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Labeling of Aluminum Content in HPN
The following article is based on information presented by Philip Schneider, MS, FASHP, John Welsey, MD, Jay Mirtallo, MS, RPh, BCNSP, FASHP, and Marc Stranz, PharmD, at a Nutrition Week workshop sponsored jointly by Baxter Healthcare, a manufacturer of IV multivitamins, and Coram Healthcare, a home infusion company.
There has been a long standing concern regarding aluminum contamination in parenteral nutrition formulas, particularly when protein hydrolysates, which are heavily contaminated with aluminum, were used in HPN solutions. Since the industry moved to using synthetic amino acid solutions in the 1970’s, the level of aluminum in HPN solutions and related complications have been substantially reduced, though there has still been pressure on the FDA to further reduce the aluminum content.
In 2000 the FDA proposed limiting the amount of aluminum in parenteral nutrition to 25 mcg/L, and requiring manufacturers to print the level of aluminum on the label of large and small volume parenterals (LVP and SVP), and pharmacy bulk packages (PBP) of products used to make HPN. The FDA delayed the effective date of the aluminum labeling requirements in 2001, and in 2002 ruled that SVPs and PBPs containing 25 mcg/L or less of aluminum did not have to declare the specific amount on the label; instead, wording such as “Contains no more than 25 mcg/L” would suffice. The labeling requirements are to take effect by July 2004. HPN consumers may not actually see the new labeling (depending on your home care company’s policy), but your pharmacist will.
Effect of Long Term Exposure
Aluminum is taken into the body through the lungs, skin, GI tract and IV solutions. Intravenous administration increases the potential exposure to aluminum because it bypasses the body’s normal barrier systems.
The tissues most sensitive to aluminum include the brain, bones, and liver. Long term exposure to toxic levels of aluminum can present clinically as bone pain, metabolic bone disease (fracturing osteomalacia), encephalopathy, impaired neurologic development and microcytic hypochromic anemia. Signs of aluminum exposure in long-term HPN patients include: a decrease in bone formation; increased aluminum levels in plasma, urine and bone; and accumulation of aluminum in the mineralization front of the bone. One major problem is that bone pain, patchy osteomalacia, and neuro toxicity can have a wide range of causes other than aluminum toxicity. The precise “safe” level of aluminum in HPN is unknown; more research is necessary and is ongoing.
The most reliable way to monitor aluminum exposure is a bone biopsy stained to show bound aluminum. A plasma analysis may also be taken (in a metal-free, royal blue test tube to eliminate any contamination from the tube); however, plasma levels do not reflect tissue levels, and therefore are not very useful.
Aluminum is normally excreted fairly well in the urine. However, patients with impaired renal function (end stage renal disease or neonates with immature renal function), are at greater risk of aluminum toxicity. Patients who are iron deficient, especially preterm infants, also face a greater risk of aluminum toxicity; aluminum shares a similar chemical makeup as iron which allows aluminum to bind to free proteins in the body, instead of iron, when the patient is anemic. Long term HPN patients may be at greater risk simply because of their greater exposure to aluminum over time, although aluminum related bone disease is relatively uncommon now.
Aluminum in HPN
Unfortunately, aluminum is found in many of the products used to make HPN. Phosphates, acetates and calcium gluconate are the primary sources, and typically account for 80-90% of the aluminum contamination in HPN. All are essential ingredients for HPN. All are packaged in small glass containers, like other SVPs, that allow aluminum to leach from the silicon in the glass into the product. Thus, the longer the product is stored in these glass containers, the greater the aluminum content.
Minor sources of aluminum contamination include many electrolytes and trace elements, and multivitamins. Other non-HPN potential parenteral sources of aluminum include heparin, albumin and other blood products.
Estimates of aluminum content vary widely, but based on data presented at Nutrition Week by Jay Mirtallo, MS, RPh, BCNSP, FASHP, the aluminum content of a sample adult PN solution could range from 8 to 31 ug/kg/day, depending on the ingredients used to make the individual patient’s formulation. It is important to note that the techniques used to estimate the aluminum content are just that: estimates, not precisely measured, that change (usually increase, and sometimes substantially) over the shelf life of the product. The FDA is requiring that the aluminum level shown on the label be the maximum amount it could reach by the product’s expiration date. Thus the amount actually in the product at the time of consumption could be much less than is shown on the label.
What is a Safe Level?
In 1997 Bishop et. al. published a study on “Aluminum neurotoxicity in preterm infants receiving intravenous-feeding solutions” in the New England Journal of Medicine (May 29, 1997;336, 22:1557-61), which showed that premature infants who received standard HPN had lower neurologic development scores than those who received a specially-made aluminum-depleted HPN solution. Based on the Bishop study, the FDA established that up to 4-5 ug/kg/day of aluminum taken parenterally was safe, with no increased amounts found in the patient’s plasma, urine or tissues. Higher levels may be safe for adults, but further research is necessary and is ongoing. The American Society for Clinical Nutrition (ASCN) and American Society for Parenteral and Enteral Nutrition (ASPEN) state that increased amounts of aluminum found in plasma, urine or tissue without overt signs of toxicity, or exposure to 15 to 30 ug/kg/day parenterally, is unsafe; while bone pain and patchy osteomalacia (shown to be due to aluminum) or exposure to 60 ug/kg/day parenterally is toxic.
As you can see, the aluminum content of an average HPN solution may be above levels considered “safe” by the FDA, but under the 25 mcg/L recommended limit. The reality of the situation is that, currently, it is not practical to get aluminum (at expiration date) levels below 12-13 ug/kg/day in a normal mix of HPN without removing essential components. The FDA cautions that it is more important to receive the essential nutrients in HPN as prescribed by your physician and compounded by your pharmacist than to omit any ingredient because of possible aluminum toxicity. We still have a lot to learn about the effects of aluminum in HPN solutions. We do know that in patients who have normal kidney functions and who are not iron deficient, aluminum administered intravenously is cleared in the urine within 24 to 48 hours.
Sometime soon your HPN or additives’ packaging may contain a new warning regarding the estimated level of aluminum found in that product. The FDA recommends no more than 25 ug/kg/L aluminum in HPN products, and considers 5 ug/kg/day to be a safe level of exposure. Manufacturers continue to work on reducing aluminum content in their products, though it is impractical as yet to get to the desired “safe” levels. Monitoring of long term HPN patients through blood work and bone biopsies may be important, especially in patients with renal insufficiency. Preventing iron deficiency is one of the best defenses against aluminum toxicity, as is maximizing EN intake to minimize dependence on IV products.
Where Does the Aluminum in HPN Come From?
The amount of aluminum contamination in an HPN solution can vary widely depending on the amount and type of additives it contains, as well as the age of the additives. As seen below in the sample HPN formulation for a 68kg patient, the largest contributors to aluminum contamination are potassium acetate (K Ac), calcium gluconate (Ca++), and to a lesser extent, sodium phosphate (NaPO4).
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