Aluminum Leaching from Fluid Warmers: Regulatory Deferral to Clinicians' Decision

In the previous two years, certain fluid-warming systems that use aluminum as their main heat conductor were found to contaminate intravenous (IV) fluids and to have the potential to lead to aluminum toxicity in patients.¹  Aluminum toxicity can lead to oxygen free radicals causing cell death and disease progression. Such contamination confers more risk to patients receiving significant volume resuscitation.

The use of fluid-warming systems is ubiquitous and necessary in surgical and other settings (e.g., trauma, critical care) in which blood loss is encountered and intravascular volume replacement is necessary. Because blood and other blood products are usually stored cold, massive transfusion resuscitation carries serious risks of hypothermia. This is underscored by the notion that hypothermia is commonly referred to as an element of the “trauma triad of death,” with acidosis and coagulopathy as the other conditions.

The clinical issue of hypothermia is exacerbated in the setting of general anesthesia because of anesthetic-induced vasodilation and depression of hypothalamic thermoregulatory systems.²  Maintaining normal body temperatures is crucial to prevent other complications, such as surgical wound infections and cardiac events.³  Accordingly, fluids or blood products are often heated during infusion via fluid warmers before administration.⁴  Most fluid warmers use direct contact via dry heat, usually delivered by a metal plate, a magnetic induction heater, or an infrared lamp.⁵  Aluminum was often favored as the heating material in these fluid-warming systems because of its cheap cost, malleability, and excellent thermal conduction. However, with recent concerns for potential to cause toxicity in patients, the commonly used aluminum fluid-warming systems have been questioned.

Knowledge of this potential for toxicity via aluminum-based fluid-warming systems led the Food and Drug Administration (FDA) to issue several warnings recently regarding potential danger of systems from specific manufacturers, most notably Smiths Medical (Minneapolis, MN), Eight Medical International BV (Rotterdam, the Netherlands), and Smisson-Cartledge Biomedical (Macon, GA).⁶  These warnings are not product recalls; the FDA specifically emphasized that use of these devices should be based on a clinical risk-benefit analysis aimed at optimizing utility for the patient in the particular given situation.

First reports of aluminum toxicity via a fluid warmer surfaced in early 2019, when the enFlow system, designed and manufactured by Vyaire Medical (Chicago, IL), was demonstrated to cause leaching of aluminum into crystalloids and blood products.⁷  Interestingly, this finding originated from a network of clinicians in the U.K. in January 2019, who noticed an increase in aluminum levels in patients receiving warmed IV fluids.⁸  In March 2019, the U.K. Medicines and Healthcare products Regulatory Agency investigated and issued a warning notifying clinicians.⁹ 

A similar time course unfolded in the U.S., where the manufacturer Vyaire Medical acknowledged the issue and initiated a Class 1 device recall in March 2019, encouraging facilities to dispose of their devices unless the facility had no alternative fluid-warming systems. The risk of inadequate resuscitation—due to lack of availability of the right fluid warmer—is contrasted with the risk of potential toxicity. Accordingly, both the U.K. and U.S. regulators acknowledged that a clinical need for the equipment could outweigh the risk of aluminum release. Because different facilities may not have an alternative fluid warmer, the regulators left the decision of whether to continue using the enFlow system to the clinicians' risk-benefit judgment.

Further investigation quantified the magnitude of aluminum release caused by the enFlow device. Taylor et al.⁷  measured the aluminum concentration in various IV fluids after using the enFlow system. For example, when using the enFlow system with sodium lactate solutions, there was a mean concentration of 223 μmol/L⁻¹, roughly 250 times the maximum limit of 0.9 μmol/L⁻¹ set by the FDA for aluminum in IV nutrition.¹⁰  In blood products, the aluminum concentration for packed red blood cells was far lower (e.g., 3.6 μmol/L⁻¹), as compared with crystalloids, but was still over the maximum limit set by the FDA.⁷ 

Because the enFlow system uses an uncoated aluminum metal plate to heat the fluid, one can surmise that it would lead to more aluminum exposure. This etiology is indeed corroborated by measurements showing that the uncoated nature of the aluminum plate is one of the main reasons leading to an increased concentration observed in fluids warmed in this manner. Coated aluminum fluid warmers, usually coated with a biocompatible coating (e.g., parylene), released anywhere from 100- to 200-times less aluminum than uncoated aluminum fluid warmers.⁴  However, even with this order of magnitude reduction, coated aluminum fluid warmers still resulted in levels higher than the recommended limits established by the FDA.

Thus far, the FDA has stated that it is unaware of any reported cases of aluminum toxicity that presented clinically subsequent to fluid warmer use.⁶  It is also interesting that warnings have not been issued for some of the current devices that demonstrated aluminum levels higher than the recommended limits. Although these devices theoretically can lead to aluminum leaching, and may have in certain patients, they have not led to any clinically recognized symptoms of aluminum toxicity. It is unclear whether these devices underwent specific testing for aluminum leaching during the rigorous design and safety verifications of the FDA. However, given the increased knowledge available today, one can ponder if regulators would act differently if these devices were now initially introduced. If the level of aluminum leaching was known at the outset when these devices were being introduced, we presume that the FDA would have objected.

There is now interest in transitioning to aluminum-free fluid warmers. Some such warmers are already in use, such as the Rapid Infuser RI-2 (Belmont Medical Technologies, Billerica, MA), which uses a stainless steel warming technology to quickly warm blood products without the risk of aluminum toxicity. However, not all hospitals carry this infuser and not all clinicians are familiar with its use. The device is designed for large-volume resuscitation of blood products and is not typically used for smaller volume transfusions or for warming IV fluids when blood is not administered. The Warrior Modulator System (QinFlow; Petah Tikva, Israel) is another device that uses a stainless steel heat transducer; however, it is only approved for use in Europe, the Middle East, Africa, and Australia, with approval in the U.S. pending.

Perhaps prophylactic treatment with an aluminum-chelating drug can be studied in patients who receive massive fluid resuscitation; however, these drugs (e.g., desferrioxamine, deferiprone) can lead to adverse effects such as seizures.¹¹  These chelators require further investigation before clinical recommendations can be made regarding their prophylactic administration prior to using a warming system known to leach aluminum or their empiric use to prevent aluminum toxicity after massive resuscitation.

Although aluminum-free fluid warmers are manufactured and sold, many healthcare providers may still opt to use their existing warming devices despite the risk of aluminum toxicity. For the time being, regulators have chosen to defer the risk-benefit analysis to clinicians' case-by-case judgment. As long as direct evidence of clinically significant aluminum toxicity from these devices is lacking, it is reasonable to expect that the regulators' position will not change. We anticipate that medical device manufacturing will shift toward designs with less potential for aluminum blood contact.