Stability of high-dose thiamine in parenteral nutrition for treatment of patients with Wernicke's encephalopathy

Journal Pre-proof Stability of high-dose thiamine in parenteral nutrition for treatment of patients with Wernicke's encephalopathy Maciej Stawny, Aleksandra Gostyńska, Rafał Olijarczyk, Anna Jelińska, Magdalena Ogrodowczyk PII:

S0261-5614(19)33170-X

DOI:

https://doi.org/10.1016/j.clnu.2019.12.003

Reference:

YCLNU 4097

To appear in:

Clinical Nutrition

Received Date: 31 July 2019 Revised Date:

28 November 2019

Accepted Date: 2 December 2019

Please cite this article as: Stawny M, Gostyńska A, Olijarczyk R, Jelińska A, Ogrodowczyk M, Stability of high-dose thiamine in parenteral nutrition for treatment of patients with Wernicke's encephalopathy, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.12.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

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Stability of high-dose thiamine in parenteral nutrition for treatment of patients with

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Wernicke's encephalopathy

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Maciej Stawny, Aleksandra Gostyńska, Rafał Olijarczyk, Anna Jelińska, Magdalena

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Ogrodowczyk

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Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences,

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6 Grunwaldzka, 60-780 Poznań, Poland

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Corresponding author:

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Dr. Maciej Stawny

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6 Grunwaldzka Street

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60-780 Poznań, Poland

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e-mail: [email protected]

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phone: +48 618546646

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Abstract

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Background & aims:

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Wernicke`s encephalopathy is associated mainly with malnourishment in alcohol-dependent

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patients but can be caused also by cancer, Crohn's disease, gastrointestinal surgery or

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prolonged parenteral nutrition (PN) without adequate supplementation of vitamins. The

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disorder, with a significant mortality rate of up to 20%, is often associated with the underlying

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disease and intensifies after administration of non-supplemented PN. Thus, it seems justified

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to add thiamine to PN admixtures prepared for parenterally fed patients. Due to the lack of

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data on the stability of thiamine in PN admixtures at concentrations exceeding 60 mg/L, we

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decided to determine the possibility of adding a high dose of thiamine (800 mg per bag, 320

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mg/L) to PN admixtures in order to treat Wernicke`s encephalopathy in malnourished

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patients.

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Methods: The study aimed to assess the stability of the physical properties of PN admixtures

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(pH, zeta potential, particle size) and to determine thiamine content using an HPLC method.

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Results: Thiamine was found to degrade regardless of the PN admixture composition and

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storage conditions. The highest decrease in thiamine content was observed at room

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temperature without light protection whereas the lowest at a temperature of 4±1°C with light

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protection.

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Conclusions: The treatment of Wernicke`s encephalopathy in parenterally fed patients is

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possible with the use of high thiamine doses (800 mg) added to PN admixtures without a

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decrease in the drug content above 10% within the first 24 h. It should be emphasized that

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thiamine as a photosensitive drug must be stored and administered under conditions ensuring

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light protection.

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Keywords: thiamine, parenteral nutrition, Wernicke's encephalopathy

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1. Introduction

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Wernicke`s encephalopathy is an acute neuropsychiatric disorder caused by thiamine

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deficiency. Thiamine is essential in the pathways of carbohydrate metabolism as a cofactor

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for transketolase, alpha‐ketoglutarate dehydrogenase, and pyruvate dehydrogenase.

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Wernicke`s encephalopathy is mainly associated with malnourishment in alcohol-dependent

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patients but can be caused also by cancer, Crohn's disease or gastrointestinal surgery.

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Prolonged parenteral nutrition (PN) without adequate supplementation of vitamins has been

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found to be another factor contributing to Wernicke`s encephalopathy [1-4], despite

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recommendations from, e.g., ESPEN and ASPEN suggesting supplementation of PN with

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vitamins (including a daily thiamine dose of 3-6 mg). The disorder, with a significant

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mortality rate of up to 20%, is often associated with the underlying disease and intensifies

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after administration of non-supplemented PN. This can be prevented by an infusion of

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appropriate doses of thiamine within the first 48-72 h (precise dosage still unspecified).

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The guidelines for diagnosis, therapy and prevention of Wernicke`s encephalopathy provided

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by the European Federation of Neurological Societies suggest intravenous infusion of 600 mg

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of thiamine daily in three doses [5]. The Royal College of Physicians recommends

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intravenous administration of thiamine at a dose of 500 mg three times daily over a period of

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three days [6]. The Cochrane review of 2013 [7] highlighted an insufficient number of

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randomized controlled trials concerning thiamine administration in patients with Wernicke–

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Korsakoff disorder, related to alcohol abuse, to recommend dosage, frequency, route or

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duration of thiamine administration. The scale of the problem may be illustrated further by the

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fact that despite scientific recommendations treatment regimens applied by various healthcare

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providers vary in thiamine dosage and administration time, with differences observed even

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within one center [8-10]. In our study, based on our own clinical practice we used a dose of

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800 mg per day, a value which has been also reported by other clinicians [11].

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Previous studies on the stability of thiamine in PN admixtures focused on low doses (3–60

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mg) and concentrations (2.32–60 mg/L) of thiamine, which are routinely used in clinical

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practice. The authors investigated both 2-in-1 and 3-in-1 PN admixtures, determining the

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effect of amino acid solution, type of lipid emulsion, temperature, light access, packaging

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material and storage time on thiamine stability [12-15]. As the said studies were concerned

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only with low doses of thiamine in PN admixtures, the aim of our work was to investigate the

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possibility of adding an 800 mg dose of thiamine to PN admixtures, which could be

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administered within the first three days of the onset of Wernicke`s encephalopathy to

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compensate thiamine deficiency.

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2. Methods

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The PN admixtures were prepared aseptically under a laminar-flow hood using a Pinnacle B.

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Braun automatic compounder (B. Braun Melsungen AG, Germany). Their quantitative and

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qualitative compositions are detailed in Table 1. 16 mL of thiamine solution for injection (800

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mg) were added to each PN admixture resulting in a thiamine concentration of 320 mg/L.

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The PN admixtures were stored at 4±1ºC with light protection, at 25±1ºC with light protection

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and at 25±1ºC without light protection. They were prepared in triplicate and stored in

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ethylene-vinyl acetate (EVA) bags. The light protected samples were shielded with dedicated

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light protection covers. The samples stored without light protection were exposed to

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laboratory light for 12 h a day to simulate daily exposure to light. The samples were stored in

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the said manner for five consecutive days and their physicochemical parameters were

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determined each day.

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Sample preparation, visual inspection, pH evaluation, and measurements of mean droplet

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diameter and zeta potential were performed as described in the methodology of our previous

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work [10].

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The chromatographic analysis was conducted using HPLC apparatus consisting of a Merck

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Hitachi L-7100 HPLC pump, an L-7455 photodiode array detector, an L-7200 autosampler, a

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D-7000 interphase module, and a column oven set at 25°C. The analytical column was a

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reverse phase C18 (LiChroCART, 5 µm) 125 mm x 4.0 mm. The mobile phase consisted of

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50 mMol/L ammonium dihydrogen phosphate buffer adjusted to pH 3.5 with concentrated

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orthophosphoric acid and acetonitrile (95:5, v/v). The flow rate, detection wavelength, and

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injection volume were 1.0 mL/min, 257 nm, and 10 µL, respectively.

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The data were analyzed using Statistica 12 software (StatSoft). Repeated-measures analyses

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of variance (ANOVAs) were used to determine whether the drug content, storage conditions

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or storage time had an effect on the pH, zeta potential and MDD of the lipid emulsion. The a

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priori level of significance was p < 0.05. In the case of a major effect or an interaction,

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significant differences between the PN admixtures with thiamine and the reference samples

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under the study conditions were identified using Tukey’s HSD post hoc tests.

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Results

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Visual inspection indicated that the PN admixtures were homogeneous oil-in-water emulsions

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and maintained their homogeneity for at least five days. No color change or significant pH

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difference (p > 0.05) was observed regardless of the storage conditions and PN admixture

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composition, with the pH ranging from 6.26 to 6.30 and from 6.28 to 6.33 on the preparation

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day and on the fifth day of storage, respectively. The MDD for all PN admixtures on the day

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of preparation was 212.3 nm, with the lowest MDD value of 205.8 nm obtained for the low-

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electrolytic composition and the highest MDD value of 216.7 nm for the basic composition.

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The MDD after five days of storage did not differ significantly (p > 0.05) from that measured

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on the day of preparation, ranging from 204.1 nm to 214.4 nm. The same tendency was

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observed for the zeta potential, with no significant (p > 0.05) changes observed between the

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first and the fifth day of storage. The average value of zeta potential for all PN admixtures on

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the day of preparation was -10.88 mV. The lowest zeta potential was -13.18 mV and the

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highest was -8.31 mV for the HC and the HE compositions, respectively. On the fifth day of

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storage the average zeta potential was -10.81 mV. It ranged from -9.09 mV for the HE

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composition stored at 4±1ºC with light protection to -13.18 mV for the HC composition

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stored at 4±1ºC with light protection and at 25±1ºC without light protection. To summarize,

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the PN admixtures demonstrated appropriate physical parameters ensuring therapeutic safety

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upon preparation and after 5 days of storage.

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The stability of thiamine was studied in the PN admixtures. The results showed that the

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vitamin degraded regardless of storage conditions or the composition of the PN admixture

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(Fig. 1). Repeated measures analysis of variance showed a statistically significant (p <0.05)

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impact of the PN admixture composition as well as conditions and time of storage on thiamine

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stability. The highest decrease in thiamine content was observed for each PN admixture stored

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at 25±1ºC without light protection, and the lowest for each PN admixture stored at 4±1ºC with

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light protection. The degradation of thiamine differed significantly (p <0.05) between 2-in-1

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(lipid-free PN admixtures) and 3-in-1 (PN admixtures containing amino acids, glucose and

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lipids). An analysis of the PN admixture composition on thiamine degradation indicated that

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the process occurred the most rapidly for the 2-in-1 formulation (the composition without

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lipid emulsion) and the most slowly for the HC formulation (the composition with the highest

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content of lipid emulsion) regardless of storage conditions. For the 3-in-1 PN admixtures, a

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significant effect of storage conditions (p <0.05) and no effect of PN admixture composition

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(p >0.05) on thiamine stability during the first 48 hours was observed.

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3. Discussion

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PN admixtures are known to be the most complex pharmacotherapies used in medicine. In

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terms of physicochemical properties, PN admixture is an oil-in-water (o/w) emulsion, which

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is a dynamic system where the oil phase remains in equilibrium with the water phase, the

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particle size not exceeding 500 nm, as larger particles could cause capillary blockage and

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serious clinical consequences including damage to blood vessels in the lungs, liver, and retina

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of the eye. According to literature data, the destabilization of lipid emulsions may occur when

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the pH falls below 5, the temperature increases above 25ºC or the concentration of cations is

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too high [17].

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It was demonstrated in our study that supplementation of PN admixtures with drugs, as was

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the case for thiamine, requires stability tests considering both the stability of the oil-water

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system (physical parameters) and the chemical stability of the drug added (quantitative

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analysis), since degradation products of the supplemented drug may not change the pH, zeta

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potential or affect the MDD of the PN admixture.

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Storage temperature, exposure to light, and the composition of the PN admixture (the content

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and the type of lipid emulsion, the type of amino acid solutions, the content of electrolytes)

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were found to have an impact on thiamine stability. Within the scope of this study we

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demonstrated that the degradation of thiamine is a pseudo-first order reaction catalyzed by

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light and temperature. We assume that an increase in the lipid emulsion content in PN

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admixtures plays a protective role against light exposure and thus reduces thiamine

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degradation.

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In conclusion, the addition of high doses of thiamine does not affect the physicochemical

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stability of PN admixtures over a period of up to 24 h provided that they are protected from

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light and stored at 4±1ºC or 25±1ºC. It should be emphasized that storing high-thiamine

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content PN admixtures for more than 24 h is not advisable due to thiamine loss exceeding

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10% in some formulations. As a photosensitive drug, thiamine requires to be stored and

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administered in PN admixtures under protection from light. We recommend administering

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high doses of thiamine for ex tempore, light-protected infusions of PN admixtures, shielding

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EVA bags with light-protection covers and applying light-protected infusion sets.

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Funding/support

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This study was supported by the grant SONATA

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National Science Centre, Poland

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Authors contributions

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M.S. designed the study, analysed the data and wrote the manuscript. R.O. collected and

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analysed the data. A.G. analysed the data, performed the statistical analyses and helped to

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draft the manuscript. M.O. analysed the data. A.J. invigilated all steps of the investigations

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and revised the manuscript. All of the authors read and approved the final manuscript.

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Conflict of interest

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All the authors declare no conflict of interest in relation to this work.

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Table 1. The composition of studied TPN admixtures Ingredients 10% Aminoplasmal (B. Braun Melsungen AG, Germany) 10% Aminoplasmal Hepa (B. Braun Melsungen AG, Germany) 40% Glucose (B. Braun Melsungen AG, Germany) Lipofundin MCT/LCT 20% (B. Braun Melsungen AG, Germany) Water for injection (B. Braun Melsungen AG, Germany) 10% Natrium chloratum (B. Braun Melsungen AG, Germany) 15% Kalium Chloratum (WZF Polfa S.A., Poland) 10% Calcium gluconate (Added Pharma, Netherlands) Glycophos (Fresenius Kabi AB, Sweden) 20% MgSO4 (Polpharma S.A, Poland) Vitaminum B1 100 mg/2mL (Sterop, Belgium) Total volume

3-in-1 HE

LE

HC

-

550

550

550

-

550

-

-

-

500

500

500

500

500

500

-

300

300

300

300

400

1330

1030

1030

988

1095

930

68

68

68

102

34

68

60

60

60

80

24

60

5

5

5

7

2

5

24

24

24

24

10

24

8

8

8

10

4

8

mg

800

800

800

800

800

800

mL

2500

2500

2500

2500

2500

2500

Unit

mL

mmol

2-in-1

Basic

HEPA

550

550

-

2-in-1: lipid-free PN admixture; 3-in-1: PN admixture containing amino acids, glucose and lipids; Basic: composition was based on the literature recommendations for adult hospitalized patients and calculated for a patient weighing 60 kg [16]; HEPA: PN admixture for patients with hepatic disorders (containing amino acids solution with higher content of branched-chain amino acids); HE: high-electrolyte content PN admixture; LE: low-electrolyte content PN admixture; HC: high-caloric content PN admixture.

4 ± 1 ºC with light protection 100

Degradation below 10%

Thiamine concentration [%]

90 Degradation above 10%

80 70 60 50 40 30 2-in-1

20

Basic

HEPA

HE

LE

HC

10 0

20

40

60

80

100

120

140

160

180

Time [h] 25 ± 1 ºC with light protection 100

Degradation below 10%

Thiamine concentration [%]

90 Degradation above 10%

80 70 60 50 40 30 2-in-1

20

Basic

HEPA

HE

LE

HC

10 0

20

40

60

80

100

120

140

160

180

Time [h] 25 ± 1 ºC without light protection 100

Degradation below 10%

Thiamine concentration [%]

90 Degradation above 10%

80 70 60 50 40 30 2-in-1

20

Basic

HEPA

HE

LE

HC

10 0

20

40

60

80

100

120

140

160

Time [h]

Fig. 1. Changes of thiamine concentration in PN admixtures over the time

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