August 31, 2008
Aluminum Exposure From Pediatric Parenteral Nutrition: Meeting the New FDA Regulation
By Poole, Robert L Hintz, Susan R; Mackenzie, Nicol I; Kerner, John A Jr
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 aluminum 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 ([mu]g/ 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 [mu]g/kg/d and [mu]g/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 50 kg. Conclusions: Currently available parenteral products used to make PN solutions contain amounts of aluminum that make it impossible to meet the new FDA rule ofOver the past 30 years, reports of aluminum toxicity have been cited in the medical literature discussing serious central nervous system, bone and liver damage, and anemia.1-7 Specific findings of this toxicity include encephalopathy, dementia and impaired neurologic development, bone pain, osteopenia, osteomalacia, 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 the leaching of aluminum from glass containers during autoclaving for sterilization.8 It is introduced as a contaminant in products used to make parenteral nutrition (PN) solutions. Several defense mechanisms of the human body act to deter significant absorption of aluminum and effectively aid in its elimination. The GI tract, which typically allows
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 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 preparation 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 product "contains no more than 25 mcg/liter" of aluminum. Although there is no specified limit for the aluminum content of small-volume parenterals or pharmacy bulk packages, 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 parenteral 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 function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate 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 [mu]g/kg/d.11- 13 All of these studies exceeded the FDA's warning label amounts of 5 [mu]g/kg/d. A key study by Bishop et al4 that contributed to the FDA decision compared neurological development in 227 infants who were 10 days, the MDI score was 10 points less than for those patients receiving the aluminum-depleted PN (P = .02).4 The authors estimated 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 products 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
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 prepare PN solutions. We then used the products with the lowest labeled aluminum content for our study. To estimate 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 institution 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 [mu]g/kg/d and [mu]g/L was determined and stratified by the patients' weights.
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
The calculated aluminum exposure is listed in Table 2 by patient weight and includes the average aluminum exposure in [mu]g/kg/d and the average amount of aluminum in [mu]g/L. The most vulnerable patients, those weighing
Data from our institution from calendar year 2004 are presented in Tables 3 and 4 for comparison to the current 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
Table 1. Patient Demographics, 2006 (n = 1003)
Table 2. Calculated Aluminum Exposure, 2006
Table 3. Patient Demographics, 2004 (n = 737)
Table 4. Calculated Aluminum Exposure, 2004
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 products with the lowest labeled aluminum content. Parenteral aluminum exposure from PN in amounts 50 kg. Premature infants, neonates, and children actively making 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 content to prepare PN solutions, the FDA-recommended safe amount of 5 [mu]g/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 calculated aluminum exposure in the 6546 neonatal PN solutions (patient weights
There are still a number of concerns and considerations 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 aluminum contamination of generic products from different manufacturers. Manufacturers must identify, develop, and adopt new methods to reduce the aluminum contamination in their products. (3) The FDA ruling set no limits for the maximum amount of aluminum content in small-volume parenterals, yet they are the largest contributors to the problem. The FDA should reassess this issue. (4) Cost: are products with greater aluminum contamination cheaper? If so, they may also become the contracted bid item in use at your institution. Health care professionals must carefully evaluate the aluminum content of parenteral products to assess the potential for toxicity. (5) Are we overestimating the aluminum content in largevolume 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 preliminary study from the Cleveland Clinic17 demonstrated that the actual aluminum exposure from PN solutions is significantly less than the estimated amount from calculations based on manufacturers' labels. Nineteen of their 20 patients had calculated aluminum exposures >5 [mu]g/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 [mu]g/kg/d. More studies measuring actual aluminum content of PN solutions and manufacturers' products are needed.
Table 5. Aluminum Content of Parenteral Nutrition Component Solutions
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
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Robert L. Poole, PharmD1; Susan R. Hintz, MD2; Nicol I. Mackenzie, MD3; and John A. Kerner Jr, MD2
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.
From 1 Lucile Packard Children's Hospital at Stanford, 2S tanford University School of Medicine, Stanford, California, and 3 Monterey Medical Solutions, Ine, 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 publication 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: email@example.com.
Copyright American Society for Parenteral and Enteral Nutrition May/ Jun 2008
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