Parenterale Ernährung mit stabilitätsgeprüften, modularen Standardnährlösungen in der Neonatologie

Parenteral nutrition with stability tested, modular standard nutrition solutions in neonatology. To improve the efficiency and safety of parenteral nutrition (PN) at the neonatal intensive care unit (NICU), stability tested standard nutrition solutions for the centralized compounding in the hospital pharmacy were designed and documented pharmaceutically. On the basis of guidelines and literature references on nutrient requirements for neonates as well as an investigation on the NICU, two standard nutrition solutions were formulated. The high caloric standard contains in 140 ml 15 g glucose, 2.5 g amino acids (Vaminolact®), 3.0 g lipids (Lipovenös® 20%), 3.0 mmol Na+, 1.5 mmol Ca2+, 0.25 mmol Mg2+, 3.0 mmol Cl , 1.5 mmol phosphate (as calcium glycerophosphate) and 2.0 mmol acetate. The daily dosis of 140 ml kg-1 body weight of the child provides around 90 kcal kg-1 d-1. Trace elements (Peditrace®), water - (Soluvit® N), and lipid soluble vitamins (Vitalipid® N Infant) are also included. Moreover, the low caloric Standard with 10 g of glucose in the same volume is provided. Up tommol K+ kg-1 d-1 may be added to both standards. The ready-to-use standard regimens are aseptically compounded fromtostable solutions (modules) in the hospital pharmacy. To rationalize production, final sterilized, stable glucose-electrolyte concentrates (glucose, Na+, Ca2+, Mg2+, Cl , phosphate, acetate) were developed as base module. The standards are administered as two-plus-one (TPO) system. For this purpose, the lipid emulsion (including vitamins) is admixed with the aqueous phase (glucose, amino acids, electrolytes, trace elements) via a three-way stopcock and infused by central venous access over 24 h. A pharmacoeconomical evaluation on variable and personnel costs of a complete, ward-prepared nutrition admixture added up to total expenses of CHF 114.55. The estimation for a centralized production resulted in CHF 103.00. Storage stability of the high and low caloric standard aqueous phase with addition ofmmol K+ kg-1 as chloride or acetate was analyzed in a factorial design over 30 days at -20, +4, and +22° C. A qualitative, light microscopic examination showed no precipitates. The pH-value remained unchanged. Orthophosphate (Pi) concentration as hydrolysis product of glycerophosphate was examined spectrophotometrically at 890 nm as molybdenum blue in the high caloric aqueous phase. Pi concentration remained constant at 1.054 ± 0.0168 mmol l-1 and was not dependent on temperature (+4 and +22° or the presence of trace elements. C) Therefore, a latent precipitation of poorly soluble phosphate salts can be excluded. Cysteine (cys) concentration as a very sensitive marker for chemical stability (oxidation) of the aqueous phase was quantified spectrophotometrically at 412 nm via Ellman reaction. Cys content showed a highly significant decrease over 30 days. Depending on test conditions, cys concentration dropped to 68 to 13% of the initial value. Time of
storage had the strongest impact on cys concentration in the aqueous phase, followed
by glucose concentration, anion configuration and temperature (-20 or +4°C). These
four factors significantly affected cys content.
Based on cys stability and on the solubility of its oxidation product cystine, practical
storage life of the aqueous phase is either 7 days at +4°C or 30 days at -20°C.
The application stability of complete standard nutrition solutions was examined by
simulating the administration via syringe pumps into an infant incubator (36 ± 0.5°C)
with a phototherapy lamp (425 - 475 nm). Orange colored syringes and infusion lines
were used for light protection. According to clinical practice, examinations took place
over 24 h.
Lipid emulsion stability (physical stability) was investigated by an established, light
microscopic method (lipid droplets (LT) � 1 μm). Peroxide concentration (chemical
stability) was detected spectrophotometrically at 560 nm by the FOX (ferrous oxidation
xylenol orange) method. The FOX assay was validated against the iodometric titration
as reference method. Both assays produce only relative values. The FOX method is
more adequate to quantify peroxide concentration differences with the conditions given
in neonatology (small volumes). The results of the FOX assay were presented in μmol
tert-butyl hydroperoxide equivalents (TBH-eq).
Different approaches for stability determination were selected:
- In a TPO system, physical stability after mixing the two phases was examined.
There was no aggregation of LT. The mean value of the largest LT per visual field
(MLTmax) amounted to 2.6 ± 1.2 μm and exhibited no trend to increase during 24 h.
- In the lipid phase, the influence of exposition time (0 - 24 h), flow rate (0.1 ml�h-1 or
0.7 ml�h-1), and light (daylight with and without phototherapy) on the physicochemical
stability was determined in a factorial approach. The microscopic LT
distribution was not dependent on any of the three influence factors. The MLTmax
averaged 3.9 ± 0.56 μm. Depending on the affecting factors, peroxide concentration
in the lipid phase rose from 24 - 37 to 119 - 596 μmol TBH-eq�l-1 within 24 h. There
was a significant difference in peroxide content between the factors. Peroxide
concentration was much stronger affected by exposition time than by flow rate or
light.
- An all-in-one (AIO) admixture (lipid emulsion admixed with aqueous phase) showed
an analogous LT distribution with a slightly increased MLTmax of 3.0 ± 1.00 μm
compared to the TPO system. There were a few aggregated LT, however.
Addition of 0.5 IU�ml-1 heparin to the AIO admixture lead to an instant, vast aggregation
of LT and therefore must not be made.
Lipid Peroxidation turned out to be the limiting factor for application stability. It was not
possible to judge whether the peroxide load was already critical for neonates, because
limits are missing.