COMMENTARy and

COMMENTARy

• The influence of other drugs and Calcium and compatibility: nutrients.4-8,10-18 Revisited again The application of knowledge about calcium and phosphate com- Da v i d W. Ne w t o n a nd Da v i d F. Dr i s c o l l patibility in i.v. therapy has been fa- 3-6 Am J Health-Syst Pharm. 2008; 65:73-80 cilitated by four hallmark articles, several editions of the Handbook on he subject of the compatibility • The clinically relevant dissocia- Injectable Drugs17 since 1983, and

between calcium and phosphates tion equilibria for which the pKa2 of Trissel’s Calcium and Phosphate Com- was revisited in an April 1994 phosphoric acid is 7.2 (i.e., the pH patibility in Parenteral Nutrition.18 T 1,2 FDA safety alert, 6–16 years after at which the concentrations or, ther- Despite the availability of these the four seminal research articles modynamically, the ionic activities of literature sources, calcium and phos- 3 4 5 2– – appeared in 1978, 1980, 1982, HPO4 and H2PO4 are equal) (Table phate compatibility continues to be a and 1988.6 In the 1980s there were 1): clinical enigma. two case reports of nonfatal adverse Physicochemical factors. Calcium – – 2– events involving calcium phosphate OH + H2PO4 ↔ HPO4 + H2O; shifts and phosphate solubility chemistry. precipitation in total parenteral nu- to right when pH increases (1) The aqueous chemistry and solubil- 7,8 – 2– + trient (TPN) admixtures. A review H2O + H2PO4 ↔ HPO4 + H3O ; ity of the two phosphate anions and of the main determinants of paren- shifts to left when pH decreases (2) their calcium salts that are important teral drug and admixture compat- to the safety of i.v. therapy are sum- ibility and stability also appeared • T h e Henderson–Hasselbach marized in Table 1. The main facts during that decade.9 Soon after equations9,19: are as follows: The lower the solution the April 1994 safety alert, several pH is below 7.2, which is the critical pH = pK + log ([A–]/[HA]); percent publications on calcium phosphate a pKa2 of phosphoric acid in practice, precipitation in TPN formulations ionized, A–, = 100/(1 + antilog the greater is the majority percentage 10-18 [pK – pH]) = 100{[A–]/([A–] + – appeared. Thus, this article is a of the desired H2PO4 anion (dihy- yet another revisit of calcium and [HA])} (3) drogen or monobasic phosphate). pH = pK + log ([HPO 2– ]/[H PO –]); – phosphate compatibility with i.v. a 4 2 4 H2PO4 , with two dissociable pro- percent HPO 2– = 100/(1 + anti- 2– formulations. 4 tons, is an acid relative to HPO4 , log [pK – pH]) = 100{[HPO 2–]/ 2– This article discusses the chem- a 4 and HPO4 (i.e., monohydrogen 2– – istry and practical compatibility ([HPO4 ] + [H2PO4 ])} (4) or dibasic phosphate) is a base or – or solubility factors relevant to the weaker acid relative to H2PO4 . • The compatibility curves for calcium safe administration of combination Ca[H2PO4]2 (calcium dihydrogen gluconate versus phosphate concen- therapy with calcium gluconate and phosphate) is 60 times more soluble trations in clinical mixtures.4,5,17,18 potassium or sodium phosphate in- than CaHPO4 (calcium monohydro- jections. Patient case reports that led to adverse events and pharmaceuti- cal and clinical factors important to calcium phosphate solubility are also Da v i d W. Ne w t o n , B.S.Ph a r m ., Ph.D., Address correspondence to Dr. Newton presented. FAPhA, is Professor and Chairman, Depart- at the Bernard J. Dunn School of Phar- pH and pK equilibria relevant ment of Biopharmaceutical Sciences, Ber- macy, Shenandoah University, 1460 Univer- a nard J. Dunn School of Pharmacy, Shenan- sity Drive, Winchester, VA 22601 (dnewton@ to calcium and phosphate compat- doah University, Winchester, VA. Da v i d su.edu). ibility. The keys to understanding the F. Dr i s c o l l , B.S.Ph a r m ., Ph.D., is Senior chemical reactions and relative risks Researcher, Department of Medicine, Beth Copyright © 2008, American Society of Israel Deaconess Medical Center, and Assis- Health-System Pharmacists, Inc. All rights for calcium phosphate precipitation tant Professor of Medicine, Harvard Medical reserved. 1079-2082/08/0101-0073$06.00. are as follows: School, Boston, MA. DOI 10.2146/ajhp070138

Am J Health-Syst Pharm—Vol 65 Jan 1, 2008 73 COMMENTARy Calcium and phosphates

of CaHPO reactions stated in the Table 1. 4 1967 source ended in 1968 with the Chemistry and Water Solubility of Phosphates and Calcium 21 Phosphates report that launched TPN, which made reactions between calcium or Salta Names Solubility (mg/mL)5,10 and phosphates in i.v. formulations a –- b c H2PO4 ­ Monobasic phosphate, dihydrogen NA ­ matter of life and death. phosphate Calcium and phosphate solubility HPO 2– Dibasicd phosphate, monohydrogen NA 4 for i.v. therapy. It is unlikely that any phosphate patient-specific i.v. admixture con- Ca[H PO ] Monobasic calciumphosphate, 18 2 4 2 taining calcium and phosphates will calcium dihydrogen phosphate exactly duplicate the compatibility CaHPO4 Dibasic calcium phosphate, calcium 0.3 monohydrogen phosphate results of published studies. Three common variables are (1) practition- a – + 2– 3– + The phosphoric acid aqueous equilibria H3PO4 ↔ H2PO4 + H (for which pKa1 = 2.1) and HPO4 ↔ PO4 + H 19 14 er and device volume-measurement (for which pKa3 = 12.3 ) are clinically negligible. b – + + Monobasic refers to neutralization of the –1 charge on H2PO4 by one +1 cation (e.g., K or Na , from bases accuracy and precision, (2) content [alkali] such as potassium hydroxide or sodium hydroxide or carbonate). cNA = not applicable. and pH ranges from The United d 2– + + Dibasic refers to neutralization of the –2 charge on HPO4 by two +1 cations (e.g., 2 K or 2 Na , or one +2 States Pharmacopeia and The Na- 2+ cation, e.g., Ca ). tional Formulary (USP) for calcium gluconate injection (i.e., 95–105% of labeled content and pH 6.0–8.2) and gen phosphate), because CaHPO4 is should be expressed in millimoles for potassium and sodium phosphate less dissociated.19,20 Note that, typi- per liter, not in milliequivalents per injections (i.e., 95–105% of labeled cal of most divalent cation–divalent liter. In the article by Schuetz and content),22 and (3) other drugs and 3 anion salts, CaHPO4 is minimally King, phosphates were reported in nutrients that may be included in i.v. dissociated into its constituent . milliequivalents per liter but without admixtures (i.e., the variable compo- 2+ – Consequently, most of the Ca and specific concentrations of H2PO4 sition of TPN formulations, which 2– 2– HPO4 ions cannot be solvated by and HPO4 . The appendix shows the are often patient specific). Even dipolar water molecules via ion– calculation for milliequivalents of small differences in the USP-allowed dipole intermolecular forces, result- potassium and for millimoles of phos- percent content ranges of calcium ing in 0.3-mg/mL solubility in water. phates per milliliter in commercial gluconate and potassium or sodium Ion–dipole forces generally result in Potassium Phosphates Injection, USP, phosphate injections may contribute greater solubility in water than do and for milliequivalents of calcium to the precipitation or nonprecipita- other types of solute–water inter- per milliliter in commercial 10% Cal- tion of CaHPO4 in clinical practice. molecular forces.19,20 The contrasting cium Gluconate Injection, USP. The main factors that are impor- high solubility of the divalent cation– Before the transition to the tant to ensuring total solubility or divalent anion, sulfate, Pharm.D. degree began achieving compatibility of calcium and phos- at more than 500 mg/mL, results national momentum in the 1970s, phates in TPN and other i.v. therapy from dipole–dipole forces between most U.S. pharmacy schools required are as follows1-18: water and the mostly nondissociated courses in qualitative and quantita-

MgSO4 ion pairs, which are dipoles. tive chemical analysis and inorganic • The mixture should be agitated to The efficient water solubility of some pharmaceutical chemistry. Those achieve homogeneity after each ingre- nonionic organic compounds (e.g., courses were particularly pertinent dient is added. sugars) results from accepting and to the solubility of calcium salts, as • Potassium or sodium phosphate donating multiple intermolecular illustrated by the following excerpt injection should be added early, and hydrogen bonds with water (i.e., one from a monograph on CaHPO4 calcium gluconate injection should hydrogen bond for at least every four in a standard pharmacy textbook be added last or nearly last to the carbon atoms).20 from 1967: “Because this salt is al- most dilute phosphate concentration – 1,2,17,18 The percentages of H2PO4 and most insoluble in water, its chemi- possible. 2– HPO4 decrease and increase, re- cal reactions are few and relatively • A 0.2-mm air-eliminating sterile spectively, by 1.6% to 5.7% for each unimportant. It is soluble in diluted inline filter should be used for non- 19 0.1 pH unit increase over the pH hydrochloric acid.” That CaHPO4 fat-emulsion-containing i.v. admix- range of 6.0–7.6.14 Because 1 meq is more soluble at increasingly acidic tures, and a 1.2-mm filter should be 2– of HPO4 corresponds to 2 meq of pH represents the leftward shift in used for fat-emulsion-containing i.v. – 1-3,10,13,14,17,18 H2PO4 , phosphate concentration equation 2, and the “unimportance” admixtures.

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• injection should example, in one study of a simulated cipitation would occur quickly and never be the calcium source in i.v. TPN admixture, the measured cal- convincingly in samples with little therapy that contains phosphate cium concentration declined expo- or no content of dextrose and amino injections, because calcium chloride nentially from 22 to 7 meq/L over 14 acids.18 After thorough mixing, the dissociates more extensively than days in 0.2-mm membrane filtrates of ingredients were added in this order: calcium gluconate, resulting in more the original admixture.14 In another potassium phosphates, 50% dextrose 2+ 2– Ca available to react with HPO4 , study of a simulated TPN admix- injection, sterile water for injection

thus increasing the likelihood of ture, an increase in CaHPO4 particles (nonbacteriostatic), amino acids, 4,5 CaHPO4 precipitation. larger than 5 mm was measured over and calcium gluconate. The sample • The intersection of final calculated 48 hours by using light obscuration, tubes were stored at 22–24 °C and calcium and phosphate concentra- and the precipitates were confirmed each day were exposed to ceiling tions in clinical i.v. admixtures must as such by petrography and infrared fluorescent illumination for 10 hours be below the typical solubility curve spectroscopy.23 and to darkness for 12 hours. (Figure 1).4,5,7,18 The typical results for the samples • A single sum or product of calcium Demonstration samples of calcium listed in Table 2 are presented in and phosphate concentrations must gluconate and potassium phosphate Table 3. Adding a few drops of 1.9% not be used as the sole criterion for injections. Table 2 illustrates the (0.05 M) disodium EDTA to sample judging compatibility, because prod- beneficial effects of the acidic pH of A or D illustrates calcium sequestra- ucts of calcium concentration (in mil- dextrose injection and of calcium tion by amino acids when the precip- liequivalents per liter) and phosphate sequestration by amino acids on itated CaHPO4 dissolves, and adding concentration (in millimoles per liter) the compatibility of i.v. calcium and a few drops of 1 N hydrochloric acid vary inconsistently as calcium con- phosphates. The approximate cal- to sample A or D illustrates the left- centration decreases and phosphate cium and phosphate concentrations shifted equilibrium in equation 2, concentration increases.4,5 of 28 meq/L and 24 mmol/L, respec- which favors calcium and phosphate • The calculated concentrations of tively, were chosen to intersect well compatibility. The change from col- calcium and phosphates in TPN for- above recommended compatibility orless to pale yellow to yellow-amber mulations must include all sources curves (Figure 1), so that visible pre- in samples F, G, and H over 14 days (e.g., amino acids injection) and not just the obvious calcium gluconate and potassium or sodium phosphate Figure 1. Composite curve for compatibility of calcium (as gluconate) with phosphates at injections. 20–25 °C and pH 6.3 in 25% dextrose injection and 4–4.25% amino acids injection.4,5 The • The lower the final pH, the greater farther concentrations are below the curve, the greater the probability of nonprecipita- – tion is, and the closer to or farther above the curve concentrations are, the greater the the percentage of H2PO4 at which – probability of precipitation of CaHPO4 is. H2PO4 forms more soluble calcium dihydrogen phosphate salt with Ca2+. Higher final concentrations of dex- 50 trose and the age-essential amino acid 45 cysteine hydrochloride and lower final i.v. fat-emulsion concentrations favor 40 lower admixture pH. 35 • The higher the final amino acid con-

centration, the less likely CaHPO4 is 30 to precipitate. Some amino acids se- quester Ca2+ (i.e., form stable soluble 25 complexes). While most pharmacists 20 are aware that disodium ethylene- Calcium (meq/L) diaminetetraacetic acid (EDTA) se- 15 2+ questers divalent ions, including Ca , 10 fewer of them identify EDTA as an amino acid.14 5 • The rates of crystalline growth and 0 precipitation of CaHPO in clini- 4 0510 15 20 25 cal admixtures may be variable and Phosphates (mmol/L) low in supersaturated mixtures. For

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Table 2. would move the curve downward Mixtures of Calcium Gluconate and Potassium Phosphates and vice versa for higher concentra- Injections, USP, Used To Demonstrate Major Variables That Affect tions of amino acids and dextrose. Calcium and Phosphate Compatibility The data used to construct the curves in references 4 and 5 were Volume (mL)b,c based on visual compatibility and 50% Dextrose 10% Amino Acids not on particle-size analysis capable Samplea Injection Injectiond Deionized Water of discerning subvisible particulate A 0 0 9.4 matter. This is an important point Be 2.0 0 7.4 recognizing that unaided visual Cf 5.0 0 4.4 identification of sparse precipitation Dg 0 1.0 8.4 is limited to approximately 50-mm Eh 0 4.0 5.4 individual particles; yet, subvisible i F 2.0 1.0 6.4 precipitates ranging from 5 to 50 m j m G 4.0 2.0 3.4 may occlude the microvasculature, Hk 5.0 4.0 0.4 such as in the pulmonary system.8,12 aAll samples were prepared nonaseptically in nonsterile 15-mL clear colorless glass tubes with plastic screw caps (Fisher Scientific, catalog number 07-250-135). They totaled approximately 10.1 mL and contained the The curve in Figure 1 represents following: 0.08 mL of 3-mmol/mL Potassium Phosphates Injection, USP, and 0.6 mL of 10% Calcium Gluconate a general guideline as one factor Injection, USP, which are equivalent to phosphates 23.8 mmol/L and calcium 27.6 meq/L. bIngredients are in-date, USP-compliant commercial injections. for judging compatibility, but it is cVolumes of 0.1 mL and less were measured with a 40-mL (0.04-mL) to 200-mL (0.2-mL) digital pipette; volumes not possible to predict the precise greater than 0.1–2.0 mL were measured with a 100-mL (0.1-mL) to 1000-mL (1-mL) digital pipette; and volumes greater than 2.0 mL were measured in a glass class B10-mL graduated cylinder scaled in 0.2-mL increments. changes in such a curve for other, un- dA crystalline amino acids product without additional electrolytes. evaluated, concentrations of dextrose eEquivalent to 10% dextrose. fEquivalent to 25% dextrose. and amino acids. The compatibility gEquivalent to 1% amino acids. curves for calcium versus phosphates hEquivalent to 4% amino acids. iEquivalent to 10% dextrose and 1% amino acids. typified by references 4 and 5 are jEquivalent to 20% dextrose and 2% amino acids. generally elbow shaped, with a slope kEquivalent to 25% dextrose and 4% amino acids. slightly left of vertical as calcium de- clines from 50 to 2 meq/L and phos- phates increase from 5 to 8 mmol/L illustrates the Maillard, or “brown- Nearly all pharmacists know the and a slope slightly below horizontal 9,24 ing,” reaction (Figure 2). This is importance of hemoglobin A1c in as calcium declines from 14 to 5 initially a covalent condensation of diabetes management, but few know meq/L and phosphates increase from primary amino groups on amino ac- that A1c, discovered in 1967, is a 8 to 23 mmol/L. For all such curves, 26 ids, R-NH2, with the acyclic aldehyde Maillard reaction product. concentration pairs beneath the anomer of dextrose (i.e., R-NH2 + Calcium versus phosphate concen- curves were judged to reflect visual 4,5,18 O=CHC5H11O5 → R-N=CC5H11O5 tration curve. To construct one cal- compatibility. 24 + H2O). The ratio of the aqueous cium phosphate solubility curve for To determine the best-fit curve ac- equilibrium of the acyclic aldehyde use as a general guideline applicable cording to the correlation coefficient to cyclic forms of dextrose at pH to TPN (Figure 1) and perform three between the Figure 1 variables of 6–7 is approximately 0.0025% to models of linear regression, a ruler calcium and phosphate concentra- 99.9975%.25 Because of the small was used to visually estimate values tions, variations in the mathematical percentage of dextrose in the reactive for 10 and 9 sets of calcium glucon- function of the concentrations were aldehyde form at any given moment, ate and phosphate concentrations applied. The regression of the natural it takes one day to one or more weeks from figure 1 by Henry et al.4 and logarithm of calcium concentration at 20 to 30 °C for Maillard reaction lower curve of figure 5 by Eggert et versus the natural logarithm of phos- products in mixtures of dextrose and al.5, respectively. The conditions in phate concentration yielded better amino acids to reach visible con- references 4 and 5 were amino acids, correlation (r = –0.99) than the re- centrations. The time lapse until the 4.25%4 and 4%5; dextrose, 25%4,5; gression of the natural logarithm of color of Maillard products becomes pH 6.3; and 20–25 °C.4,5 Lower calcium concentration versus phos- apparent decreases as the concentra- amino acid and dextrose concen- phate concentration and the regres- tions of dextrose and amino acids trations, which are consistent with sion of calcium concentration versus increase and increases as the con- low-osmolality and low-osmolarity phosphate concentration. Products centrations decrease (e.g., sample F parenteral nutrient formulations of calcium concentration (in mil- compared with sample H in Table 3). for peripheral vein administration, liequivalents per liter) with phos-

76 Am J Health-Syst Pharm—Vol 65 Jan 1, 2008 COMMENTARy Calcium and phosphates phate concentration (in millimoles sulted in patient harm or death are gluconate 10 meq/L and phosphate per liter) vary inconsistently from reviewed below (Figure 3). 80 mmol/L (evenly divided between 130 to 1704 and from 100 to 1905 as Report by Robinson and Wright.7 the sodium and potassium salts). calcium concentration decreases and A right subclavian catheter became This phosphate concentration greatly phosphate concentration increases. occluded after 64 days of continuous exceeds the right-hand limit of 25 This is why a single product should TPN therapy. The TPN admixture mmol/L on the phosphate axis in not be used as a sole criterion for consisted of 500 mL of 8.5% amino Figure 3. The patient survived, prob- judging compatibility. acids injection and 500 mL of 50% ably because a 0.22-mm inline filter Case reports. The calcium and dextrose injection in a 1000-mL was used. phosphate concentrations that re- formula that also contained calcium Report by Knowles et al.8 A patient who had been receiving home TPN therapy for five years developed diffuse granulomatous interstitial Table 3. pneumonitis due to exposure to pre- Appearance of Samples of Calcium Gluconate and Potassium cipitated CaHPO4. The TPN formu- Phosphates Injections, USP, after Standing at 22–24 °C lation contained 4.25% amino acids Visual Appearance at Interval Indicateda,b injection and 5% dextrose injection; Sample 10 min 1 hr 1 Day 5 Days 9 Days 14 Days this is a low-osmolality and low- A 3c 3 3d 3d 3d 3d osmolarity formulation that would B 0 0 0 0 0 0 be expected to be more susceptible C 0 0 0 0 0 0 to calcium and phosphate precipita- D 1c 1 1e 1e 1e 1e tion than, for example, the dextrose E 0 0 0 0 0 0, Y concentrations described by Henry et F 0 0 0 0 Y 0, Y al.,4 Eggert et al.,5 and Fausel et al.14 G 0 0 0 0, Y 0, YA 0, YA 1 1 Report by Hill et al.12 This report, H 0 0 0, Y 0, YA 0, YA 0, YA 1 2 3 which prompted the FDA safety a0 = no precipitate or color change, 1 = faint turbidity from CaHPO precipitate, 3 = intense turbidity from 1,2 4 alert, involved four patients who CaHPO4 precipitate, Y = pale yellow, YA1 = pale yellow-amber, YA2 = darker yellow-amber than YA1, YA 3 = darker yellow-amber than YA2. had been receiving a low-osmolality bSample tubes were gently agitated at each observation time to swirl any possible scant crystalline TPN admixture via a peripheral vein precipitate from the bottoms. White or black fungi and mold may appear as fluffy masses after several days in dextrose-containing samples, but those are easily distinguished from precipitated CaHPO4. during hospitalization at Tripler cPrecipitation occurred instantly upon the addition of calcium gluconate injection. Army Medical Center in Honolulu dClear supernatant over approximately 0.75 in-thick sediment of gelatinous-appearing precipitate. eClear supernatant over approximately 0.75 in-thick sediment of gelatinous-appearing precipitate. and who developed sudden and un-

Figure 2. Calcium gluconate and potassium phosphate injection samples A–H (see Tables 2 and 3) photographed at 14 days.

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Figure 3. Calcium and phosphate concentrations that resulted in patient harm or death, superimposed over the compatibility curve shown in Figure 1. Ref. 12a represents values for the total volume of total parenteral nutrient (TPN) formulation to which calcium glu- conate injection was added; Ref. 12 represents values for only 46% of the total TPN admixture volume.

50

45 Ref. 8

40 Ref. 12 Ref. 15 35 Report by author D.W.N. 30 Ref. 12a

25

20 Calcium (meq/L) 15

10

5

0 0 5 10 15 20 25

Phosphates (mmol/L)

explained respiratory distress, which to dissolve, nor was the formulation in a lawsuit involving a baby’s death was fatal in two cases. Postmortem agitated sufficiently. (after 2001) caused by precipitation 15 examination of lung tissue identified Report by Shay et al. This retro- of CaHPO4 during an i.v. dextrose in- CaHPO4 crystals in the pulmonary spective cohort study reviewed all fusion. The confidential information microvasculature. Table 4 compares hospitalized patients who received a provided indicated that (1) relevant the institution’s peripheral-vein and low-osmolality and low-osmolarity literature sources4,5,17,18 were either central-vein TPN formulations and formulation (peripheral-vein par- misinterpreted or not reviewed, (2) illustrates most of the important enteral nutrient [PN] formulation) the curve for calcium concentration calcium and phosphate compatibility containing calcium and phosphate versus phosphate concentration was factors. The deaths were attributed over a 16-month period. The defini- interpreted as a downward-slanting to an unfavorable mixing sequence, tion for possible calcium phosphate straight line,4,5,17,18 (3) a compat- lack of inline filtration, and a short precipitation and harm was met if ibility chart for amounts of calcium time from compounding to admin- “while receiving [peripheral-vein] gluconate and potassium phosphate istration.12 The calcium and phos- PN during the study period, [the injected was based on a final volume phate concentrations did not exceed patient] developed unexplained of x mL, but the actual volume com- the solubility limit in the final TPN chest pain, dyspnea, or cardiopul- pounded was 0.5x mL, resulting in admixture volume, but CaHPO4 monary arrest of noncardiac etiology twice the assumed concentrations of precipitated when calcium gluconate or had new, unexplained bilateral calcium and phosphates, and (4) an was added before 70% dextrose injec- interstitial infiltrates noted on chest inline filter was not used. One phy- tion to only 46% of the final volume radiograph.” Of the 50 patients who sician who attempted to rescue the of the TPN admixture. There was not received the therapy, 5 met this defi- baby stated “Ten to 15 minutes into adequate time between the comple- nition, and 4 of them died. resuscitation, the lower 1–2 cm of the tion of compounding and the start of Report by author. One of the au- baby’s i.v. fluid bag, as well as the i.v. infusion for the precipitated CaHPO4 thors (D.W.N.) served as a consultant tubing, showed precipitation.”

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monobasic anion, H PO –, to convert Table 4. 2 4 to the dibasic anion, HPO 2–, as de- Calcium and Phosphate Compatibility Factors in Central- and 4 picted in equation 1. In the study by Peripheral-Vein Parenteral Nutrient Formulations at Tripler Army Wong et al., samples were evaluated Medical Center on three occasions between 0 and 27 Content hours after admixture preparation. Ingredient Central-Vein Formulationa Peripheral-Vein Formulation12 Only 1 of 45 sample measurements Dextrose 24% 7%b exceeded pH 6 (i.e., 6.06) whereas Freamine III with most of the TPN admixtures studied electrolytes 41 g 33 gc by Henry et al.,4 Eggert et al.,5 and Fat from i.v. Fausel et al.14 had a pH of 6.3. Wong d emulsion 28 g 39 g et al.27 would have identified CaHPO Phosphoruse 14 mmol 15 mmolf 4 precipitation in more samples if the Calciumg 5 meq/L 10 meq/Lh pH had been higher. aFrom confidential documents provided to author (D.W.N.) as a consultant for a lawsuit in 1997. bA lower final dextrose concentration favors a higher final mixture pH, which favors a higher percentage of Conclusion. Understanding the 2– phosphate as HPO4 , which favors greater formation of the least-soluble CaHPO4 salt. chemical and practical compatibility cA lesser amino acids concentration reduces Ca2+ sequestration, which increases the free Ca2+ concentration available to react with phosphates. of calcium gluconate and potassium dA higher fat content favors a higher final mixture pH, from the alkaline pH of fat emulsion, which favors a or sodium phosphate injections is 2– higher percentage of phosphate as HPO4 , which favors greater formation of the least-soluble CaHPO4 salt. eFrom potassium phosphate injection. critical to ensuring the safe i.v. ad- f A higher final phosphate concentration favors greater 4CaHPO formation, which increases precipitation ministration of these supplements potential. gFrom calcium gluconate injection. and preventing patient harm. h A higher final calcium concentration favors greater CaHPO4 formation, which increases precipitation potential. References 1. Lumpkin MM, Burlington DB. FDA safe- ty alert: hazards of precipitation associ- ated with parenteral nutrition. Rockville, Preventing future harm. All centrations was employed, and only MD: Food and Drug Administration; institutions must establish calcium 1994 Apr 18. visual identification of precipitation, 2. Food and Drug Administration. Safety and phosphate mixing guidelines which can be highly variable, was alert: hazards of precipitation associ- that are supported by peer-reviewed performed. Recent studies employing ated with parenteral nutrition. Am J Hosp literature and the manufacturers’ Pharm. 1994; 51:1427-8. particle detection and size measure- 3. Schuetz DH, King JC. Compatibility and product information. The compat- ment by light obscuration provide stability of electrolytes, vitamins and an- ibility guidelines should be based objective evidence of subvisible tibiotics in combination with 8% amino on actual clinical conditions and be 23 acids solution. Am J Hosp Pharm. 1978; microprecipitation, which can be 35:33-44. reviewed and approved by the phar- clinically dangerous. 4. Henry RS, Jurgens RW Jr, Sturgeon R macy and therapeutics committee. Careful interpretation of the cal- et al. Compatibility of calcium chloride Low-osmolality and low-osmolarity and calcium gluconate with sodium cium and phosphate compatibility phosphate in a mixed TPN solution. Am J formulations, such as PN admixtures literature is necessary before applica- Hosp Pharm. 1980; 37:673-4. administered through a peripheral tion to clinical practice. For example, 5. Eggert LD, Rusho WJ, Mackay MW et al. vein, are notorious for calcium and 27 Calcium and compatibility Wong et al. recently suggested in parenteral nutrition solutions for neo- phosphate incompatibility; thus, that calcium and phosphate con- nates. Am J Hosp Pharm. 1982; 39:49-53. they should be avoided when pos- centrations in TPN admixtures for 6. Lenz GT, Mikrut BA. Calcium and sible. A recent investigation of such phosphate solubility in neonatal par- neonates could be doubled to meet enteral nutrient solutions containing compatibility for peripheral-vein PN fetal accretion rates by using a for- TrophAmine. Am J Hosp Pharm. 1988; admixtures (≤3% amino acids and mulation containing only monoba- 45:2367-71. ≤5% dextrose) showed that the upper sic potassium phosphate, KH PO . 7. Robinson LA, Wright BT. Central venous 2 4 catheter occlusion caused by body-heat- limit of compatibility was calcium This claim was based on the correct mediated calcium phosphate precipita- gluconate 5 meq/L and sodium phos- premise that the divalent phosphate tion. Am J Hosp Pharm. 1982; 39:120-1. phates 15 mmol/L, or approximately anion, HPO 2–, is the culprit in cal- 8. Knowles JB, Cusson G, Smith M et al. 4 Pulmonary deposition of calcium phos- half the parenteral equivalent of the cium phosphate precipitation in phate crystals as a complication of home recommended daily allowance of TPN formulations. However, it did total parenteral nutrition. JPEN J Parenter these minerals.23 Enteral Nutr. 1989; 13:209-13. not emphasize that increasing pH 9. Newton DW. Introduction: physico- In the early TPN studies used to (e.g., pH in TPN formulations that is chemical determinants of incompatibility 4,5 and instability of drugs for injection and construct the curve in Figure 1, a much higher than pH in the KH2PO4 limited range of macronutrient con- injection product) will cause the infusion. In: Trissel LA, ed. Handbook on

Am J Health-Syst Pharm—Vol 65 Jan 1, 2008 79 COMMENTARy Calcium and phosphates

injectable drugs. 3rd ed. Bethesda, MD: 25. Murray RK, Granner DK, Mayes PA et tion, aging, and disease. Ann N Y Acad Sci. American Society of Hospital Pharma- al. Harper’s biochemistry. Stamford, CT: 2005; 1043:9-19. cists; 1983:xiii-xv. Appleton & Lange; 1996:137-9. 27. Wong JC, McDougal AR, Tofan M et al. 10. Driscoll DF, Newton DW, Bistrian BR. 26. Rahbar S. The discovery of glycated he- Doubling calcium and phosphate concen- Precipitation of calcium phosphate from moglobins. In: Baynes JW, Monnier VM, trations in neonatal parenteral nutrition parenteral nutrient fluids. Am J Hosp Ames JM et al., eds. The Maillard reac- solutions using monobasic potassium Pharm. 1994; 51:2834-6. Letter. tion: chemistry at the interface of nutri- phosphate. J Am Coll Nutr. 2006; 25:70-7. 11. Maswoswe JJ, Okpara AU, Hilliard MA. An old nemesis: calcium and phosphate interaction in TPN admixtures. Hosp Pharm. 1995; 30:579-86. 12. Hill SF, Heldman LS, Goo ED et al. Fatal microvascular pulmonary emboli from Appendix—Calculation of calcium concentration in Calcium Gluconate Injection, precipitation of a total nutrient admix- USP, and phosphorus and potassium concentrations in Potassium Phosphates ture solution. JPEN J Parenter Enteral Injection, USP Nutr. 1996; 20:81-7. 13. Newton DW. Rx: calcium, phosphate, Calcium Gluconate Injection, USP and secundum artem. Nutrition. 1997; 1. Selected information from The United States Pharmacopeia and the National Formulary 13:390-1. (USP) 22: Contains 95–105% of labeled strength of calcium gluconate. A small amount of calcium 14. Fausel CA, Newton DW, Driscoll DF et content from the gluconate salt may be replaced by calcium saccharate or other calcium salts for al. Effect of fat emulsion and supersatu- stabilization. ration on calcium phosphate solubility 2. Typical commercial product label information: strength, 10%; calcium 0.465 meq/mL; content, in parenteral nutrient admixtures. Int J calcium gluconate monohydrate 98 mg/mL and calcium saccharate tetrahydrate 4.6 mg/mL.

Pharm Compound. 1997; 1:54-9. 3. Chemical formulas and weights: calcium gluconate monohydrate, Ca(C6H11O7)2·H2O, 448.39 g;

15. Shay DK, Fann LM, Jarvis WR. Respira- calcium saccharate tetrahydrate, CaC6H8O8·4H2O, 320.26 g.

tory distress and sudden death associated 4. Calcium gluconate monohydrate calculation

______

with receipt of a peripheral parenteral 98 mg g ___mol 2 eq 1000 meq 0.437 meq

______nutrition admixture. Infect Control Hosp _ mL · 1000 mg · 448.39 g · mol · eq = mL Epidemiol. 1997; 18:814-7. 16. Reedy JS, Kuhlman JE, Voytovich M. Mi- 5. Calcium saccharate tetrahydrate calculation

crovascular pulmonary emboli second-

_ ___

ary to precipitated crystals in a patient 4.6 mg g mol 2 eq_ 1000 meq 0.029 meq

______receiving total parenteral nutrition: a mL · 1000 ___mg · 320.26 g · mol · eq = mL case report and description of the high- resolution CT findings. Chest. 1999; 6. Sum of answers for steps 4 and 5 is 0.466 meq/mL. 115:892-5. 7. Calcium equivalencies: 1 mmol = 2 meq (because of 2+ calcium ion valence), 1 meq = 20.04 mg, 17. Trissel LA. Handbook on injectable 1 mmol = 40.08 mg. drugs. 12th ed. Bethesda, MD: American Potassium Phosphates Injection, USP Society of Health-System Pharmacists; 1. Selected USP monograph information: Contains 95–105% of labeled strengths of monoba- 2007:242-58. sic and dibasic potassium phosphates. 18. Trissel LA. Trissel’s calcium and phos- 2. Typical commercial product label information: phosphorus, 3 mmol/mL; potassium, 4.4 phate compatibility in parenteral nutri- meq/mL; anhydrous monobasic potassium phosphate, KH2PO4, 224 mg/mL; anhydrous tion. Houston: Tripharma; 2001. dibasic potassium phosphate, K2HPO4, 236 mg/mL. 19. Soine TO, Wilson CO. Roger’s inorganic 3. Chemical formulas and weights: KH2PO4, 136.09 g; K2HPO4, 174.18 g. a pharmaceutical chemistry. 8th ed. Phila- 4. Phosphorus calculation delphia: Lea & Febiger; 1967:141-2,170-

2,388. a. KH2PO4 contribution

_

20. Allen LV Jr, Popovich NG, Ansel HC. 0.224 g ___mol 1000 mmol 1.65 mmol ___ · _ · = Ansel’s pharmaceutical dosage forms mL 136.09 g mol mL and delivery systems. 8th ed. Balti-

more: Lippincott Williams & Wilkins; b. K2HPO4 contribution

_

2005:338,341. 0.236 g ___mol 1000 mmol 1.35 mmol

___ 21. Dudrick SJ, Wilmore DW, Vars HM et al. mL · 174.18 _g · mol = mL Long-term total parenteral nutrition with growth, development, and positive nitro- 5. Sum of answers for steps 4a and 4b is 3 mmol/mL. gen balance. Surgery. 1968; 64:134-42. 6. Potassium calculation 22. The United States pharmacopeia, 30th

rev., and The national formulary, 25th ed. a. KH2PO4 contribution

_ ___

Rockville, MD: United States Pharmaco- 0.224 g mol __eq 1000 meq 1.65 meq

__ _ peial Convention; 2006:1600,2993. mL · 136.09 g · mol___ · eq = mL 23. Driscoll DF, Joy J, Silvestri AP et al. Cal-

cium (Ca) and phosphate (P) compatibil- b. K2HPO4 contribution

_

__

ity in low osmolality parenteral nutrition 0.236 g ___mol 2 eq 1000 meq 2.71 meq

_ ___ (PN) mixtures. Clin Nutr. 2005; 24:695. mL · 174.18 g · mol · __eq = mL 24. Newton DW, Narducci WA. Extempo- raneous formulations. In: King RE, ed. 7. Sum of answers for steps 6a and 6b is 4.36 or 4.4 meq/mL. Dispensing of medication. 9th ed. Chap 12. Easton, PA: Mack; 1984:258-88. a1 mmol of any compound contains 1 mmol of each of its constituent atoms or ions.

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