Original Communications
`Aluminum Exposure From Pediatric
`Parenteral Nutrition: Meeting the
`New FDA Regulation
`
`Robert L. Poole, PharmD1; Susan R. Hintz, MD2;
`Nicol I. Mackenzie, MD3; and John A. Kerner Jr, MD2
`
`Journal of Parenteral and
`Enteral Nutrition
`Volume 32 Number 3
`May/June 2008 242-246
`© 2008 American Society for
`Parenteral and Enteral Nutrition
`10.1177/0148607108316187
`http://jpen.sagepub.com
`hosted at
`http://online.sagepub.com
`
`Financial disclosure: This work was supported in part by the Carl and Patricia Dierkes Endowment for Nutrition Support and Home
`Care, and an Innovations in Patient Care Grant from the Lucile Packard Children’s Hospital at Stanford.
`
`Background: Aluminum toxicity can cause serious central
`nervous system and bone toxicities. Aluminum is a contaminant
`of parenteral nutrition (PN) solution components. Premature
`neonates requiring high doses of calcium and phosphate to
`mineralize their bones, children with impaired renal function,
`and children on PN therapy for prolonged duration are at the
`highest risk. Effective in July 2004, the U.S. Food and Drug
`Administration (FDA) mandated labeling requirements for alu-
`minum content in all PN solution components. To assess the
`aluminum exposure in neonatal and pediatric populations, this
`study aims to determine patients’ daily aluminum load (μg/kg/d)
`delivered from PN solutions. Methods: The study included all
`inpatients who received PN during calendar year 2006 (13,384
`PN patient days). The calculated parameters of μg/kg/d and μg/L
`of parentally administered aluminum were stratified according to
`patient age and weight. Aluminum content by product and
`
`manufacturer were tabulated. Results: Forty-nine percent of the
`PN patient days were in patients weighing < 3 kg. These patients
`also received the largest amounts of aluminum (range, 30-60
`μg/kg/d). Meeting the FDA regulation was possible only in patients
`weighing > 50 kg. Conclusions: Currently available parenteral
`products used to make PN solutions contain amounts of alu-
`minum that make it impossible to meet the new FDA rule of
`< 5 μg/kg/d of aluminum exposure. Manufacturers must iden-
`tify, develop, and adopt new methods to reduce the aluminum
`contamination in their products. Health care professionals should
`calculate aluminum loads in patients and make informed deci-
`sions when choosing PN products. (JPEN J Parenter Enteral
`Nutr. 2008;32:242-246)
`
`Keywords:
`parenteral nutrition; pediatric; aluminum; toxic-
`ity; FDA regulation
`
`Over the past 30 years, reports of aluminum toxic-
`
`ity have been cited in the medical literature dis-
`cussing serious central nervous system, bone and
`liver damage, and anemia.1-7 Specific findings of this tox-
`icity include encephalopathy, dementia and impaired
`neurologic development, bone pain, osteopenia, osteoma-
`lacia, microcytic anemia, and cholestasis. Aluminum is
`the most abundant metal in our environment. Aluminum
`is found not only in raw materials but also is incorporated
`into products during the manufacturing process and from
`
`From 1Lucile Packard Children’s Hospital at Stanford, 2Stanford
`University School of Medicine, Stanford, California, and
`3Monterey Medical Solutions, Inc, Salinas, California.
`This work was presented in part at a platform scientific session at
`Clinical Nutrition Week on February 14, 2006, Dallas, Texas.
`Received for publication April 10, 2007; accepted for publica-
`tion January 21, 2008.
`Address correspondence to: Robert L. Poole, PharmD, Lucile
`Packard Children’s Hospital at Stanford, Pharmacy Department,
`725 Welch Road, Palo Alto, CA 94087; e-mail: rpoole@lpch.org.
`
`242
`
`the leaching of aluminum from glass containers during
`autoclaving for sterilization.8 It is introduced as a con-
`taminant in products used to make parenteral nutrition
`(PN) solutions. Several defense mechanisms of the
`human body act to deter significant absorption of alu-
`minum and effectively aid in its elimination. The GI tract,
`which typically allows < 1% of ingested aluminum into
`the bloodstream, is circumvented when PN is adminis-
`tered intravenously into the circulation. The elimination
`of aluminum occurs primarily via renal excretion.
`Accumulation and toxicity can be substantial in neonates
`who have immature kidneys and premature infants who
`have yet to mineralize their bones. Also at risk are
`children with renal failure on dialysis and infants and
`children who receive long-term PN therapy with high
`aluminum content.
`In an effort to limit patients’ exposure to aluminum
`and to prevent cases of aluminum toxicity, the U.S. Food
`and Drug Administration (FDA) amended its “Regulations
`on Aluminum in Large and Small Volume Parenterals
`Used in Total Parenteral Nutrition” with the January
`2000 Final Rule. The implementation of the Final Rule
`was delayed several times to allow pharmaceutical
`
`
`
` 1
`
`EXELA 2012
`Eton Pharmaceuticals v. Exela Pharma Sciences
`PGR2020-00086
`
`

`

`Aluminum Exposure From Pediatric Parenteral Nutrition / Poole et al 243
`
`manufacturers time to comply and was finally put into
`effect July 26, 2004.9 The FDA now requires manufacturers
`of large- and small-volume parenterals, used in the prepa-
`ration of parenteral nutrition solutions, to add certain
`information to their product’s labels and package inserts.10
`Large-volume parenteral labeling must state that the prod-
`uct “contains no more than 25 mcg/liter” of aluminum.
`Although there is no specified limit for the aluminum con-
`tent of small-volume parenterals or pharmacy bulk pack-
`ages, the manufacturers are required to label their
`products with the maximum aluminum content at the
`product’s expiry.
`The FDA has also required that the following be
`included in the package insert for all products used in the
`preparation of PN solutions:
`
`WARNING: This product contains aluminum that may be
`toxic. Aluminum may reach toxic levels with prolonged par-
`enteral administration if kidney function is impaired.
`Premature neonates are particularly at risk because their
`kidneys are immature, and they require large amounts of
`calcium and phosphate solutions, which contain aluminum.
`Research indicates that patients with impaired kidney func-
`tion, including premature neonates, who receive parenteral
`levels of aluminum at greater than 4 to 5 mcg/kg/day accu-
`mulate aluminum at levels associated with central nervous
`system and bone toxicity. Tissue loading may occur at even
`lower rates of administration.
`
`Previous studies of aluminum exposure from PN
`solutions have reported aluminum intakes in the range of
`10.8 - 60 μg/kg/d.11-13 All of these studies exceeded the
`FDA’s warning label amounts of 5 μg/kg/d. A key study by
`Bishop et al4 that contributed to the FDA decision com-
`pared neurological development in 227 infants who were
`<34 weeks of gestational age, with a birth weight under
`1850 g, who received a standard PN formula or an alu-
`minum-depleted formula for a period of 5 - 16 days. The
`median aluminum content in the standard PN, 45 μg/kg/d,
`was compared to an aluminum-depleted PN solution with
`an aluminum content of 4 - 5 μg/kg/d. Bayley Mental
`Development Index (MDI) assessed neurologic develop-
`ment at a postterm age of 18 months. For the group of
`infants receiving the standard PN for >10 days, the MDI
`score was 10 points less than for those patients receiving
`the aluminum-depleted PN (P = .02).4 The authors esti-
`mated that for infants receiving the standard PN solution,
`the expected reduction in the Bayley MDI score would be
`1 point per day of intravenous feeding.
`The purpose of our study was to calculate the daily
`amounts of aluminum that neonatal and pediatric patients
`at our institution would receive from parenteral nutrition
`solutions if they were made from currently available prod-
`ucts labeled with the least aluminum content. Using those
`products would in theory minimize the patient’s aluminum
`exposure. We also tested the feasibility of meeting the FDA’s
`
`recommendation of limiting aluminum exposure to < 5
`μg/kg/d. We did not measure serum aluminum concentra-
`tions or report any toxicities that may have occurred from
`aluminum loading in patients.
`
`Methods
`
`All pediatric inpatients who received PN at our institution
`during the calendar year of 2006 were identified through
`the pharmacy PN database and included in the study. The
`study patient population ranged in age from premature
`infants up to 18 years, regardless of patient weight.
`Patient data were stratified by weight, number of PN
`orders, and number of PN days per patient. To estimate
`the total aluminum exposure from PN, we collected the
`aluminum content of 114 marketed products used to pre-
`pare PN solutions. We then used the products with the
`lowest labeled aluminum content for our study. To esti-
`mate the minimum possible aluminum exposure per
`patient resulting from PN, the aluminum contents of
`these products were entered into the calculation files of
`our PN software. The PN software14 used at our institu-
`tion calculates the aluminum content of each patient’s
`solution using the manufacturer’s labeled concentrations
`and includes that data in the PN database. The database
`created by the software captures all aspects of each
`patient’s daily PN therapy and provides a historical record
`for future studies. All aluminum calculations were based
`on the exact volume of PN ordered for each patient in
`mL/kg/d. The calculated daily aluminum load in μg/kg/d
`and μg/L was determined and stratified by the patients’
`weights.
`
`Results
`
`The study included 13,384 PN patient days in 1003
`patients. Patient demographics are displayed in Table 1.
`We found that 49% of the PN days were among patients
`weighing <3 kg, the highest risk patient category.
`The calculated aluminum exposure is listed in Table
`2 by patient weight and includes the average aluminum
`exposure in μg/kg/d and the average amount of aluminum
`in μg/L. The most vulnerable patients, those weighing <3
`kg, received the largest total daily dose of aluminum
`(range, 30.3-59.9 μg/kg/d). The calculated aluminum
`exposure in these infants was approximately 6-12 times
`the recommended safe amount.
`Data from our institution from calendar year 2004
`are presented in Tables 3 and 4 for comparison to the cur-
`rent 2006 study data (Tables 1 and 2). In 2004, there
`were 8334 patient days in 737 patients. Similarly, 41% of
`the PN days were in patients weighing <3 kg, and their
`calculated aluminum exposure ranged from 29.4 to 50.7
`μg/kg/d (6-10 times the recommended safe amount).
`
`2
`
`

`

`244
`
`Journal of Parenteral and Enteral Nutrition / Vol. 32, No. 3, May/June 2008
`
`Table 1. Patient Demographics, 2006 (n = 1003)
`
`Table 3. Patient Demographics, 2004 (n = 737)
`
`No. of
`Patients
`
`No. of
`Patient Days
`
`Average
`Parenteral
`Nutrition
`Days/Patient
`
`Range of
`Parenteral
`Nutrition
`Days/Patient
`
`34
`237
`192
`187
`46
`54
`124
`49
`31
`49
`
`1230
`3370
`1946
`1735
`435
`1048
`1555
`585
`506
`974
`
`36.2
`14.2
`10.1
`9.3
`9.5
`19.4
`12.5
`11.9
`16.3
`19.9
`
`1-46
`1-74
`1-84
`1-138
`1-97
`1-177
`1-93
`1-102
`1-91
`1-116
`
`Weight, kg
`0-<1
`1-<2
`2-<3
`3-<4
`4-<5
`5-<10
`10-<20
`20-<35
`35-<50
`50-<100
`
`No. of
`Patients
`
`No. of
`Patient Days
`
`Average
`Parenteral
`Nutrition
`Days/Patient
`
`Range of
`Parenteral
`Nutrition
`Days/Patient
`
`23
`149
`134
`138
`54
`74
`91
`26
`21
`27
`
`577
`1594
`1205
`1486
`582
`866
`1143
`320
`279
`282
`
`25.1
`10.7
`9.0
`10.8
`10.8
`11.7
`12.6
`12.3
`13.3
`10.4
`
`1-27
`1-67
`1-64
`1-80
`1-81
`1-78
`1-76
`1-86
`1-36
`1-61
`
`Weight, kg
`0-<1
`1-<2
`2-<3
`3-<4
`4-<5
`5-<10
`10-<20
`20-<35
`35-<50
`50-<100
`
`Table 2. Calculated Aluminum Exposure, 2006
`
`Table 4. Calculated Aluminum Exposure, 2004
`
`Patient
`Weight, kg
`0-<1
`1-<2
`2-<3
`3-<4
`4-<5
`5-<10
`10-<20
`20-<35
`35-<50
`50-<100
`
`Expected Average
`Aluminum
`Exposure, μg/kg/d
`
`Parenteral
`Nutrition Average
`Solution Aluminum
`Concentration, μg/L
`
`59.9
`40.1
`30.3
`27.2
`22.8
`16.3
`12.3
`8.4
`8.1
`6.0
`
`248.0
`230.6
`226.2
`234.9
`218.4
`173.8
`178.6
`143.3
`190.8
`165.2
`
`Patient
`Weight, kg
`0-<1
`1-<2
`2-<3
`3-<4
`4-<5
`5-<10
`10-<20
`20-<35
`35-<50
`50-<100
`
`Expected Average
`Aluminum
`Exposure, μg/kg/d
`
`Parenteral
`Nutrition Average
`Solution Aluminum
`Concentration, μg/L
`
`50.7
`34.8
`29.4
`26.6
`23.8
`18.7
`13.5
`9.3
`7.5
`5.1
`
`245.8
`233.6
`239.3
`255.7
`230.8
`207.8
`182.0
`182.6
`185.5
`189.5
`
`Table 5 shows the 23 products with the lowest
`labeled amounts of aluminum available on the market;
`these are the products used in this study. The results of
`our study showed that it was not possible to meet the
`FDA mandate when using currently available PN prod-
`ucts with
`the
`lowest
`labeled aluminum content.
`Parenteral aluminum exposure from PN in amounts <5
`μg/kg/d was possible only in patients weighing >50 kg.
`Premature infants, neonates, and children actively mak-
`ing bone have calcium and phosphate requirements that
`can lead to aluminum toxicity if they are receiving all of
`their nutrition parenterally.
`
`Discussion
`
`There have been numerous reports of aluminum toxicity
`from the contamination of PN solutions over the past 3
`decades.1-7 This led the FDA to require products used to
`prepare PN solutions be labeled with their aluminum
`content.
`
`The results of our study showed that by using the
`products with the least amount of labeled aluminum con-
`tent to prepare PN solutions, the FDA-recommended safe
`amount of 5 μg/kg/d could not be met. The patients at
`highest risk for aluminum toxicity are premature
`neonates who may have compromised renal function and
`also receive prolonged courses of PN therapy. The calcu-
`lated aluminum exposure in the 6546 neonatal PN solu-
`tions (patient weights <3.0 kg) in our study exceeded the
`FDA limit by factors of 6-12 times (30 - 60 μg/kg/d).
`Smith et al15 recently reported similar numbers (13 - 56
`μg/kg/d) in their study of 8 neonatal PN solutions (patient
`weights <3.0 kg) in which the aluminum content was
`minimized in the same method as in our study.
`There are still a number of concerns and considera-
`tions that must be addressed: (1) Patients are exposed to
`other therapies that also contain significant amounts of
`aluminum (eg, albumin, blood products, L-cysteine, and
`heparin),16 and (2) there is also huge variability in the alu-
`minum contamination of generic products from different
`manufacturers. Manufacturers must identify, develop,
`
`3
`
`

`

`Aluminum Exposure From Pediatric Parenteral Nutrition / Poole et al 245
`
`Table 5. Aluminum Content of Parenteral Nutrition Component Solutions
`
`Product
`
`Container Size
`
`Manufacturera
`
`Expected Aluminum
`Content at Expiry, μg/L
`
`Amino acids
`TrophAmine 10%
`Aminosyn 10%
`Aminosyn RF 5.2%
`Dextrose 70%
`Fat emulsion 20%
`Sterile water injection
`Sodium acetate 2 mEq/mL
`Sodium chloride 2.5 mEq/mL
`Sodium phosphate 3 mM/mL
`Potassium acetate 2 mEq/mL
`Potassium chloride
`Potassium phosphate 3 mM/mL
`Magnesium sulfate 50%
`Calcium gluconate 100 mg/mL
`Multi Trace-4 pediatric
`MVI pediatric
`MVI adult
`Vitamin K 1 mg/0.5 mL
`Trace elements
`Zinc chloride 1 mg/mL
`Selenium 40 μg/mL
`Copper chloride 0.4 mg/mL
`L-cysteine 50 mg/mL
`
`500-mL bottle
`1000-mL bag
`500-mL bag
`2000-mL bag
`100-mL bag
`3000-mL bag
`100-mL bulk
`200-mL bulk
`50-mL SDV
`100-mL bulk
`250-mL bulk
`50-mL SDV
`50-mL SDV
`200-mL bulk
`3-mL SDV
`5-mL SDV
`10-mL SDV
`0.5-mL amp
`50-mL bulk
`10-mL vial
`10-mL SDV
`10-mL vial
`50-mL vial
`
`B. Braun
`Hospira
`Hospira
`Hospira
`Fresenius Kabi
`Baxter
`APP
`APP
`APP
`APP
`Baxter
`APP
`APP
`APP
`American Regent
`aaiPharma
`Mayne
`Hospira
`Hospira
`Hospira
`APP
`Hospira
`American Regent
`
`<25
`<25
`<25
`<25
`<25
`<25
`100
`<25
`7050
`50
`<25
`21,000
`105
`4000
`5000
`42
`78
`100
`570
`150
`708
`3400
`5000
`
`SDV, single-dose vial.
`aaaiPharma, Lake Forest, Illinois; American Regent, Shirley, New York; APP, Schaumburg, Illinois; Baxter, Deerfield, Illinois; B.
`Braun, Bethlehem, Pennsylvania; Fresenius Kabi, Uppsala, Sweden; Hospira, Lake Forest, Illinois; Mayne, Lake Forest, Illinois.
`
`and adopt new methods to reduce the aluminum contam-
`ination in their products. (3) The FDA ruling set no lim-
`its for the maximum amount of aluminum content in
`small-volume parenterals, yet they are the largest contrib-
`utors to the problem. The FDA should reassess this issue.
`(4) Cost: are products with greater aluminum contamina-
`tion cheaper? If so, they may also become the contracted
`bid item in use at your institution. Health care profes-
`sionals must carefully evaluate the aluminum content of
`parenteral products to assess the potential for toxicity. (5)
`Are we overestimating the aluminum content in large-
`volume parenterals? By allowing manufacturers to label
`their products as “contains no more than 25 mcg/liter,”
`calculated aluminum content may be greater than the
`actual content amount. Labeled amounts of aluminum
`are based on the highest aluminum concentration of the
`first 5 batches of product produced after the effective
`date of the rule.9 Future studies must document actual
`measured amounts of aluminum and not calculated
`amounts, as the actual amounts vary from lot to lot based
`on raw materials and manufacturing processes. A prelim-
`inary study from the Cleveland Clinic17 demonstrated
`
`that the actual aluminum exposure from PN solutions is
`significantly less than the estimated amount from calcu-
`lations based on manufacturers’ labels. Nineteen of their
`20 patients had calculated aluminum exposures >5
`μg/kg/d. In contrast, only 6 of their 20 patients (4 infants
`and 2 adults) had measured levels of aluminum in their
`PN solutions >5 μg/kg/d. More studies measuring actual
`aluminum content of PN solutions and manufacturers’
`products are needed.
`
`Conclusions
`
`Currently available parenteral products, used to make PN
`solutions for pediatric and neonatal patients, contain
`amounts of aluminum that make it impossible to meet the
`July 2004 FDA rule of <5 μg/kg/d of aluminum exposure.
`Manufacturers must identify, develop, and adopt new
`methods to reduce the aluminum contamination in their
`products. The FDA mandate allows clinicians to calculate
`the approximate aluminum exposure that patients may
`be receiving. However, we may be overestimating the
`
`4
`
`

`

`246
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`Journal of Parenteral and Enteral Nutrition / Vol. 32, No. 3, May/June 2008
`
`aluminum content in large-volume parenterals as manu-
`facturers are allowed to label their products “contains no
`more than 25 mcg/liter” (of aluminum). The FDA did not
`set a maximum for the amount of aluminum allowable in
`small-volume parenterals, where the content may be very
`high (eg, calcium gluconate, potassium and sodium phos-
`phates, potassium and sodium acetates). Manufacturers
`should be required to label their products with the actual
`aluminum content at product release and not with an
`estimate of what the concentration will be at the prod-
`uct’s expiration date. The current labeling requirement
`places responsibility on health care professionals to cal-
`culate (or automate the calculations of) aluminum loads
`in patients, and to make informed decisions when choos-
`ing PN products.16 Future studies should focus on deter-
`mining the actual aluminum content of PN solutions
`compared with the calculated amounts based on PN
`product labels at expiry. Pharmacists should evaluate
`their PN process and select products with the lowest alu-
`minum content to help prevent future cases of aluminum
`loading and toxicity in infants and children.
`
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`5
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