Reports of aluminum (Al) toxicity among infants and children have been cited in the medical literature for several decades describing serious central nervous system, bone and liver damage, and anemia. Signs and symptoms of Al toxicity include encephalopathy, dementia, impaired neurological development, bone pain, osteopenia, osteomalacia, microcytic anemia, and cholestasis (1,2). Accumulation and toxicity can be significant in infants with immature renal function and in children or infants with renal failure. The potential for toxicity may be most significant in preterm infants who require substantial concentrations of the highest Al-containing parenteral nutrition (PN) components, such as calcium gluconate and phosphate salts. These infants may also be exposed to PN for prolonged periods.
In an effort to limit patients' exposure to Al and to prevent cases of Al toxicity, the US 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 (3,4). The implementation of the Final Rule was delayed several times to allow pharmaceutical manufacturers time to comply and was finally put into effect from July 2004. The FDA now requires manufacturers of large- and small-volume parenterals, used in the preparation of PN solutions, to add certain information to their products' labels and package inserts. Large-volume parenteral labeling must state that the product “contains no more than 25 μg/L” of Al. Although there is no specified limit for the Al content of small-volume parenterals, the manufacturers are required to label their products with the maximum Al content at the products' date of expiration.
In response to the 2004 FDA guidelines for Al exposure, we reported the difficulty of meeting the FDA's guidelines in a cohort of pediatric and neonatal patients from our institution that received PN (5). In that study we determined the amount of Al exposure per patient per day by using the Al content from the manufacturer's component product labels to calculate the total daily Al load. We found that the calculated Al exposure in these patients was 6 to 12 times the FDA limit of less than or equal to 5 μg · kg−1 · day−1.
However, it is not known whether the Al content from manufacturers' labels reflect actual measured concentrations. If manufacturers have overestimated Al content in PN components, then the risk for Al toxicity could be less than previously suggested. Conversely, if manufacturers have underestimated actual Al content, then the risk for Al toxicity could be greater. In either case, if actual measured Al concentrations reflect daily Al exposure exceeding recommended limits, then such a finding would warrant further efforts to reduce Al contamination.
Given the substantial vulnerability of neonates to Al toxicity, both because of high Al exposure from PN and potentially impaired Al elimination, further study should naturally focus on this patient group. Therefore, the objectives of the present study were to determine the actual Al content of neonatal PN solutions, compare these values to the calculated amounts from manufacturers' PN product labels, and ascertain whether the actual Al exposure exceeds the FDA recommended maximum of 5 μg · kg−1 · day−1.
MATERIALS AND METHODS
Forty neonatal patient orders for PN solutions were randomly selected by the investigators for sampling during the month of March 2007. To decrease order variability, only PN solution orders for infants in the neonatal intensive care unit and intermediate intensive care nursery were included because their nutritional requirements are similar.
Once marked for sampling, the patient identifiers were removed. The orders were then numbered sequentially from 001 to 040. There were no other inclusion or exclusion criteria.
The study protocol was submitted to our medical center's institutional review board and approved before initiation of this research.
All PN solution orders were reviewed by pharmacy staff and then sent for compounding. PN solutions were compounded into ethylene-vinyl-acetate total PN bags using the Baxa Exacta-Mix 2400 Compounder (Baxa Corporation, Englewood, CO) under aseptic conditions. Before PN solutions were removed from the sterile hood, samples for Al measurement were collected by study personnel. A 2-mL sample was removed aseptically from the bag using a Monoject 3-mL syringe with a stainless steel needle to minimize any additional Al contamination. All of the samples were then injected into metal-free collection tubes. Once all of the samples were collected, they were sent to the hospital's clinical laboratory for shipping to Mayo Laboratories in Rochester, MN.
In addition to direct measurement of Al concentration for each of the patient PN solutions as described above, Al concentration was also measured for PN component solutions. The 16 component solutions tested were as follows: sterile water, 70% dextrose, TrophAmine (B. Braun Medical Inc, Bethlehem, PA) 10% amino acids, Intralipid (Fresenius Kabi, Bad Homburg, Germany) 20% fat emulsion, calcium gluconate, potassium salts (phosphate, acetate, and chloride), sodium salts (phosphate, acetate, and chloride), zinc chloride, magnesium sulfate, selenium, pediatric multivitamin, and pediatric trace elements. All testing at Mayo Laboratories used the inductively coupled plasma mass spectrometer) method done on a Perkin-Elmer Elan 6100 DRC II inductively coupled plasma mass spectrometer machine (PerkinElmer Life and Analytical Sciences Inc, Waltham, MA). Each sample was analyzed in duplicate and the average Al concentration was reported to the investigators.
The calculated Al concentrations of all of the samples were determined from the manufacturers' labeled Al concentrations based on the dates of expiry of the products, using our hospital's PN software (Infusion Studio; Monterey Medical Solutions Inc, Monterey, CA). Product variability was minimized by using 1 manufacturer and 1 lot number for each component solution.
Mean calculated and measured daily Al exposure was determined and compared and stratified by patient weight. Statistical analysis was performed using the Student t test.
PN solutions from 40 neonatal patient orders were sampled for Al content determination. Samples were also taken from 16 manufacturers' component products for Al content measurement.
The measured and calculated Al contents of the 40 neonatal patient PN solutions are listed in Table 1 by patient weight. The mean measured Al daily exposure by weight was significantly lower than the mean calculated Al daily exposure for all weight ranges (P < 0.05). The highest measured and calculated Al content was found among the smallest patients in the neonatal intensive care unit (≤1.0 kg) who had a measured daily Al exposure of 23.1 μg · kg−1 · day−1. These extremely low-birth-weight premature infants have large calcium and phosphate requirements to mineralize their bones (eg, 500–600 mg · kg−1 · day−1 of calcium gluconate and 1–2 mmol · L−1 · kg−1 · day−1 of phosphate). When comparing our patient PN solutions with the FDA limit, the actual measured Al content was 3 to 5 times the FDA limit of ≤5 μg · kg−1 · day−1, and the calculated Al content was 5 to 10 times the FDA limit.
The measured versus calculated Al content in the 16 PN component products are listed in Table 2, including the expiration dates of the sampled stock solutions. The measured Al concentration was less than the calculated Al concentration for all component products tested. Calcium gluconate, potassium phosphate, and sodium phosphate contained the highest concentrations of Al both measured and calculated. Conversely, sterile water, TrophAmine 10% amino acids, potassium chloride, sodium chloride, and 70% dextrose had low levels of measured Al.
Aluminum is one of the most abundant metals in our environment. It is found in raw materials and is incorporated into products during manufacturing (6–8). Aluminum is likewise introduced as a contaminant in products used to make PN solutions. The PN components that have the highest amounts of Al include calcium gluconate, potassium phosphate, and sodium phosphate (8,9). The human body has several mechanisms to prevent significant absorption of dietary Al and to aid its elimination. The elimination of Al occurs primarily via renal excretion. The gastrointestinal tract, which typically allows <1% of ingested Al into the bloodstream, is bypassed because PN is administered intravenously into the circulation (10).
Previous studies of Al exposure from PN solutions have reported Al intakes in the range of 10.8 to 60 μg · kg−1 · day−1(11,12). All of these studies exceeded the FDA's recommended exposure limit of 5 μg · kg−1 · day−1. A key study by Bishop et al (13) that contributed to the FDA decision compared neurological development in premature infants who received a standard PN formula or an Al-depleted formula for a period of 5 to 16 days. The median Al content in the standard PN, 45 μg · kg−1 · day−1, was compared with an Al-depleted PN solution with an Al content of 4 to 5 μg · kg−1 · day−1. The authors estimated that for infants receiving the standard PN solution, the expected reduction in the Bayley Mental Development Index score would be 1 point per day of intravenous feeding (5,13). These results suggest that total Al exposure from prolonged PN use may be a previously unacknowledged contributing factor to adverse neurodevelopmental childhood outcomes among extremely preterm infants.
Although the results of our study show that the measured daily Al exposure was significantly less than that calculated from manufacturers' labels, both the measured and calculated Al concentrations of actual patient PN solutions are well above the FDA guidelines for safe Al exposure. This confirms the preliminary findings of Speerhas and Seidner (14), in which all 6 of their pediatric/neonatal PN solutions had measured levels of Al in excess of the FDA recommended guidelines. Similarly, the actual measured amount of Al in the stock solutions used to make the individual patient PN solutions was less than the expected amount based on the manufacturers' label. We suggest this difference is because of the following: lot-to-lot variation in products, differences in raw materials and manufacturing processes, and overstating the products' maximum Al content at the products' labeled date of expiry. We also found that the component stock solutions with the highest Al concentrations were calcium gluconate, potassium phosphate, and sodium phosphate.
The inability to meet the FDA guidelines of <5 μg · kg−1 · day−1 Al exposure in our patient population is most likely due to the higher need for calcium and phosphate in infants compared with adults. A study by Mouser et al found that 81% of the Al contamination in neonatal PN could be attributed to calcium gluconate (11). It is widely known that solutions such as calcium gluconate, sodium phosphate, and sodium acetate form complex ions with Al in the glass containers during the manufacturing process. This corresponds to our finding that the samples with the lowest levels of measured Al were the solutions with lower amounts of calcium.
The results of this study confirm the need for changes in the manufacturing process for PN solution components (15). Finding ways to produce calcium gluconate in nonglass containers or developing methods to combine calcium gluconate with calcium chloride or calcium acetate in the compounding process would likely decrease the current level of Al contamination (16,17). Clinicians involved in providing PN to patients can also play an important role in monitoring the safety of patients receiving PN by actively evaluating current practices in their hospitals to reduce potential sources of Al contamination. In addition, manufacturers must continue to work on developing methods to optimize calcium and phosphate delivery to patients while minimizing Al contamination. Health professionals must now look for methods to decrease the risk for Al toxicity and demand a more proactive role from industry to eliminate potential long-term effects from PN use in infants (18–20). Periodic monitoring of Al levels may be indicated in patients with prolonged courses of therapy with high Al exposures. Additional studies are needed to determine which manufacturer's products have the lowest measured Al content. Using labeled concentrations that will not be exceeded at the product's expiry does not allow clinicians to accurately determine the patient's actual exposure to Al.
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