Pediatrics and Neonatology (2020) 61, 331e337

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Original Article

Use of sodium glycerophosphate in neonatal

parenteral nutrition solutions to increase
calcium and phosphate compatibility for
preterm infants
Hsueh-Ju Wang a, Ya-Ting Hsieh a, Ling-Yu Liu a,
Chih-Fen Huang a, Shu-Chiao Lin a, Po-Nien Tsao b,
Hung-Chieh Chou b, Ting-An Yen b, Chien-Yi Chen b,*

a
Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan
b
Department of Pediatrics, National Taiwan University Children’s Hospital, National Taiwan University
College of Medicine, Taipei, Taiwan

Received Aug 19, 2019; received in revised form Dec 26, 2019; accepted Feb 15, 2020
Available online 22 February 2020

Key Words Background: Preterm infants require higher calcium and phosphate intake than term infants to
calcium; facilitate adequate bone growth, but this is rarely met in parenteral nutrition (PN) solution
compatibility; because of the limited solubility of calcium and phosphate. This study aimed to evaluate
organic phosphate; the solubility of organic phosphate with calcium gluconate in neonatal PN solutions, simulating
parenteral nutrition its clinical use.
Methods: PN solutions were composed of calcium gluconate at 50 mEq/L and sodium glycero-
phosphate (NaGP) at 25 mmol/L. Another component included 1% or 4% amino acid and 10% or
20% dextrose. For comparison, PN solution composed of potassium phosphate was also evalu-
ated. Each solution was evaluated using the following methods: visual inspection, light obscu-
ration particle count test, and pH measurement. To simulate the clinical condition, the
solution was tested after compounding, after being stored at 25  C for 24 h, and after being
stored at 2 C-8 C for 2 or 9 days and subsequently at 25  C for 24 h.
Results: There was no visual deposition in PN solution using NaGP in any of the concentrations
and under any stored condition. The solution fulfilled the criteria of physical compatibility as <
25 particles/mL measuring 10 mm in diameter and <3 particles/mL measuring 25 mm in
diameter. On the contrary, visual deposition was evidently noted in PN solution using potas-
sium phosphate after its formulation, and the particle count significantly exceeded the range
of physical compatibility.

* Corresponding author.
E-mail address: [email protected] (C.-Y. Chen).

https://doi.org/10.1016/j.pedneo.2020.02.004
1875-9572/Copyright ª 2020, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
332 H.-J. Wang et al

Conclusion: NaGP and calcium gluconate have significantly good compatibility in PN solution.
The use of NaGP in neonatal PN prevents calcium and phosphorus precipitation, hence
increasing their supply to preterm infants in meeting their growth requirement.
Copyright ª 2020, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).

1. Introduction when providing PN to individualized patients. The most

promising intervention to prevent precipitation is to change
With the advancement in neonatal care, the survival rates the type of salts. Compared to inorganic salts, organic
of very-low-birth-weight (VLBW) preterm infants increased calcium and phosphate have higher compatibility and lower
significantly in recent decades.1 Hence, aggressive nutri- propensity to precipitate.12e15 Organic calcium salts such
tion support is one of the key factors that improve the as calcium gluconate have been widely used in neonatal PN,
survival rates of VLBW preterm infants.2e4 Preterm infants whereas organic phosphate such as sodium glycer-
require higher nutrient intake than term infants to meet ophosphate (NaGP) or sodium glucose-1- phosphate is still
their rapid intrauterine growth rate. Moreover, adequate not available in many countries.
calcium and phosphate supplement is of paramount In our hospital, aggressive PN policy, including early PN
importance because of the infants’ rapid bone growth rate. with starter solution and high protein supplement, has
If VLBW infants have inadequate calcium and phosphate to established as a routine care for VLBW infants since 2013.
maintain appropriate bone accretion, metabolic bone dis- However, since then, early hypophosphatemia has also
ease of prematurity may develop, which leads to osteo- been observed because of low phosphate intake. To in-
malacia, fracture, and impaired linear growth.5 However, crease calcium and phosphate intake in preterm infants, we
with an immature gastrointestinal tract, infants’ enteral plan to introduce NaGP to the current PN program in our
nutrition is generally limited; thus, early parenteral nutri- hospital. Several reported studies have shown the high
tion (PN) is usually required in VLBW infants to meet their compatibility of organic phosphate with both organic and
nutritional demands. inorganic calcium salts and different concentrations of
Calcium phosphate precipitation is the major problem protein and glucose.13e17 However, neonatal PN is formu-
that is observed when PN is performed in preterm infants, lated with different components, concentrations, and
and some equations and graphs have been developed to conditions in Taiwan. Since the previous reports did not
guide practitioners in preventing calcium phosphate pre- provide sufficient reference to evaluate the risk of pre-
cipitation.6e8 As a result, calcium and phosphate intake is cipitation under our usual conditions, we conducted a se-
seldom sufficient to meet the infants’ requirement for bone ries of studies to assess the compatibility of inorganic
mineralization. For growing preterm infants, the updated phosphate and calcium gluconate in neonatal PN, simu-
European Society of Paediatric Gastroenterology, Hepatol- lating its clinical practice.
ogy and Nutrition (ESPGHAN) guidelines have recommended
PN administration of calcium 1.6e3.5 mmol/kg/day
2. Methods
(64e140 mg/kg/day) and phosphate 1.6e3.5 mmol/kg/day
(50e108 mg/kg/day), with a molar calcium:phosphate ratio
around 1.3 (mass ratio around 1.7).9 For example, in our 2.1. Formulation of parenteral nutrition
institution, the average supplementation of calcium and
phosphate are 19.8  11.3 mg/kg/day and 20.1  10.9 mg/ All PN solutions were aseptically prepared in a horizontal
kg/day, respectively, for LBW infants (internal data). As a laminar airflow hood using an automated compounding
result, a preterm infant who cannot tolerate enteral machine (Baxa Exacta-Mix 2400 compounder). The compo-
feeding well is usually at risk of metabolic bone disease nents of PN are listed in Table 1. After reviewing the past
after long-term PN. A systematic review has demonstrated formulation of PN in our neonatal intensive care unit
that PN predisposes the infant to metabolic bone disease (NICU), the minimum and maximum concentrations of
and suggested the administration of PN solutions with high- dextrose (10% and 20%) and amino acid (1% and 4%) were
dose calcium and phosphorus supplementation.10 chosen for testing. The final concentrations of other com-
Increasing calcium and phosphate concentrations without ponents included the following: calcium at 25 mmol/L,
increasing the risk of precipitation is an important issue phosphate at 25 mmol/L, sodium at 50 mEq/L, potassium at
that enhances bone health in preterm infants. 40 mEq/L, and magnesium at 5 mEq/L. Each concentration
There are several factors, including temperature, pH of was formulated as 250 mL per bag and in 3 repetitions.
the solution, the composition and concentration of amino Precipitation may take time to form. In the clinical
acid and glucose, presence of lipid, length of storage, and condition, PN solution may be stored at different temper-
the nature of calcium and phosphate (organic or inorganic), atures for different periods before or during infusion. To
affecting calcium phosphate solubility in PN solution.11 assess the compatibility of formulated PN solution under
Most of these factors, such as the use of amino acid, different clinical conditions, PN solution composed of NaGP
glucose, and lipid, are already unchangingly determined was stored under several conditions before analysis (Fig. 1).
Solubility of organic phosphate in neonatal PN 333

Table 1 Composition of parenteral nutrition solution.

Component Product Manufacturer Concentration Added volume
Dextrose Glucose Y.F. (Taiwan) 50% 50 or 100 mL
Amino acid Aminosteril Infant Fresenius Kabi (Austria) 10% 25 or 100 mL
Calcium Calgon (calcium gluconate) Y.F. (Taiwan) 10% 27 mL
Organic phosphate Glycophos Fresenius Kabi (Norway) Na: 2 mEq/mL 6.25 mL
P: 1 mmol/mL
Inorganic phosphate Potassium phosphate U-Liang (Taiwan) K: 4.4 mEq/mL 2.08 mL
P: 3 mmol/mL
Sodium chloride 3% sodium chloride Y.F. (Taiwan) Na: 0.513 mEq/mL 0 or 17.8 mL
Cl: 0.513 mEq/mL
Na acetate Na acetate Kingdom (Taiwan) Na acetate: 4 mEq/mL 0 or 0.85 mL
Potassium chloride Potassium chloride C.C.P.C. (Taiwan) K Cl: 2 mEq/mL 0.45 or 5 mL
Magnesium sulfate Magnesium sulfate C.C.P.C. (Taiwan) 10% 1.55 mL
Water Water for injection Y.F. (Taiwan) 0.27e135.2 mL
C.C.P.C.: China Chemical and Pharmaceutical Co., Ltd.
Kingdom: Synpac-Kingdom Pharmaceutical Co., Ltd.
U-Liang: U-Liang Pharmaceutical Co., Ltd.
Y.F.: Y F CHEMICAL CORP.

Figure 1 The parenteral nutrition solution composed of NaGP was stored under several conditions before analysis.

For comparison, PN composed of inorganic phosphate (po- were performed in each bag using a validated pH meter
tassium phosphate), 10% or 20% dextrose, and 1% or 4% (Radiometer PHM210, Lyon, France). The pH was assessed
amino acid was also formulated and analyzed after by a mean of 3 counts of PN solution for each sample.
formulation.
2.3. Statistical analysis
2.2. Analysis
The result of the pH value and particle count in each group
was presented as mean  standard deviation. Since the aim
Each solution was visually inspected and then analyzed by
of the study is to evaluate the condition of precipitation in
light obscuration particle count test using the United States
each preparation and the criteria to pass are well defined in
Pharmacopeia (USP) 788 standards.18 A suitable apparatus
the above method, comparisons between groups were not
(APS 2000 Particle Measuring Systems, Boulder, CO, USA)
performed because no further information would be
based on the principle of light blockage was used, which
provided.
allows an automatic determination of the size of the par-
ticles and the particle count according to size. The test was
performed in a laminar flow cabinet, and particle count 3. Results
S10 mm and S25 mm in each sample was counted. Particle
counts were assessed by a mean of 3 counts of 10 mL of PN There was no visual deposition in the PN solution using
solution for each sample. Solutions are considered physi- NaGP in 10% and 20% dextrose or 1% and 4% amino acid after
cally compatible if the average particle count <25 parti- formulation. Lower pH value was noted in the solution with
cles/mL measuring 10 mm in diameter and <3 particles/ 4% amino acid compared to 1%, but the particle counts were
mL measuring 25 mm in diameter. Measurements of pH within the normal range (Table 2). Nearly no large particles
 334
Table 2 pH value and particle counts after formulation in parenteral nutrition solution composed of inorganic or organic phosphate.
Type of phosphate K3PO4 NaGP
Dextrose 10% 20% 10% 20% 10% 20% 10% 20%
Amino acid 1% 1% 4% 4% 1% 1% 4% 4%
pH 6.07  0.02 6.02  0.02 6.11  0.01 6.05  0.02 6.79  0.01 6.66  0.02 6.39  0.02 6.34  0.01
S10 mm particle (per mL) 7793.5  1309.8 11134.2  2168.6 481.2  156.3 415.3  429.1 5.2  2.1 7.3  1.8 8.2  3.6 9.1  3.5
S25 mm particle (per mL) 8892.6  4391.8 814.6  770.1 11.7  8.5 29.0  45.2 0.2  0.2 0.1  0.1 0.2  0.2 0.3  0.3
Compatibility Exceeding compatible range Within compatible range
K3PO4, tripotassium phosphate; NaGP, sodium glycerophosphate.

Table 3 pH value and particle count in parenteral nutrition solution after storage.
Day 1 Day 3 Day 10
Dextrose 10% 20% 10% 20% 10% 20% 10% 20% 10% 20% 10% 20%
Amino acid 1% 1% 4% 4% 1% 1% 4% 4% 1% 1% 4% 4%
pH 6.73  0.01 6.64  0.01 6.40  0.01 6.31  0.01 6.77  0.01 6.67  0.01 6.44  0.02 6.34  0.01 6.78  0.01 6.68  0.01 6.44  0.00 6.36  0.01
S10 mm 3.1  2.7 0.8  0.7 1.6  0.8 1.4  0.6 1.7  1.4 0.9  0.4 0.3  0.3 0.5  0.3 0.7  0.4 0.5  0.5 0.8  0.4 0.7  0.6
particle (per mL)
S25 mm 0.2  0.2 0.1  0.1 0.1  0.2 0.2  0.2 0.2  0.2 0.2  0.2 0.1  0.2 0.1  0.2 0.1  0.1 0.1  0.1 0.2  0.3 0.1  0.2
particle (per mL)
Compatibility Within compatible range

H.-J. Wang et al
Solubility of organic phosphate in neonatal PN 335

(S25 mm) were found, and few smaller particles (S10 mm) dependent on the manufacturer of different amino acid
were noted. On the contrary, visual deposition was products. Although aggressive protein intake is highly rec-
evidently noted in PN solution using tripotassium phosphate ommended in the current nutritional care of preterm in-
(K3PO4) after its formulation in both 10% and 20% dextrose fants, the appropriate supplementary doses of calcium and
and 1% amino acid. PN solution containing K3PO4 was more phosphate are still not achieved even in PN solution with
acidic compared to PN solution containing NaGP. The par- relatively high amino acid concentration.
ticle counts, both S25 mm in diameter and S10 mm in Several studies outlined the improved solubility of PN
diameter particles, significantly exceeded the USP limits. when organic phosphate is used in place of inorganic phos-
Table 3 shows the pH value and particle counts in PN phate, which allows practitioners to provide adequate cal-
containing NaGP with 10% or 20% dextrose and 1% or 4% cium and phosphorus to meet the needs of preterm
amino acid after several conditions of storage as a simu- infants.13e17 Most of these studies use NaGP as the source of
lating clinical condition. PN solution was administered to organic phosphate, but the composition of PN solution and
infants by continuous infusion for 24 h after formulation. the timing to test the compatibility differed among studies
To assess the compatibility of organic phosphate in PN so- (Table 4). Although NaGP has been approved for use in
lution during infusion, a set of PN solution was stored at Europe, there is no Food and Drug Administration approval of
25  C for 1 day and was subsequently analyzed. According NaGP in Taiwan, and NaGP is only temporarily imported
to the result on the Day 1 group, the pH value did not during a national shortage of inorganic phosphate. Most of
change after storage in all test concentrations. Particle the pharmacists and neonatologists in Taiwan are hesitant to
count S10 mm decreased more compared to the particle use NaGP to increase calcium and phosphate levels because
count after formulation. Particle count S25 mm remained guidelines on the use of organic phosphate are not yet
at low level. established. The published studies of compatibility as shown
For the infants who need PN support during weekends, in Table 4 were conducted in definite standard PN solutions of
PN solution is formulated on Friday and stored in the their institution, which differ from the PN solutions produced
refrigerator before use. To simulate the clinical condition, in Taiwan. Therefore, this study aimed to assess the risk of
PN solution was stored at 2 C-8 C for 2 days after prepa- precipitation when NaGP was used instead of potassium
ration (mixed on Friday for use on Sunday) and subse- phosphate in the usual compounding component and con-
quently stored at 25  C for an additional day before analysis centration in our NICU. Compared to other reports, our study
(infusion for 24 h). The pH value was still unchanged in the is the only one study to use Aminosteril Infant as preparation
Day 3 group, and the particle counts remained low in for amino acid, to check the compatibility in higher dextrose
different dextrose and amino acid concentrations. concentration (20%), and to test at different timing in the
According to the regulation of the United States Phar- clinical scenario. All of these factors are important for clin-
macopeia chapter 797, a pharmacy-prepared PN formula- ical practitioners in Taiwan, because they represent the
tion stored under refrigeration has a beyond-use date of up difference between our daily practices and reported refer-
to 9 days after preparation. To evaluate the stability of ence. The result of our study demonstrated that the use of
organic phosphate after maximum storage days, PN solution NaGP significantly increased the compatibility of calcium and
was analyzed after it was stored at 2 C-8 C for 9 days and phosphate when neonatal PN was composed of the commonly
then at 25  C for 1 day. The particle count and pH value used components and concentrations in our hospital even
were still in normal range in this Day 10 group in all test after its 10-day storage. Using NaGP as the source of phos-
concentrations. phate would eliminate the need to use calcium phosphate
solubility curves when administering PN and increase the
final calcium and phosphate concentration in solution.
4. Discussion Optimal ratio of calcium:phosphate is also an important
issue for adequate retention of mineral for bone accre-
Administration of neonatal PN is significantly complicated tion.19,20 Since 2005, the ESPGHAN guideline recommended a
because large amounts of nutrients are required to be calcium:phosphate ratio (mol/mol) in the range of
supplied in a limited volume of solution. It is particularly 1.3e1.7.21 However, early hypophosphatemia emerged as a
challenging to supply adequate calcium and phosphate in new problem since the introduction of early aggressive
such highly concentrated solution since it is often near the nutrition.22,23 Very low birth weight and small for gestational
calcium phosphate saturation point. Some factors, such as age infants are especially at risk for early hypophosphatemia
higher concentration of glucose, lower temperature, and owing to their high P needs for growth.20,24,25 Mulla et al.26
lower pH, may improve calcium and phosphate solubility.11 reported that reverting from a PN calcium:phosphate molar
Hyperglycemia is one of the common complications in ratio of 1.3e1.5:1 to a ratio of 1.0:1 was associated with a
preterm infants treated with PN, limiting the concentration lower incidence and severity of hypophosphataemia and
of glucose in the solution. The temperature of PN solution hypercalcaemia in preterm infants given higher concentra-
during infusion depends on the environment, which is usu- tions of amino acids from postnatal day one. Therefore, the
ally not low because of possible hypothermia in preterm recently published ESPGHAN guideline recommended use of
infants. The pH value of PN solution is determined by the a molar calcium:phosphate ratio below 1 (0.8e1.0) to reduce
additive, and one of the important components is the the incidence of early postnatal hypercalcaemia and hypo-
amino acid. Higher concentrations of amino acid lead to phosphataemia in early PN with low calcium and phosphorus
more acidic solution, which allows higher calcium phos- intakes and optimized protein and energy.9 In the present
phate compatibility. The maximum allowable calcium and study, the concentration of calcium in PN preparation is 50
phosphate concentration in PN solution is usually mEq/L, and the phosphate is 25 mmol/L. The molar ratio of
336 H.-J. Wang et al

Table 4 List of study for physical compatibility in neonatal parenteral nutrition.

Authors, Dextrose Amino acid Calcium Phosphate Analysis method Timing
publication year
Bouchoud, 2010.13 3% Vaminolact: Calcium chloride/ G1P: Visual inspection 4  C for 2 d then
0.4% calcium glubionate: 10e50 mmol/L Particle counts 32  C for 1 d
10e50 mmol/L
MacKay, 2015.14 15% TrophAmine: Calcium gluconate: NaGP: Visual inspection 37  C for 1 d
1.5%, 4% 10, 20, 30, 40, 10, 20, 30, 40, Particle counts
50 mEq/L 50 mmol/L Turbidimeter
Anderson, 2016.15 15% TrophAmine: Calcium chloride: NaGP: Visual inspection 37  C for 1 d
1.5%, 4% 10, 20, 30, 40, 10, 20, 30, 40, Particle counts
50 mEq/L 50 mmol/L Crystal count
Thowladda, 10% Aminoven Infant: Calcium gluconate: NaGP: Visual inspections 1. After mixing
2016.16 2% 20, 30 mmol/L 20, 50 mmol/L Spectrophotometry 2.30  C for 1 d
Particle size 3.4  C for 1 d
4.4  C for 7 d
Lee, 2017.17 7.1% Vaminolact: Calcium gluconate: NaGP: laboratory of 2 C-8 C for 7 d,
2% 15, 20, 25, 30 mmol/L 12, 15, 19, Fresenius Kabi then 25  C for 1 d,
23 mmol/L then 37  C for 4 h
Our study 10%, 20% Aminosteril Infant: Calcium gluconate: NaGP: Visual inspections 1. After mixing
1%, 4% 50 mEq/L 25 mmol/L Particle counts 2.25 C for 1 d
3.2 C-8 C for 2 d,
then 25 C for 1 d
4.2 C-8 C for 9 d,
then 25 C for 1 d
G1P, disodic glucose-1-phosphate (Phocytan) (Aguettant, Lyon, France); NaGP, sodium glycerophosphate.

calcium:phosphate was 1.0, which is compatible for use in Declaration of Competing Interest
early PN in the current guideline.
This study has several limitations. First, we assessed the The authors have no conflicts of interest to disclose.
solubility in limited groups. The concentration of dextrose
in this study was chosen from the starter (10%) to the most
common upper limit (20%). In some extreme conditions, PN
containing <10% or >20% dextrose may be required, but References
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