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
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.
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 :
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 : • added trace elements
• trace elements contamination
[ In some cases calcium and phosphate is a
mixing infusion solutions in that the • physicochemical stability of the lipid
] • dissolved oxygen
• extended storage
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 . 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
• the final concentration of glucose . 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 . 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 . 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 . Ultimately, the trivalent cations . um, and may shift the phosphate equilib-
final pH will, however, be dominated by rium from monobasic to dibasic salt ,
the buffering capacity of the amino acid However, CAN is not the gold standard decreasing solubility (i.e. precipitation
and phosphate . 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 , 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 . and the dibasic (HPO42-). take up to 24-48 hours after mixing to
become visually evident . 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 . 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 . 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 , 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 . 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 . 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 .
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 . 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) . Photodegradation is mainly due also ferric, zinc and manganese ions . 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- email@example.com
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 . multilayered bags . 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 . 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 . 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  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 . 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 . 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 . 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 . 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