Invited Commentary
`Aluminum Contamination of
`Parenteral Nutrition Fluids
`
`Jay M. Mirtallo, MS, RPh, BCNSP, FASHP
`
`Journal of Parenteral and
`Enteral Nutrition
`Volume 34 Number 3
`May 2010 346-347
`© 2010 American Society for
`Parenteral and Enteral Nutrition
`10.1177/0148607110361906
`http://jpen.sagepub.com
`hosted at
`http://online.sagepub.com
`
`It has been >25 years since the clinical manifestations
`
`of aluminum ingestion from parenteral fluids were
`reported.1,2 Impaired bone growth, especially in
`adults, and delays in mental development in neonates are
`the predominant effects observed. Aluminum is ubiqui-
`tous, which unfortunately leads to its undesired presence
`in parenteral products. Of these parenteral products,
`parenteral nutrition (PN) is a substantial source of alumi-
`num.3 Normally, aluminum is easily eliminated in the
`urine. Adult patients with renal compromise and neonates
`are the patient populations at greatest risk of developing
`toxicity from the aluminum present in parenteral fluids.
`As a result, the U.S. Food and Drug Administration
`(FDA) published a rule4 requiring manufacturers of prod-
`ucts used in the preparation of PN fluids to label the
`content of aluminum in their products. For large-volume
`parenterals, there should not be >25 µg/L aluminum; for
`small-volume parenterals, the potential maximum amount
`at expiry of the product should be on the label. The label
`should include a warning that patients with impaired
`renal function, including premature neonates, who
`receive >4–5 µg/kg/d of aluminum may experience central
`nervous system and bone toxicity. Because this regulation
`applies to industry only, there was confusion among clini-
`cians as to what their role should be.5 A.S.P.E.N. issued a
`statement on aluminum in PN solutions6 that provides
`some guidance to clinicians:
`
` • Those ordering and preparing PN should be
`aware of the potential for aluminum contami-
`nants in these products.
` • The compounding pharmacy may wish to
`develop a database of the aluminum content of
`products used in preparation of PN.
` • Clinicians may want to purchase equivalent
`products that have the lowest aluminum content
`and monitor changes in the pharmaceutical mar-
`ket that affects aluminum concentrations.
`
`From the Ohio State University Medical Center, Columbus,
`Ohio.
`
`Address correspondence to: Jay M. Mirtallo, Ohio State University
`Medical Center, DN 368, 410 W. 10th Ave, Columbus, OH 43210;
`e-mail: jay.mirtallo@osumc.edu.
`
` • All healthcare providers involved with PN
`should attempt to limit aluminum exposure in
`at risk patients.
` • Patient monitoring of aluminum toxicity may not
`be possible or reliable in many clinical settings.
`
`Since the FDA rule, we have learned more about alu-
`minum in PN fluids as well as other sources of aluminum
`in patients receiving parenteral therapy. In PN, calcium
`and phosphate salts as well as cysteine hydrochloride are
`major contributors to the overall aluminum content in
`adult and neonatal formulations.3,7 Using the labeled
`amount of aluminum in PN products to estimate alumi-
`num content, Driscoll and Driscoll8 found that it is virtu-
`ally impossible to prepare a PN that is less than the FDA
`limit of 5 µg/kg/d and meet the nutritional needs of the
`patient. Speerhas and Seidner9 found that the measured
`content of aluminum was 7–10 times lower than that esti-
`mated from the product labels. However, the amount of
`aluminum in all of the neonatal and pediatric solutions
`tested exceeded the FDA limits whereas only 2 of the adult
`formulations exceeded the limit. Canada10 reviewed the
`studies of aluminum contamination in PN fluids and
`found that those prepared in other countries had less alu-
`minum than those prepared in the United States. The
`lower aluminum content was attributed to the use of an
`organic phosphorus source that contains less aluminum
`than the inorganic salts used in the United States. The
`organic phosphorus is also more compatible with calcium
`chloride, which has lower aluminum content than the
`gluconate salt. Canada also reported on the success in
`Germany by Frey and Maier11 in reducing aluminum con-
`centration by 96% as the result of repackaging calcium
`gluconate from glass containers to polyethylene vials. This
`reduced the daily intake of pediatric patients receiving PN
`from a range of 30–40 µg/kg/d down to 2–3 µg/kg/d.
`Bohrer et al7,12,13 and de Oliveira et al14 provide fur-
`ther credence to the FDA rule and remind us that alumi-
`num continues to be a concern that should be addressed.
`In previous publications, this group demonstrated that
`aluminum in commercial products was present in the raw
`materials of the product but the amount did not fully
`explain the entire content of aluminum measured.7 This
`group also determined that the amount of aluminum
`
`346
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` 1
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`EXELA 2011
`Eton Pharmaceuticals v. Exela Pharma Sciences
`PGR2020-00086
`
`

`

`leached from glass containers with rubber closures is a
`significant contributor to aluminum present in parenteral
`products.12,13 In their article published in this issue of
`JPEN, de Oliveira et al14 demonstrate that product manip-
`ulation during preparation and the products used for
`parenteral administration contribute significantly to the
`amount of aluminum infused to neonates. All steps
`involved in the preparation and administration of intrave-
`nous solutions for premature infants were assessed for
`potential contribution to the daily aluminum load being
`administered. Commercial products used in PN prepara-
`tion, injectable medications, and products used in packag-
`ing and administering parenteral products (bags, burettes,
`syringes, and administration sets) were contaminated with
`aluminum. Although commercial products were the main
`source of aluminum, product manipulation, containers,
`and administration sets increased aluminum levels by
`40%. This is a substantial amount of aluminum not origi-
`nally considered in the FDA rule.
`Neonates are the patient population most likely to
`be adversely affected by aluminum loads infused in
`parenteral therapy. In the United States, calcium and
`phosphorus intakes need to be eliminated or substan-
`tially decreased below nutritional needs for neonates in
`order to limit the aluminum load presented by PN. An
`alternative to reducing aluminum loads to neonates is
`to not administer PN because the aluminum content of
`PN prepared in the United States is too high. These are
`not acceptable options to clinicians caring for neonates.
`Aluminum is present in all products used in parenteral
`therapy. Even though PN contributes the majority of alu-
`minum that is infused, drug products, administration sets,
`and product manipulation will also influence the final
`amount of aluminum infused on a daily basis. The new
`information provided by de Oliveira et al14 reinforces the
`recommendation that clinicians have a heightened aware-
`ness of aluminum contamination of parenteral products
`ordered and administered in their daily practice. Ingredients
`with the lowest amount of aluminum should be used in the
`preparation of PN. The use of products packaged in glass
`containers with rubber closures should be avoided. We as
`clinicians should insist that small-volume parenterals be
`packaged in polyethylene containers. Finally, it may be
`
`Aluminum Contamination / Mirtallo    347
`
`time to partner with manufacturers to bring to the U.S.
`market organic phosphorus products for PN compounding
`like those that have allowed our European colleagues to
`substantially limit the amount of aluminum contamination
`in their PN fluids.
`
`References
`
` 1. Klein GL, Targoff CM, Ament ME, et al. Bone disease associated
`with parenteral nutrition. Lancet. 1980;2:1041-1044.
` 2. Sedman AB, Klein GL, Merritt RJ, et al. Evidence for aluminum
`loading in infants receiving intravenous therapy. N  Engl  J  Med.
`1985;312:1337-1343.
` 3. ASCN/A.S.P.E.N. workgroup on standards for aluminum content
`of parenteral solutions. Am J Clin Nutr. 1991;53:399-402.
` 4. U.S. Food and Drug Administration. Aluminum in large and small
`volume parenterals used in total parenteral nutrition. Fed Regist.
`2000;65:103-111.
` 5. Young D. FDA aluminum rule poses challenges for industry, phar-
`macists. Am J Health-Syst Pharm. 2004;61:742, 744.
` 6. Charney PJ. A.S.P.E.N. statement on aluminum in parenteral
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` 7. Bohrer D, Do Nascimento PC, Binotto R, Becker E, Pomblum S.
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` 8. Driscoll M, Driscoll DF. Calculating aluminum content in total
`parenteral nutrition admixtures. Am  J  Health-Syst  Pharm.
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` 9. Speerhas RA, Seidner DL. Measured versus estimated aluminum
`content of parenteral nutrient solutions. Am J Health-Syst Pharm.
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`10. Canada TW. Aluminum exposure through parenteral nutrition
`formulations: mathematical versus clinical relevance. Am J Health-
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`11. Frey OR, Maier L. Polyethylene vials of calcium gluconate reduce
`aluminum contamination of TPN. Ann  Pharmacother. 2000;
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`12. Bohrer D, Do Nascimento PC, Binotto R, et al. Influence of glass
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`minum, part 1: salts, glucose, heparin and albumin. J Trace Elem 
`Med Biol. 2001;15:95-101.
`13. Bohrer D, Do Nascimento PC, Binotto R, Pomblum S. Influence
`of glass packing on the contamination of pharmaceutical products
`by aluminum, part 3: interaction container-chemicals during the
`heating of sterilization. J Trace Elem Med Biol. 2003;17:107-115.
`14. de Oliveira SR, Bohrer D, Garcia SC, do Nascimento PC, Noremberg
`S. Aluminum content in intravenous solutions for administration to
`neonates: role of product preparation and administration methods.
`JPEN J Parenter Enteral Nutr. 2010;34(3):322-328.
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