ALUMINUM TOXICITY AND ITS CONTROL IN PATIENTS RECEIVING TOTAL PARENTERAL NUTRITION
Guest editor:
Gordon L. Klein, MD, MPH
Professor of Pediatrics and Preventive Medicine
University of Texas Medical Branch
Galveston, Texas
On January 26, 2001, the new FDA rule was to take effect concerning aluminum contamination of parenterals and injectables used for total parenteral nutrition (TPN). The rule, published 1 year previously in the Federal Register,1states that all large-volume parenterals, such as dextrose and water solutions, saline solutions, and crystalline amino acids, must contain no more than 25 µg/L of aluminum. Small-volume additives, such as calcium gluconate and phosphate salts, must have their aluminum content determined at the end of their shelf life with the aluminum content noted on the label. Furthermore, the package insert must state that certain patients with impaired or underdeveloped renal function, such as uremics and preterm infants, respectively, may accumulate toxic amounts of aluminum in various tissues.1,2 Moreover, manufacturers of both large- and small-volume parenterals must have a validated method of measuring aluminum content. The method employed must be FDA-approved. The rule goes on to state that no one should receive more than 5 µg/kg/day,1 currently considered to be a safe amount.3,4 It is hoped that the eventual federal requirement of noting aluminum content on the label of small-volume parenterals will provide an incentive for the manufacturers to reduce aluminum contamination.
This rule was designed to protect patients from the known toxicities of aluminum. These include an encephalopathy with dementia in uremic patients2,5 and neurodevelopmental retardation in premature infants.4 The mechanism by which aluminum crosses the blood-brain barrier is uncertain. In both uremics6 and TPN patients,7 aluminum is taken up by the bones at the mineralization front, the site of newly mineralized bone. There it appears to block calcium deposition in the bone matrix and may interfere with osteoblast function as well.2,5 Thus, aluminum could contribute to the patchy osteomalacia seen with aluminum loading in TPN patients. Aluminum also accumulates in the parathyroid glands and evidence suggests that it interferes with the secretion of parathyroid hormone (PTH), which perhaps contributes to the low bone-turnover state seen in patients with aluminum toxicity.2,5,8 Furthermore, animal studies have suggested that aluminum may contribute to cholestasis both in rats and in piglets and appears to alter bile acid conjugation in rats.2,5
While aluminum is one of the most abundant elements in the earth's crust, there is no identified physiological requirement for it, and the body has evolved to protect itself from excessive ingestion. For example, the respiratory and gastrointestinal tracts are natural barriers to aluminum entry into the blood.5 However, TPN introduces aluminum directly into the circulation, bypassing these natural barriers. Approximately 95% of aluminum circulates bound to plasma proteins, primarily transferrin.2,5,8 Thus, only 5% of circulating aluminum is filtered via the kidneys, the main route of aluminum excretion. Circulating aluminum likely enters into an equilibrium with the tissues, especially bone, liver, and spleen. When aluminum administration is stopped, such as when TPN therapy is discontinued or if a lower-aluminum-containing product is substituted for one that is more highly contaminated, there is a rapid reduction in circulating aluminum and urinary aluminum excretion.8 However, elevated concentrations persist in both the blood and urine and are thought to reflect the egress of aluminum from tissues into the circulation.5 Elevated urinary aluminum content has been observed in adult long-term TPN patients for up to 2 years following substitution of low-aluminum-containing crystalline amino acids for aluminum-laden casein hydrolysate as the protein source.2,9
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| Manufacturer or Distributor |
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| M.V.I.-12® (Multi-Vitamin Infusion) |
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Unit vial |
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Single dose (vials 1 and 2) |
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Multi-dose |
| M.V.I. Pediatric™ (Multi-Vitamins for Infusion) |
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| aaiPharma LLC |
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| aaiPharma LLC |
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| ≤78µg/L1 |
| ≤183 µg/L1 |
| ≤43 µg/L1 |
| ≤42 µg/L2 |
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Infuvite™ Pediatric
(Multiple Vitamins for Infusion) |
| Infuvite™ Adult (Multiple Vitamins for Infusion) |
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Baxter International, Inc.
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| Baxter International, Inc. |
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Vial 1 contains less
than 800 ppB3 |
Vial 2 contains less
than 275 ppB3 |
Vial 1 contains less
than 700 ppB3 |
Vial 2 contains less
than 50 ppB3 |
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*µg/L = ppB per the U.S. Geological Survey Web site. 2002. Available at http://www.usgs.gov/. Accessed October 31, 2002.
Under certain circumstances, aluminum will cross the blood-brain barrier. Thus, in patients with renal failure, it is postulated that uremic toxins or citrate ingestion may promote aluminum accumulation in the brain. However, aluminum entry into the brains of infants receiving long-term TPN has been less documented. Nevertheless, certain unidentified factors must be active to facilitate this process, whether it is immaturity of the blood-brain barrier or increased permeability due to acute illness or life-threatening crises. Aluminum may be removed from the brain by prompt use of a chelator, such as deferoxamine, in uremic patients.One reported attempt to treat an infant with deferoxamine resulted in sustained hypocalcemia,10 perhaps due to aluminum chelation from osteopenic bones and the strong need for calcium by the bones. This is known as the "hungry bone syndrome."2 If aluminum is not promptly chelated from the brain, however, it may be very difficult to remove.
Pharmacists and other health care providers should remain vigilant in order to be aware of the amount of aluminum their patients may be receiving from multiple sources in a single day, and to be
cognizant of manufacturers who are not currently in compliance with the rule. Once instituted, reports of noncompliance can be made to the FDA via MedWatch at 1-800 FDA-1088 by phone, or at 1-800-FDA-0178 by fax.
References
1. Department of Health and Human Services. Food and Drug Administration. Aluminum in large and small volume parenterals used in total parenteral nutrition. Final rule. Federal Register. 2000;65:4103-4111.
2. Klein GL. Aluminum in parenteral solutions revisited-again. Am J Clin Nutr. 1995;61:449-456.
3. Naylor KE, Eastell R, Shattuck KE, Alfrey AC, Klein GL. Bone turnover in preterm infants. Pediatr Res.1999;45:363-366.
4. Bishop NJ, Morley R, Day JP, Lucas A. Aluminum neurotoxicity in preterm infants receiving intravenous feeding solutions. N Engl J Med. 1997;336:1557-1561.
5. Klein GL, Nutritional aspects of aluminum toxicity. Nutr Res Rev. 1990;3:117-141.
6. Ott SM, Maloney NA, Coburn JW, et al. The prevalence of bone aluminum deposition in renal osteodystrophy and its relation to the response to calcitriol therapy. N Engl J Med. 1982;307:709-713.
7. Ott SM, Maloney NA, Klein GL, et al. Aluminum is associated with low bone formation in patients receiving chronic parenteral nutrition. Ann Intern Med. 1983;98:910-914.
8. Klein GL, Ott SM, Alfrey AC, et al. Aluminum as a factor in the bone disease of long-term parenteral nutrition. Trans Assoc Am Physicians. 1982;95:155-164.
9. Vargas JH, Klein GL, Ament ME, et al. Metabolic bone disease of total parenteral nutrition: course after changing from casein to amino acids in parenteral solutions with reduced alumunum content. Am J Clin Nutr. 1988;48:1070-1078.
10. Klein GL, Snodgrass WR, Griffin MP, Miller NL, Alfrey AC. Hypocalcemia complicating deferoxamine therapy in an infant with parenteral nutrition-associated aluminum overload:
evidence for a role of aluminum in the bone disease of infants.
J Pediatr Gastroenterol Nutr. 1989;9:400-403.
References for chart
1. M.V.I.-12® Package label. Data on file, aaiPharma LLC.
2. M.V.I. Pediatric™ Package label. Data on file, aaiPharma LLC.
3. Baxter Healthcare Clintec Professional Services.
1-800-422-2751. July 2002.
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