The first report on aluminum (Al) toxicity is from the late 1970s, when Alfrey et al (1) linked a progressive encephalopathy in uremic patients receiving hemodialysis treatment to the deposit of Al in the brain of these patients (1). Afterwards, in 1980, Al was detected in the bones of patients receiving total parenteral nutrition (PN), who were suffering from bone pain (2,3). Since then Al has been cited as the cause of encephalopathy (4), dementia and impaired neurological development (5), osteopenia, and osteomalacia (6).
The first report on Al loading in infants receiving intravenous therapy was published in 1985 by Sedman et al (7). They measured plasma and urinary Al concentrations in 18 premature infants receiving PN and compared them with the levels found for 8 term infants receiving no intravenous therapy. The results showed that premature infants receiving PN had high plasma and urinary Al concentrations, as compared with controls.
The Committee on Nutrition of the American Academy of Pediatrics issued the first policy statement on Al toxicity in pediatrics in 1986 (8), which was updated in 1996 (9) and reaffirmed in 2004 (10). In these statements, efforts to reduce the levels of Al in products used for premature infants were recommended.
In 1990, the US Food and Drug Administration (FDA) published a document requesting information on the contamination of parenteral drug products with Al (11). As a consequence, the American Society for Clinical Nutrition and the American Society for Parenteral and Enteral Nutrition published in 1991 (12) a document to inform physicians and pharmacists who prescribe and prepare PN solutions as to the safe and toxic amounts of Al. In 1998, the North American Society for Pediatric Gastroenterology and Nutrition published a position statement on the presence of Al in parenterals as a response to the FDA-proposed rule of 1998 (13,14). The society endorsed the FDA proposal of limiting the Al content of large-volume parenterals to 25 μg/L, and for small volume parenterals, the Al concentration would not be above the value cited on the label.
In 2000, the FDA announced the Regulations on Aluminum in Large and Small Volume Parenterals Used in Total Parenteral Nutrition. The implementation of the rule was put into effect in July 2004 (15). The FDA required that manufacturers of products used to make PN solutions add a warning to their product labels, notifying consumers that the product contained Al, which could be toxic. The label was also required to state that research indicated that patients with impaired kidney function, including premature neonates, who received parenteral levels of Al >4 to 5 μg · kg−1 · day−1, accumulated Al at levels associated with central nervous system and bone toxicity.
Nevertheless, Al continues to be a contaminant in PN solutions. Only a few studies dedicated to this subject were carried out since the earlier investigations from the 1990s. In 2003 Advenier et al (16) compared the contamination level of PN solutions administered to patients at the Hospital Necker-Enfants Malades in Paris in the years 1990, 1995, and 2003. The authors concluded that contamination and, consequently, Al intake decreased, but in spite of that, the plasma Al and the Al excretion remained above normal standards for the study subjects, children ages 1.5 to 16 years. An investigation on pediatric Al exposure during the year 2006 at the Lucile Packard Children's Hospital in Stanford, California, showed that with the parenteral products available at that time, it was impossible to keep the daily Al intake below 5 μg/kg, the FDA limit for Al exposure (17).
The aims of the present study were to evaluate Al intake by a group of preterm infants during the period they were in the intensive care unit (NICU) receiving total PN and to quantify the Al eliminated by the patients. All of the fluids given intravenously to the patients during the period, including nutrition and medication, were collected and analyzed. The balance between the Al ingested and excreted in the period was evaluated by measuring the daily Al urinary excretion.
PATIENTS AND METHODS
Ten premature neonates in the intensive unit care of the Santa Maria University Hospital were selected for the study. The inclusion criteria were gestational age between 32 and 36 weeks, normal renal function, and the absence of genetic syndromes. The patients were receiving only intravenous feeding. Table 1 displays the characteristics of the patients.
Infusion, Medication, and Nutrition Solutions
All of the daily infusion bags administered to the neonates during the period at the NICU were collected after their use. This included infusion and nutrition solutions as well as the medication administered intravenously. When the burette apparatus was used, the infusion solution was collected from this dispositive. Samples were collected just after administration. The same was done with the syringes in which the medication was diluted; after administration to the patients, the solution remaining in the syringe was collected. Although the individual components of the infusion and nutrition solutions were not analyzed, the products used for compounded bags and the medication administered to the patients are listed in Table 2.
Routine urine samples were collected once per day for the evaluation of clinical parameters. From these samples, an aliquot was separated (in a previously decontaminated container) for our measurements. To calculate the 24-hour urine volume, the diapers used by the babies during that period were weighed before and after use. The difference furnished the mass of urine produced in the period. Using the density (measured in the collected urine sample) the 24-hour volume was calculated.
The blood of the patients was collected at birth (admission in NICU) and on the last day in the NICU (in previously decontaminated containers). The statistical significance between values of Al serum level collected at birth and at the end of the NICU period was measured using the paired t test. P < 0.05 was taken to demonstrate a significant difference.
Al measurement was carried out in an Analytik Jena AG (Jena, Germany) ZEEnit 600 atomic absorption spectrometer equipped with an MPE 60z autosampler and transversal Zeeman-effect background correction system. The 309.3-nm resonance line was used.
An Al standard solution containing 1000 mg/L Al (Merck, Darmstadt, Germany) was used to prepare working standard solutions. Solutions and sample dilutions were prepared with distilled then deionized water (Milli-Q high purity grade, Millipore, Bedford, MA).
To avoid contamination, all of the laboratory ware was plastic and was immersed for at least 48 hours in 10% HNO3 in an ethanol (v/v) mixture and washed with Milli-Q purified water shortly before use (18). To avoid air contamination, all of the steps in the sample preparation were carried out in a class 100 clean bench.
Although no additional blood or urine samples were collected, the protocol for the present study was approved by the research ethical committee of the Federal University of Santa Maria. Informed consent was obtained from the subjects' parents.
Table 3 summarizes the results for each patient: the Al administered together with infusion solutions and medication during the NICU period, the Al urinary excretion, and the Al blood level on the first and last days. From the sum of the Al in infusion solutions and medications, the total Al administered was calculated.
The mean daily Al intake was 28.5 μg with a relative standard deviation (RSD) of 68%, whereas the mean daily excretion was 9.3 μg with an RSD of 36% (Fig. 1). The mean daily Al intake was evaluated in 15.2 ± 8.0 μg/kg.
The amount of Al retained in the body was calculated from the difference between total Al administered and that excreted in urine, which gave a mean value of 56.2 ± 22.7%.
The Al level in serum on the first day ranged from 7.8 to 73.4 μg/L, and the mean presented a decrease regarding the mean of the last day, from 41.2 ± 23.3 to 23.5 ± 11.2 μg/L.
Because none of the infants presented with impaired renal function, the urinary excretion could be considered normal. The results apparently showed that the amount excreted did not correlate with the amount ingested. The RSD of the daily Al intake and excretion (Fig. 1) suggests that elimination was more closely related to patient prematurity and birth weight than to the amount of Al ingested. In Figure 2 the percentage of Al excreted in relation to Al intake is related to the patients' weight. Excluding patients 1 and 3, both parameters correlate well (r2 = 0.8). Patients 1 and 3 also presented the highest daily Al intake per kilogram, 27.3 and 20.7 μg, respectively, for a mean of 15.2 ± 8.0 μg · kg−1 · day−1 (Table 3).
The Al level in serum on the first day is similar to that found in other studies (Table 4), although only 1 of these studies referred to blood collection on the first day (7). In that study, the group included 9 premature infants (out of 18) for which the plasma Al level on the first day of life ranged from <2 to 49 μg/L.
Also important is the decrease in mean serum Al from the first to the last day, 41.2 ± 23.3 to 23.5 ± 11.2 μg/L, in spite of the continuous Al intake during the period. This finding, in conjunction with the percentage of Al not excreted, allowed us to conclude that the difference was accumulated in the patients' bodies.
Finally, the mean daily Al intake was in only 2 patients (20%) <5 μg · kg−1 · day−1, the recommended FDA limit. The data in Table 4 show a survey of research on Al intake by preterm infants. The articles were chosen based on the similarity of evaluation parameters. It is possible to see that our study, carried out 1 or 2 decades later, presented practically the same results. This shows that little has changed since the FDA regulation went into effect. Because the commercial products used in Brazil are the same commercialized all over the world, this is not a localized but rather a general problem.
Although Al contamination of intravenous formulations and the evidence of its toxicologic role in the neurological impairment in preterm infants have been recognized since the 1980s, little has changed to reduce contamination. Little has been published since then, and the scenario remains practically the same. We confirm that because of the high Al level present in solutions parenterally administered to premature infants, urinary excretion is not able to eliminate all of the Al ingested.
Because in this study premature neonates received 3 times the amount of Al considered safe by the FDA, it would be advisable to conduct additional studies with a broader range of premature neonate gestational ages with prolonged exposures to PN solutions and, additionally, carry out follow-ups with these neonates to assess potential long-term effects.
The authors are grateful to the nursery staff in the NICU who facilitated sample collections, and to DAAD (Deutscher Akademischer Austausch Dienst, Germany) for the financial support. We gratefully acknowledge the help and expertise of Dr Angela Weinmann.
1. Alfrey AC, LeGengre GR, Kaehny WD. The dialysis encephalophaty syndrome: possible aluminum intoxication. N Engl J Med 1976; 294:184–188.
2. Klein GL, Targoff CM, Ament ME, et al
. Bone disease associated with parenteral nutrition. Lancet 1980; 2:1041–1044.
3. 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.
4. Alfrey AC. Dialysis encephalopathy syndrome. Annu Rev Med 1978; 29:93–98.
5. Bishop NJ, Morley R, Day JP, et al
. Aluminum neurotoxicity in preterm infants receiving intravenous-feeding solutions. N Engl J Med 1997; 336:1557–1561.
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. Sedman AB, Klein GL, Merritt RJ, et al
. Evidence of aluminum loading in infants receiving intravenous therapy. N Engl J Med 1985; 312:1337–1343.
8. Committee on Nutrition. American Academy of Pediatrics. Aluminum toxicity
in infants and children. Pediatrics
9. Committee on Nutrition. American Academy of Pediatrics. Aluminum toxicity
in infants and children. Pediatrics
10. Committee on Nutrition. American Academy of Pediatrics. Aluminum toxicity
in infants and children. Pediatrics
11. Department of Health and Human Services, Food and Drug Administration. Parenteral drug products containing aluminum as an ingredient or a contaminant: notice of intent and request for information. Federal Register
12. American Society for Clinical Nutrition/American Society for Parenteral and Enteral Nutrition Working Group on Standards for Aluminum Content of Parenteral Nutrition Solutions. Parenteral drug products containing aluminum as an ingredient or a contaminant: response to Food and Drug Administration notice of intent and request for information. Am J Clin Nutr
13. Klein GL, Leichtner AM, Heyman MB. The Patient Care Committee of the North American Society for Pediatric Gastroenterology and Nutrition: aluminum in large and small volume parenterals used in total parenteral nutrition: response to the Food and Drug Administration Notice of Proposed Rule by the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 1998; 27:457–460.
14. Department of Health and Human Services, Food and Drug Administration. Aluminum in large and small volume parenterals used in total parenteral nutrition: proposed rule. Federal Register
15. Department of Health and Human Services, Food and Drug Administration. Amendment of regulations on parenteral nutrition; delay of effective date. Fed Reg
16. Advenier E, Landry C, Colomb V, et al
. Aluminum contamination of parenteral nutrition and aluminum loading in children on long-term parenteral nutrition. J Pediatr Gastroenterol Nutr 2003; 36:448–453.
17. Poole RL, Hintz SR, Mackenzie NI, et al
. Aluminum exposure from pediatric parenteral nutrition: meeting the new FDA regulation. J Parenter Enteral Nutr 2008; 32:242–246.
18. Bohrer D, Dessuy MB, Kaizer R, et al
. Tissue digestion for aluminum determination in experimental animal studies. Anal Biochem 2008; 377:120–127.
19. Koo WWK, Kaplan LA, Krugwispe SK, et al
. Response of preterm infants to aluminum in parenteral nutrition. J Parenter Enteral Nutr 1989; 13:516–519.
20. Bougle D, Bureau F, Voirin J, et al
. A cross-sectional study of plasma and urinary aluminum levels in term and preterm infants. J Parenter Enteral Nutr 1992; 16:157–159.
21. Moreno A, Domínguez C, Ballabriga A. Aluminium in the neonate related to parenteral nutrition. Acta Paediatr 1994; 83:25–29.
22. Naylor KE, Eastell R, Shattuck KE, et al
. Bone turnover in preterm infants. Intern Pediatr Res Found 1999; 45:363–366.