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Journal of Parenteral and Enteral Nutrition
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Techniques, Materials, Devices

Physicochemical Stability of Parenteral Nutrition Supplied as All-in-One for Neonates

Maria Skouroliakou, PhD1, Chrysoula Matthaiou, MSc2, Antonia Chiou, PhD2, Demosthenes Panagiotakos, PhD2, Antonis Gounaris, PhD3, Tony Nunn, PhD4 and Nikolaos Andrikopoulos, PhD2

From 1 Harokopio University, IASO Maternity Hospital, Athens, Greece; 2 Harokopio University, Athens, Greece; 3 Neonatal Unit, Medical School, University of Thessalia, Thessalia, Greece; and 4 Royal Liverpool Children's NHS Trust, Liverpool, UK.

Address correspondence to: Maria Skouroliakou, Harokopio University, El. Venizelou 70, 17671, Athens, Greece; e-mail: silia1000{at}yahoo.gr.

Background: Common clinical practice for the provision of parenteral nutrition of neonates is to administer the nutrients in separate solutions. The aim of this study was to introduce and examine an alternative way of parenteral feeding for neonates, providing all-in-one parenteral regimes. Methods: Stability studies were carried out on 2 all-in-one admixtures. Stability assays consisted of the assessment of the admixture's (1) macroscopic aspect, (2) drop size measurement, (3) pH measurement, (4) peroxide value, and (5) {alpha}-tocopherol concentration. For the measurements, the admixtures were stored at 2 different temperatures, 4°C (storage) and 25°C (compounding), and then analyzed at a starting time, 24 hours, 48 hours, and 7 days after compounding. Results: The 2 all-in-one parenteral admixtures for neonates were shown to be physically stable under analysis conditions, and there were no particles larger than 1 µm. The maximum loss of {alpha}-tocopherol was approximately 24%. In all-in-one admixtures, lipid peroxide occurred within 24 hours after the addition of the lipid emulsion. Conclusions: The addition of fat emulsion and fat-soluble vitamins did not alter the physical stability of parenteral admixtures for neonates. Moreover, the admixtures examined were relatively chemically stable for 24 hours, as far as vitamin E is concerned. Lipid peroxidation was the limiting factor for application stability of an all-in-one neonatal parenteral regimen.

Key Words: parenteral nutrition • infants • all-in-one • lipid emulsions • stability

Parenteral nutrition (PN) includes IV administration of amino acids, glucose, lipids, electrolytes, vitamins, and trace elements. These nutrients are commonly admixed into 1 container, a term known as the all-in-one (AIO) concept. The AIO parenteral admixtures have been shown to be clinically and economically advantageous.1,2

Although Solassol et al3 reported the use of the AIO or total nutrient admixture solution in PN years ago, its adoption has varied considerably. The benefits of an AIO admixture are limited by physicochemical stability, as the lipid emulsions are prone to affecting the stability of the admixture.

The stability may be compromised in a number of ways. The mixture may show physical and chemical incompatibilities; thus, careful control is required during the compounding phase and in clinical practice. The main problems include the formation of large lipid globules, precipitation of insoluble salts, lipid peroxidation, and degradation of certain vitamins and amino acids.4 The most critical parameter of admixtures is particle diameter, which must be in the range of 0.4-1 µm to mimic the size of chylomicrons. Patients require protection from particles in the range of 5-10 µm, as this is the size range likely to be trapped in capillary beds such as the lungs.5 Several methods are available to evaluate particle size changes: visual inspection, optical microscopy, electron microscopy, nefelometry, coulter counter, laser diffraction spectroscopy, photon correlation spectroscopy, and acoustic attenuation spectroscopy.6

There has not been much research about the chemical constituents of lipid emulsions and their relative stability during compounding, storage, and administration. Ideally, all ingredients should be assessed for stability in each mixture, but in practice, this task is not feasible. Consequently, certain more unstable ingredients can be used as markers of chemical stability. The polyunsaturated fatty acids (PUFAs) within the lipid moiety represent the critical component of chemical instability, namely, lipid peroxidation. This chemical reaction occurs in vitro and in vivo, is complex, leads to a variety of labile intermediates, and thus has a dynamic character depending on specific conditions.7 Lipid peroxidation is initiated by the interaction of a singlet oxygen with a hydrogen atom in the fatty acid chain. The hydroxyl radicals so formed interact with the lipids producing peroxyl radicals. The peroxyl radicals mediate the peroxidation of PUFAs to form lipid hydroperoxyl radicals and, by further interaction with the lipid alkyl radicals, form lipid hydroperoxides. The latter is a starting compound for a range of breakdown products (aldehydes such as 4-hydroxynoneal or malondialdehyde, peptane, and polymerization products) with toxic properties. Free radicals may attack a broad range of substrates in vivo such as lipids, proteins, or DNA, leaving cell damage and mutagens, and therefore may be a critical factor in the progression or resolution of disease.8

A major scavenger for free radicals is vitamin E. Tocopherols inhibit lipid peroxidation by scavenging lipid peroxyl radicals much faster than the radicals can react with the fatty acid side chains, thus breaking the chain reaction. Theoretically, there is an increased prevention of lipid peroxidation of the PUFA moiety when intravenous lipids are supplemented with liposoluble vitamin E.9

AIO admixtures for adults are today well established by many investigations.10-13 Acceptable standard ranges for nutrient contents have been developed to alert pharmacists to potential problems with formulation compatibility, stability, and deviation from normal clinical requirements. In contrast to PN for adults, there is little information about the stability of lipid-containing PN for children and even less for infants. The administration of PN is an essential part of the therapy given to infants in the neonatal intensive care unit. PN bags for neonates consisted of binary admixtures, with fat emulsion being administered to the patient via a Y connection on the catheter.14

The aim of this study is to assess the stability of AIO parenteral admixtures using a range of neonatal formulations under conditions simulating typical clinical use. Stability assays consisted of the assessment of the admixture's (1) macroscopic aspect, (2) drop size measurement, (3) pH measurement, (4) peroxide value, and (5) {alpha}-tocopherol concentration.


   Materials and Methods
Top
Materials and Methods
Results
 Discussion
 Conclusions
 
Preparation of PN Admixtures
Stability studies were carried out on 2 compounded AIO admixtures for neonates. The admixtures were prepared at the IASO maternity hospital of Athens into ethylvinyl acetate plastic bags by means of an automated filling system. The automated compounder that is used is MicroMacro 12 (Baxa, Englewood, CO). The preparation of a daily formula for PN for a neonate is a complex procedure. Numerous factors such as weight, age, clinical state of the neonate, environmental conditions (type of incubator, phototherapy, etc) should be taken into consideration. Four protocols were created at the IASO hospital according to the gestational age of the infant (< 26 weeks, 26-28 weeks, 29-32 weeks, and 33-40 weeks) through collected literature and clinical experience of the authors.14-27 In Table 1, the nutrition requirements of a neonate with a gestational age < 26 weeks and >33 weeks are depicted. These 2 extremes chosen for testing corresponded to 2 different formulations (Table 2) and represented a broad range of weights found in infants. The lowest (AIO A) and highest (AIO B) levels of nutrient intake designed for preterm (born before 37 weeks' gestational age) and sick term (unable to be fed orally) infants were selected for the present study.


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  		Table 1. Nutrition Requirements of a Neonate at Gestational Age <26 Weeks and >33 Weeks

 

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  		Table 2. Composition of the 2 Tested All-in-One Admixtures

 

Two other emulsions (A1, B1) were also produced to serve as control for just the test assessing the peroxide value. A1 and B1 have the same composition as A and B, respectively, but without lipid-soluble vitamins, they do not include Vitalipid.

Study Protocol
The AIO admixtures were stored at 2 different temperatures—4°C and 25°C—then were analyzed at starting time (0 hours) and at 24 hours, 48 hours, and 7 days. The particle diameter was determined by means of the Laser Diffraction Malvern 2000, peroxide concentration was measured spectrophotometrically by the ferrous oxidation xylenol orange (FOX) assay, and for the determination of {alpha}-tocopherol concentration, the AIO admixtures were analyzed by high-performance liquid chromatography (HPLC). These admixtures were also visually inspected, and their pH was determined at the aforementioned time periods.

{alpha}-Tocopherol, butylated hydroxytoluene (BHT), Tert-butyl hydroperoxide (TBH), and xylenol orange were purchased from Sigma (St Louis, MO); sodium chloride, sodium sulfate anhydrous, analytical grade chloroform, and HPLC-grade ethanol, methanol, acetonitrile, and 2-propanol were obtained from SDS (Peypin, France).

Visual Inspection
For visual inspection of PN mixtures, the bags were inverted for sampling 5-10 times, which redisperses flocs or sedimented droplets while free oil continues to adhere to the bag as a yellow-brown deposit or rapidly rises to the surface to be visible as globules. To observe the surface of the emulsion, a sample was placed in a beaker under normal light. The appearance of large colorless or yellow droplets visible at the surface indicates an unsatisfactory emulsion system.

pH Study
pH was monitored with a Beckman 71 pH meter.

Particle Diameter Determination
Compared with other particle-sizing techniques, laser diffraction has the advantage of high speed, good reliability, and high reproducibility.28 Particle size distribution was determined by integrated light scattering using a Mastersizer X (Malvern Instrument Ltd, Malvern, UK) fitted with a small-volume sampler. A low-power helium-neon laser ({lambda} = 633 mm) provides a collimated and monochromatic beam of light.29 Particles scatter light as a function of their optical properties, the wavelength of their light, and the size and shape of the particle.30 The smallest is the size of particles; the largest is the diffraction angle of light.

A 45-mm focal lens was used for the measurements, to cover the size range of 0.1-80 µm.

The instrument used both Fraunhofer diffraction theory and Mie theory, as the former is more accurate for sizing of particles >20 µm and the latter is more accurate at <5 µm.31 In the case of a fat emulsion, there is an uneven distribution of fat droplet sizes: relatively small ones where Mie theory applies and larger globules where the Fraunhofer diffraction theory must be used. The ultimate goal of a laser diffraction–based instrument is to produce an accurate overall droplet/globule size distribution, ideally spanning a range from 0.05 to 0.1 µm to 50 µm or larger, depending on the quality and stability of the fat emulsion in question.32

After the electrical and solution background was measured, the scattering was set to zero, and an aliquot of test sample was added to the stirrer sample cell until a final reading of 20% (±1%) obscuration was reached. The stirrer was adjusted to 50% maximum speed, and the test sample was continuously circulated throughout the system. The sample was then measured in triplicate over a 6-second period, allowing 3000 individual measurements for a single run.

Peroxide Value
Peroxide concentration (µmol TBH-eq/l) was measured spectrophotometrically at 560 nm by the FOX assay.33 TBH served as a reference. The ferrous oxidation of xylenol orange assay was developed to analyze hydroperoxides formed from lipid peroxidation. This method is based on the fact that hydroperoxides oxidize ferrous to ferric iron, and the resulting ferric iron binds to xylenol orange to produce a colored complex with a strong absorbance at 560 nm.34

To test the influence of {alpha}-tocopherol content on the sensitivity of emulsion to peroxidation, we studied another 2 emulsions with the same compositions as A and B but not including Vitalipid. These vitamin-free lipid emulsions (A1, B1) served as controls.

Vitamin E Determination
An aliquot of the admixture (5 mL) was pipetted into a glass tube. Subsequently, sodium chloride (1 g) and ethanol (1 mL) were added and vortex mixed, followed by extraction with chloroform (4 x 3 mL) containing BHT (100 µg/mL). The organic layers were combined, dried over Na2SO4 (0.5 g), and evaporated under a stream of nitrogen. The residue was dissolved in chloroform-isopropanol 3:1 (1 mL) and subjected to HPLC analysis. The recovery of {alpha}-tocopherol was tested by the addition of standard {alpha}-tocopherol, as a solution in ethanol, at concentrations corresponding to the addition of 25 µg and 8 µg {alpha}-tocopherol/mL PN admixture A. Subsequent treatment was performed as described above. All experiments were performed in triplicate under light protection. Samples were kept at –4°C in dark glass vials until analysis.

HPLC analysis was carried out on an Agilent Technologies (former Hewlett-Packard [HP], Avontale, PA) series HP 1050 system equipped with an autosampler and an HP1046A fluorescence detector connected to an HP integrator and an HP Chemstation. A Nucleosil 120-5 C18 column (Macherey-Nagel, Düren, Germany) was used. Reversed-phase HPLC, resulting in detection of tocopherols, was performed as previously described35 by using a quaternary solvent system consisting of water (acidified with phosphoric acid at pH 3), methanol, acetonitrile, and isopropanol, with gradient elution on the column and fluorescence detection. The excitation wavelength was set at 295 nm and the emission wavelength at 330 nm. Injections of 50 µL were performed.

Data Analysis
Data are presented as the mean ± standard deviation (SD). Comparisons between different time and temperature points were performed using the nonparametric Friedman test for ranked values. P values <.05 were considered statistically significant. All hypotheses tested were 2-sided. All analyses were performed in SPSS 14 statistical software (SPSS Inc, Chicago, IL).


   Results
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Materials and Methods
 Results
Discussion
 Conclusions
 
Visual Inspection
Visual examination for emulsion status was performed by using the criteria of creaming, flocculation, and coalescence.36 The presence of a cream layer—a dense white layer at the top of the admixture—was visible in the admixtures A and B after 24 hours at room temperature and after 48 hours at 4°C. In all cases, the boundary between phases was well defined, and redispersiblity of the cream layer occurred after 5-7 gentle inversions. No discoloration of the cream layer was seen, and no oil globules or yellow traces were observed in any admixture studied, so coalescence did not occur.

pH Study
pH findings are listed in Table 3. The pH values of the mixtures varied between 4.8 and 5.6, without statistically significant changes at different times and temperatures. Admixture A was more acidic than admixture B.


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  		Table 3. pH of the Parenteral Nutrition Solutions

 

Particle Diameter Determination
The AIO parenteral admixtures for neonates tested were shown to be physically stable under analysis conditions. The analysis results did not point out particle diameter larger than 4 µm. The globule size distribution of the admixtures show that >99% of the distribution is < 1 µm. There was not a statistically significant difference among the admixtures at different times and temperatures.

Peroxide Value
Peroxide concentration in the lipid emulsion rose from 30 to 780 µmol TBH equivalent L–1, and was influenced by time and temperature (Table 4). Peroxide concentration in the soybean lipid emulsion increased about 14 times during 7 days. There was a statistically significant increase in peroxide concentration during time (P = .001 for both admixtures A and B) and at room temperature (P = .002 for both admixtures A and B).


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  		Table 4. Peroxide Concentration (µmol TBH-eq/l) of Admixtures A, B and A1, B1 (Without Vitalipid)

 

To check the influence of tocopherol, we assessed {alpha}-tocopherol by an HPLC (results below). Lipid-soluble vitamin-free admixtures showed an increased peroxide load at 24 hours and 48 hours. The lipid peroxide concentrations in the A and B emulsions were significantly lower than in the A1 and B1 emulsions, respectively: A vs A1, P = .013, and B vs B1, P = .026.

Vitamin E Determination
The determination of {alpha}-tocopherol was performed after liquid-liquid extraction of the AIO parenteral admixtures. Tocopherol concentration was calculated by means of an external standard method; the chromatographic peak area was evaluated. {alpha}-Tocopherol values were expressed as the mean ± standard deviation. The {alpha}-tocopherol content of the AIO parenteral admixtures A and B, after being stored at 4°C and at room temperature for several time periods, is presented in Tables 4 and 5, respectively. The initial amounts of {alpha}-tocopherol theoretically contained in parenteral admixtures A and B were 27.9 µg/mL and 18.7 µg/mL, respectively, while HPLC analysis revealed the presence of 26.0 ± 0.5 µg/mL and 18.4 ± 0.6 µg/mL, respectively. These rather small differences between the theoretical and the calculated amounts may be attributed either to the recovery of tocopherol from the admixtures or to minor variations of the added vitamin volumes. {alpha}-Tocopherol proved to be relatively stable under the conditions tested. In both admixtures, the highest possible loss determined was approximately 24% (Tables 6 and 7), as compared with the initial vitamin amounts calculated by HPLC. This loss was observed after storage of admixtures for 7 days. In the case of parenteral admixture B, a 22.6% loss was calculated after being stored at 25°C for 48 hours. In all analyzed samples, the presence of other tocopherol vitamers ({delta}-tocopherol and {gamma}- and/or β-tocopherol) was also detected. This can be attributed to the tocopherol naturally occurring in soybean oil, that is, contained both in Soluvit and Vitalipid. Based on peak area calculations, the content of the other tocopherols was not drastically altered during time in the PN admixtures (data not shown).


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  		Table 5. Percentage of Globules >1 µm but <4 µm in Admixtures A and B at 0 Hours, 24 Hours, 48 Hours, and 7 Days After Preparation

 

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  		Table 6. {alpha}-Tocopherol Content of All-in-One Admixture A at 0 Hours, 24 Hours, 48 Hours, and 7 Days After Preparation

 

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  		Table 7. {alpha}-Tocopherol Content of All-in-One Admixture B at 0 Hours, 24 Hours, 48 Hours, and 7 Days After Preparation

 


   Discussion
Top
Materials and Methods
 Results
 Discussion
Conclusions
 
There are few reports regarding AIO formulations provided for infants and very young children. Previous studies have provided evidence, some of it conflicting, regarding the stability of AIO admixtures intended for the very young. The physical stability of AIO parenteral admixtures for children with chemotherapy-linked hyperhydration was assessed, and the examined parenteral mixtures proved to be stable for 48 hours at 37°C if the calcium concentration is <16 mmol/L, the phosphate concentration is <52 mmol/L, and the product of both concentrations is <250 mmol/L.25 Another study showed that the losses of fat-soluble vitamins are essentially nil in AIO admixtures for neonates and children during 24 hours.37 The physical stability of various IV lipid emulsions (IVLEs) as AIO admixtures intended for the very young was examined, and the results suggest that AIOs made of IVLEs that contained medium-chain triglycerides/long-chain triglycerides are more stable than those made from pure long-chain triglycerides.38 The investigation into the physical stability of a neonatal PN formulation has demonstrated that mixes of lipid emulsion and an amino/glucose mixture is unstable, with coalescence occurring almost immediately after preparation.39 Gräflein and Mühlebach40 showed that peroxide concentration in a soybean lipid emulsion increased 4-16 times during 24-hour delivery simulation of neonatal PN.

Changes (creaming) that were observed by visual examination were all reversible. It is important to recognize the point at which gross coalescence has occurred and also to distinguish it from reversible flocculation. From the results of acidity, decreasing pH is related to high peroxide levels. The possible hypotheses for the pH drop are an accelerated and sustained rate of triglyceride hydrolysis, chemical reactions leading to acidic products, and an enrichment of volatile acidic breakdown products of lipid peroxidation. The optimum pH of the AIO parenteral emulsion is in the general range of 6-7.41 It is not clear yet whether acidity is a causative factor or a coincidental finding to instability.42 Amino acid solutions exert a protective effect by enhancing buffering capacity. Pediatric amino acid profiles have a higher content of branched-chain amino acids and contain taurine so they are more acidic; this is why pediatric parenteral admixtures are more acidic.

The present results showed that in an AIO admixture, lipid peroxidation occurs within 24 hours after the addition of a lipid emulsion to a PN solution. After 7 days, the peroxidation potential increased about 14 times. The peroxidation potential seems to be related to the {alpha}-tocopherol concentration. Admixtures (A1, B1) that do not include vitamin E had an increased peroxide rate, although after 7 days, the peroxide concentration was at the same range as admixtures A and B. These data are consistent with previous studies demonstrating a delay of the initiation of the peroxidative process proportional to the {alpha}-tocopherol content in fat emulsions.43 The determination of vitamin E revealed a 24% loss during time; this is quite significant, as we normally expect to find 90%-110% retention during stability studies with pharmaceuticals. Analysis results have pointed out that dependence of vitamin E on time was significant and that the vitamin concentration begins to decrease for admixture A 48 hours and for admixture B 24 hours after compounding. The temperature affected vitamin E stability only in admixture B. As far as the physical stability of the admixtures is concerned, there were no particles >4 µm during 7 days at the 3 tested temperatures. It has been suggested that an admixture can be considered as unfit for human administration when droplets >5 µm in diameter constitute > 0.4% of fat within the system.44

The inclusion of IV fat emulsion into a PN admixture changes the conventional nutrition solution into an emulsion that is thermodynamically unstable.45 The stability of the lipid emulsion is maintained by mechanical and electrostatic repulsive forces counteracting the coalescence of small oil droplets dispersed by an emulsifier agent.46 The anionic egg yolk phosphatides mixture, which is the most used emulsifier, forms an interfacial film around each fat droplet.47 The result is a closely packed molecular film that absorbs the oil-water interface, bridging the phases and producing a mechanical barrier to coalescence. Ionization of the phosphate group within the aqueous phase provides the second barrier to coalescence. The resulting net negative charge exerted at the surface of its droplet establishes mutual repulsion between lipid droplets through a common surface charge.48 Each additive of AIO initially diffuses into the outer layer of the droplet, altering the surface charge. The possible causes of fat emulsion instability in AIO mixtures are increased cation load, especially divalent and trivalent ions; low pH (<5); the composition of the amino acid solution; low concentrations of amino acids; low and high glucose concentrations; low fat concentration; aging of fat emulsion; and the ingredients of the fat emulsion.49

Vitamins are commonly believed to be among the least stable ingredients in PN mixtures, and it is generally recommended that vitamins should be added immediately before commencing infusion or that infusion should be commenced within 24-48 hours of addition.8 Vitamins' stability may be affected by various factors of the PN mixture itself, such as pH, electrolytes, trace elements, and other vitamins, and environmental conditions including temperature, storage time, light exposure, the type of plastic used to manufacture the PN container, and infusion equipment.50 Tocopherol can be oxidized rapidly, and this reaction is activated by ultraviolet light. As the mechanism involves a photocatalyzed reaction with oxygen, factors influencing the availability of oxygen will influence the rate and degree of vitamin degradation.51 Photo-oxidation of tocopherol could therefore be influenced by the presence of ascorbic acid, which will compete for oxygen, and the type of bag used, since the multilayered bags substantially reduce oxidation reactions by preventing oxygen transfer from air into the PN.52 Consequently, AIO parenteral admixtures should be light-protected during preparation, storage, and administration. These admixtures may also be strongly bound to plastic, and losses by adsorption to the administration set have been shown to be significant.53 Losses before administration should not exceed 10% of the amount of any ingredient added to the mixture.54 However, in most circumstances, this will not be achievable because of the poor stability of certain ingredients. The alternative criterion then applied is that the mixture must deliver at least the minimum daily requirement as indicated by current guidelines.


   Conclusions
Top
Materials and Methods
 Results
 Discussion
 Conclusions
 
AIO therapy represents the consummate dosage form in that it provides the entire nutrition needs of the patient in a single vehicle. This varied mixture of chemical entities provides the potential for a number of chemical and physicochemical interactions that can compromise the clinical safety and efficacy of the product.

Thirty years after the establishment of the AIO technique, we still do not have agreement on the definition of stability and what is going on with admixtures intended for neonates. This is partly because many of the instrumental techniques require considerable capital investment and yet none provide the whole picture of what is happening in a complex system.

Our results demonstrate that within therapeutic demands, AIO mixtures are suitable for neonates, as they proved to be physically stable for 7 days and relatively chemically stable for 24 hours. In these admixtures, almost 90% of the nominal amounts of vitamin E will reach the patient, while no particles larger than 4 µm will be detected, indicating that these AIO admixtures are stable and safe. Twenty-four hours after the preparation of AIO admixtures, the peroxide load increased about 8 times. This possibility underlines the importance of better defining the peroxide potential of AIO admixtures to address the production process, the pharmaceutical handing, and clinical use. Further research should be undertaken on other components and admixtures in other clinical concentrations to further ensure the suitability of administrating the AIO admixtures for neonates. The clinical issue of providing adequate nutrients to the patient influences the final composition of the formulation and must be balanced against the pharmaceutical concerns associated with emulsion stability.

The authors gratefully acknowledge Pfizer Pharmaceutical for the donation of the HPLC apparatus, Mamidakis Brothers Group, and the editorial assistance of Steven Kompogiorgas. We also thank Ball Patrick, a professor in the School of Pharmacy, University of Otago, Dunedin, New Zealand, for the useful advice to dispatch this project.


  
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Materials and Methods
 Results
 Discussion
 Conclusions
 
Financial disclosure: none declared.

Received for publication July 1, 2007. Accepted for publication September 5, 2007.

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Journal of Parenteral and Enteral Nutrition, Vol. 32, No. 2, 201-209 (2008)
DOI: 10.1177/0148607108314768
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