JPPT
`
`CLINICAL INVESTIGATION
`
`Aluminum in Pediatric Parenteral Nutrition Products:
`Measured Versus Labeled Content
`
`Robert L. Poole, PharmD,1 Kevin P. Pieroni, MD,2 Shabnam Gaskari, PharmD,1 Tessa K. Dixon, PharmD,1
`KT Park, MD,2 and John A. Kerner, Jr, MD2
`
`1Department of Pharmacy, Lucile Packard Children’s Hospital at Stanford, and 2Department of Pediatrics, Division of
`Gastroenterology, Hepatology, and Nutrition, Stanford University School of Medicine, Palo Alto, California
`
`OBJECTIVE Aluminum is a contaminant in all parenteral nutrition solutions. Manufacturers currently
`label these products with the maximum aluminum content at the time of expiry, but there are no published
`data to establish the actual measured concentration of aluminum in parenteral nutrition solution products
`prior to being compounded in the clinical setting. This investigation assessed quantitative aluminum
`content of products commonly used in the formulation of parenteral nutrition solutions. The objective of
`this study is to determine the best products to be used when compounding parenteral nutrition solutions
`(i.e., those with the least amount of aluminum contamination).
`
`METHODS All products available in the United States from all manufacturers used in the production of
`parenteral nutrition solutions were identified and collected. Three lots were collected for each identified
`product. Samples were quantitatively analyzed by Mayo Laboratories. These measured concentrations were
`then compared to the manufacturers’ labeled concentration.
`
`RESULTS Large lot-to-lot and manufacturer-to-manufacturer differences were noted for all products.
`Measured aluminum concentrations were less than manufacturer-labeled values for all products.
`
`CONCLUSIONS The actual aluminum concentrations of all the parenteral nutrition solutions were
`significantly less than the aluminum content based on manufacturers’ labels. These findings indicate that
`1) the manufacturers should label their products with actual aluminum content at the time of product
`release rather than at the time of expiry, 2) that there are manufacturers whose products provide
`significantly less aluminum contamination than others, and 3) pharmacists can select products with the
`lowest amounts of aluminum contamination and reduce the aluminum exposure in their patients.
`
`INDEX TERMS aluminum, parenteral nutrition, toxicity
`
`ABBREVIATIONS FDA, Food and Drug Administration; PN, parenteral nutrition
`
`J Pediatr Pharmacol Ther 2011;16(2):92–97
`
`INTRODUCTION
`
`aluminum exposure causes little harm as a result of
`pharmacokinetic properties characterized by a poor
`oral bioavailability. The gastrointestinal tract al-
`lows less than 1% of ingested aluminum into the
`bloodstream. Renal excretion removes 99% of the
`aluminum that enters the bloodstream.1 Despite
`these protective mechanisms, aluminum toxicity has
`been documented in the medical literature for over
`30 years.1–8 Recorded manifestations of aluminum
`toxicity include fracturing osteomalacia and re-
`duced bone mineralization, neurological dysfunc-
`tion and dialysis encephalopathy, microcytic
`hypochromic anemia, and cholestasis. Parenteral
`J Pediatr Pharmacol Ther 2011 Vol. 16 No. 2  www.jppt.org
`
`Aluminum is the most abundant metallic ele-
`ment on earth and is naturally occurring in certain
`minerals, ores, oxides, and silicates. Humans are
`exposed to aluminum on a regular basis through
`drinking water, various foods, medications, dust,
`and deodorants. In an average, healthy individual,
`
`Address correspondence to: Robert L. Poole, PharmD,
`FPPAG, Department of Pharmacy, Lucile Packard Children’s
`Hospital at Stanford, 725 Welch Road, Palo Alto, CA 94304,
`email: rpoole@lpch.org
`Ó 2011 Pediatric Pharmacy Advocacy Group
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`sium sulfate, sodium acetate, potassium chloride,
`sodium chloride, selenium, zinc chloride, zinc
`sulfate, pediatric multivitamins, and pediatric trace
`elements. The largest available product size was
`selected among products available in multiple sizes
`from the same manufacturer. Samples were pre-
`pared by drawing 2 mL of each solution into 3-mL
`Monoject syringes fitted with aluminum-free nee-
`dles. Samples were transferred into metal-free
`transport tubes, each assigned with a code identi-
`fiable by investigators. Quantitative aluminum
`analysis was performed by the Mayo Clinic
`Laboratories (Rochester, MN) using inductively
`coupled plasma mass spectrometry conducted on a
`Perkin-Elmer Elan 6100 DRC II inductively cou-
`pled plasma mass spectrometer (PerkinElmer Life
`and Analytical Sciences Inc, Waltham, MA).
`Aluminum concentrations were reported to the
`investigators in ‘‘mcg/L’’ units. The Student’s t-test
`was used to determine the statistical difference
`between the aluminum concentration on the man-
`ufacturer’s labels and the mean measured alumi-
`num concentration.
`
`RESULTS
`
`Aluminum in Pediatric Parenteral Nutrition Products
`
`nutrition (PN) has long been implicated as a major
`source of aluminum exposure as a result of
`contamination of the component ingredients. These
`component products are contaminated with alumi-
`num in raw materials as well as through byproducts
`from the manufacturing process, during which
`aluminum leaches from glass vials during autoclav-
`ing.9–11 Patients at greatest risk for aluminum
`toxicity from PN include those with underlying
`renal dysfunction and prolonged courses of paren-
`teral nutritional support. Premature infants are
`particularly at high risk of aluminum accumulation
`and toxicity as they often require days of PN
`support and have immature kidneys that are
`incapable of excreting aluminum efficiently. Calci-
`um gluconate and phosphate salts are known to be
`especially high in aluminum content and are often
`administered to premature infants in substantial
`amounts to promote bone mineralization.9,12
`In an attempt to limit the risk of aluminum
`toxicity, the U.S. Food and Drug Administration
`(FDA) modified its ‘‘Regulations on Aluminum in
`Large and Small Volume Parenterals Used in Total
`Parental Nutrition’’ with the January 2000 Final
`Rule, enacted in July 2004.13,14 The Final Rule
`limits the aluminum concentration of large-volume
`parenteral products to 25 mcg/L. Small-volume
`parenteral products must state the maximum
`aluminum concentration at the time of product
`expiry on the product’s label, but no maximum
`aluminum concentration is otherwise specified.
`Manufacturers of all PN products must also include
`a package insert with a standardized warning
`describing the presence of aluminum in the product;
`the risk of using the products in infants and patients
`with impaired kidney function; and a recommended
`maximum daily aluminum dose of 4 to 5 mcg/kg/
`day to prevent accumulation and toxicity.
`The purpose of this study was to quantitatively
`determine the actual aluminum concentrations of
`all commercially available products used to prepare
`PN solutions from all available manufacturers and
`to determine the best (least contaminated with
`aluminum) products on the market.
`
`A total of 18 PN components consisting of 33
`products from 6 available manufacturers in the
`States were sampled. The measured and labeled
`aluminum contents of the 33 products, along with
`days from expiry and p-values, are listed in Tables 1
`through 3. Among all manufacturers, there was
`large lot-to-lot variability, but even more striking
`was the manufacturer-to-manufacturer difference
`between products.
`The measured aluminum concentrations were
`significantly lower ( p,0.05)
`than the labeled
`concentrations in all products except sodium
`chloride 2.5 mEq/L. All of the calcium gluconate
`and potassium phosphate products contained high
`amounts of aluminum in both the measured and
`labeled concentrations. Likewise, the labeled and
`measured concentrations of aluminum in the
`American Regent sodium phosphate product con-
`tained a high concentration of aluminum. Although
`these products contain the highest aluminum
`concentration, calcium gluconate, potassium phos-
`phate, and sodium phosphate contained 20% to
`The Stanford University Medical Center Insti-
`30%, 8% to 16%, and 13% to 16% of
`the
`tutional Review Board approved this study. PN
`aluminum, respectively, compared to the labeled
`products available in the United States from all
`concentrations. Sterile water, amino acids,
`fat
`manufacturers were identified and collected for
`emulsion, potassium chloride, sodium chloride,
`evaluation. Three separate lots from each manu-
`70% dextrose, sodium acetate, potassium acetate,
`facture of the following products were tested: sterile
`magnesium sulfate, trace elements, multivitamin,
`water for injection, dextrose 70%, amino acids, fat
`zinc chloride, zinc sulfate, and selenium all had low
`emulsion, calcium gluconate, sodium phosphate,
`aluminum concentrations.
`potassium phosphate, potassium acetate, magne-
`J Pediatr Pharmacol Ther 2011 Vol. 16 No. 2  www.jppt.org
`
`METHODS
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`RL Poole, et al
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`Table 1. Aluminum Content of Various Products Used in Parenteral Nutrition Solutions
`
`Manufacturer (NDC)
`
`Sterile water
`
`American Regent
`(0517-3050-25)
`
`Days From
`Expiry (Range)
`
`1270 (1239-1299)
`
`Mean Aluminum
`Content (mcg/L)
`
`Labeled Measured (Range)
`25
`
`,5 (,5)
`
`p-Value
`
`,0.0001
`
`American Pharmaceutical
`Partners (63323-185-50)
`
`511 (356-666)
`
`Hospira (0409-7990-09)
`
`584 (507-635)
`
`B. Braun (0264-7850-00)
`
`786 (702-844)
`
`Baxter (0338-0013-08)
`
`241 (215-270)
`
`Dextrose 70%
`
`Hospira (0409-7120-07)
`
`642 (625-661)
`
`B. Braun (0264-1290-50)
`
`239 (50-427)
`
`B. Braun (0264-9341-55)
`
`579 (539-599)
`
`Amino acids,
`TrophAmine 10%
`
`25
`
`25
`25
`
`25
`
`25
`25
`25
`
`5 (,5)
`
`,0.0001
`
`6.6 (,5-10)
`
`0.0004
`
`,5 (,5)
`
`,5 (,5)
`
`14 (11-16)
`
`20 (19-21)
`
`,0.0001
`
`,0.0001
`
`0.02
`
`0.001
`
`7 (,5-11)
`
`0.0008
`
`Fat emulsion,
`intralipid 20%
`
`Fresenius Kabi
`(0338-0519-03)
`
`Calcium gluconate,
`100 mg/mL
`
`American Pharmaceutical
`Partners (63323-311-61)
`
`377 (209-507)
`
`25
`
`11 (,5-17)
`
`0.05
`
`583 (570-599)
`
`9400
`
`2812 (1969-3495)
`
`0.004
`
`American Regent
`(0517-3900-25)
`
`416 (415-417)
`
`12,500
`
`2487 (1928-2887)
`
`0.0008
`
`Magnesium
`sulfate 50%
`
`American Pharmaceutical
`Partners (63323-064-20)
`
`234 (81-386)
`
`300
`
`109 (99-199)
`
`0.03
`
`Hospira
`(00409-2168-03)
`
`American Regent
`(0517-2650-25)
`
`360 (296-417)
`
`280
`
`122 (103-134)
`
`0.004
`
`552 (537-580)
`
`12,500
`
`165 (113-201)
`
`,0.0001
`
`NDC, National Drug Code
`
`DISCUSSION
`
`reduction in the Bayley Mental Development Index
`score would be 1 point per day of PN. A follow-up
`There have been numerous reports1–8 of alumi-
`study of these former infants looked at their bone
`num toxicity resulting from the contamination of
`mineralization 15 years later.6 Dual-energy radio-
`PN solutions over the past 3 decades. A key study
`graph absorptiometry showed that the now-adoles-
`by Bishop et al.5 that contributed to the FDA’s
`cent patients who had received the aluminum-
`decision to have PN solutions labeled with their
`depleted PN solutions during prematurity had a
`aluminum content compared neurological develop-
`higher bone mineral content and bone area than did
`ment in premature infants who received a standard
`those who received the standard PN solution. These
`PN formula or an aluminum-depleted formula for a
`findings indicate that
`total aluminum exposure
`period of 5 to 16 days. The median aluminum
`from prolonged PN is a contributing factor in
`content in the standard PN, 45 mcg/kg/day, was
`adverse neurologic and bone development among
`compared with that of an aluminum-depleted PN
`premature infants.
`solution with an aluminum content of 4 to 5 mcg/
`Since the FDA modified its regulations in 2000,
`several studies15,16 have demonstrated that manu-
`kg/day. The authors estimated that for infants
`facturers are not able to meet
`these stricter
`receiving the standard PN solution, the expected
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`Table 2. Aluminum Content of Potassium and Sodium Products Used in Parenteral Nutrition Solutions
`
`Product
`(Concentration)
`
`Potassium phosphate
`(3 mmol/mL)
`
`Potassium acetate
`(2 mEq/mL)
`
`Manufacturer (NDC)
`
`Days from
`Expiry (Range)
`
`Mean Aluminum
`Content (mcg/L)
`
`Labeled Measured (Range)
`
`p-Value
`
`Hospira (0409-4201-01)
`
`435 (387-482)
`
`51,000
`
`4040 (3647-4434)
`
`0.005
`
`American Regent
`(0517-2350-25)
`
`290 (203-327)
`
`62,500
`
`9972 (6512-16,818)
`
`0.004
`
`Hospira (0409-3294-06)
`
`350 (296-417)
`
`200
`
`22 (11-42)
`
`0.003
`
`American Regent
`(00517-2400-25)
`
`495 (368-610)
`
`25,000
`
`744 (521-1120)
`
`,0.0001
`
`Potassium chloride
`(2 mEq/mL)
`
`American Pharmaceutical
`Partners (63323-967-30)
`
`282 (276-387)
`
`100
`
`6.5 (,5-8)
`
`0.01
`
`Sodium phosphate
`(3 mmol/mL)
`
`Hospira (00409-1513-02)
`
`116 (31-174)
`
`Hospira (0409-7391-72)
`
`479 (360-568)
`
`100
`
`180
`
`5.3 (,5-6)
`
`,0.0001
`
`29 (17-38)
`
`0.001
`
`American Regent
`(00517-3450-25)
`
`378 (296-451)
`
`25,000
`
`3242 (3177-3281)
`
`,0.0001
`
`400 (276-478)
`
`360
`
`73 (54-85)
`
`0.0001
`
`Sodium acetate
`(2 mEq/mL)
`
`Hospira (00409-1513-02)
`
`American Regent
`(0517-2500-25)
`
`NDC, National Drug Code
`
`525 (396-610)
`
`25,000
`
`103 (74-138)
`
`,0.0001
`
`Table 3. Aluminum Content in Multivitamins and Trace Elements
`
`Manufacturer (NDC)
`
`Days From
`Expiry (Range)
`
`Mean Aluminum
`Content (mcg/L)
`
`Labeled Measured (Range)
`
`p-Value
`
`Hospira (0409-4090-01)
`
`411 (386-451)
`
`150
`
`11 (5-18)
`
`0.0007
`
`Zinc chloride
`(1 mg/mL)
`
`Zinc sulfate
`(1 mg/mL)
`
`American Regent
`(0517-6110-25)
`
`Selenium
`(40 mcg/mL)
`
`American Regent
`(0517-6510-25)
`
`604 (568-635)
`
`2500
`
`249 (54-359)
`
`0.002
`
`481 (386-549)
`
`2500
`
`285 (106-599)
`
`0.005
`
`Pediatric trace
`elements
`
`American Regent Multitrace-4
`(0517-9310-25)
`
`518 (518)
`
`2500
`
`101 (101)*
`
`NS
`
`American Regent Pediatric
`Trace Elements (0517-9203-25)
`
`442 (386-518)
`
`5000
`
`574 (316-739)
`
`0.0009
`
`Pediatric
`multivitamin
`
`Baxter (54643-5647-0)
`
`261 (239-306)
`
`Hospira (61703-421-53)
`
`99 (56-123)
`
`30
`
`42
`
`28 (26-29)
`
`18 (14-25)
`
`0.1
`
`0.02
`
`NDC, National Drug Code; NS, not specified.
`* Only 1 lot was sampled for this product.
`
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`RL Poole, et al
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`recently demonstrated that aluminum contamina-
`tion can occur throughout
`the formulation of
`aluminum-containing infusions, but that 56% of
`the aluminum content came from the commercial
`products prior to any manipulation in the hospital
`setting.20 These studies again illustrate the need for
`changes in the manufacturing process for PN
`solution components. Manufacturers must find
`ways to more precisely label the aluminum content
`of PN products since the current
`labeling of
`concentrations that will not be exceeded at the
`product’s expiry does not allow health professionals
`to properly assess the aluminum exposure in their
`patients. A more precise method may require
`manufacturers to label
`their products with the
`actual aluminum content at the time of product
`release rather than at the time of expiry.
`Health professionals and manufacturers need to
`develop better methods for decreasing the risk of
`aluminum toxicity and eliminating potentially long-
`term adverse effects, especially to infants who
`receive PN.21,22 Additional studies are needed to
`determine whether the FDA’s recommendation of
`less than 5 mcg/kg/day is attainable when the least-
`contaminated products are used to make PN
`solutions. Data from this article need to be applied
`to actual PN patient orders to make this determi-
`nation.
`
`CONCLUSION
`
`regulations. This is particularly true in premature
`infants because of their higher calcium and phos-
`phate requirements compared to adults. A 2006
`study by Poole et al.15 calculated the expected daily
`aluminum exposure from pediatric PN solutions
`based on the manufacturer-stated aluminum con-
`centration. Even when selecting products allegedly
`containing the lowest aluminum concentration,
`expected average aluminum exposure in infants
`was 59.9 mcg/kg/day, exceeding the FDA recom-
`mended limit by a 12-fold measure. The FDA’s
`recommended limit of 5 mcg/kg/day was only
`feasible in patients weighing over 50 kg. In a 2010
`follow-up study by Poole et al.,16 the measured
`aluminum content of compounded PN solutions
`was found to be significantly less than the
`calculated content from the manufacturer’s label.
`Despite this, aluminum assays of compounded
`neonatal PN solutions still exceeded the FDA limit
`of 5 mcg/kg/day by 3 to 5 times. As part of this
`study, 16 standard PN solution components were
`measured to determine each of the components’
`aluminum concentrations. The study reported that
`there were significant differences in the measured
`aluminum concentrations compared to the manu-
`facturers’ labeled concentrations. Our study vali-
`dates these earlier findings that there is significantly
`less aluminum in PN solution components.
`A study by Mouser et al.17 found that 81% of
`aluminum contamination in neonatal PN was
`attributed to calcium gluconate. It is widely known
`that solutions such as calcium gluconate, sodium
`phosphate, and sodium acetate form complex ions
`with aluminum in the glass containers during the
`manufacturing process.10,11 The findings in this
`study support previous reports that calcium and
`phosphate solutions contain high concentrations of
`aluminum compared to other solutions. Since
`calcium is the major contributor to aluminum
`contamination, methods of producing calcium
`gluconate in nonglass containers or the develop-
`ment of methods to combine calcium gluconate
`with calcium chloride or calcium acetate in the
`compounding process would likely decrease the
`level of aluminum contamination.18,19 Our study
`was not powered or designed to serially monitor the
`aluminum concentration as the product remained in
`glass containers and neared its expiration date. This
`may be worth investigating in future studies to see if
`there is a significant change in aluminum concen-
`tration over the shelf life of the product.
`The manufacturer-to-manufacturer variation in
`ACKNOWLEDGMENTS This work was supported, in
`aluminum content of the PN solutions, as found in
`part, by the Carl and Patricia Dierkes Endowment for
`this study, indicates that the different processing
`Nutrition and Home Care and an Innovations in Patient
`methods of these solutions during manufacturing
`Care Grant from the Lucile Packard Children’s Hospital
`can considerably alter the degree of aluminum
`at Stanford. Poster presentation at the North American
`contamination of PN solutions. De Oliveira et al.
`Society of Pediatric Gastroenterology, Hepatology, and
`J Pediatr Pharmacol Ther 2011 Vol. 16 No. 2  www.jppt.org
`
`The actual aluminum concentrations of all of the
`PN solutions were significantly less than the
`aluminum contents based on the manufacturers’
`labels. These findings indicate that if manufacturers
`measure the actual aluminum content at the time of
`product release, this method may improve accuracy
`in labeling compared to an estimation at the time of
`expiry. These findings also show that there are
`manufacturers whose products result in less alumi-
`num contamination than those of others. By
`identifying the least-contaminated products, phar-
`macists are able to choose products for their
`patients with the least amount of aluminum
`contamination and are thus able to reduce alumi-
`num exposure and the potential for aluminum
`toxicity.
`
`DISCLOSURE The authors have declared no potential
`conflicts or financial interest in any product or service
`mentioned in the manuscript.
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`Nutrition Annual Meeting in New Orleans, Louisiana,
`October 21, 2010. Oral presentation at the American
`College of Nutrition Annual Meeting in New York, New
`York on October 9, 2010. Oral presentation at the
`American Society for Parenteral and Enteral Nutrition
`Annual Meeting in Vancouver, British Columbia, Canada
`on January 30, 2011.
`
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