REVIEW
`
` CURRENTOPINION Aluminum contamination in parenteral products
`
`Kathleen M. Guraa,b
`
`Purpose of review
`In 1986, the US Food and Drug Administration issued an aluminum mandate in hopes of minimizing
`patient exposure to aluminum contaminates contained in parenteral nutrition additives. The purpose of this
`article is to revisit the status of aluminum contamination as it relates to parenteral nutrition and to survey the
`recent literature to determine if any new findings have emerged. A special emphasis will be placed on the
`complications associated with aluminum toxicity.
`
`Recent findings
`In addition to metabolic bone disease, patients with aluminum toxicity are also prone to other
`complications such as neurodevelopmental delays and cholestasis. Other potentially serious consequences,
`including osteoporosis, growth failure, and dementia, can arise years after the initial exposure to
`aluminum, showing that preventing toxicity is imperative.
`
`Summary
`Unlike the rapid response to eliminating aluminum toxicity in the dialysis patient population, similar successes
`have not been realized in patients receiving parenteral nutrition solutions. Product formulation changes have
`been slow to emerge from manufacturers. It remains the responsibility of healthcare practitioners to recognize
`the patient populations at risk for toxicity and act accordingly. Monitoring aluminum status and purchasing
`products known to possess the least amount of aluminum are two such approaches.
`
`Keywords
`aluminum, metabolic bone disease, parenteral nutrition
`
`INTRODUCTION
`The 1986 US Food and Drug Administration (FDA)
`aluminum mandate was issued to minimize patient
`exposure to aluminum in parenteral nutrition addi-
`tives [1&]. In 2000, probably in response to the sheer
`difficulty in manufacturing aluminum-free paren-
`terals in a cost-effective manner, the mandate was
`modified such that the FDA simply required that the
`aluminum concentration be noted on the labels of
`all additives used to compound parenteral nutrition.
`Large-volume parenterals (that is, sterile water for
`injection, amino acids, dextrose) had established
`limits on the maximum aluminum concentration
`(25 mg/l), but small-volume parenterals were simply
`required to label their products with the maximum
`aluminum content at the time of the expiry. Phar-
`macists were expected to use these values to calcu-
`late the maximal amount of aluminum contained in
`a patient’s parenteral nutrition formula and inform
`the prescriber of the potential for aluminum loading
`and toxicity. As these calculations are based on the
`aluminum content on product label when the prod-
`uct expires and not the actual amount contained
`at the time of compounding, the potential for
`overestimation exists. As a result, many practitioners
`
`opted to monitor their patient’s serum aluminum
`concentrations, rather than to make clinical deci-
`sions based on a theoretical risk [1&]. The purpose
`of this article is to revisit the status of aluminum
`contamination as it relates to parenteral nutrition
`and describe the potential complications associated
`with excessive aluminum intake.
`
`BACKGROUND
`The third most abundant mineral within the earth’s
`crust, aluminum is found in almost every plant and
`animal tissue [1&]. Most adults ingest between 3 and
`5 mg aluminum on a daily basis [2&]. The first cases
`of aluminum toxicity were reported in the 1970s
`
`aDepartment of Pharmacy, Boston Children’s Hospital and bMCPHS
`University, Boston, Massachusetts, USA
`
`Correspondence to Kathleen M. Gura, PharmD, BCNSP, FASHP,
`FPPAG, Clinical Pharmacist GI/Nutrition, Team Leader, Surgical Pro-
`grams, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA
`02115, USA. Tel: +1 617 355 2336; fax: +1 617 730 0601; e-mail:
`Kathleen.Gura@childrens.harvard.edu
`Curr Opin Clin Nutr Metab Care 2014, 17:551–557
`
`DOI:10.1097/MCO.0000000000000091
`
`1363-1950 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
`www.co-clinicalnutrition.com
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
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`

`Micronutrients
`
`KEY POINTS
` Little progress has been made in reducing the amount
`of aluminum contamination present in additives used to
`compound parenteral nutrition solutions.
` In addition to metabolic bone disease, other
`complications associated with aluminum toxicity include
`growth delays, parenteral nutrition associated
`cholestasis, and anemia.
` Many complications associated with excessive
`aluminum intake do not manifest until years after
`exposure.
` Infants and children appear to be particularly
`susceptible to aluminum toxicity-related complications.
`
`when reports of osteomalacia and encephalopathy
`secondary to aluminum exposure were observed in
`dialysis patients [1&]. Similar symptoms began to
`appear in the 1980s when parenteral nutrition use
`became more prevalent. Cases of encephalopathy
`and osteopenia were linked to parenteral nutrition
`aluminum contaminates [1&]. Although the renal
`community was able to minimize exposure by
`changing how water used in dialysis baths was pre-
`pared, similar changes in manufacturing methods
`have not occurred with parenteral nutrition addi-
`tives.
`
`ALUMINUM PHARMACOKINETICS
`The systemic absorption of aluminum is minimized
`by numerous natural protective barriers. Healthy
`adults absorb 0.3–0.5% of the 5 mg/day aluminum
`[1&]. Although
`present
`in a typical oral diet
`aluminum absorption can occur at low or neutral
`pH,
`like most medications,
`little occurs in the
`stomach. In the alkaline environment of the small
`intestine, aluminum is converted to insoluble salts
`and is not available for uptake. Aluminum may be
`absorbed in the small intestine if it has previously
`been complexed with organic molecules in the
`stomach, allowing it to remain soluble in the higher
`pH environment. [2&] In fact, large intakes of citric
`acid, such as in orange and lemon juice, can
`enhance enteral aluminum absorption by forming
`nonionized aluminum citrate that can pass through
`the gastrointestinal barrier. The aluminum that does
`get absorbed and reaches the systemic circulation
`becomes protein bound and renally excreted with
`small amounts cleared in the bile [1&]. More than
`95% of aluminum is renally excreted, following a
`biphasic pattern [2&]. Initially, during the first hours
`after intravenous administration, levels are low but
`
`gradually rise and peak within 24–48 h. In instances
`of excessive intake, the limits of total fecal excretion
`are exceeded and additional aluminum can be
`absorbed and reach the systemic circulation. Intra-
`venous administration of aluminum-contaminated
`products bypasses the protective barrier of the
`gastrointestinal tract and accumulates in bone, liver,
`kidney, brain, and other tissues. The amount of
`aluminum that can be deposited varies with age.
`In neonates, approximately 75% of parenterally
`infused aluminum is retained, in comparison to
`40% in adults [2&]. Moreover, once deposited in
`the body, aluminum can remain in tissues for years
`with a half-life as long as 7 years [1&].
`
`DIAGNOSING ALUMINUM TOXICITY
`There is no standardized test to make a diagnosis of
`aluminum toxicity. It is often made after obtaining a
`thorough medical history and evaluating clinical
`signs and symptoms along with imaging and labora-
`tory studies. Nonspecific symptoms such as mental
`status changes, bone pain, and multiple nonhealing
`fractures may be present [1&,2&]. In patients with
`renal disease, plasma aluminum levels have long
`been used as a predictor of metabolic bone disease.
`Likewise, blood levels continue to be a poor predic-
`tor of presence or absence of toxicity. Reference
`ranges are used as guidelines to identify populations
`at risk for toxicity but may not reflect exposure or
`the potential to cause adverse effects. Because
`aluminum is ubiquitous, obtaining and analyzing
`samples with minimal contamination remains a
`challenge. Moreover, circadian rhythm changes in
`aluminum levels (that is, higher in the morning and
`lowest in the early evening) make timing of sample
`collection an additional consideration. A recent
`study showed that there was a wide variation in
`reference aluminum ranges even if the same ana-
`lytical method was used [3&]. Urine concentrations
`have also been used, but the relationship of these
`levels to disease severity has not been clearly
`demonstrated [1&]. Likewise, assessment of hair
`aluminum content is not considered a standard
`(or optimal) test for monitoring aluminum status
`[2&]. The deferoxamine infusion test has been used
`to determine aluminum load [1&]. Deferoxamine, a
`chelating agent, removes aluminum from tissue
`stores and allows for more accurate assessment of
`serum aluminum levels. As part of this diagnostic
`test, baseline aluminum levels are obtained, an
`infusion of deferoxamine is administered, followed
`by a repeat serum aluminum level. Toxicity is
`present if the serum aluminum rises after the
`deferoxamine infusion. Although this test has been
`used to determine aluminum toxicity in dialysis
`
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`patients, there is no standard protocol to guide
`practitioners in the assessment aluminum toxicity
`secondary to parenteral nutrition exposure [1&].
`Because of the difficulties in recognizing toxicity
`and accurately measuring aluminum levels, the
`actual prevalence of aluminum toxicity in the
`parenteral nutrition dependent patient still remains
`unknown. Other complications that appear years
`later, such as osteoporosis, may offer some insight.
`
`MANAGEMENT STRATEGIES
`of
`Treatment
`options
`in the management
`aluminum toxicity remain limited. Deferoxamine
`chelation therapy has been used to treat parenteral
`nutrition associated aluminum toxicity [4&]. This
`therapy, however, has its own risks, including hypo-
`calcemia [1&,5]. Prevention of toxicity by reducing
`or eliminating aluminum-rich additives continues
`to be the most effective means of management.
`Other measures that can potentially minimize
`the complications associated with aluminum toxicity
`include the provision of the amino acid taurine and
`correcting any underlying iron deficiency. Taurine
`mitigates aluminum toxicity by improving the cel-
`lular antioxidant defense system by stabilizing the
`cell membrane, thus preventing lipid peroxidation. It
`may also help decrease aluminum-associated hepa-
`toxicity, given its similar chemical activity as acetyl-
`cysteine and its precursor cysteine that has been
`shown to have some efficacy as an antioxidant [6].
`More recent evidence suggests that pretreatment
`with taurine confers the similar protection against
`aluminum-induced nephrotoxicity [7&].
`Supplementing with iron can also reduce
`aluminum toxicity by binding to transferrin, the
`primary aluminum-binding ligand. By preventing
`iron deficiency,
`the affinity of
`transferrin to
`aluminum is reduced and less free aluminum is
`available to be deposited into tissues [1&].
`
`Aluminum contamination in parenteral products Gura
`
`PATIENTS AT RISK
`Three groups have emerged as being at risk for
`developing aluminum toxicity: parenteral nutri-
`tion-dependent patients, plasmapheresis patients
`receiving large amounts of albumin, and burn
`patients receiving large amounts of albumin to
`maintain oncotic pressure [1&]. The patients at great-
`est risk, however, are those with renal insufficiency,
`[1&,2&]. Toxicity
`especially premature
`infants
`appears to be inversely related to gestational age.
`In addition to having immature renal function,
`premature infants are more prone to aluminum
`toxicity because of their increased calcium and
`phosphorus requirements, two additives known to
`be rich in aluminum contaminants [1&]. Conversely,
`because of their reduced calcium and phosphorus
`needs, along with an overall larger body size, paren-
`teral nutrition-dependent adolescents and adults
`do not appear to be significantly impacted by
`aluminum contaminants as neonates [1&]. Older
`patients receive approximately 2 mg/kg/day of alumi-
`num compared with 10–20 mg/kg/day seen in neo-
`natal studies [2&]. Geriatric patients may also be at
`risk. With advancing age, aluminum absorption
`becomes more efficient; thus toxicity may not be
`the result of renal insufficiency but rather due to a
`weakened gastrointestinal protective barrier [8&].
`The fetus is also susceptible to aluminum
`contamination [1&]. Once maternal aluminum is
`absorbed,
`it
`is transferred transplacentally and
`accumulates in fetal tissue. Aluminum competes
`with essential trace elements whose requirements
`are greatest during periods of rapid growth and
`development, such as during the last trimester of
`pregnancy or in early infancy. In utero, fetal mal-
`formations, delayed ossification, growth, and
`impaired neurodevelopment can occur. Aluminum
`does not appear to transfer into breast milk in any
`appreciable quantities. In animal studies, less than
`2% of a daily dose reaches breast milk [1&].
`
`ALUMINUM CONTAMINANTS IN
`PARENTERAL NUTRITION SOLUTIONS
`Since the 1980s, aluminum contamination of paren-
`teral nutrition additives has been a recognized prob-
`lem. The majority of evidence supporting the need
`to reduce aluminum exposure, however, is more
`than 30 years old. Earlier studies estimated the daily
`aluminum intake to be 3–4 mmol/kg/day, 50–100
`times higher than the estimated mean intake using
`currently available products [1&]. Supporting evi-
`dence consisted mainly of case reports or small
`studies, implying that other additives apart from
`those addressed by the FDA mandate could also
`contribute to aluminum loading.
`
`COMPLICATIONS OF ALUMINUM
`TOXICITY
`Depending upon the duration of exposure and
`the amount of aluminum that is present in the
`systemic circulation, resulting complications will
`vary dramatically. All organ systems can potentially
`be impacted.
`
`Metabolic bone disease
`Aluminum impacts bone development via a variety
`of mechanisms [1&,2&]. Mineralization is impaired
`when high levels are present
`in bone tissue.
`Aluminum impacts bone mineralization by affecting
`
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`Micronutrients
`
`the renal enzyme 1,25-dihydroxyvitamin D-1-alpha
`hydroxylase, thereby decreasing the conversion of
`25-hydroxyvitamin D, the major circulating form of
`vitamin D, to its biologically active form, 1,25-dihy-
`droxyvitamin D [9&&]. Aluminum impairs the bone’s
`uptake of calcium, thus interfering with osteoblast
`proliferation [1&,2&]. Through its binding to phos-
`phorus, aluminum acts directly on bone by inducing
`a state of phosphate deficiency [1&]. Bone remodeling
`becomes compromised by aluminum indirectly by
`becoming deposited into the parathyroid gland,
`inhibiting parathyroid hormone secretion [1&,8&].
`Patients with aluminum loading due to parenteral
`nutrition have lower serum concentrations of para-
`thyroid hormone than those receiving parenteral
`nutrition with little or no aluminum exposure.
`Metabolic bone disease (MBD) is a well known
`complication of prolonged parenteral nutrition use,
`first reported in 1982 [1&]. MBD secondary to
`aluminum contamination affected up to 84% of
`patients receiving home parenteral nutrition for
`more than 6 months. Signs and symptoms included
`hypercalciuria, increased serum alkaline phospha-
`tase levels, and severe bone pain [1&]. Serum
`aluminum levels typically exceed 30 mg/l and stains
`show aluminum 30% of the trabecular bone surface
`[2&]. Patchy osteomalacia may be evident in bone
`biopsies. In infants, the onset of MBD is more rapid
`and can occur within 3 weeks of initiation of paren-
`teral nutrition [9&&]. Subsequent research linked the
`aluminum contamination with common parenteral
`nutrition additives such as calcium and phosphorus
`salts, and heparin [2&]. The extent of bone turnover
`appears to be related to duration of parenteral nutri-
`tion use. In almost all patients receiving long-term
`parenteral nutrition (that is, parenteral nutrition use
`>1 year), serum osteocalcin was in the low or low–
`normal range indicative of a low bone formation
`rate [1&,9&&]. Accumulation occurred at the mineral-
`ization front of bone, which was attributed to
`aluminum toxicity [1&]. High serum aluminum con-
`centrations have also been observed without any
`accumulation in bone. For example, neonates
`receiving parenteral nutrition for 3 weeks did not
`experience a decrease in bone formation, provided
`the average intake of 0.1 to 0.2 mmol/kg/day was not
`exceeded [1&]. Similar reports have been observed in
`adults receiving prolonged courses of parenteral
`nutrition [10&&]. Osteoporosis and the resulting frac-
`ture risk are typified by the depletion of bone
`mineral mass, along with the deterioration of bone
`microarchitecture [11].
`Given there is no cure, early identification of
`causative factors is important as it may minimize the
`risk of osteoporosis. There is a strong link that early
`aluminum exposure in life subsequently impacts
`
`peak bone mass. Bone mineral density (BMD) fol-
`lows childhood and adolescent growth rates into
`adulthood. Increased fracture rates have been linked
`with reduced peak BMD, suggesting that childhood
`BMD may be one of the best indicators of fracture
`risk later in life, particularly in females [9&&]. The
`significance of early aluminum exposure on bone
`health was reported by Fewtrell et al. [12]. As part of
`their 15-year follow-up of their landmark study of
`aluminum exposure in premature infants receiving
`parenteral nutrition, they noted that aluminum
`exposure impaired long-term bone mineralization.
`Infants receiving aluminum-depleted parenteral
`nutrition had significantly higher bone mineral
`content (BMC) of the lumbar spine, independent
`of body or bone size; the hip bone mineral content
`decreased by 7.6% in children whose aluminum
`exposure exceeded 55 mg/kg/day. These findings
`support the premise that early aluminum exposure
`can lead to the development of long-term compli-
`cations, such as osteoporosis and hip fracture.
`More recently, the impact of aluminum toxicity
`was investigated as it relates to growth. A recent
`cross-sectional study comparing pediatric patients
`with parenteral nutrition-dependent intestinal fail-
`ure with age-matched, sex-matched, and race-
`matched controls to determine whether BMC and
`BMD was lower in the intestinal failure cohort than
`in healthy controls and to identify potential caus-
`ative factors [9&&]. They found that in intestinal
`failure PN-dependent patients, BMC was 15% and
`BMD was 12% lower than in controls. Furthermore,
`intestinal
`failure patients had higher
`serum
`aluminum concentrations (23 vs. 7 mg/l), higher
`25-hydroxy vitamin D concentrations
`(40 vs.
`30 ng/ml), and lower parathyroid hormone concen-
`trations (51 vs. 98 pg/ml) than controls. The authors
`concluded growth was negatively impacted by
`excessive aluminum exposure.
`
`Anemia
`The potential for hematologic complications of
`aluminum exposure is closely related to a patient’s
`iron stores. Iron deficiency anemia is an often unrec-
`ognized confounder of aluminum toxicity. As much
`as 90% of all aluminum binding is with the iron
`transport protein transferrin, which also serves as
`the primary aluminum-binding ligand [13]. When
`iron is bound to transferrin, the affinity of trans-
`ferrin for aluminum is reduced. Provided that there
`are adequate iron stores, elevations in plasma
`aluminum concentrations will not result in the dis-
`placement of transferrin-bound iron, thereby reduc-
`ing the potential for toxicity. Aluminum inhibits
`erythropoiesis and iron metabolism by obstructing
`
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`hemoglobin synthesis and erythroid cell matu-
`ration. Because of its binding to transferrin, hypo-
`chromic microcytic anemia that is refractory to
`erythropoietin has been observed in patients with
`aluminum toxicity [13]. Patients may have mild
`hypochromic, ferropenic, and microcytic anemia.
`An increased reticulocyte count may also be present.
`
`Neurologic complications
`The neurotoxic properties of aluminum were first
`recognized more than 100 years ago [1&]. Specific
`neurologic complications include memory loss and
`ataxia. Aluminum-associated dialysis encephalop-
`athy was first described in 1976 and has been essen-
`tially eliminated with the introduction of reverse
`osmosis water purification systems and the avail-
`ability of aluminum-free phosphate binders [1&].
`Parenteral nutrition-associated aluminum neu-
`rotoxicity is also a concern. Aluminum interferes
`with the uptake of trace elements and may contrib-
`ute to developmental delay [14]. Transferrin recep-
`tors present in the capillaries of the brain aid in the
`uptake of transferrin-bound aluminum to cross the
`blood–brain barrier and be deposited [1&,2&]. In one
`study of 227 preterm infants of more than 34 weeks’
`gestation evaluated for the impact of aluminum
`exposure from parenteral nutrition, infants receiv-
`ing aluminum-rich parenteral nutrition solutions
`(approximately 45 mg/ kg/day) for 10 days had a
`10-point deficit in their Mental Developmental
`Index scores and were twice as likely to have scores
`below 88 [15]. These scores were compared to age-
`matched controls who received parenteral nutri-
`tion solutions that contained 4 to 5 mg/kg/day of
`aluminum for a comparable time period. Unfortu-
`nately, although this study served as the impetus for
`the establishment of the FDA aluminum mandate,
`the researchers based their conclusions solely on
`the aluminum content of the parenteral nutrition
`additives and did not consider other sources of
`aluminum, nor did they assess urine or serum
`aluminum concentrations to determine if there
`was indeed toxicity present.
`Aluminum toxicity has also been associated
`with structural and physiological ocular damage
`[16]. Rats given excessive amounts of parenteral
`aluminum demonstrated prominent retinal changes
`including photoreceptor cell damage [1&]. Theoreti-
`cally, aluminum contamination may exacerbate
`retinal abnormalities that are often present in pre-
`mature infants.
`Similar to the neurodevelopmental delays seen
`in neonates, recent evidence suggests that pro-
`longed exposure to aluminum can lead to neuro-
`degeneration and may actively promote the onset
`
`Aluminum contamination in parenteral products Gura
`
`and progression of Alzheimer’s disease [17&]. Low
`levels of aluminum exposure over prolonged periods
`of time may lead to excess inflammatory activity
`within the aging brain, leading to neurologic impair-
`ment.
`
`Parenteral nutrition-associated liver disease
`In addition to the aforementioned complications,
`aluminum toxicity has been shown to increase the
`risk of parenteral nutrition-associated liver disease
`(PNALD) [1&]. The exact mechanism is not known,
`although research has shown that at excessive doses,
`parenterally infused aluminum, can cause hepatic
`injury similar to that seen in PNALD. In a porcine
`model, it was shown that the duration of aluminum
`exposure directly correlated with serum total bile
`acids and hepatic aluminum concentrations [18].
`Marked blunting of bile canaliculi microvilli, a com-
`mon structural change seen in cholestasis, was
`observed in hepatic tissue in aluminum-exposed
`piglets but not controls. As these microvilli are
`the site of bile acid transporter proteins important
`in bile secretion, any damage to the microvilli
`results in a loss of these transporter proteins and a
`reduction in bile flow [19]. Premature infants may
`have pre-existing abnormalities in bile acid metab-
`olism; thus, any loss of bile acid proteins secondary
`to microvilli damage may increase the risk of
`PNALD. Furthermore, developmental differences
`in bile acid transporter activity may explain the
`variation in the severity of PNALD among infants
`of similar gestational age and feeding history [18].
`Another way aluminum exposure can promote
`hepatoxicity is through its role as an intracellular
`reactive oxygen species generator that triggers a
`metabolic shift toward lipogenesis in the hepato-
`cytes [20]. Aluminum may reduce L-carnitine pro-
`duction that interferes with the beta-oxidation of
`fatty acids within the mitochondria. This can result
`in dyslipidemia, and fat can accumulate in the liver
`and lead to cholestasis. This may also play a factor in
`the neurologic complications seen in aluminum
`toxicity as similar metabolic derangements may
`occur within the astrocytes [1&].
`
`PARENTERAL NUTRITION ADDITIVES
`ASSOCIATED WITH ALUMINUM
`CONTAMINATION
`The typical additives used in parenteral nutrition
`compounding have some degree of aluminum con-
`tamination. Multivitamins, trace elements, calcium,
`and phosphate salts all contain appreciable amounts
`of aluminum [1&]. Other additives often adminis-
`tered to patients requiring parenteral nutrition, such
`
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`Micronutrients
`
`as heparin and albumin, may also contain consider-
`able amounts of aluminum. Another under-
`appreciated source of aluminum contamination is
`natural products. Natural products manufactured
`in China generally had higher levels of aluminum
`in comparison with those from other countries
`and can contribute to a patient’s overall aluminum
`burden [21&].
`
`FACTORS THAT IMPACT ALUMINUM
`CONTAMINATION
`There are numerous factors that influence the
`extent of aluminum contamination in a parenteral
`additive. The source of the raw material and con-
`tainer design can influence aluminum content [1&].
`Glass containers and rubber vial stoppers have con-
`siderably more aluminum contamination than
`plastic does. Even the type of fluid packaged in glass
`will impact the amount of leaching. For example,
`both calcium and phosphorus salts have a high
`affinity for aluminum that can enhance leaching.
`Other factors that impact the extent of aluminum
`contamination are storage conditions and assigned
`expiration dates. The longer a product remains in
`storage,
`the greater the potential
`for leaching
`aluminum from the glass vial into the solution.
`Practitioners must continue to consider other
`potential sources of aluminum contamination in
`addition to that contributed by parenteral nutrition
`additives. Depending upon the country, current
`labeling standards may not require aluminum con-
`tent to be reported. As would be expected, par-
`enteral medications, because of their route of
`administration, have the greatest potential
`for
`aluminum contamination. In one study evaluating
`medication use of patients receiving regular dialysis
`treatments, patients receiving intravenous forms of
`iron, erythropoietin, and insulin had higher blood
`aluminum levels in comparison with those patients
`receiving the same medications via an alternative
`route of administration or simply avoiding their use
`[22].
`
`FOOD AND DRUG ADMINISTRATION
`MANDATE AND IMPACT ON PARENTERAL
`NUTRITION COMPOUNDING
`Since the implementation of the FDA mandate, it
`has been difficult to achieve the desired goal of
`parenteral nutrition patients receiving less than
`5 mg/kg/day of aluminum. Although the aluminum
`content
`included on the manufacturer’s
`label
`reflects the amount present at the product’s expiry,
`the actual content may be far less if newly manufac-
`tured products are used. One study directly assayed
`
`freshly com-
`the aluminum concentrations of
`pounded parenteral nutrition solutions and com-
`pared this value with the estimated aluminum
`content based on the manufacturer’s label; the
`actual measured aluminum content was 7–10 times
`less than the calculated value [23]. In a review of 13
`384 parenteral nutrition patient-days of pediatric
`patients receiving parenteral nutrition, it was found
`that it was only possible to meet the FDA mandate in
`patients weighing more than 50 kg;
`in patients
`weighing less than 50 kg, it was unachievable [24].
`Similarly, a recent study showed a significant
`decrease (40–44%) in aluminum exposure in neo-
`nates when the least contaminated additives were
`used to formulate a parenteral nutrition, but they
`still were unable to achieve the desired FDA ‘safe’
`limit of less than 5 mg/kg/day [25].
`Additional research has been conducted to
`determine if newer products manufactured since
`the establishment of the FDA aluminum mandate
`have impacted aluminum levels in patients. In 2009,
`Popinska et al. [26] assessed aluminum concen-
`trations in children receiving long-term parenteral
`nutrition. Serum aluminum concentrations were
`obtained in 24 patients whose duration of parenteral
`nutrition exposure ranged from 2 to 14.7 years.
`Serum levels were then compared to the aluminum
`content present in the parenteral nutrition addi-
`tives. In all cases, aluminum intake exceeded the
`FDA recommendations. There was an inverse
`correlation between daily intake of aluminum and
`patient body weight and age as smaller, younger
`patients had higher calcium intakes (due to their
`higher requirements) in comparison with older
`children.
`
`CONCLUSION
`Unlike the rapid response to eliminating aluminum
`toxicity in the dialysis patient population, similar
`successes have not been realized in patients
`receiving parenteral nutrition. Product formulation
`changes are slow to emerge from the manufacturers.
`It remains the responsibility of practitioners to
`recognize the patient populations at risk for toxicity
`and act accordingly. Monitoring aluminum status
`and purchasing products known to possess the least
`amount of aluminum are two such approaches. The
`need to balance the risk of developing neurologic
`disease, hepatotoxicity, metabolic bone disease, and
`other complications due to aluminum toxicity vs.
`suboptimal calcium and phosphate intake in paren-
`teral nutrition must also be considered whenever
`attempts are made to reduce aluminum load.
`Additional research in this area continues to be
`warranted.
`
`Volume 17  Number 6  November 2014
`556
`www.co-clinicalnutrition.com
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`6
`
`

`

`Acknowledgements
`None.
`
`Conflicts of interest
`Dr Gura is a member of the pharmaceutical advisory
`board for Alkymos Inc., Lexington, KY, USA.
`
`REFERENCES AND RECOMMENDED
`READING
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`&& of outstanding interest
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