Parenteral nutrition calcium phosphate precipitation

Besides local toxicity, discussed above, there are numerous other modes of potential adverse interactions involving excipients (19,20). Many of these pose little threat provided the amounts of excipients are constrained to certain levels. Excessive amounts, however, can cause problems, particularly for patients who are intolerant of even modest levels. Commonly used phosphate buffers may cause calcium loss with formation of insoluble calcium phosphates when such buffers are administered in over-ambitious amounts (21). Calcium phosphate precipitation has been noted particularly in nutritional parenteral admixtures for neonates because of the high nutrient requirements. Similarly, renal toxicity has been associated with depletion of zinc and other trace metals caused by large parenteral doses of ethylenediaminete-traacetic acid (EDTA) (22). Excessive absorption of glycine solutions, when used as irrigants during transurethral resections, can cause hyponatremia, hypertension, and confusion (23). The use of preservatives has been associated with cardiac effects in a few patients (24). Premature neonates were found to be at risk for receiving toxic amounts of benzoic acid or benzyl alcohol in bacteriostatic solutions used to flush intravenous catheters (25). 

Physicochemical incompatibilities are of particular concern when parenteral administration is planned. For example, when calcium and phosphate ion concentrations are excessively high in a total parenteral nutrition (TPN) solution, precipitation will occur. Similarly, the simultaneous administration of antacids or products high in metal content may compromise the absorption of many drugs in the intestine, eg, tetracyclines. The package insert and the Handbook on Injectable Drugs (Trissel 2003) are good sources for this information. 

Precipitates can develop in parenteral nutrition admixtures because of a number of factors such as the concentration, pH, and phosphate content of the amino acid solutions, the calcium and phosphorus additives, the order of mixing, or the mixing process. The consequences can be serious. In one cohort study of hospitalized patients who received peripheral parenteral nutrition, a subgroup developed unexplained chest pain, dyspnea, cardiopulmonary arrest, or new interstitial infiltrates on chest radiograph. A change in the amino acid source of a parenteral nutrition mixture was associated with respiratory adverse events that ranged from interstitial infiltrates to sudden death. The events apparently resulted from infusion of calcium phosphate precipitate in an opaque admixture, and the deposition of the crystals in the pulmonary microvasculature (147). 

FDA Safety Alert Hazards of Precipitation Associated With Parenteral Nutrition The Food and Drug Administration warned against the risk of precipitations in parenteral nutrition mixtures in 1994 [55]. This warning occurred after two deaths and at least two patients with dyspnoea after infusion of all-in-one nutrition admixmres. The FDA suspected that these admixtures contained calcium phosphate precipitates. 

The United States Food and Drug Administration issued a safety alert in 1994 regarding the potentially life-threatening formation of precipitates in parenteral nutrition admixtures (148). They had received reports of two deaths and at least two cases of respiratory distress during intravenous infusion of a three-in-one parenteral nutrition mixture (amino acids, carbohydrates, lipids). The mixture contained 10% FreAmine III (amino acids -I- magnesium acetate -I- phosphoric acid -I- potassium chloride -I- sodium acetate -I- sodium chloride), dextrose, calcium gluconate, potassium phosphate, other minerals, and a lipid emulsion. The solution may have contained a precipitate of calcium phosphate. Autopsies revealed diffuse microvascular pulmonary emboli containing calcium phosphate. 

The solubility of calcium and phosphate in total parenteral nutrition (TPN) solutions is dependent on the pH of the solution. TPN solutions are, of course, clinically acceptable only when precipitation can be guaranteed not to occur. Dibasic calcium phosphate, for example, is soluble only to the extent of 0.3 g dm whereas monobasic calcium phosphate has a solubility of 18 g dm . At low pH the monobasic form predominates, while at higher pH values the dibasic form becomes available to bind with calcium and precipitates tend to form. ... 

The solubility of calcium phosphate depends on the type of amino acid product used, the type of calcium and phosphate salts used, temperature, magnesium concentration, and the final volume of the admixture. The pH of the parenteral nutrition admixture influences the equilibrium between the trivalent phosphate ion and its monobasic (H2P04 ) and dibasic (HP04 ) forms. The aqueous solubility of the monobasic and dibasic calcium phosphate amounts to 18 g/L and 0.3 g/L, respectively. At the physiological pH of 7.4 about 60 % of the phosphate exists in the poorly soluble dibasic form. If the pH of the nutrition admixture is lower than pH 6.4, the monobasic form is the predominant one and the chance of precipitation is diminished (see Sect. 18.1.1). 

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See also in sourсe #XX -- [ , ]

See also in sourсe #XX -- [ , ]

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