, the bags hold between 350 mL and 635 mL of solution. 
         [0012]    Preferably, the IDPN solutions of the invention are packaged in sterile containers so that the sterile container holds one dose of IDPN solution for administration to a patient. Preferably the dose of IDPN solution has a volume between 100 mL of IDPN solution and 2 liters of IDPN solution. More preferably, the dose of IDPN solution has a volume between 350 mL or 635 mL of IDPN solution. More preferably, the dose of IDPN solution has a volume of 300, 342, 350, 383, 400, 419, 427, 450, 483, 500, 540, 550, 600, 613, 635, 700 or 809 mL. In conjunction with a volume associated with the IDPN solution of the invention, the term “about” means +/−10 mL per dose. 
         [0013]    Preferably, a dose of the IDPN solution of the invention contains between 10 and 50 g of dextrose. More preferably, a dose of the IDPN solution contains between 20 and 45 g of dextrose. More preferably, a dose of the IDPN solution contains 20, 23, 26, 30, 35 and 41 g of dextrose. In conjunction with an amount of dextrose associated with the IDPN solution of the invention, the term “about” means +/−1 g per dose. 
         [0014]    In some embodiments of the IDPN solution of the invention, the amount of dextrose in the IDPN solution is dependent upon the mass of the patient receiving the IDPN treatment. Generally, the IPDN solution of the invention contains a dose of dextrose less than 1 g/kg of body mass of the patient. For example, a patient with a mass between 34 and 39 kg would receive an IDPN solution containing 20 g of dextrose, a patient with a body mass between 40 and 44 kg would receive an IDPN solution containing 23 g of dextrose, a patient with a body mass between 45 and 51 kg would receive an IDPN solution containing 26 g of dextrose, a patient with a body mass between 52 and 59 kg would receive an IDPN solution containing 30 g of dextrose, a patient with a body mass between 60 and 69 kg would receive an IDPN solution containing 35 g of dextrose, and a patient with a body mass of 70 kg, or greater, would receive an IDPN solution containing 41 g of dextrose 
         [0015]    Preferably, the IDPN solutions of the invention contain between 0.10 and 0.20 g/mL of amino acids in solution. Preferably the IDPN solutions of the invention contain between 0.12 and 0.18 g/ml of amino acids in solution. More preferably the IDPN solutions of the invention contains between 0.15 and 0.17 g/mL of amino acids in solution. In various embodiments of the IDPN solutions of the invention, the solutions contain 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19 or 0.20 g/mL of dextrose in solution. In other embodiments of the IDPN solutions of the invention, the solutions contain 0.150, 0.151, 0.152, 0.153, 0.154, 0.155, 0.156, 0.157, 0.158, 0.159, 0.160, 0.161, 0.162, 0.163, 0.164, 0.165, 0.166, 0.167, 0.168, 0.169 or 0.170 g/mL of amino acids in solution. 
         [0016]    Preferably, a dose of the IDPN solution of the invention contains between 30 and 120 g of amino acids. More preferably, a dose of the IDPN solution contains between 51 and 110 g of amino acids. More preferably, a dose of the IDPN solution contains 50, 52, 52.5, 55, 60, 65, 68, 70, 75, 78, 80, 85, 90, 95, 100, 105 and 110 g of amino acids. In conjunction with an amount of amino acids associated with the IDPN solution of the invention, the term “about” means +/−3 g per dose. 
         [0017]    In some embodiments of the IDPN solution of the invention, the amount of amino acids in a dose of the IDPN solution is dependent upon the mass of the patient receiving the IDPN treatment. For example, a patient with a body mass between 34 and 39 kg would receive an IDPN solution containing 51 g of amino acids, a patient with a body mass between 40 and 44 kg would receive an IDPN solution containing 60 g of amino acids, a patient with a body mass between 45 and 51 kg would receive an IDPN solution containing 68 g of amino acids, a patient with a body mass between 52 and 59 kg would receive an IDPN solution containing 78 g of amino acids, a patient with a body mass between 60 and 69 kg would receive an IDPN solution containing 90 g of amino acids, and a patient with a body mass of 70 kg, or greater, would receive an IDPN solution containing 105 g of amino acids. 
         [0018]    In some embodiments of the IDPN solution of the invention, the solution also contain lipids. Preferably the lipids are emulsions of purified vegetable oil from soybean (Intraliipid® from Kabi Vitrum or Travamulsion® from Travenol) or safflower oil (Liposyn® from Abbott). IDPN solutions of the invention with lipids contain 5-30% lipid by volume. Preferably, IDPN solutions of the invention with lipids contain 10-20% lipid by volume. Lipids should not be added to IPDN solutions administered to patients with hyperlipemia, acute pancreatitis, lipid nephrosis or allergic reactions to eggs. 
         [0019]    In preferred embodiments of the IDPN solution of the invention, the solution is lipid free. 
         [0020]    In some embodiments of the IDPN solution of the invention, the solution also contains micronutrients such as vitamins, trace elements and/or minerals. Vitamins and minerals that are optionally added to the IDPN solutions of the invention include water soluble vitamins such as vitamin C, folic acid, vitamin B 1 , and vitamin B 6 , as well as multivitamins lacking vitamin K, and trace elements such as zinc, selenium, copper, chromium, and manganese. Minerals also include mineral salts such as sodium phosphate, and magnesium sulfate. 
         [0021]    In some embodiments of the IDPN solution of the invention, the solution also contains pharmaceutical compositions. One example of a pharmaceutical composition appropriate for inclusion in the IPDN solution of the invention is insulin. In some embodiments, insulin is added to the IDPN solution just prior to administration to the patient, because many solution container materials will absorb insulin. Preferably, insulin is coadministered independent of the IDPN solution. For example, the insulin can be subcutaneously injected during treatment with IDPN. Preferably 5-20 units of insulin is added with one dose of IDPN. 
         [0022]    Preferably, the IDPN solution of the invention is administered to dialysis patients who are suffering from malnutrition. A dialysis patient suffering from malnutrition can be identified by detecting evidence of protein or energy malnutrition and inadequate dietary protein intake, evidence of the inability to administer or tolerate adequate oral nutrition inclusive of supplements and tube feeding, and evidence that the combination or oral and/or enteral intake when combined with IDPN will meet the patient&#39;s nutritional needs. 
         [0023]    Administration of the IDPN solution of the invention generally coincides with the start of hemodialysis on a patient. During IDPN solution administration the patient should be monitored for glucose tolerance, protein status and/or fat status. Glucose monitoring includes blood glucose level before, during and after IDPN administration and monitoring the patient for symptoms of hyper or hypoglycemia. The symptoms of hyperglycemia include nausea, thirst, headache, vomiting and weakness. The symptoms of hypoglycemia include headache, dizziness, tremors, cold sweat, confusion, and faintness. The presence of hyper or hypoglycemia can then be confirmed through blood sugar analysis, such as via a fingerstick or arterial glucose level. To treat hyperglycemia, insulin is administered. To treat hypoglycemia the patient should receive 20-30 g of simple carbohydrates orally. Protein monitoring includes the monitoring of blood urea nitrogen (BUN) prior to dialysis and Kt/V which is a measure of dialysis adequacy. 
         [0024]    Fat monitoring includes a pre-dialysis triglyceride test prior to lipid infusion and then another following first lipid infusion to ensure that the patient is clearing lipids from the bloodstream. Also, sodium, potassium, phosphorus and magnesium levels should be monitored for the presence of refeeding syndrome. 
         [0025]    Generally, the IDPN solution of the invention is administered through a port post dialyzer of the dialysis machine being used to perform hemodialysis on the patient. In a preferred embodiment, the IDPN infusion is performed through the venous chamber of the dialysis machine. Examples of routes of parenteral administration include intravenous, intradermal, subcutaneous, and intraperitoneal administration. Any pharmaceutically acceptable carrier can be used in conjunction with the IDPN solution of the invention. The IDPN solution of the invention can be administered in the same manner prior art IDPN solutions have been administered. 
       EXAMPLES 
     Protein Repletion Formulas 
       [0026]    The following IDPN formulas were developed. These formulas are administered to a MHD patient requiring 3.25 hours or longer dialysis treatment time. The formulas are fat free and micronutrient free, but these components could easily be added. 
         [0000]                                                                          TABLE 1                               Total   FINAL       WEIGHT   CHO   AA   VOL   Kcals   (g/dl)                                34-39 Kg   29   ml   255   ml   (Approx. 50 cc   272 kcals   D5.9           20   gm   51   gm   fill) 334 ml       15.3AA       40-44 Kg   33   ml   300   ml   383 ml   318 kcals   D6.0           23   gm   60   gm           15.7AA       45-51 Kg   37   ml   340   ml   427 ml   360 kcals   D6.1           26   gm   68   gm           15.9AA       52-59 Kg   43   ml   390   ml   483 ml   414 kcals   D6.2           30   gm   78   gm           16.1AA       60-69 Kg   50   ml   450   ml   550 ml   479 kcals   D6.4           35   gm   90   gm           16.4AA            70+ Kg   59   ml   525   ml   635 ml   560 kcals   D6.5           41   gm   105   gm           16.6AA                    
The infusion rate schedule for subjects of each weight class are shown in Table 2, below.
 
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Weight class 
                 Week 1 Infusion Rate 
                 Week 2 Infusion Rate 
               
               
                   
               
             
             
               
                 34-39 kg 
                 50 mL/hour 
                 105 mL/hour 
               
               
                 40-44 kg 
                 60 mL/hour 
                 120 mL/hour 
               
               
                 45-51 kg 
                 65 mL/hour 
                 135 mL/hour 
               
               
                 52-59 kg 
                 75 mL/hour 
                 150 mL/hour 
               
               
                 60-69 kg 
                 85 mL/hour 
                 170 mL/hour 
               
               
                   70+ kg 
                 100 mL/hour  
                 195 mL/hour 
               
               
                   
               
             
          
         
       
     
         [0027]    The following formulations were made with a more dilute commercially available source of amino acids. 
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                   
                   
                   
                   
                 Total 
                 FINAL 
               
               
                 WEIGHT 
                 CHO 
                 AA 
                 VOL 
                 Kcals 
                 (g/dl) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 34-39 Kg 
                 29 
                 ml 
                 340 
                 ml 
                 (Approx. 50 cc 
                 272 kcals 
                 D4.8 
               
               
                   
                 20 
                 gm 
                 51 
                 gm 
                 fill) 419 ml 
                   
                 12.2AA 
               
               
                 40-44 Kg 
                 33 
                 ml 
                 400 
                 ml 
                 483 ml 
                 318 kcals 
                 D4.8 
               
               
                   
                 23 
                 gm 
                 60 
                 gm 
                   
                   
                 12.4AA 
               
               
                 45-51 Kg 
                 37 
                 ml 
                 453 
                 ml 
                 540 ml 
                 360 kcals 
                 D4.8 
               
               
                   
                 26 
                 gm 
                 68 
                 gm 
                   
                   
                 12.6AA 
               
               
                 52-59 Kg 
                 43 
                 ml 
                 520 
                 ml 
                 613 ml 
                 414 kcals 
                 D4.9 
               
               
                   
                 30 
                 gm 
                 78 
                 gm 
                   
                   
                 12.7AA 
               
               
                 60-69 Kg 
                 50 
                 ml 
                 600 
                 ml 
                 700 ml 
                 479 kcals 
                 D5.0 
               
               
                   
                 35 
                 gm 
                 90 
                 gm 
                   
                   
                 12.9AA 
               
               
                      70+ Kg 
                 59 
                 ml 
                 700 
                 ml 
                 809 ml 
                 560 kcals 
                 D5.1 
               
               
                   
                 41 
                 gm 
                 105 
                 gm 
                   
                   
                 13.0AA