There have been numerous reports of aluminum toxicity from the contamination of PN solutions over the past 3 decades [2
]. A key study by Bishop et al that contributed to the FDA’s decision to have PN component solutions labeled with their aluminum content compared neurological development in 277 premature infants who received a standard PN formula or an aluminum-depleted PN formula for a period of 5 to 16 days [6
]. The median aluminum content in their standard PN, 45 μg/kg/day, was compared with an aluminum-depleted PN solution with an aluminum content of 4 to 5 μg/kg/day. 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 parenteral nutrition. A 15 year follow up study of 59 children from these former premature infants examined their bone mineralization [7
]. Dual-energy radiograph absorptiometry (DEXA) showed that the now adolescent patients who had received the standard PN solution had lower mineral content and bone area compared to those who had received the aluminum-depleted PN. Their reduced lumbar spine and hip bone mass are potential risk factors for later osteoporosis and hip fractures These findings suggest that total aluminum exposure from prolonged PN is a contributing factor in adverse neurologic and bone development among premature infants.
Since the FDA modified its regulations in 2000, several studies have demonstrated that manufacturers are not able to meet these stricter regulations [15
]. This is particularly true in premature infants due to their higher calcium and phosphate requirements compared to adults. A 2006 study calculated the expected daily aluminum exposure from pediatric PN solutions based on the manufacturer-stated aluminum concentration [17
]. Even when selecting products reportedly to contain the lowest aluminum concentration, the calculated average aluminum exposure in infants was 59.9 μg/kg/day, exceeding the FDA recommended limit by twelve times the upper limit. The FDA’s recommended limit of 5 μg/kg/day was only feasible in patients weighing over 50 kg. In our 2010 follow-up study, measured aluminum content of compounded PN solutions for neonates was found to be significantly less than the calculated content from the manufacturer’s label [18
]. Despite this, aluminum assays of compounded neonatal PN solutions still exceeded the FDA limit of 5 μg/kg/day by 3 to 5 times, (range: 14.9–23.1 μg/kg/day). Our study confirms that by using the least contaminated PN solution products this daily exposure can be reduced to 8.8–12.9 μg/kg/day, which is a 41%–44% reduction from our previous study.
The American Society for Parenteral and Enteral Nutrition Aluminum Task Force published its “Statement on Aluminum in Parenteral Nutrition Solutions” in August 2004 [19
]. The Task Force recognized that the FDA regulations only pertain to industry, but acknowledged that safety is the first and foremost consideration. In order to promote safety, the Task Force recommended that all those involved in ordering and preparing PN solutions should be aware of the potential toxicity from aluminum contaminants in the component solutions. The Task Force also recommended that compounding pharmacies may desire to develop a database containing the aluminum content of products used in parenteral nutrition solutions. The Task Force finally recommended that clinicians may want to purchase equivalent products with the lowest aluminum content when possible and should monitor changes in the pharmaceutical market that may affect aluminum concentrations. Our study elucidates another method that can further decrease aluminum exposure in high risk patients. These data can help compounding pharmacies update their practice and insure that the patients are receiving the least aluminum exposure possible with the current products that are available. Health professionals and manufacturers need to continue to develop better methods todecrease the risk of developing aluminum toxicity and eliminating the potential for long-term adverse effects, especially in infants that receive prolonged PN therapy [20
]. If a purified form of calcium gluconate were available that greatly reduced the amount of Al contamination, it might be possible to meet FDA recommendations. Currently, there are no guidelines for monitoring serum Al levels in patients on long-term PN, but periodic monitoring of Al levels may be indicated in patients with prolonged courses of therapy with high Al exposures [22