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					                                                             Total Parenteral Nutrition
    References                                            expenditure in the critically ill: estimations                                    hazards of precipitation associated with
    1. Shanbhogue RL, Bistrian BR, Jenkins RL,            versus measurement. Br J Surg. 1988;75:                                           parenteral nutrition. Am J Hosp Pharm. 1994;
       Benottie PN, Blackburn GL. Increased pro-          875-8.                                                                            51:1427-8.
       tein catabolism without hypermetabolism         4. Shizgal HM, Martin MF. Caloric requirement
                                                                                                                                         7. Newton DW, Driscoll DF. Calcium and phos-
       after human orthotopic liver transplantation.      of the critically ill patient. Crit Care Med.
                                                                                                                                            phate compatibility: revisited again. Am J
       Surgery. 1987;101:146-9.                           1988;16:312-7.
    2. Driscoll DF, Bistrian BR. Clinical issues in                                                                                         Health-Syst Pharm. 2007;65:73-80.
                                                       5. Mirtallo JM, Jozefczyk KG, Hale KM,
       the therapeutic monitoring of parenteral           Grauer DW, Ebbert ML, Fabri PJ. Providing                                      8. Driscoll DF. Drug-induced metabolic disorders
       nutrition. Clin Lab Med. 1987;7:699-714.           24-hour nutrient infusions to critically ill                                      and parenteral nutrition in the intensive care
    3. Hunter DC, Jaksic T, Lewis D, Benotti PN,          patients. Am J Hosp Pharm. 1986;43:2205-8.                                        unit: A pharmaceutical and metabolic perspecti-
       Blackburn GL, Bistrian BR. Resting energy       6. Food and Drug Administration. Safety alert:                                       ve. DICP, Ann Pharmacother. 1989; 23:363-71.
For personal use only. Not to be reproduced without permission of the publisher (LT@ejhp.org).
                            TOTAL PARENTERAL NUTRITION —
                            PROBLEMS IN COMPATIBILITY AND
                            STABILITY
                             Allan Mikael Schrøder, MScPharm
    Adding calcium, trace elements and vitamins could turn parenteral nutrition into a dangerous product,
    which could harm the patient. This article focuses on the major pharmaceutical problems of parenteral
    nutrition when adding nutritional compounds.

    Introduction
    Dieticians, doctors and nurses focus on            Infusions for parenteral nutrition are                                            Of special significance, phase separa-
    the nutritional, metabolic and venous              complex and can contain more than 50                                              tion of emulsions and chemical precipi-
    access requirements of patients receiv-            different chemical entities. This makes it                                        tation can harm the patient in the short
    ing parenteral nutrition. Hospital phar-           nearly impossible to predict what can                                             term, while degradation of vitamins
    macists should be advisers, or even a              happen when we add other entities to the                                          will lower the nutritional value, and in
    part of the team, in order to ensure               infusion solution, but we do know of                                              the long term give deficiency symp-
    patient safety through their knowledge             potentially clinically significant formu-                                         toms.
    of the physical and chemical reactions             lation problems when we try to meet the
    which can occur when prescribing par-              nutritional requirements of the patient.                                          There are many factors which affect an
    enteral nutrition.                                                                                                                   AIO mixture [3]:
                                                       Compatibility and stability                                                       • lower pH
    Parenteral nutrition is a pharmaceutical           Major stability and compatibility issues                                          • divalent cations
    challenge. A significant risk exists when          can be divided into [2]:                                                          • added trace elements
                                                                                                                                         • trace elements contamination



    [         In some cases calcium and phosphate is a
                        hazardous cocktail.

    mixing infusion solutions in that the              • physicochemical stability of the lipid
                                                                                                                             ]           • dissolved oxygen
                                                                                                                                         • extended storage
                                                                                                                                         • daylight.

                                                                                                                                         pH
                                                                                                                                         There are different factors which deter-
    final formulation may not meet the                   emulsion                                                                        mine the final pH:
    requirements set out for the individual            • chemical instabilities due to incompat-                                         • the commercial source of the amino
    additive monographs in The European                  ibility between amino acids and glu-                                              acid infusion from different manufac-
    Pharmacopoeia. The monograph defines                 cose in aqueous phase of the all-in-one                                           tures varies in pH between approxi-
    infusions to be clear and practically free           (AIO) mixture                                                                     mately 5.0 and 7.4
    from particles when examined under                 • precipitation of chemical components                                            • the concentration of amino acids in the
    suitable conditions of visibility and that           in the aqueous phase                                                              final AIO mixture
    emulsion for infusions do not show any             • stability and compatibility of vitamins,                                        • the source of and the final concentra-
    evidence of phase separation [1].                    trace elements and added drugs.                                                   tion of phosphate


                      • Volume 14 • 2008/1                 EJHP is the Official Journal of the European Association of Hospital Pharmacists (EAHP)                   www.ejhp.eu    65
Feature
• the final concentration of glucose [4].        One way to assess the effects of cations         Temperature is another factor which has
Glucose varies in pH between 3.5 to 6.5          on lipid stability is through the equation       an influence on the compatibility of cal-
among manufacturers and within batch-            known as the critical aggregation con-           cium and phosphate because the dissoci-
es [2]. This is due to the breakdown of          centration or CAN.                               ation of the organic calcium salts, and
glucose by heat. Glucose breaks down                                                              possibly the equilibrium between the
first to form 5-(hydroxymethyl)-2-fur-           CAN (mmol/L) = a+ 64b+ 729c                      different phosphate species, is depend-
analdehyde and then to formic acid and                                                            ent on the temperature [4]. Raising the
levulinic acid. Only a small amount of           where a is the concentration of monova-          temperature causes greater dissociation
glucose decomposition is needed to effect        lent cations, b divalent cations and c           of the calcium compound to free calci-
a marked fall in pH [2]. Ultimately, the         trivalent cations [2].                           um, and may shift the phosphate equilib-
final pH will, however, be dominated by                                                           rium from monobasic to dibasic salt [4],
the buffering capacity of the amino acid         However, CAN is not the gold standard            decreasing solubility (i.e. precipitation
and phosphate [4].                               in predicting aggregation because other          with phosphates) and increasing the
                                                 factors contribute to stabilising/destabil-      danger of the infusion.
The ionisation state of the hydrophilic          ising the emulsion [2], so you cannot
area of the phospholipids in the lipid           rely on CAN alone.                               A precipitation of calcium phosphate
emulsion is dependent on the pH. A                                                                can also arise during the mixing process
change in pH will determine the surface          In some cases, calcium and phosphate is          or over time. Precipitation during the
potential and thereby the stability of the       a hazardous cocktail, and one of the impor-      mixing process is due to poor mixing
lipid droplets. Reduction of pH leads to a       tant factors affecting the risk of harm is the   with layering of different ingredients.
more neutral charge of the hydrophilic           final pH of the parenteral nutrition admix-      The phosphate additive should always
region and at approximately pH 3 there is        ture. In aqueous solutions, phosphate is         be added first, and thoroughly mixed,
no charge and the droplets aggregate due         present in three ionic forms – the trivalent     before finally adding calcium [4, 7].
to the lack of repulsive forces and the fact     phosphate (PO43-), the monobasic (H2PO4-)        Formation of calcium phosphate may
that only attractive forces remain [2].          and the dibasic (HPO42-).                        take up to 24-48 hours after mixing to
                                                                                                  become visually evident [4]. Precipi-
Amino acids are strong buffers and the           The trivalent phosphate (PO43-) is only          tation in parenteral nutrition without
buffering capacity is dependent on the           present at high pH and will not normally         lipid emulsion can be seen by visual
final concentration in the AIO mixture.          be present in parenteral nutrition admix-        inspection, although special lighting
Therefore, amino acids can stabilise             tures. Therefore, our interest should con-       may be needed, whereas in AIO mix-
against lowering the pH and protect the          centrate on the monobasic (H2PO4-) and           tures precipitation cannot readily be
lipid emulsion [2].                              the dibasic phosphate (HPO42-). Mono-            detected by visual inspection. This is
                                                 basic calcium phosphate, Ca(H2PO4)2,             based on personal experiences from
Divalent cation – Calcium                        has a solubility of 18 g/L and the dibasic       All-in-One meetings by Fresenius-Kabi,
The effect of electrolytes on the instability    form, CaHPO4, has a solubility of 0.3            Uppsala, Sweden, with Dr Allan Cosslett
of lipid emulsion is another problem. The        g/L [6]. The physiologic pH is about 7.4         as chairman.
lipid droplets are negatively charged on         and at this pH approximately 60% of the
their surface and cationic electrolytes have     phosphate will be in the dibasic form            Trace elements
an opposite charge. Therefore, cationic          [4], but at pH levels typical of parenter-       Addition of trace elements to parenteral
electrolytes will reduce the surface poten-      al nutrition (i.e. <6.4), the amounts are        nutrition admixtures may affect the
tial of the droplets. As the surface potential   much lower and the risk of calcium               admixture stability and the concentra-
on the droplets falls then the repulsive force   phosphate precipitation are less.                tion of all the trace elements reduce in
between the droplets decreases. The result                                                        storage [3]. The very low concentration
is aggregation of the lipid droplets and         Calcium is a divalent ion and is available as    of trace elements added to the parenteral
instability of the emulsion.                     an inorganic or organic salt. The degree of      nutrition solution makes for an analyti-
                                                 dissociation of the calcium compound is          cal challenge. The reduction in storage is
The destabilising power of cations on            also important for formation and precipita-      not totally understood. Sorption onto the
emulsion is linked to the valence of the         tion of calcium phosphate. As the inorgan-       container could be an explanation as
cation. Trivalent cations such as Fe3+           ic calcium chloride is highly dissociated, it    well as precipitation [3]. Trace element
(from iron dextran) and Al3+ (contamina-         is more likely to precipitate with phos-         additives may affect lipid peroxidation
tion) are much more disruptive than diva-        phate salts than the organic calcium com-        and lowering the pH in emulsions. The
lent cations [2, 5]. Monovalent cations can      pounds. Therefore, organic calcium salts         lowering of pH in AIO solutions is par-
be added in larger amounts before they           are the preferred source of calcium as an        tially offset by the buffering capacity of
will produce instability to the emulsion.        additive in parenteral nutrition.                the amino acids [3].


66                     • Volume 14 • 2008/1                                                                                     www.ejhp.eu
                                                    Total Parenteral Nutrition
Vitamin stability                              solved in the solution. This reaction is                                         neonates and children there are no such
Vitamin losses can occur through different     catalysed by light. The rate and extent is                                       solutions. Hospital pharmacists also
degradation pathways:                          dependent on the amount of oxygen [9].                                           need to have knowledge on parenteral
• photodegradation/oxidation reactions                                                                                          nutrition, not only handling but also
• sorption losses                              Ascorbic acid is unstable when added to                                          compounding, to safely meet the needs
• co-precipitaion from degradation prod-       parenteral nutrition mixtures. Ascorbic                                          of these young patients.
  ucts.                                        acid is known as an antioxidant and
                                               readily reacts with oxygen. The total
Degradation of vitamins by light expo-         amount of ascorbic acid lost after adding
sure is important. There can be huge           to the parenteral nutrition depends on the
losses, and this is most important for         amount of oxygen present. Other impor-                                           Author
retinol (vitamin A), tocopherol (vitamin       tant factors are temperature and trace                                           Allan Mikael Schrøder, MScPharm
E), vitamin K and riboflavin (vitamin          metal catalysts, especially copper, but                                          The Pharmacy of The Capital Region of
B2) [8]. Photodegradation is mainly due        also ferric, zinc and manganese ions [4].                                        Denmark
to UV-light (290-320 nm) and therefore         Oxygen comes from dissolved air in the                                           Medicine Information Centre
prolonged exposure to sunlight degrades        infusions, by aeration during transfer                                           Bispebjerg Hospital
these vitamins, while most artificial light    from bag or bottle and as residual air in                                        Bispebjerg Bakke
sources can be largely ignored. It is          parenteral nutrition bag and by entering                                         DK-2400 Copenhagen NV, Denmark
worth noting that light treatment of           the bag through the bag wall during stor-                                        asch0052@bbh.regionh.dk
icterus neonatorum is not with UV-light        age. Infusion bags made of EVA are
but with blue light on wavelength 400-         much more permeable to air than the                                              References
500 nm [8].                                    multilayered bags [4]. Losses amounted                                           1. Council of Europe (COE) - European
                                               to between 10% and 80% over a 48 hour                                               Directorate for the Quality of Medicines. The
Losses due to light exposure depend on         period at 25°C depending on the amino                                               European Pharmacopoeia. 6th ed. Stras-
a number of factors. The intensity of          acid preparation and the type of bag [4].                                           bourg (France): Council of Europe; 2007.
daylight is obviously important, but                                                                                            2. Barnett MI, Cosslett AG. Parenteral nutrition
factors such as infusion rate, infusion        The first step in degradation of ascorbic                                           formulation. In artificial nutrition support in
tubing length, the composition of the          acid is reversible and the degradation                                              clinical practice. 2nd ed. Payne-James J,
parenteral nutrition solution and vitamin      product has biological activity similar to                                          Grimble G, Silk D, eds.             Cambridge
                                                                                                                                   University Press; 1995.
concentrations are also important [9].         that of ascorbic acid. The next and later
                                                                                                                                3. Ball PA. Methods of assessing stability of
Pharmacists have discussed light protec-       steps are not reversible and the products
                                                                                                                                   parenteral nutrition regimens. Curr Opin Clin
tion of AIO solutions for years. It has        have no biological activity. Oxalic acid
                                                                                                                                   Nutr Metab Care. 2001 Sep;4(5):345-9.
been claimed that light protection is not      is a final degradation product, and this
                                                                                                                                4. Allwood MC, Kearney MCJ. Compatibility
necessary because of a light protective        increases the possibility to form calcium                                           and stability of additives in parenteral nutri-
effect from the lipid emulsion. Allwood        oxalate precipitations. The solubility of                                           tion admixtures. Nutr. 1998;14(9):697-706.
and Martin concluded that all parenteral       calcium oxalate is 0.007 g/L [6] which is                                        5. ASPEN. Safe Practices for Parenteral
nutrition solutions should be light pro-       less than dibasic calcium phosphate.                                                Nutrition Formulations. National Advisory
tected during administration [9]. Their                                                                                            Group on Standards and Practice Guidelines
investigations showed losses of retinol        Conclusion                                                                          for Parenteral Nutrition. J Parenter Enteral
amounting to between 60% and 80%               Investigation, testing and quality control                                          Nutr. 1998;22(2):49-66.
during administration in daylight [9].         of parenteral nutrition is an analytical                                         6. Weast RC, ed. CRC Handbook of chemistry
There are conflicting data on sorption of      challenge. Therefore, hospital pharma-                                              and physics. 60th ed. Boca Raton (FL): CRC
retinol to infusion bags and administra-       cists need to cooperate with the pharma-                                            Press; 1979.
tion set. It seems that sorption depends       ceutical industry. We need statements on                                         7. Food and Drug Administration. Safety alert:
on the ester used and the plastic materi-      stability and storage conditions in order                                           hazards of precipitation associated with
al. The acetate ester is shown to bind         to advise dieticians and doctors when                                               parenteral nutrition. Am J Hosp Pharm.
strongly to PVC [4]. Riboflavin is also        prescribing parenteral nutrition and also                                           1994;51:1427-8.
degraded by exposure to daylight but it is     to plan the logistics required to meet the                                       8. Krasilnikoff PA, Holmberg L, Lie SO,
less sensitive than retinol. Simulated infu-   needs of the patient, especially those                                              Schiøtz PO, Visakorpi JK. Nordisk Lærebog
sion of an AIO parenteral nutrition mix-       requiring home parenteral nutrition.                                                i Pædiatri. 1993 10th Edition, p.140-1.
ture has showed losses of riboflavin of 10-                                                                                     9. Allwood MC, Martin HJ. The photodegrada-
20% over 24 hours in direct daylight           The pharmaceutical industry produces                                                tion of vitamins A and E in parenteral nutrition
exposure [4]. Degradation of tocopherol        and sells parenteral nutrition for adults                                           mixtures during infusion. Clin Nutr. 2000;
occurs due to a reaction with oxygen dis-      in two or three chamber bags, but for                                               19(5):339-42.



                • Volume 14 • 2008/1              EJHP is the Official Journal of the European Association of Hospital Pharmacists (EAHP)                   www.ejhp.eu     67