AHFS Class:

40:12 Replacement Preparations

Generic Name

• Calcium Chloride

Calcium chloride is available as a 10% solution (100 mg/mL) in 10-mL single-dose vials and prefilled syringes containing 1 g of calcium chloride.²⁸³; ³⁰⁹ Each mL of solution contains calcium chloride dihydrate 100 mg (equivalent to 27 mg of elemental calcium) in water for injection, and provides 1.4 mEq each of calcium and chloride ion.²⁸³ The pH may have been adjusted with hydrochloric acid and/or sodium hydroxide.²⁸³ Aluminum also is present.²⁸³; ³⁰⁹

pH

From 5.5 to 7.5 diluted in water to a 5% concentration.²⁸³

Osmolarity

The 10% injection has a calculated osmolarity of 2.04 mOsm/mL.²⁸³

Osmolality

The osmolality of a calcium chloride 10% solution was determined by osmometer to be 1765 mOsm/kg.¹²³³

Aluminum Content

Calcium chloride injection (Hospira, American Regent) contains up to 1000 mcg of aluminum per L.²⁸³; ³⁰⁹

Calcium chloride is administered by slow intravenous injection, preferably into a central or deep vein, at a rate not exceeding 1 mL/min of a 10% solution.²⁸³ It must not be injected intramuscularly or subcutaneously.²⁸³ The manufacturers recommend warming the solution to body temperature prior to administration if time permits.²⁸³; ³⁰⁹ Calcium chloride injection causes venous irritation; care should be taken to avoid extravasation or accidental injection into perivascular tissues which may result in severe necrosis and sloughing.²⁸³

Calcium chloride injection is a clear solution.²⁸³ Intact containers should be stored at controlled room temperature.²⁸³; ³⁰⁹ Unused portions of single-dose containers should be discarded.²⁸³; ³⁰⁹

Calcium chloride injection under simulated summer conditions in paramedic vehicles was exposed to temperatures ranging from 26 to 38°C over 4 weeks. Analysis found no loss of the drug under these conditions.²⁵⁶²

Additive Compatibility

Drugs in Syringe Compatibility

Y-Site Injection Compatibility (1:1 Mixture)

Additional Compatibility Information

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

1. “The amounts of phosphorus and of calcium added to the admixture are critical. The solubility of the added calcium should be calculated from the volume at the time the calcium is added. It should not be based upon the final volume.
   Some amino acid injections for TPN admixtures contain phosphate ions (as a phosphoric acid buffer). These phosphate ions and the volume at the time the phosphate is added should be considered when calculating the concentration of phosphate additives. Also, when adding calcium and phosphate to an admixture, the phosphate should be added first.
   The line should be flushed between the addition of any potentially incompatible components.
2. A lipid emulsion in a 3-in-1 admixture obscures the presence of a precipitate. Therefore, if a lipid emulsion is needed, either (1) use a 2-in-1 admixture with the lipid infused separately, or (2) if a 3-in-1 admixture is medically necessary, then add the calcium before the lipid emulsion and according to the recommendations in number 1 above.
   If the amount of calcium or phosphate which must be added is likely to cause a precipitate, some or all of the calcium should be administered separately. Such separate infusions must be properly diluted and slowly infused to avoid serious adverse events related to the calcium.
3. When using an automated compounding device, the above steps should be considered when programming the device. In addition, automated compounders should be maintained and operated according to the manufacturer’s recommendations.
   Any printout should be checked against the programmed admixture and weight of components.
4. During the mixing process, pharmacists who mix parenteral nutrition admixtures should periodically agitate the admixture and check for precipitates. Medical or home care personnel who start and monitor these infusions should carefully inspect for the presence of precipitates both before and during infusion. Patients and care givers should be trained to visually inspect for signs of precipitation. They also should be advised to stop the infusion and seek medical assistance if precipitates are noted.
5. A filter should be used when infusing either central or peripheral parenteral nutrition admixtures. At this time, data have not been submitted to document which size filter is most effective in trapping precipitates.
   Standards of practice vary, but the following is suggested: a 1.2-µm air-eliminating filter for lipid-containing admixtures and a 0.22-µm air-eliminating filter for non-lipid-containing admixtures.
6. Parenteral nutrition admixtures should be administered within the following time frames: if stored at room temperature, the infusion should be started within 24 hours after mixing; if stored at refrigerated temperatures, the infusion should be started within 24 hours of rewarming. Because warming parenteral nutrition admixtures may contribute to the formation of precipitates, once administration begins, care should be taken to avoid excessive warming of the admixture.
   Persons administering home care parenteral nutrition admixtures may need to deviate from these time frames. Pharmacists who initially prepare these admixtures should check a reserve sample for precipitates over the duration and under the conditions of storage.
7. If symptoms of acute respiratory distress, pulmonary emboli, or interstitial pneumonitis develop, the infusion should be stopped immediately and thoroughly checked for precipitates. Appropriate medical interventions should be instituted. Home care personnel and patients should immediately seek medical assistance.”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 acid solutions inherently contain calcium and phosphate, which must be considered in any projection of compatibility.

A study determined the maximum concentrations of calcium (as chloride and gluconate) and phosphate (as sodium phosphates) that can be maintained without precipitation in a parenteral nutrition solution consisting of FreAmine II 4.25% and dextrose 25% for 24 hours at 30°C. It was noted that the amino acids in parenteral nutrition solutions form soluble complexes with calcium and phosphate, reducing the available free calcium and phosphate that can form insoluble precipitates. The concentration of calcium available for precipitation is greater with the chloride salt compared to the gluconate salt, at least in part because of differences in dissociation characteristics. Consequently, a greater concentration of calcium gluconate than calcium chloride can be mixed with sodium phosphate.⁶⁰⁸

In addition to the concentrations of phosphate and calcium and the salt form of the calcium, the concentration of amino acids and the time and temperature of storage altered the formation of calcium phosphate in parenteral nutrition solutions. As the temperature was increased, the incidence of precipitate formation also increased. This finding was attributed, at least in part, to a greater degree of dissociation of the calcium and phosphate complexes and the decreased solubility of calcium phosphate. Therefore, a solution possibly may be stored at 4°C with no precipitation, but on warming to room temperature a precipitate will form over time.⁶⁰⁸

The maximum allowable concentrations of calcium and phosphate in a 3-in-1 parenteral nutrition mixture for children (TNA #192 in Appendix) were reported. Added calcium was varied from 1.5 to 150 mmol/L, and added phosphate was varied from 21 to 300 mmol/L. These 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

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 play a role in the solubility or precipitation of a given combination, including:⁶⁰⁸; ⁶⁰⁹; ¹⁰⁴²; ¹⁰⁶³; ¹²¹⁰; ¹²³⁴; ¹⁴²⁷; ²⁷⁷⁸

1. Concentration of calcium
2. Salt form of calcium
3. Concentration of phosphate
4. Concentration of amino acids
5. Amino acids composition
6. Concentration of dextrose
7. Temperature of solution
8. pH of solution
9. Presence of other additives
10. Order of mixing

Enhanced precipitate formation would be expected from such factors as high concentrations of calcium and phosphate, increases in solution pH, decreases in amino acid concentrations, increases in temperature, addition of calcium before 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.

ASHP^® Injectable Drug Information^TM. Selected Revisions December 5, 2024. © Copyright, 2024. American Society of Health-System Pharmacists^®, 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.