Вы находитесь на странице: 1из 8

COMMENTARy Calcium and phosphates

COMMENTARy

Calcium and phosphate compatibility: The influence of other drugs and


nutrients.4-8,10-18

Revisited again The application of knowledge


about calcium and phosphate com-
David W. Newton and David F. Driscoll patibility in i.v. therapy has been fa-
Am J Health-Syst Pharm. 2008; 65:73-80 cilitated by four hallmark articles,3-6
several editions of the Handbook on

T
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 Trissels Calcium and Phosphate Com-
was revisited in an April 1994 phosphoric acid is 7.2 (i.e., the pH patibility in Parenteral Nutrition.18
FDA safety alert,1,2 616 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-
appeared in 1978, 3 1980, 4 1982, 5 HPO42 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
events involving calcium phosphate OH + H2PO4 HPO42 + H2O; shifts and phosphate solubility chemistry.
precipitation in total parenteral nu- to right when pH increases (1) The aqueous chemistry and solubil-
trient (TPN) admixtures.7,8 A review H2O + H2PO4 HPO42 + 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 H e n d e r s o n H a s s e l b a c h 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
publications on calcium phosphate pH = pKa + log ([A]/[HA]); percent pKa2 of phosphoric acid in practice,
precipitation in TPN formulations ionized, A, = 100/(1 + antilog the greater is the majority percentage
appeared.10-18 Thus, this article is [pKa pH]) = 100{[A]/([A] + of the desired H2PO4 anion (dihy-
yet another revisit of calcium and [HA])} (3) drogen or monobasic phosphate).
phosphate compatibility with i.v. pH = pKa + log ([HPO42 ]/[H2PO4]); H2PO4, with two dissociable pro-
formulations. percent HPO42 = 100/(1 + anti- tons, is an acid relative to HPO42,
This article discusses the chem- log [pKa pH]) = 100{[HPO42]/ and HPO 42 (i.e., monohydrogen
istry and practical compatibility ([HPO42] + [H2PO4])} (4) or dibasic phosphate) is a base or
or solubility factors relevant to the weaker acid relative to H 2 PO 4 .
safe administration of combination The compatibility curves for calcium Ca[H 2PO 4] 2 (calcium dihydrogen
therapy with calcium gluconate and gluconate versus phosphate concen- phosphate) is 60 times more soluble
potassium or sodium phosphate in- trations in clinical mixtures.4,5,17,18 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 D avid W. N ewton , B.S.P harm ., P h .D., Address correspondence to Dr. Newton
presented. FAPhA, is Professor and Chairman, Depart- at the Bernard J. Dunn School of Phar-
pH and pKa equilibria relevant ment of Biopharmaceutical Sciences, Ber- macy, Shenandoah University, 1460 Univer-
nard J. Dunn School of Pharmacy, Shenan- sity Drive, Winchester, VA 22601 (dnewton@
to calcium and phosphate compat- doah University, Winchester, VA. D avid su.edu).
ibility. The keys to understanding the F. Driscoll, B.S.Pharm., 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 PharmVol 65 Jan 1, 2008 73


COMMENTARy Calcium and phosphates

Table 1. of CaHPO4 reactions stated in the


Chemistry and Water Solubility of Phosphates and Calcium 1967 source ended in 1968 with the
Phosphates report that launched TPN,21 which
made reactions between calcium
Ion or Salta Names Solubility (mg/mL)5,10 and phosphates in i.v. formulations a
H2PO4- Monobasicb phosphate, dihydrogen NAc matter of life and death.
phosphate Calcium and phosphate solubility
HPO42 Dibasicd phosphate, monohydrogen NA for i.v. therapy. It is unlikely that any
phosphate patient-specific i.v. admixture con-
Ca[H2PO4]2 Monobasic calcium phosphate, 18
taining calcium and phosphates will
calcium dihydrogen phosphate
CaHPO4 Dibasic calcium phosphate, calcium 0.3
exactly duplicate the compatibility
monohydrogen phosphate results of published studies. Three
common variables are (1) practition-
a
The phosphoric acid aqueous equilibria H3PO4 H2PO4 + H+ (for which pKa1 = 2.1) and HPO42 PO43 + H+
(for which pKa3 = 12.319) are clinically negligible.14 er and device volume-measurement
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).
c
NA = not applicable. and pH ranges from The United
d
Dibasic refers to neutralization of the 2 charge on HPO42 by two +1 cations (e.g., 2 K+ or 2 Na+, or one +2 States Pharmacopeia and The Na-
cation, e.g., Ca2+).
tional Formulary (USP) for calcium
gluconate injection (i.e., 95105% of
labeled content and pH 6.08.2) 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., 95105% of labeled
cal of most divalent cationdivalent liter. In the article by Schuetz and content),22 and (3) other drugs and
anion salts, CaHPO4 is minimally King,3 phosphates were reported in nutrients that may be included in i.v.
dissociated into its constituent ions. milliequivalents per liter but without admixtures (i.e., the variable compo-
Consequently, most of the Ca2+ and specific concentrations of H 2PO4 sition of TPN formulations, which
HPO42 ions cannot be solvated by and HPO42. 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
Iondipole 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 solutewater 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, magnesium 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 dipoledipole 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 CaHPO 4 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
The percentages of H2PO4 and most insoluble in water, its chemi- possible.1,2,17,18
HPO42 decrease and increase, re- cal reactions are few and relatively A 0.2- m m 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-
0.1 pH unit increase over the pH hydrochloric acid.19 That CaHPO4 fat-emulsion-containing i.v. admix-
range of 6.07.6.14 Because 1 meq is more soluble at increasingly acidic tures, and a 1.2-mm filter should be
of HPO42 corresponds to 2 meq of pH represents the leftward shift in used for fat-emulsion-containing i.v.
H 2PO 4, phosphate concentration equation 2, and the unimportance admixtures.1-3,10,13,14,17,18

74 Am J Health-Syst PharmVol 65 Jan 1, 2008


COMMENTARy Calcium and phosphates

Calcium chloride 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
Ca2+ available to react with HPO42, 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,
CaHPO4 precipitation.4,5 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 2224 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. 2025 C and pH 6.3 in 25% dextrose injection and 44.25% 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-
the percentage of H2PO4 at which tion is, and the closer to or farther above the curve concentrations are, the greater the
H2PO4 forms more soluble calcium probability of precipitation of CaHPO4 is.
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-
Calcium (meq/L)

centration, the less likely CaHPO4 is 30


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

Am J Health-Syst PharmVol 65 Jan 1, 2008 75


COMMENTARy Calcium and phosphates

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
Fi 2.0 1.0 6.4
precipitates ranging from 5 to 50 mm
Gj 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
a
All 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.
b
Ingredients are in-date, USP-compliant commercial injections.
for judging compatibility, but it is
c
Volumes 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 0.12.0 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-
d
A crystalline amino acids product without additional electrolytes. evaluated, concentrations of dextrose
e
Equivalent to 10% dextrose.
f
Equivalent to 25% dextrose.
and amino acids. The compatibility
g
Equivalent to 1% amino acids. curves for calcium versus phosphates
h
Equivalent to 4% amino acids.
i
Equivalent to 10% dextrose and 1% amino acids.
typified by references 4 and 5 are
j
Equivalent to 20% dextrose and 2% amino acids. generally elbow shaped, with a slope
k
Equivalent 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
ing, reaction (Figure 2).9,24 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,
ids, R-NH2, with the acyclic aldehyde Maillard reaction product.26 concentration pairs beneath the
anomer of dextrose (i.e., R-NH2 + Calcium versus phosphate concen- curves were judged to reflect visual
O=CHC5H11O5 R-N=CC5H11O5 tration curve. To construct one cal- compatibility.4,5,18
+ H2O).24 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
67 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 2025 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 PharmVol 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 2224 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, YA1 0, YA1
Report by Hill et al.12 This report,
H 0 0 0, Y 0, YA1 0, YA2 0, YA3
which prompted the FDA safety
a
0 = no precipitate or color change, 1 = faint turbidity from CaHPO4 precipitate, 3 = intense turbidity from alert,1,2 involved four patients who
CaHPO4 precipitate, Y = pale yellow, YA1 = pale yellow-amber, YA2 = darker yellow-amber than YA1, YA3 = darker
yellow-amber than YA2. had been receiving a low-osmolality
b
Sample 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
c
Precipitation occurred instantly upon the addition of calcium gluconate injection. Army Medical Center in Honolulu
d
Clear supernatant over approximately 0.75 in-thick sediment of gelatinous-appearing precipitate.
e
Clear 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 AH (see Tables 2 and 3) photographed at 14 days.

Am J Health-Syst PharmVol 65 Jan 1, 2008 77


COMMENTARy Calcium and phosphates

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.
Calcium (meq/L)

30 Ref. 12a

25

20

15

10

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 babys death
was fatal in two cases. Postmortem agitated sufficiently. (after 2001) caused by precipitation
examination of lung tissue identified Report by Shay et al.15 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 institutions 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 CaHPO 4 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 12 cm of the
tion of compounding and the start of Report by author. One of the au- babys 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.

78 Am J Health-Syst PharmVol 65 Jan 1, 2008


COMMENTARy Calcium and phosphates

Table 4.
monobasic anion, H2PO4, to convert
Calcium and Phosphate Compatibility Factors in Central- and
to the dibasic anion, HPO42, as de-
Peripheral-Vein Parenteral Nutrient Formulations at Tripler Army
picted in equation 1. In the study by
Medical Center
Wong et al., samples were evaluated
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
emulsion 28 g 39 gd
et al.27 would have identified CaHPO4
Phosphoruse 14 mmol 15 mmolf
Calciumg 5 meq/L 10 meq/Lh
precipitation in more samples if the
pH had been higher.
a
From confidential documents provided to author (D.W.N.) as a consultant for a lawsuit in 1997.
b
A lower final dextrose concentration favors a higher final mixture pH, which favors a higher percentage of Conclusion. Understanding the
phosphate as HPO42, which favors greater formation of the least-soluble CaHPO4 salt. chemical and practical compatibility
c
A lesser amino acids concentration reduces Ca2+ sequestration, which increases the free Ca2+ concentration
available to react with phosphates. of calcium gluconate and potassium
d
A higher fat content favors a higher final mixture pH, from the alkaline pH of fat emulsion, which favors a or sodium phosphate injections is
higher percentage of phosphate as HPO42, which favors greater formation of the least-soluble CaHPO4 salt.
e
From potassium phosphate injection. critical to ensuring the safe i.v. ad-
f
A higher final phosphate concentration favors greater CaHPO4 formation, which increases precipitation ministration of these supplements
potential.
g
From calcium gluconate injection. and preventing patient harm.
h
A higher final calcium concentration favors greater CaHPO 4 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 acids solution. Am J Hosp Pharm. 1978;
microprecipitation,23 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 Calcium and phosphorus compatibility
Wong et al. 27 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 7. Robinson LA, Wright BT. Central venous
sic potassium phosphate, KH2PO4. 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 8. Knowles JB, Cusson G, Smith M et al.
anion, HPO42, is the culprit in cal- 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
construct the curve in Figure 1,4,5 a much higher than pH in the KH2PO4 and instability of drugs for injection and
limited range of macronutrient con- infusion. In: Trissel LA, ed. Handbook on
injection product) will cause the

Am J Health-Syst PharmVol 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. Harpers 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 AppendixCalculation 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 95105% 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)2H2O, 448.39 g;
15. Shay DK, Fann LM, Jarvis WR. Respira- calcium saccharate tetrahydrate, CaC6H8O84H2O, 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-
6. Sum of answers for steps 4 and 5 is 0.466 meq/mL.
resolution CT findings. Chest. 1999;
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 95105% of labeled strengths of monoba-
2007:242-58. sic and dibasic potassium phosphates.
18. Trissel LA. Trissels 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. Rogers inorganic 3. Chemical formulas and weights: KH2PO4, 136.09 g; K2HPO4, 174.18 g.
pharmaceutical chemistry. 8th ed. Phila- 4. Phosphorus calculationa
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
mL 136.09 _g ___
mol = mL
Ansels pharmaceutical dosage forms
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.
a
1 mmol of any compound contains 1 mmol of each of its constituent atoms or ions.

80 Am J Health-Syst PharmVol 65 Jan 1, 2008

Вам также может понравиться