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e-SPEN Journal xxx (2013) e1ee6

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Review of drug stability in parenteral nutrition admixtures

Daniel Cardona a, *, Maria Nadal b, Joan Estelrich c, M. Antnia Mangues a

Pharmacy Department, Hospital Santa Creu i Sant Pau, 167-08025 Barcelona, Spain Primary Care Pharmacist, Catalan Health Institute, Girona, Spain c Physicochemical Department, Universitat de Barcelona, Spain

a r t i c l e i n f o
Article history: Received 30 November 2012 Accepted 6 June 2013 Keywords: Parenteral nutrition admixtures Peripheral parenteral nutrition admixtures Drugs Incompatibility Physical emulsion stability Drug stability

a b s t r a c t
Background and aims: The addition of drugs to parenteral nutrition admixtures (PNA) or simultaneous Ysite administration is a concern in daily practice. We present a literature review studies on the physicochemical stability of drugs using both methods. Methods: We performed a search of electronic databases and publications about drug stability in PNA. We prioritized studies that used two methods for obtaining samples: the reproduction of clinical administration conditions or centrifugation. Results: Forty-two studies met all inclusion criteria and covered a total of 118 drugs with the following characteristics: simultaneous Y-site administration [20 studies and 115 drugs], and administration in PNA [24 studies and 13 drugs]. Eighty drugs administered in PNA via Y-site were compatible and 26 incompatible, while 9 results depended on the study conditions. Twelve out of 13 drugs included in the PNA were compatible for more than 24 h at room temperature. Conclusions: The results of drug stability tests depend on the sampling methodology. Most of the results were obtained by the centrifugation method. Although the clinical method is much more reliable and offers a higher reproducibility of physicochemical stability, we found it was used by very few studies. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism.

1. Introduction Two methods are used to administer drugs with parenteral nutrition admixtures (PNA): simultaneous Y-site infusion or inclusion in the PNA. The former normally consists of an intermittent infusion of drugs with PNA in simultaneous Y-site administration. The liquid content in the nutrient admixture is used as a vehicle for introducing the drugs into the patient. Once the admixture is prepared, the contact time between drugs and admixture can range from 10 min to 12 h. In the second method, the drug is mixed with the PNA and the period of co-infusion is the same, usually up to 24 h. However, this method is not usual in daily clinical practice due to the problems arising from a possible lack of physicochemical


Abbreviations: CC, Coulter Counter; CR, counted radioactivity recovered after Iodine labelling; EMIT, enzyme multiple immunoassay; EVA, ethylene vinyl acetate; FACS, uorescence activated cell sorter; FPI, Fluorescence polarization immunoassay; HPLC, high-performance liquid chromatography; LD, laser diffraction; PCS, photon correlation spectroscopy; PN, parenteral nutrition; PNA, parenteral nutrition admixtures; PPNA, peripheral parenteral nutrition admixures; PVC, polyvinyl chloride; RIA, radioimmunoassay; RT, room temperature. * Corresponding author. Tel.: 34 93 553 74 58; fax: 34 93 553 74 71. E-mail address: dcardona@santpau.cat (D. Cardona).

stability of the nutrients included in the PNA or absence of chemical stability data. Separate administration of drugs and PNA is not always possible, even though multi-lumen catheters are used, since some situations require a high number of intravenous administrations (polypharmacy). Although pharmacists are frequently consulted about the administration of drugs via PNA there is a lack of information about compatibility due to the high variability in PNA composition. Therefore, pharmacists are required to interpret the results of existing stability studies, since working conditions cannot always be guaranteed to be the same. Before adding a drug to a PNA or delivering it by simultaneous Ysite infusion, its physicochemical stability must be reviewed in order to maintain the stability of the nutritive admixture (avoiding emulsion breaking, creaming or precipitations) and the concentration of the drug in the mixture must be 90% of the initial concentration.1 There are several reviews about drug compatibility with PNA and drug stability in ternary mixtures (containing amino acids, dextrose, lipids, with electrolytes, trace elements and vitamins).2e4 The aim of the current work was to review the literature about physicochemical stability of drugs administered by simultaneous Ysite infusion or in PNA. We also focused on peripheral and central administration.

2212-8263/$36.00 Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. http://dx.doi.org/10.1016/j.clnme.2013.06.001

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2. Methodology 2.1. Search strategy We performed a search in MEDLINE/PubMed (January 1967e May 2011) and EMBASE (January 1974eMay 2011) for articles published in English and Spanish using the search terms [total parenteral nutritition admixtures or 3-in-1 parenteral nutrition or total parenteral nutrition] and [drugs or medication] and [incompatibility or compatibility or stability or instability] and [physical or chemical]. Additionally, we searched in nutrition-specic journals (Clinical Nutrition, The Journal of Parenteral and Enteral Nutrition) and also reviewed Pharmacy-specic journals (Nutricin Hospitalaria or American Journal of Health-System Pharmacists, Pharmacy World & Science and Farmacia Hospitalaria) and abstracts from scientic meetings in parenteral nutrition. 2.2. Study ndings 2.2.1. Sampling methods The articles selected for this review describe the use of at least one of the following sampling methods: 1) simultaneous Y-site administration conditions (Fig. 1); 2) centrifugation of an

Fig. 2. Centrifugation method. Clinical method simulating Y-site administration of drug (previously diluted or not) with TPNA more centrifugation 1:1 V/V ratio.

Fig. 1. Clinical method simulating Y-site administration of drug (previously diluted or not) with TPNA.

admixture of the drug and PNA (Fig. 2); and 3) an injection of drugs within the PNA (Fig. 3). For the simultaneous Y-site infusion, two procedures are described. On one hand, Baptista et al simulated clinical administration conditions by infusing a volume of the PNA into 14 minibottles of different antibiotics for 30 min,5 while the other method reproduced administration conditions used in daily clinical practice.6e8 The samples were obtained from a Y-site administration of drugs via a running PNA line. All the tested drug solutions were infused in the appropriate time (ranging from 10 min to 12 h). The PNA was administered for a period of 24 h. The volume analysed corresponded to the amount of administered drug plus the simultaneous PNA volume administered. Najari et al6 studied 3 drugs, which were administered by a Ysite technique with the PNA, in accordance with common practices in bone marrow transplant units. A lter system with a gridded 0.8 mm membrane lter disk was placed at the end of the intravenous set to collect any precipitates. The drug was considered

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solution, trace elements and multivitamins. It had 900 non protein calories and osmolarity 600 mOsm/L. In all studies, drugs within the PNA should remain stable for more than 24 h at room temperature. Stability analysis method. The stability analysis in most studies was mainly limited to the classical parameters of PNA physical stability (colour change, determination of pH, osmolarity and presence of precipitates), and determination of globule size distribution. Different methods are used to assess changes in globule size distribution, which are specied in the results. The most frequently used methods for drug chemical evaluation are high-performance liquid chromatography (HPLC) and radioimmunoassay (RIA). 2.2.2. Lipid sources in PNA Lipid emulsion sources included in the studies are: 100% soy oil (Intralipid 20%; Lyposin III 20%; Lipovenos 20%; Ivelip 20% and Soyacal 20%); 50% soy and 50% safower oil (Lyposin II 20%); 50% soy and 50% coconut oil (Lipofundina MCT/LCT 20%); 20% soy and 80% olive oil (Clinoleic 20% and Etolipid); 64% soy and 36% coconut oil (Structolipid 20%) and 30% soy oil; 30% medium chain triglycerides; 25% olive oil and 15% sh oil (Smoipid). 2.2.3. Globule size distribution analysis Different methods are used to assess changes in globule size distribution, including: visual examination, optical microscopy, zeta potential, light obscuration, electrical-sensing zone (Coulter Counter, CC), PCS, laser diffraction (LD), Fluorescence Activated Cell Sorter (FACS), ow cytometer and multiple light scattering (Turbiscan). Gonzalo11 and Muntada12 used a new technique for doubtful cases, the Sudan red stain assay, which analyses the stability of the lipid phase. When emulsion disruption occurs, oil drops are stained orange heterogeneously, while there is physical compatibility if a single spherical drop is formed. The USP has proposed specic limits for lipid globule size distribution of PN emulsions.13 It requires the use of two complementary analytical methods to assess the droplet size and emulsion distribution. The rst method determines the central tendency of the population, where the acceptable upper limit of the mean droplet size (MDS), obtained by PCS, is set at 500 nm. The second method studies the weight percentage of droplets greater than 5 mm (PFAT5) using light obscuration and setting the acceptable upper limit of PFAT5 at 0.05%.

Fig. 3. Drug in TPNA.

incompatible if the number of particles exceeded the number stated in the USP guidelines (12 particles measuring 10 mm in diameter). Husson et al7 assessed the compatibility of 7 common parenteral drugs, 3 of which were prepared in three-chamber plastic bags during a Y-site infusion. Samples were collected at time: 0, 30, 60 and 75 min. Size particle, zeta potential and pH were determined and the solution was visually inspected. Following the same method, Sabin et al8 studied 6 antibiotics, but they also performed a chemical analysis of the drugs. Four authors simulated a Y-site administration of drugs (previously diluted or not) with PNA in a 1:1 volume/volume ratio.9e12 The samples of each combination were centrifuged. Trissel et al10 evaluated physical compatibility phenomena during Y-site administration, examining the samples immediately after mixing and after one hour, while Bullock et al9 visually inspected the samples at 1 and 6 h after drug addition for signs of emulsion instability, using interference microscopy and analysing drug concentrations by a uorescence polarization immunoassay (FPI). Finally, Gonzalo et al11 and Muntada et al12 studied 13 and 8 drugs, respectively. They followed the Trissel method9 but also determined the inuence of different lipid emulsions on drug compatibility with PNA. They used visual examination and other complementary tests: optic microscopy, the Sudan red stain assay and photon correlation spectroscopy (PCS). Evaluations were carried out initially after mixing and after 1, 2 and 4 h at 23  C. Before and after centrifugation, a visual examination was performed by normal diffuse uorescent light to nd any precipitate or emulsion disruption. Another group, following the Sabin et al8 methodology, studied different samples obtained from Y-site administration of 5 drugs via a running peripheral parenteral nutrition admixture (PPNA) line.18e22 All the drug solutions tested were prepared in the required solution and administered in a period of 30 min, via a running PPNA line with the following composition for 2800 mL: 2.3% amino acid, 3.5% dextrose, 1.8% lipids, electrolyte standard

3. Results Forty-two studies met all inclusion criteria and included a total of 118 drugs with the following characteristics: simultaneous Y-site infusion or mixing volumes of the drug and PNA plus centrifugation [20 studies and 115 drugs], and in PNA [24 studies (2 of them also analysed by simultaneous Y-site infusion) and 13 drugs (10 of them also studied in Y-site infusion). In the tables, we summarise the results published in the literature: compatible and incompatible drugs administered at the Ysite with PNA (Table 1) or PPNA (Table 2), drugs with controversial compatibility in Y-site administration (Table 3), drugs compatible when infused directly in PNA (Table 4) and nally, drugs with controversial compatibility with PNA (Table 5). Each table includes the following data for every drug: pH, sample nal concentration (mg/mL), sampling method (except Tables 4 and 5), method used to determine physical and chemical stability, compatibility results, lipid source, globule size distribution analysis technique and reference.

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The results of the studies on stability of drugs administered at the Y-site with PNA were: 80 compatible (54 were physically stable in studies using centrifugation; 19 were physicochemically stable using both centrifugation and reproduction of clinical practice administration; and, nally, 7 were only physically stable following the clinical practice), 26 incompatible (due to precipitation, emulsion disruption and concentration loss) and the results of 9 depended on the study conditions (sampling method, lipid composition and drug concentration). Nevertheless, only 18 drugs (15.7%) in 21 studies were investigated for their chemical stability by HPLC. The methods used to assess changes in the globule size distribution are heterogeneous with the sampling methods. The most commonly used techniques to assess physical stability in centrifuged samples were visual examination and optic microscopy, while in the studies using clinical administration methodology, the main techniques were CC and PCS. Additionally, ve of these drugs were studied when administered by Y-site infusion with PPNA following clinical administration conditions.8 All were physicochemical stable, except for mycophenolat mofetil, due to immediate precipitation. In 24 studies, 11 of the 13 drugs included in PNA were compatible for more than 24 h at RT, with the exception of omeprazole which was stable for only 12 h, as well as 1 out of 4 studies of ranitidine. Only methylprednisolone sodium and aminophylline were stable >48 h under refrigeration and for 24 h at RT. Chemical stability of somatostatin is controversial. In 20 studies involving 11 drugs, chemical stability was analysed mainly by HPLC, whereas CC was used to assess changes in the globule size distribution. 4. Discussion In an evaluation of 106 drugs in 9 different PNA by Trissel et al,10 Y-site administration of the drugs via a running PNA line was simulated. The samples of each combination were subjected to centrifugation. In a visual examination, 23 drugs showed various incompatibilities, including precipitation and oiling out from cracked emulsions. It has been described that the centrifugation step does not crack the fat emulsion in the admixtures. After centrifugation, the fat component appears as a narrow, white, uniform layer at the top of the samples. Additionally, when drugs interact with fat particles, a 20-minute centrifugation accelerates separation and oiling out, resulting in cracked or disrupted emulsions. Trissel reported that the emulsion electrical charge can be modied rapidly by the addition of incompatible drugs. The time required to see emulsion instability (coalescence and oil formation) in normal gravity is governed by Stokes Law. Trissels pending question is whether drug-damaged emulsions remain useable for a period of time under normal gravity conditions. We should keep in mind that the estimation of emulsion creaming determined by Stokes law is only strictly applicable to rigid aggregated spheres at innite dilution. Moreover, ow conditions must correspond to a laminar Newtonian regime. The droplets of an oil/water emulsion can be considered as spherical. However, the rheological behaviour of lipid emulsions corresponds to a nonNewtonian uid. Hence, it is not possible to determine exactly the speed of precipitation in lipid emulsions using Stokes law.47 On the other hand, the centrifugation method cannot study lipid globule size distribution, as proposed by the USP. The presence of particles greater than 5 mm in the circulation is claimed to involve a risk of pulmonary embolism, but, this has only been observed in animal studies.14,15 Despite using the centrifugation method, Trissel and Bullocks results in 9 drugs (ampicillin, cefotaxime, cefoxitin, ceftazidime,

ciprooxacin, clindamycin, uconazole, gentamicin and metronidazole) are equivalent to those obtained by Sabin et al,8 who reproduced the conditions used in clinical practice. Other authors11,12 following Trissels centrifugation method have observed emulsion disruption using a physical method with different lipid emulsions. In Y-site drug administration with PPNA (Table 2), a lower amino acid concentration in PPNA (2.3e2.5%) can decrease the buffer effect on lipid emulsion stability and phosphateecalcium precipitation. Simultaneous Y-site administration of aminoglycosides, cyclosporine and heparin with PNA is controversial. Amikacin was physicochemically compatible in samples obtained by a clinical method,6,7,17 as well as when using a centrifugation method for low doses (<5 mg/mL).10 However, at high doses (125 mg/mL) when centrifuged,9 probably due to differences in acidity. In two studies employing the clinical practice method, cyclosporine23,24 was physicochemically stable after a 12-h and 4h simultaneous Y-administration, respectively. This result differs from other studies using the centrifugation method,6,10,11 which found precipitate and emulsion disruption. Sodium heparin is also controversial at different concentrations. At 50 UI/mL, immediate emulsion disruption has been reported in all admixtures,10 with contradictory precipitation with Lipofundina MCT/LCT, despite using different types of lipid emulsion.11 On the other hand, at 9e20 IU/mL, heparin sodium is physically compatible in three different types of lipid emulsions.7 However, in one study at very low concentrations (0.25e4 IU/mL)25 and using 3 different lipid sources, the stability was 72 h at RT. After 24 h, heparin was physically compatible in all concentrations and emulsions except with olive oil. A visual inspection showed some oil droplets on the surface 24e48 h after the mixture was prepared. Other problems were also caused by the type of lipid emulsion, mainly polar lipid sources such as Lipofundin (MCT/LCT), which affected the results with dopamine, granisetron, imipenemecilastatin sodium, piperacillinetazobactam and morphine sulphate.10e12 As for H2RAs, there are controversial results in numerous studies on the stability and compatibility of ranitidine hydrochloride in PNA. The main reason for chemical degradation appears to be a temperature and pH-dependant hydrolysis catalysed by oxygen. In some studies,31,43 ranitidine was stable for 24 h at RT, while in others,42 it remained stable for 48 h at 4  C when protected from light in an EVA bag and the PNA had no trace elements and vitamins. However, Cano et al42 found that in EVA containers it was stable for 12 h at RT. As for cimetidine29e31 and famotidine,33e35 both are stable for 48e72 h at RT and in EVA bags. Omeprazole is stable at pH 9e10 but suffers an increased rate of degradation in PNA with a pH of 5.5e6.5. The only study of omeprazole in PNA found it to be physicochemically stable for 12 h at RT when in EVA bags.40 The use of insulin in PNA has declined in ICU patients due to insulin pump infusion according to glycaemic values and the introduction of insulin glargine.48 However, the use of insulin in PNA remains an option for stable patients on wards and in home parenteral nutrition. Bassons et al36 determined the total recovery of insulin simulating a 24 h infusion in ve solutions (without trace elements), that contained: 50% dextrose alone, or idem plus 10% amino acids, or both plus 20% Intralipid plus vitamins plus electrolytes. All solutions were assayed with PVC and EVA containers and insulin was added to Intralipid before the component mixture. A mixture with PNA in both containers, gave a good reproducible recovery of 87e98%. Particle size distribution or insulin binding to infusion material was tested in another study after adding 36 or 64 I.U. of insulin to a PNA or fat-free PN in EVA bags.37 The results were an

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insulin availability of >90% in PNA and 50% in fat-free PN after a 24hour storage at 4  C. However, in a simulated 24-hour infusion, insulin binding to infusion material was 81e87% in PNA and 43e 45% in lipid-free PN. Particle size distribution in both studies was stable. Aminophylline, the soluble salt of theophylline, was found to be physicochemically stable for 96 h at 4  C or RT at a concentration of 0.4 and 0.164 mg/mL in PVC and EVA bags, respectively, in two studies.26,28 In another study using two different dosages (0.9 mg/ kg/h and 0.4 mg/kg/h), aminophylline was also physicochemically stable at RT for 24 h when using EVA bags.27 As for digoxin, Mass et al found to be stable at 0.125 mg/mL in PNA for 96 h at RT or refrigerated.32 Gellis et al38 performed an in vitro study of methylprednisolone sodium succinate (MSS) stability in PNA mixtures and in lipid-free PN for paediatric patients at a concentrations of 25, 63 and 125 mg/ mL. MSS was stable in all mixtures for at least 7 days when stored at 4  C and for 24 h of additional storage in RT and protected from light. The most common route of administration of octeotride is currently subcutaneous injection, but intravenous administration is also possible. Octeotride acetate is physicochemically stable at a concentration of 45 mg/dL in 600 mL in glass and EVA containers for 7 days when refrigerated and 24 h at RT.39 There are two studies on somatostatin stability in PNA with controversial results.45,46 Montoro et al45 noticed adsorptionliberation with 3 mg/mL of somatostin both in glass and EVA containers with a rapid decrease in somatostatin concentration from 0.3 to 0.6 mg/mL in few seconds. However, Ronchera et al46 found physicochemical stability for at least 7 days in EVA containers. 5. Summary Most of the reviewed literature concerns Y-site drug administration with PNA but without considering chemical stability, and the results are limited to the classical parameters of physical stability studies. We found that drug stability depends on the sampling methodology and conicting results arise from the use of different methods, such as centrifugation, that do not reproduce clinical conditions. All studies on the administration of drugs in PNA consider both chemical and physical stability. Finally, the results described in this review should be approached with a certain amount of caution, since some of the studies were carried out several years ago. It is also important to emphasise that the results depend on the branded product used in the studies. Sources of funding This study has not received any funding. Statement of authorship Daniel Cardona. Conceived the study, participated in its design and coordination, helping to draft the manuscript, and in the decision to submit the manuscript for publication. Maria Nadal. Carried out the review studies and data analyses. Joan Estelrich. Participated in data physicochemical analyses. Ma Antnia Mangues. Participated in discussion about the paper. Conict of interest None of the authors declares any conict of interest.

Acknowledgements The authors thank Ma Dolors Pujol, Pharm D, Organic Chemistry Department, Pharmacy School, Barcelona University and her team, for their help in the drug analysis. We also wish to thank Lucy Brzoska for English language assistance. Finally, we also want to acknowledge the help of two pharmacy residents, Judit Aliberas and Neus Pags, with the nal revision. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.clnme.2013.06.001. References
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Please cite this article in press as: Cardona D, et al., Review of drug stability in parenteral nutrition admixtures, e-SPEN Journal (2013), http:// dx.doi.org/10.1016/j.clnme.2013.06.001