40:12 Replacement Preparations
Generic Name
| Special Alerts:
February 9, 2023 TOPIC: Unapproved Potassium Phosphates Drug Product by Hospira: Safety Alert - Infants at Risk for Aluminum Toxicity AUDIENCE: Patient, Health Professional, Pharmacy, Pediatrics ISSUE: The FDA is warning health care professionals and pharmacies to avoid using Hospira's unapproved potassium phosphates drug product in pediatric patients because the aluminum exposure from this product is unsafe for this population. This product alone may produce daily aluminum exposures of up to twice the FDA-recommended limit for parenteral nutrition, with additional aluminum exposure expected from the other components of parenteral nutrition. Patients on prolonged courses of parenteral nutrition support are at greatest risk of exposure to toxic levels of aluminum. Exposure to toxic levels of aluminum can lead to softening of the bones (osteomalacia), reduced bone mineralization, neurological dysfunction, microcytic hypochromic anemia, and reduction or stoppage of bile flow (cholestasis). BACKGROUND: The potassium phosphates injections are phosphorus replacement products intended for use as a source of phosphorus in IV fluids to correct hypophosphatemia and for parenteral nutrition in adults and pediatric patients. RECOMMENDATIONS: The FDA recommends health care providers use an FDA-approved potassium phosphates injection product with the aluminum content level considered acceptable for each patient based on age, weight, and recommended dose of phosphorus. These FDA-approved products provide detailed dosing instructions for preparation and administration to minimize the risk of aluminum toxicity.
For more information, see the full alert on the FDA website: www.fda.gov/drugs/drug-safety-and-availability/infants-risk-aluminum-toxicity-unapproved-potassium-phosphates-drug-product. |
Potassium phosphates is available as a concentrate for injection in 5- or 15-mL single-dose vials and in a 50-mL pharmacy bulk package.3594; 3595; 3596 The concentrate for injection must be diluted for use.3594; 3595; 3596
Each mL of the Fresenius Kabi and Hospira products contains monobasic potassium phosphate 224 mg and dibasic potassium phosphate 236 mg in water for injection.3594; 3596 The phosphate concentration of the concentrate for injection is 3 mmol/mL, and the potassium concentration is 4.4 mEq/mL.3594; 3596
Each mL of the CMP Pharma product contains monobasic potassium phosphate 175 mg and dibasic potassium phosphate 300 mg in water for injection.3595 The phosphate concentration of the concentrate for injection is 3 mmol/mL, and the potassium concentration is 4.7 mEq/mL.3595
The relationship between milliequivalents and millimoles of phosphate is expressed in the following equation:
mEq phosphate = mmol phosphate × valence
However, the average valence of phosphate changes with changes in pH. Consequently, it is necessary to specify a pH before the valence, and therefore the milliequivalents, can be determined. To avoid this problem, it has been suggested that doses of phosphate be expressed in terms of millimoles, which is independent of valence.178; 716; 717; 718 Alternatively, the dose may be expressed in terms of milligrams of phosphorus: 1 millimole of phosphorus equals 31 mg.205; 717; 3594; 3595; 3596
pH
Potassium phosphates injection (Fresenius Kabi) is stated to have a pH of 6 to 7.3594
Potassium phosphates injection (CMP Pharma) is stated to have a pH of 6.5 to 7.5.3595
Osmolarity
The calculated osmolarity of potassium phosphates injection (Fresenius Kabi, Hospira) is 7.4 mOsm/mL.3594; 3596
The calculated osmolarity of potassium phosphates injection (CMP Pharma) is 7.7 mOsm/mL.3595
Aluminum Content
Potassium phosphates injection (Fresenius Kabi) contains no more than 2000 mcg of aluminum per L.3594
Potassium phosphates injection (CMP Pharma) contains no more than 15,000 mcg of aluminum per L.3595
Potassium phosphates injection (Hospira) contains no more than 31,000 mcg of aluminum per L.3596
Potassium phosphates injection is administered by intravenous infusion only after dilution or admixing in a larger volume of fluid; the concentrate for injection is not for direct infusion.3594; 3595; 3596 Administration of undiluted or insufficiently diluted potassium phosphates injection and administration by rapid infusion (e.g., over 1 to 3 hours) or by bolus or rapid intravenous push has resulted in serious and sometimes fatal adverse effects.3594; 3595
When the drug is used diluted in intravenous fluids for the correction of hypophosphatemia in adults and pediatric patients 12 years of age or older, the appropriate dose of potassium phosphates should be diluted to a total volume of 100 to 250 mL in sodium chloride 0.9% or dextrose 5%.3594; 3595 For peripheral venous administration, Fresenius Kabi states that the maximum recommended concentration is 6.8 mmol of phosphate/100 mL and the maximum recommended rate of administration is 6.8 mmol of phosphate/hr.3594 For peripheral venous administration, CMP Pharma states that the maximum recommended concentration is 6.4 mmol of phosphate/100 mL and the maximum recommended rate of administration is 6.4 mmol of phosphate/hr.3595 For central venous administration, manufacturers state that the maximum recommended concentration is 18 mmol of phosphate/100 mL and the maximum recommended rate of administration is 15 mmol of phosphate/hr.3594; 3595
When the drug is used diluted in intravenous fluids for the correction of hypophosphatemia in pediatric patients less than 12 years of age, the appropriate dose of potassium phosphates should be diluted in the smallest recommended volume, taking into consideration the daily fluid requirements and the maximum concentrations recommended for peripheral and central venous administration.3594 For peripheral venous administration, the manufacturer states that the maximum recommended concentration is 0.27 mmol of phosphate/10 mL.3594 For central venous administration, the manufacturer states that the maximum recommended concentration is 0.55 mmol of phosphate/10 mL.3594
When the drug is used in parenteral nutrition admixtures, the appropriate dose of potassium phosphates injection should be added to the parenteral nutrition solution after the addition of amino acids, dextrose, and electrolyte solutions and prior to the addition of lipid emulsion, if included.3594; 3595 Selection of the peripheral or central venous route depends upon the osmolarity of the final infusate.3594; 3595 Manufacturers state that solutions with an osmolarity of 900 mOsm/L or more must be infused through a central vein.3594; 3595
The infusion set and catheter should be checked periodically during administration for precipitates.3594; 3595 Peripheral venous administration of the diluted and admixed drug can cause thrombophlebitis.3594; 3595 If thrombophlebitis develops, the catheter should be removed as soon as possible and appropriate treatment should be initiated.3594; 3595
Potassium phosphates injection is a clear and colorless solution.3594; 3595; 3596 Intact vials of potassium phosphates injection (Fresenius Kabi, Hospira) should be stored at controlled room temperature.3594; 3596 Intact vials of potassium phosphates injection (CMP Pharma) should be stored at 2 to 8°C and should not be frozen.3595
Solutions should be visually inspected for particulate matter and discoloration prior to and after dilution, and again prior to administration of the diluted solution for infusion or admixture.3594; 3595; 3596
Fresenius Kabi states that diluted solutions of potassium phosphates for infusion in dextrose 5% and sodium chloride 0.9% are stable for 4 hours at 20 to 25°C and 14 days at 2 to 8°C.3594 CMP Pharma states that diluted solutions of potassium phosphates for infusion in dextrose 5% and sodium chloride 0.9% are stable for 48 hours at 20 to 25°C and 2 to 8°C.3595
Manufacturers state that parenteral nutrition admixtures to which potassium phosphates injection has been added should be inspected both after mixing and prior to administration to ensure that precipitates have not formed and that the emulsion has not separated, in the case that lipid emulsion has been added.3594; 3595 Parenteral nutrition admixtures to which potassium phosphates injection has been added should be used promptly after mixing.3594; 3595 Any storage of the admixtures should be limited to no longer than 24 hours at 2 to 8°C protected from light.3594; 3595 After removal from refrigeration, admixtures should be allowed to come to room temperature and should be used promptly, with completion of the infusion within 24 hours.3594; 3595 Any admixture remaining after that time should be discarded.3594; 3595
Unused portions of single-dose vials should be discarded.3594; 3595; 3596 The pharmacy bulk package should be discarded within 4 hours of initial entry.3594
Drugs in Syringe Compatibility
Y-Site Injection Compatibility (1:1 Mixture)
Additional Compatibility Information
Infusion Solutions
Potassium phosphates injection diluted for infusion should not be infused with calcium-containing intravenous fluids.3594; 3595
Calcium and Phosphate
UNRECOGNIZED CALCIUM PHOSPHATE PRECIPITATION IN A 3-IN-1 PARENTERAL NUTRITION MIXTURE RESULTED IN PATIENT DEATH.
The potential for the formation of a calcium phosphate precipitate in parenteral nutrition solutions is well studied and documented,1771; 1777 but the information is complex and difficult to apply to the clinical situation.1770; 1772; 1777 The incorporation of lipid emulsion in 3-in-1 parenteral nutrition solutions obscures any precipitate that is present which has led to substantial debate on the dangers associated with 3-in-1 parenteral nutrition mixtures and when or if the danger to the patient is warranted therapeutically.1770; 1771; 1772; 2031; 2032; 2033; 2034; 2035; 2036 Because such precipitation may be life-threatening to patients,2037; 2291 FDA issued a Safety Alert containing the following recommendations:1769
Calcium Phosphate Precipitation Fatalities
Fatal cases of paroxysmal respiratory failure in 2 previously healthy women receiving peripheral vein parenteral nutrition were reported. The patients experienced sudden cardiopulmonary arrest consistent with pulmonary emboli. The authors used in vitro simulations and an animal model to conclude that unrecognized calcium phosphate precipitation in a 3-in-1 total nutrition admixture caused the fatalities. The precipitation resulted during compounding by introducing calcium and phosphate near to one another in the compounding sequence and prior to complete fluid addition. This resulted in a temporarily high concentration of the drugs and precipitation of calcium phosphate. Observation of the precipitate was obscured by the incorporation of 20% lipid emulsion, intravenous, into the nutrition mixture. No filter was used during infusion of the fatal nutrition admixtures.2037
In a follow-up retrospective review, 5 patients were identified who had respiratory distress associated with the infusion of the 3-in-1 admixtures at around the same time. Four of these 5 patients died, although the cause of death could be definitively determined for only 2.2291
Calcium and Phosphate Conditional Compatibility
Calcium salts are conditionally compatible with phosphate in parenteral nutrition solutions. The incompatibility is dependent on a solubility and concentration phenomenon and is not entirely predictable. Precipitation may occur during compounding or at some time after compounding is completed.
NOTE: Some amino acids solutions inherently contain calcium and phosphate, which must be considered in any projection of compatibility.
The compatibility of calcium and phosphate in several parenteral nutrition formulas for newborn infants was evaluated. Calcium gluconate 10% (Cutter) and potassium phosphate (Abbott) were used to achieve concentrations of 2.5 to 100 mEq/L of calcium and 2.5 to 100 mmol/L of phosphorus added. The parenteral nutrition solutions evaluated were as shown in Table 1. The results were reported as graphic depictions.
Table 1. Parenteral Nutrition Solutions Evaluated609
| Solution Number | ||||
|---|---|---|---|---|
| Component | #1 | #2 | #3 | #4 |
| FreAmine III | 4% | 2% | 1% | 1% |
| Dextrose | 25% | 20% | 10% | 10% |
| pH | 6.3 | 6.4 | 6.6 | 7.0a |
aAdjusted with sodium hydroxide.
The pH dependence of the phosphate-calcium precipitation has been noted. Dibasic calcium phosphate is very insoluble, while monobasic calcium phosphate is relatively soluble. At low pH, the soluble monobasic form predominates; but as the pH increases, more dibasic phosphate becomes available to bind with calcium and precipitate. Therefore, the lower the pH of the parenteral nutrition solution, the more calcium and phosphate can be solubilized. Once again, the effects of temperature were observed. As the temperature is increased, more calcium ion becomes available and more dibasic calcium phosphate is formed. Therefore, temperature increases will increase the amount of precipitate.609
Similar calcium and phosphate solubility curves were reported for neonatal parenteral nutrition solutions using TrophAmine (McGaw) 2, 1.5, and 0.8% as the sources of amino acids. The solutions also contained dextrose 10%, with cysteine and pH adjustment being used in some admixtures. Calcium and phosphate solubility followed the patterns reported previously.609 A slightly greater concentration of phosphate could be used in some mixtures, but this finding was not consistent.1024
Using a similar study design, 6 neonatal parenteral nutrition solutions based on Aminosyn-PF (Abbott) 2, 1.5, and 0.8%, with and without added cysteine hydrochloride and dextrose 10% were studied. Calcium concentrations ranged from 2.5 to 50 mEq/L, and phosphate concentrations ranged from 2.5 to 50 mmol/L. Solutions sat for 18 hours at 25°C and then were warmed to 37°C in a water bath to simulate the clinical situation of warming prior to infusion into a child. Solubility curves were markedly different than those for TrophAmine in the previous study.1024 Solubilities were reported to decrease by 15 mEq/L for calcium and 15 mmol/L for phosphate. The solutions remained clear during room temperature storage, but crystals often formed on warming to 37°C.1211
However, these data were questioned. The similarities between the Aminosyn-PF and TrophAmine products were noted, and little difference was found in calcium and phosphate solubilities in a preliminary report.1212 In the full report,1213 parenteral nutrition solutions containing Aminosyn-PF or TrophAmine 1 or 2.5% with dextrose 10 or 25%, respectively, plus electrolytes and trace metals, with or without cysteine hydrochloride, were evaluated under the same conditions. Calcium concentrations ranged from 2.5 to 50 mEq/L, and phosphate concentrations ranged from 5 to 50 mmol/L. In contrast to the previous results,1024 the solubility curves were very similar for the Aminosyn-PF and TrophAmine parenteral nutrition solutions but very different from those of the previous Aminosyn-PF study.1211 The authors again showed that the solubility of calcium and phosphate is greater in solutions containing higher concentrations of amino acids and dextrose.1213
Calcium and phosphate solubility curves for TrophAmine 1 and 2% with dextrose 10% and electrolytes, vitamins, heparin, and trace elements were reported. Calcium concentrations ranged from 10 to 60 mEq/L, and phosphorus concentrations ranged from 10 to 40 mmol/L. Calcium and phosphate solubilities were assessed by analysis of the calcium concentrations and followed patterns similar to those reported previously.608; 609 The higher percentage of amino acids (TrophAmine 2%) permitted a slightly greater solubility of calcium and phosphate, especially in the 10 to 50-mEq/L and 10 to 35-mmol/L ranges, respectively.1614
The maximal product of the amount of calcium (as gluconate) times phosphate (as potassium) that can be added to a parenteral nutrition solution, composed of amino acids 1% (Travenol) and dextrose 10%, for preterm infants was reported. Turbidity was observed on initial mixing when the solubility product was around 115 to 130 mmol2 or greater. After storage at 7°C for 20 hours, visible precipitates formed at solubility products of 130 mmol2 or greater. If the solution was administered through a barium-impregnated silicone rubber catheter, crystalline precipitates obstructed the catheters in 12 hours at a solubility product of 100 mmol2 and in 10 days at 79 mmol2, much lower than the in vitro results.1041
The solubility of calcium and phosphorus in neonatal parenteral nutrition solutions composed of amino acids (Abbott) 1.25 and 2.5% with dextrose 5 and 10%, respectively, was evaluated. Also present were multivitamins and trace elements. The solutions contained calcium (as gluconate) in amounts ranging from 25 to 200 mg/100 mL. The phosphorus (as potassium phosphate) concentrations evaluated ranged from 25 to 150 mg/100 mL. If calcium gluconate was added first, cloudiness occurred immediately. If potassium phosphate was added first, substantial quantities could be added with no precipitate formation in 48 hours at 4°C (Table 2). However, if stored at 22°C, the solutions were stable for only 24 hours, and all contained precipitates after 48 hours.1210
Table 2. Maximum Calcium and Phosphorus Concentrations Physically Compatible for 48 Hours at 4°C1210
| Phosphorus (mg/100 mL) | ||
|---|---|---|
| Calcium (mg/100 mL) | Amino Acids 1.25% + Dextrose 5%a | Amino Acids 2.5% + Dextrose 10%a |
| 200b | 50 | 75 |
| 150 | 50 | 100 |
| 100 | 75 | 100 |
| 50 | 100 | 125 |
| 25 | 150b | 150b |
aPlus multivitamins and trace elements.bMaximum concentration tested.
The physical compatibility of calcium gluconate 10 to 40 mEq/L and potassium phosphates 10 to 40 mmol/L in 3 neonatal parenteral nutrition solutions (TPN #123 to #125 in Appendix), alone and with retrograde administration of aminophylline 7.5 mg diluted with 1.5 mL of sterile water for injection was reported. Contact of the alkaline aminophylline solution with the parenteral nutrition solutions resulted in the precipitation of calcium phosphate at much lower concentrations than were compatible in the parenteral nutrition solutions alone.1404
The maximum allowable concentrations of calcium and phosphate in a 3-in-1 parenteral nutrition mixture for children (TNA #192 in Appendix) reported. Added calcium was varied from 1.5 to 150 mmol/L, while added phosphate was varied from 21 to 300 mmol/L. The mixtures were stable for 48 hours at 22 and 37°C as long as the pH was not greater than 5.7, the calcium concentration was below 16 mmol/L, the phosphate concentration was below 52 mmol/L, and the product of the calcium and phosphate concentrations was below 250 mmol2/L2.1773
Additional calcium and phosphate solubility curves were reported for specialty parenteral nutrition solutions based on NephrAmine and also HepatAmine at concentrations of 0.8, 1.5, and 2% as the sources of amino acids. The solutions also contained dextrose 10%, with cysteine and pH adjustment to simulate addition of lipid emulsion used in some admixtures. Calcium and phosphate solubility followed the hyperbolic patterns previously reported.609 Temperature, time, and pH affected calcium and phosphate solubility, with pH having the greatest effect.2038
The maximum sodium phosphate concentrations were reported for given amounts of calcium gluconate that could be admixed in parenteral nutrition solutions containing TrophAmine in varying quantities (with cysteine hydrochloride 40 mg/g of amino acid) and dextrose 10%. The solutions also contained magnesium sulfate 4 mEq/L, potassium acetate 24 mEq/L, sodium chloride 32 mEq/L, pediatric multivitamins, and trace elements. The presence of cysteine hydrochloride reduces the solution pH and increases the amount of calcium and phosphate that can be incorporated before precipitation occurs. The results of this study cannot be safely extrapolated to TPN solutions with compositions other than the ones tested. The admixtures were compounded with the sodium phosphate added last after thorough mixing of all other components. The authors noted that this is not the preferred order of mixing (usually phosphate is added first and thoroughly mixed before adding calcium last); however, they believed this reversed order of mixing would provide a margin of error in cases in which the proper order is not followed. After compounding, the solutions were stored for 24 hours at 40°C. The maximum calcium and phosphate amounts that could be mixed in the various solutions were reported tabularly and are shown in Table 3.2039 However, these results are not entirely consistent with another study. See Table 4.
Table 3. Maximum Amount of Phosphate (as Sodium) (mmol/L) Not Resulting in Precipitation.2039 See CAUTION below.a
| Amino Acid (as TrophAmine) with Cysteine HCl 40 mg/g of Amino Acid | |||||
|---|---|---|---|---|---|
| Calcium (as Gluconate) | 0% | 0.4% | 1% | 2% | 3% |
| 9.8 mEq/L | 0 | 27 | 42 | 60 | 66 |
| 14.7 mEq/L | 0 | 15 | 18 | 30 | 36 |
| 19.6 mEq/L | 0 | 6 | 15 | 27 | 30 |
| 29.4 mEq/L | 0 | 3 | 6 | 21 | 24 |
aCAUTION: The results cannot be safely extrapolated to other solutions. See text.
The temperature dependence of the calcium-phosphate precipitation has resulted in the occlusion of a subclavian catheter by a solution apparently free of precipitation. The parenteral nutrition solution consisted of FreAmine III 500 mL, dextrose 70% 500 mL, sodium chloride 50 mEq, sodium phosphate 40 mmol, potassium acetate 10 mEq, potassium phosphate 40 mmol, calcium gluconate 10 mEq, magnesium sulfate 10 mEq, and Shil’s trace metals solution 1 mL. Although there was no evidence of precipitation in the bottle, tubing and pump cassette, and filter (all at approximately 26°C) during administration, the occluded catheter and Vicra Loop Lock (next to the patient’s body at 37°C) had numerous crystals identified as calcium phosphate. In vitro, this parenteral nutrition solution had a precipitate in 12 hours at 37°C but was clear for 24 hours at 26°C.610
Similarly, a parenteral nutrition solution that was clear and free of particulates after 2 weeks under refrigeration developed a precipitate in 4 to 6 hours when stored at room temperature. When the solution was warmed in a 37°C water bath, precipitation occurred in 1 hour. Administration of the solution before the precipitate was noticed led to interstitial pneumonitis due to deposition of calcium phosphate crystals.1427
Calcium phosphate precipitation phenomena was evaluated in a series of parenteral nutrition admixtures composed of dextrose 22%, amino acids (FreAmine III) 2.7%, and lipid emulsion (Abbott) 0, 1, and 3.2%. Incorporation of calcium gluconate 19 to 24 mEq/L and phosphate (as sodium) 22 to 28 mmol/L resulted in visible precipitation in the fat-free admixtures. New precipitate continued to form over 14 days, even after repeated filtrations of the solutions through 0.2-µm filters. The presence of the amino acids increased calcium and phosphate solubility, compared with simple aqueous solutions. However, the incorporation of the lipid emulsion did not result in a statistically significant increase in calcium and phosphate solubility. The authors noted that the kinetics of calcium phosphate precipitate formation do not appear to be entirely predictable; both transient and permanent precipitation can occur either during the compounding process or at some time afterward. Because calcium phosphate precipitation can be very dangerous clinically, the use of inline filters was recommended. The authors suggested that the filters should have a porosity appropriate to the parenteral nutrition admixture—1.2 µm for fat-containing and 0.2 or 0.45 µm for fat-free nutrition mixtures.2061
Laser particle analysis was used to evaluate the formation of calcium phosphate precipitation in pediatric TPN solutions containing TrophAmine in concentrations ranging from 0.5 to 3% with dextrose 10% and also containing L-cysteine hydrochloride 1 g/L. The solutions also contained in each liter sodium chloride 20 mEq, sodium acetate 20 mEq, magnesium sulfate 3 mEq, trace elements 3 mL, and heparin sodium 500 units. The presence of L-cysteine hydrochloride reduces the solution pH and increases the amount of calcium and phosphate that can be incorporated before precipitation occurs. The results of this study cannot be safely extrapolated to TPN solutions with compositions other than the ones tested. The maximum amount of phosphate that was incorporated without the appearance of a measurable increase in particulates in 24 hours at 37°C for each of the amino acids concentrations is shown in Table 4.2196 These results are not entirely consistent with previous results.2039 See above. The use of more sensitive electronic particle measurement for the formation of subvisible particulates in this study may contribute to the differences in the results.
Table 4. Maximum Amount of Phosphate (as Potassium) (mmol/L) Not Resulting in Precipitation.2196 See CAUTION below.a
| Amino Acid (as TrophAmine) plus Cysteine HCl 1 g/L | ||||||
|---|---|---|---|---|---|---|
| Calcium (as Gluconate) (mEq/L) | 0.5% | 1% | 1.5% | 2% | 2.5% | 3% |
| 10 | 22 | 28 | 38 | 38 | 38 | 43 |
| 14 | 18 | 18 | 18 | 38 | 38 | 43 |
| 19 | 18 | 18 | 18 | 33 | 33 | 38 |
| 24 | 12 | 18 | 18 | 22 | 28 | 28 |
| 28 | 12 | 18 | 18 | 18 | 18 | 18 |
| 33 | 12 | 12 | 12 | 12 | 12 | 12 |
| 37 | 12 | 12 | 12 | 12 | 12 | 12 |
| 41 | 9 | 9 | 9 | 12 | 12 | 12 |
| 45 | 0 | 9 | 9 | 12 | 12 | 12 |
| 49 | 0 | 9 | 9 | 9 | 12 | 12 |
| 53 | 0 | 9 | 9 | 9 | 9 | 9 |
aCAUTION: The results cannot be safely extrapolated to solutions with formulas other than the ones tested. See text.
Calcium and phosphate compatibility was evaluated in a series of adult formula parenteral nutrition admixtures composed of FreAmine III, in concentrations ranging from 1 to 5% (TPN #258 through #262). The solutions also contained dextrose ranging from 15% up to 25%. Also present were sodium chloride, potassium chloride, and magnesium sulfate in common amounts. Cysteine hydrochloride was added in an amount of 25 mg/g of amino acids from FreAmine III to reduce the pH by about 0.5 pH unit and thereby increase the amount of calcium and phosphates that can be added to the TPN admixtures as has been done with pediatric parenteral nutrition admixtures. Phosphates as the potassium salts and calcium as the gluconate salt were added in variable quantities to determine the maximum amounts of calcium and phosphates that could be added to the test admixtures. The samples were evaluated at 23 and 37°C over 48 hours by visual inspection in ambient light and using a Tyndall beam and electronic measurement of turbidity and microparticulates. The addition of the cysteine hydrochloride resulted in an increase of calcium and phosphates solubility of about 30% by lowering the solution pH 0.5 pH unit. The boundaries between the compatible and incompatible concentrations were presented graphically as hyperbolic curves.2469
The presence of magnesium in solutions may also influence the reaction between calcium and phosphate, including the nature and extent of precipitation.158; 159
The interaction of calcium and phosphate in parenteral nutrition solutions is a complex phenomenon. Various factors have been identified as playing a role in the solubility or precipitation of a given combination, including:608; 609; 1042; 1063; 1404; 1427; 2778
Enhanced precipitate formation would be expected from such factors as high concentrations of calcium and phosphate, increases in solution pH, decreased amino acid concentrations, increases in temperature, addition of calcium prior to the phosphate, lengthy standing times or slow infusion rates, and use of calcium as the chloride salt.854
Even if precipitation does not occur in the container, it has been reported that crystallization of calcium phosphate may occur in a Silastic infusion pump chamber or tubing if the rate of administration is slow, as for premature infants. Water vapor may be transmitted outward and be replaced by air rapidly enough to produce supersaturation.202 Several other cases of catheter occlusion have been reported.610; 1427; 1428; 1429
For a list of references cited in the text of this monograph, search the monograph titled References.