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Doubling Calcium and Phosphate Concentrations in Neonatal Parenteral Nutrition Solutions Using Monobasic Potassium Phosphate

Department of Pharmacy (J.C.W., A.R.M., M.T.)
Division of Neonatology (J.A., P.C.)
Children’s and Women’s Health Centre of BC, Vancouver, British Columbia, Department of Pharmacy, Hospital Ste-Justine, Montreal, Quebec (M.P.), CANADA

Address correspondence to: Philippe Chessex, M.D., FRCP_C, Division of Neonatology, Children’s and Women’s Health Centre of BC, 4480 Oak Street, Vancouver, British Columbia V6H 3V4, CANADA. E-mail: pchessex{at}cw.bc.ca

	ABSTRACT

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Background: Premature infants require high intakes of Ca and P to mimic fetal accretion rates. With the current phosphate salt used, adequate amounts cannot be provided due to the precipitation of Ca and P in TPN solutions.

Objective: To compare monobasic potassium phosphate (monobasic regimen) and monobasic plus dibasic potassium phosphate (dibasic regimen) on calcium phosphate solubility in 5 amino acid products, and to determine whether solubility differences observed in these products can be explained by buffering capacity.

Methods: TPN solutions were prepared according to standard clinical practice. The following amino acid products were used at 3% concentrations: Primene, Vamin N, TrophAmine, Aminosyn-PF, and Travasol. Dextrose 10%, standard electrolytes, heparin, vitamins and trace elements were added. Calcium (as gluconate) and phosphate (as monobasic or dibasic regimen) were added in one-to-one molar ratios from 0–45 mmol/L. Solutions were inspected macroscopically and microscopically for precipitation under three conditions: immediately, 24 h after preparation at room temperature, and 3 h later in a 37°C water bath. Buffering capacity was determined for each amino acid product by titrating with standardized 0.1 M NaOH.

Results: Variations in Ca:P solubility and buffer capacity exist between amino acid solutions. With Primene and Vamin no macroscopic or microscopic precipitation was detected up to 45 mmol/L using monobasic regimen, compared to 25 mmol/L using dibasic regimen with Trophamine. Buffer capacity did not account for the solubility differences observed between the five amino acid products, which were related to the pH of the final solution.

Conclusions: These data will allow clinicians to double the current concentrations of calcium and phosphate in neonatal TPN solutions using monobasic regimen. Although this is particularly relevant to situations when fluid intake is restricted, the effect of the acid load needs to be investigated in extremely low birth weight infants.

Key words: total parenteral nutrition, mineral content, solubility, phosphate, calcium, neonatal

	INTRODUCTION

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Premature neonates and neonates requiring prolonged total parenteral nutrition (TPN) are susceptible to the development of osteopenia and bone fractures [1–3]. Although the pathogenesis is multifactorial, it is generally accepted that the main cause is insufficient intake of calcium and phosphorus [4–6]. There is no consensus on optimal parenteral requirements for calcium and phosphorus, but the third-trimester fetal accretion rates of 3.5 mmol/kg/day (140 mg/kg/day) for calcium and 2.4 mmol/kg/day (75 mg/kg/day) for phosphorus are commonly used as guidelines [6]. The ability to provide neonates with these amounts is restricted due to the precipitation of calcium and phosphate in TPN solutions. This incompatibility is of concern due to the limited bioavailability of these minerals and the potential for serious clinical complications [7] including death [8]. In addition, catheter occlusion represents a clinical problem in relation to vascular access [9–12].

There are many factors which affect the solubility of calcium and phosphate, including pH, temperature, time, calcium and phosphate concentrations, amino acid concentration [13–21], amino acid product [13,19,21], lipid emulsions [13,17,21], inorganic or organic phosphates [22–24], dextrose concentration [13,14,16], order of addition of calcium and phosphate [15], calcium salt [25], and magnesium concentration [26]. A critical component of the calcium phosphate compatibility issue is the nature of the phosphate salts used. Traditionally, potassium phosphate has been supplied in TPN solutions as a mixture of monobasic and dibasic salts (henceforth "dibasic regimen"). Monobasic potassium phosphate (henceforth "monobasic regimen") is also available in Canada.

The greatest danger of precipitation in TPN solutions results from the formation of dibasic calcium phosphate, which is practically insoluble in water (30mg/100 mL). Monobasic calcium phosphate is approximately 60 times more soluble (1800mg/100 mL) [27]. As pH rises, more dibasic phosphate becomes available to bind with calcium and precipitate [13]. This is governed by the phosphate equilibrium:

At physiological pH (7.4), approximately 60% of the phosphate is in the dibasic form. Although this increase in pH would seem to favour formation of dibasic calcium phosphate, precipitation on contact with the bloodstream is unlikely because of rapid hemodilution [27]. Several studies have found that relatively small changes in solution pH cause dramatic changes in calcium and phosphate solubility. This suggests that the intrinsic titratable acidity of the various amino acid products may have the most significant influence on solubility [19,21]. The titratable acidity will also depend on the buffering capacity of the various preparations [28].

As increased parenteral intakes of calcium and phosphorus result in greater retention of these minerals and greater bone mineral content [29], the objective of this study was to investigate ways of increasing calcium and phosphate concentrations in TPN solutions by influencing solubility using different phosphate salts and amino acid products. To achieve this objective, we compared the effect of monobasic regimen and dibasic regimen on calcium phosphate solubility in five clinically relevant amino acid products, and determined whether solubility differences in various amino acid products can be explained by buffering capacity.

	METHODS

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Solution Preparation
All solutions were prepared according to standard clinical practice. Each solution was compounded using aseptic techniques in 2 L polyvinyl chloride bags under a Class 100 laminar airflow hood at room temperature (25°C). An Automix® 3 + 3 Compounder (Clintec Nutrition Company, Deerfield, Illinois, USA) was used to pump each bag with amino acid solution, dextrose 50% (Baxter Corporation, Toronto, Ontario, Canada), and sterile water for injection (Baxter Corporation). A Micromix® Compounder (Clintec Nutrition Company) was used to add all other components of a complete TPN solution except for calcium and phosphate, including sodium, magnesium, zinc, heparin, multivitamins, and trace elements. Since Vamin N and TrophAmine are pre-manufactured with various electrolytes, the quantities added were adjusted to meet standard concentrations. The five most common amino acid solutions in Canada [30] were used: Primene 10% (Baxter Corporation), Vamin N 7% (Fresenius Kabi AB, Uppsala, Sweden), TrophAmine 10% (B. Braun Medical Inc., Irvine, CA, USA), Aminosyn-PF 10% (Abbott Laboratories, Ltd., Saint-Laurent, Quebec, Canada), and Travasol 10% Blend C (Baxter Corporation). All amino acid solutions were prepared in concentrations of 3%. The composition of these bulk solutions is shown in Table 1. The "fill-up sequence" was determined by the stability of the various components and according to manufacturers’ recommendations. Following the manufacturers recommendation Trophamine 10% and Aminosyn-PF 10% were supplemented with 40 mg HCl cysteine/g amino acid [31,32]. The experiments were also repeated without the addition of cysteine to Trophamine and Aminosyn-PF. This was justified by reporting the potential effects that intermittent difficulties in provisioning HCl cysteine may have on Ca-P solubility. Cysteine was not added to the other studied solutions either because they already contain this amino acid (Primene and Vamin) or because it is not specifically recommended by the manufacturer (Travasol). We did not attempt to normalize cysteine concentration between the studied amino acid solutions because cysteine has been shown to have poor bioavailability due to formation of adducts with dextrose in TPN solutions [33,34].

Macroscopic and Microscopic Analysis
Samples were examined under three different conditions by a single observer (JA): immediately after preparation (t = 0 h), 24 hours after preparation at room temperature (t = 24 h), and 3 hours after incubation in a 37°C water bath (t = 27 h). Under each condition, macroscopic and microscopic analyses were performed. The macroscopic analysis involved vigorous agitation of each mini-bag prior to inspection for the presence of haze or gross precipitation using a strong light and a dark background. The microscopic analysis involved examination of two drops of each solution using a light microscope (Carl Zeiss, West Germany) under powers of 10x, 40x, and 100x to detect the presence of calcium phosphate crystals. Precipitation was deemed to occur with the presence of a single crystal. Three determinations were performed for each sample. This technique was validated by verifying that the limit of precipitation detected microscopically did not vary over multiple samples of the same TPN solution. A 3 mL aliquot of each sample was withdrawn to determine the pH at each phase using a PerpHecT Meter Model 320 (Thermo Orion, Beverly, MA, USA) calibrated to pH 4.0 and 7.0.

Determination of Titratable Acidity
Sodium hydroxide (NaOH) was standardized to 0.1036 M by titration with three samples of potassium hydrogen phthalate (Sigma-Aldrich Co., St. Louis, MO, USA). Each amino acid solution was diluted with sterile water for injection to achieve a concentration of 3.0%. A 25 mL aliquot was measured with a volumetric pipette, transferred to a beaker and titrated with 0.1036 M NaOH. The solution was continuously mixed using a magnetic stir rod. A 1 cm thick styrofoam sheet was placed between the stirring motor and the beaker to prevent transfer of heat and alteration of pH. The burette was covered with parafilm to prevent NaOH degradation. The pH was recorded after each 0.5 mL addition of NaOH up to a pH of 7. Each solution was titrated in triplicate. Buffer capacity was calculated as follows [28,35]:

where V_NaOH is the volume (mL) of sodium hydroxide added to the solution; M_NaOH is the molarity (mmol/mL) of sodium hydroxide; V_S is the volume (L) of amino acid solution titrated; and pH is the difference between the solution’s initial pH and the endpoint pH.

Statistics
Results are expressed as mean ± standard deviation. Analysis of variance was performed on repeated measures to document the differences in buffering capacity and the effect of monobasic and dibasic phosphorus on pH of solutions compared to control. Linear regression was used to analyze the difference in buffering capacity between amino acids solutions. The level of significance was set at p < 0.05.

	RESULTS

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Fig. 1 illustrates the effect of the phosphate salt and the selection of amino acid solution on the solubility of calcium and phosphate. The bar graphs represent the maximum concentration attainable without macroscopic or microscopic evidence of precipitation under any condition of time and temperature. The maximum concentration achievable was 1.7–3.5 times greater with use of the monobasic regimen. Using monobasic phosphate, the solubility was greatest in Primene and Vamin N solutions, allowing for solubilization of at least 45 mmol/L of calcium and phosphate. Using the dibasic regimen the solubility was greatest in Trophamine +HCl cysteine, allowing for a solubilization of 25 mmol/L compared to 10 mmol/L of Ca and P without the addition of HCL cysteine (data not shown). For Aminosyn PF the amounts of calcium and phosphorus solubilized with and without added HCL cysteine were 15 and 10 mmol/L, respectively.

View larger version (45K): [in this window] [in a new window]   Fig. 1. Maximum concentration of calcium and phosphate attainable without macroscopic or microscopic evidence of precipitation in various amino acid solutions using monobasic or dibasic regimen. Trophamine and Aminosyn-PF are prepared with 40 mg HCL cysteine/g amino acid.

View larger version (53K): [in this window] [in a new window]   Fig. 2. Evidence of precipitation using the dibasic regimen in various amino acid solutions at increasing calcium and phosphate concentrations in a 1:1 molar ratio. Solutions were observed at three phases: immediately (t = 0 h), 24h after preparation (ppt) at room temperature (t = 24 h), and 3 hours at 37°C following 24h at room temperature (t = 27 h). Within each phase, macroscopic analysis was performed with subsequent microscopic analysis. Trophamine and Aminosyn-PF are prepared with added 40 mg HCL cysteine/g amino acid.

View larger version (52K): [in this window] [in a new window]   Fig. 3. Evidence of precipitation using the monobasic regimen in various amino acid solutions at increasing calcium and phosphate concentrations in a 1:1 molar ratio. Solutions were observed at three phases: immediately (t = 0 h), 24h after preparation (ppt) at room temperature (t = 24 h), and 3 hours at 37°C following 24h at room temperature (t = 27 h). Within each phase, macroscopic analysis was performed with subsequent microscopic analysis. Trophamine and Aminosyn-PF are prepared with added 40 mg HCL cysteine/g amino acid.

View larger version (20K): [in this window] [in a new window]   Fig. 4. Titration curves of five 3% amino acid solutions using standardized 0.1 M sodium hydroxide. Variance is not depicted when it is smaller than the size of the symbol. Trophamine and Aminosyn-PF are prepared with added 40 mg HCL cysteine/g amino acid.

	DISCUSSION

In preterm neonates, greater protein intakes are required to achieve fetal intrauterine protein accretion rates. Thureen et al. reported that high (3 g/kg/day) amino acid intakes were well tolerated in the early neonatal period and resulted in increased protein accretion [36]. In this study, we used 3.85 g/kg/day of amino acids which is recommended to achieve intrauterine accretion rates. We also used a 1:1 molar ratio (1.3:1 weight/weight ratio) of calcium to phosphate. Pelegano et al [37] showed that the 1.3:1 Ca:P molar ratio was associated with the optimal mineral retention, when comparing three different Ca:P malor ratios (1.6:1; 1.3:1; 1:1). Although the best Ca:P ratio for achieving an optimal solubility in TPN solutions may not coincide with the best Ca:P ratio for promoting optimal mineral retention, future studies should consider evaluating the use of a 1.3:1 molar ratio (1.7:1 weight/weight ratio).

There are conflicting reports of the effect of lipid emulsions on pH, with some studies showing a decrease in pH [17], and some showing an increase [13,21]. Since it is impossible to inspect a solution for signs of precipitation in the presence of lipids, studies have mimicked the final pH of a 3-in-1 mixture by using hydrochloric acid or sodium bicarbonate [13,17,21]. In these studies, the change in pH was usually 0.1 units [17,21], particularly with higher concentrations of amino acids [13].

Temperature and time are also factors affecting calcium phosphate solubility. An increase in temperature increases the dissociation of calcium and allows more free calcium to precipitate with phosphate [13]. In contrast to previous studies in which solutions were warmed for 30 minutes [13,17], we proposed that 3 hours would be a clinically more relevant time to allow precipitation to occur, because of the slow infusion rates used in the nursery. It can take up to 4 hours for a TPN solution to travel through the tubing from the bag to a neonate [38], with up to 2h spent transiting through the incubator where the environmental temperature can reach 37°C.

As emphasized in previous studies, solutions are clinically acceptable only if the absence of precipitation can be guaranteed under all conditions [17]. In this study, we included any sign of macroscopic or microscopic precipitation that occurred, regardless of temperature or time. We simulated a clinical scenario in which TPN solutions may sit at room temperature for 24 hours, pass into a heated incubator through a catheter, and slowly infuse into a neonate. All components of a complete TPN solution were added. Although monovalent ions rarely cause solubility issues [39], magnesium has been reported to be an issue [26].

Several authors have studied alternate methods of increasing calcium phosphate solubility, including lowering pH, using organic phosphate salts, and alternating calcium and phosphate infusions. The manufacturers of TrophAmine and Aminosyn-PF advocate the use of cysteine hydrochloride with their products to produce plasma amino acid concentrations similar to those of breast-fed infants [31,32]. Our results confirm that the addition of cysteine increases the threshold of calcium and phosphate precipitation due to its pH-lowering effects [17–19,21].

Organic phosphates (glucose-1-phosphate, glycerophosphate, and fructose-1,6-diphosphate) have been studied in an effort to achieve greater calcium and phosphate compatibility [22–24,40–42]. Since the phosphate group is not fully ionized, the potential for precipitation with calcium ions is limited [42]. Calcium glycerophosphate has been evaluated in one pediatric study, which showed no evidence of precipitation in comparison to calcium gluconate and dibasic regimen [23]. However, Ca & P concentrations were lower than in the present study. Alternate day calcium and phosphate solutions have been abandoned due to serum calcium and phosphate disturbances, secondary hyperparathyroidism, increased urinary excretion and poor mineral retention [43,44].

Use of monobasic regimen allows solubilization of high amounts of calcium and phosphate without evidence of macroscopic or microscopic precipitation. This margin of safety is important to allow room for variability in the clinical setting limiting total fluid intake. It is beneficial in circumstances in which lipid emulsions are desired [13] or there are changes in enteral intake, fluctuations in albumin, elevated core body temperature and changes in medications that may affect solubility [45]. In addition, there is considerable variation in the pH of some TPN constituents, particularly dextrose which can vary from 3.2 to 6.5 [46].

The maintenance potassium range for a neonate is 2–3 mmol/kg/day. Monobasic regimen provides an equivalent amount of potassium for each mmol of phosphate. Recommendations for TPN solutions are to provide 19.2 mmol/L (2.5 mmol/kg/day) of potassium [47]. Assuming an intake of 130 ml/kg/day of amino acid solution, we are able to solubilize sufficient minerals to provide 1.6 mmol/kg/day calcium (63 mg/kg/day) and dibasic phosphate (48 mg/kg/day). By doubling the concentration to 24 mmol/L (3.2 mmol/kg/day) with monobasic phosphate, we would be within the limitations of recommended potassium intake (3.1 mmol/kg/day) and achieve calcium provisions of 125 mg/kg/day and phosphorus provisions of 97 mg/kg/day. These amounts approach intrauterine accretion rates during the last trimester.

Upon doubling the current concentrations of calcium and phosphate, concern exists that the solutions would be hyperosmolar. However, a solution containing Primene 3% and dextrose 10% would have the following calculated osmolarities: (a) using 12 mmol/L of calcium and dibasic phosphate (the current regimen): 847.9 mOsm/L; and (b) using 24 mmol/L of calcium and monobasic phosphate (the proposed regimen): 901.5 mOsm/L. This increase in osmolality may limit the use of peripheral iv. sites, as osmolality has been shown to limit venous patency in those conditions [48].

We have previously evaluated the use of monobasic phosphate in sixteen parenterally fed low birth weight infants [49]. No difference was observed between monobasic and dibasic regimens on balance data or biochemical monitoring with concentrations of calcium at 0.9 mmol/kg/day (35 mg/kg/day) and phosphorus at 1 mmol/kg/day (30 mg/kg/day). The monobasic regimen enabled increased intakes of calcium (1.8 mmol/kg/day; 70 mg/kg/day) and phosphorus (1.7 mmol/kg/day; 55 mg/kg/day) resulting in improved mineral balance, but also increased calciuria and metabolic acidosis. This could be explained by the liberation of hydrogen ions, once monobasic potassium phosphate reaches the higher pH of the bloodstream and reverts to its physiological equilibrium with dibasic phosphate salts. On the other hand, it could be indirect evidence of enhanced bone mineralization through the formation of hydroxyapatite and the release of hydrogen ions. The paper by Prestridge et al reporting the effect of increased mineral intakes did however not indicate whether the resulting increase in bone mineral content was associated with acidosis [29]. Complications related to metabolic acidosis should be closely monitored when infusing monobasic regimen in more immature preterm infants, if they receive TPN regimens that have a lower pH or if they receive higher mineral intakes. By partly replacing chloride with acetate in neonatal solutions of parenteral nutrition there is a documented reduction in hyperchloremia and in metabolic acidosis with a subsequent decrease in the use of alkali treatment [50]. A greater number of neonatal centers have been using acetate successfully in clinical practice [51]. In addition, increased calciuria should be monitored despite the lack of a strong cause-to-effect relationship between increased calciuria on nephrocalcinosis, both associated with the use of diuretics in premature infants [52].

In conclusion, use of the monobasic regimen greatly enhances the solubility of calcium and phosphate. It grants clinicians a greater degree of flexibility when prescribing neonatal TPN solutions without the complications of calcium phosphate precipitation. The difference in calcium phosphate solubility documented between various amino acid preparations is not attributable to observed differences in buffering capacity.

	ACKNOWLEDGMENTS

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The authors would like to thank the Department of Pharmacy, Children’s and Women’s Health Centre of B.C., and the B.C. Research Institute for Children’s & Women’s Health Centre, for their support of this project.

Received December 17, 2004. Accepted October 11, 2005.

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