Di(2-ethylhexyl)phthalate (DEHP)
A chaotic week for IV tubing
Massive chaos erupted last week in the hospital and home infusion space after BD released an “URGENT: Medical Device Product Advisory” indicating IV tubing sets have been incorrectly labeled as “DEHP-Free” and that the labeling would be updated to “Contains or presence of phthalate: DEHP”.
What is DEHP? Why does it matter? And what happens going forward?
I thought I had a pretty good understanding of it all, but I’ve learned a lot this week. So let’s dig into it, and if you have answers or other perspectives please send them over. I will update or correct this as needed.
Many medical components (including IV bags and tubing) are made with the plastic polyvinyl chloride (PVC). PVC is naturally hard and brittle, so insert (literally) DEHP. DEHP is a chemical that is used to make plastics more flexible. It is (or used to be) used in basically every flexible plastic you can think of (shower curtains, tablecloths, shoes, etc.), and obviously we need the IV tubing to be pliable. Because of the chemical characteristics of PVC and DEHP, they do not chemically bind to each other and DEHP is lipophilic (this will be important later).
So who cares, flexible plastic is great! Of course, but DEHP exposure has some potentially negative effects. Exposure can affect the immune and reproductive systems,1 and may cause or increase the risk of cancer.2 3 DEHP4 is prohibited in all toys and childcare articles in Europe, and at levels greater than 0.1% in California. The European Public Health guidance lists the “no-observed adverse effect” level for reproductive and developmental effects at 4.8 mg/kg/day, and the tolerable daily intake of 0.05 mg/kg/day (they also interestingly state that it does not represent a relevant risk for cancer development in doses observed in humans). California Prop 65 lists the maximum allowable dose level as 4200 micrograms/day for adults, 600 micrograms per day for 29 day to 24 month infants, and 210 micrograms per day for less than 29 day old infants.
Those of us that have worked in IV compounding have long had to manage PVC vs. DEHP-Free IV bags.
I always had the understanding that the main reason for using DEHP-Free bags for some medications was to prevent compatibility issues such as the the drug breaking down sooner, or the drug binding to the plastic, and therefore under-dosing the patient.
This was incorrect.
The issue is that some medications interact with DEHP in a manner that causes it to leach into solution. Once it’s in solution, and this solution is infused into the patient, the patient is exposed to DEHP, and may potentially experience some of the negative effects described above.
What causes some medications to leach DEHP? This is still not 100% clear to me.
Etoposide is a great example of a medication that definitely causes DEHP to leach. As shown in the IV bag example above, the answer to avoid DEHP in IV bags is to use different types of plastics, however, the answer in IV tubing has been to use coextruded or triple layered tubing, where PVC & DEHP is the outer layer of the tubing, with an inner layer of polyethylene. The thought being this layer of polyethylene will act as a barrier and not allow the drug to contact the DEHP and therefore no DEHP will leach into solution. At least one study5 indicates that is not what is actually happening, and when an Etoposide infusion is infused through coextruded or triple-layered tubing, DEHP rapidly leaches into solution. Another confounder is that the amount of DEHP in different tubing sets varies widely. Some as high as 30% others with only 0.3%. It appears that the sets impacted by this product advisory have 0.3% or less DEHP in the outer layer.
Other drugs that indicate DEHP should be avoided include taxanes and lipids (including TPN). All three of the above examples are lipophilic, which given the chemical characteristics and interactions of PVC and DEHP, it isn’t surprising leaching occurs. Are there other medication characteristics that cause DEHP leaching?
As with many things in healthcare the more you dig in and learn the why behind what’s happening, the more confused you get, and more you start to wonder if all this even matters at all (which is a main reason I’m posting this). So does any of this matter, what should we do?
The previously labeled “DEHP-Free” tubing you’ve been using for years to administer all of these medications is, in my opinion, fine to continue to use. The percent DEHP is very low, and the risk of any impact of exposure is also low. NICU TPN is one medication I would look closer at. Administration of lipids over long periods of time to extremely small neonates, at a time where DEHP could have an outsized impact should push us to minimize exposure. There may be a few other situations where this approach is prudent, but overall it seems like what we’ve been doing is fine to continue.
Unfortunately, this outcome at the end of a chaotic week of working in healthcare is not uncommon. We’ve learned something, but nothing really came of it.
Thank you for reading. I hope this was informational, please comment if there’s anything here you disagree with or if you have anything to add to the discussion. I’m sure I said something above I will need to edit, but thank you for reading through.
https://wwwn.cdc.gov/TSP/substances/ToxSubstance.aspx?toxid=65
https://www.p65warnings.ca.gov/fact-sheets/di2-ethylhexylphthalate-dehp
https://ec.europa.eu/health/scientific_committees/opinions_layman/en/phthalates-school-supplies/l-2/5-safe-daily-exposure.htm
All phthalates are banned, DEHP is in the phthalate chemical family
Sandrine Bagel-Boithias, Valeérie Sautou-Miranda, Daniel Bourdeaux, Violaine Tramier, Anne Boyer, Jean Chopineau, Leaching of diethylhexyl phthalate from multilayer tubing into etoposide infusion solutions, American Journal of Health-System Pharmacy, Volume 62, Issue 2, 15 January 2005, Pages 182–188, https://doi.org/10.1093/ajhp/62.2.182
Still a very puzzling communication from BD and very little helpful info from them or the FDA. It would be helpful to have clear insights on the 0.3% value and what the exposure may be for various therapies. How do you reconcile the multilayer PE lining focused insights to the multiple products that were in the advisory? (Gravity and blood tubing; extension sets, filters, burettes- all impacted).
Really appreciated the article. I feel that there is a institution that is uniquely designed to study this and provide us usable information- USP. Consistently disappointed their recommendations are rarely evidence based or studied in house. This is another safety compounding issue that is often discussed or debated but until real diligent studies are conducted there will be mass differences in practice. Or even worse, their may be standardization based on theory alone.