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What are current recommendations for filtering parenteral nutrition (PN) admixtures?

Introduction
Parenteral nutrition (PN) delivers calories and essential fatty acids to patients who are either unable to receive nutrition or cannot achieve adequate nutritional intake through oral or enteric routes.1 The Institute for Safe Medication Practices (ISMP) lists parenteral nutrition (PN) as a high-alert medication due to its high potential for adverse events.2 Filtration during preparation or administration is an important strategy to minimize harm from parenteral solutions including PN.3 However, filtering recommendations have changed over time and have conflicted among professional societies and manufacturers, leading to varied approaches in practice.

In 2020, the American Society for Parenteral and Enteral Nutrition (ASPEN) authored a guidance document on filtering PN solutions.4 In addition, the Infusion Nurses Society (INS) updated their Standards of Practice in 2021.3 This article will review pertinent issues related to filtering of PN solutions and summarize these 2 documents, which together represent the latest recommendations on filtering PN solutions.3,4

Particle- and Pathogen-related Safety Concerns of Parenteral Nutrition
Universal safety concerns with all parenteral solutions include particulate and pathogen exposure.4 Parenteral nutrition solutions have a high likelihood of containing both particulates and pathogens due to their composition and the complexity of the preparation process. Lipid and dextrose-containing solutions can promote bacterial and fungal growth, and the use of multiple components in the compounding process can increase the potential for both pathogen contamination and the introduction of foreign particles.

The chance of an adverse reaction increases proportionally to the number of parenteral solution particles that reach the patient.5 Particles can enter a PN product in many ways, including precipitation due to drug incompatibilities, glass from ampules, rubber from bottle or vial stoppers, plastic from infusion sets, and contamination from the environment or personnel.6,7

Short-term safety concerns of particle exposure range from local effects such as vein irritation, phlebitis, and capillary occlusion to more severe end-organ effects including venous thromboembolism, particle deposition in the lungs, and rhabdomyolysis.7,8 Long-term safety concerns of particle exposure include pulmonary talcosis and renal pathologies caused by particle deposition in the kidney (eg, granulomatous glomerulonephritis, interstitial nephritis). The risk of these events may be minimal with short-term PN use, but PN is often given in larger volumes and longer durations than other solutions which could increase the risk.

Although animal studies and observational studies in intravenous drug users suggest that particles in parenteral solutions can cause harm, definitive evidence of harm from unfiltered PN solutions is limited.5,8 Cases of respiratory distress and sudden death after exposure to the amino acid component of a PN solution and subsequent deposition of calcium-phosphate crystals in the lungs support these concerns.9 Filtration during administration could reduce the potential for patient exposure to particulates and pathogens, thus minimizing the potential for harm. Still, many clinicians may consider the data insufficient to support routine filtering of PN solutions.4 A 2012 survey conducted by ISMP documented that only 58% of organizations had policies aimed at reducing harm from PN.1 In another survey conducted in 2017, the proportion of respondents that reported not filtering total nutrient admixtures (TNA, admixtures that contain dextrose, amino acids, and lipids), dextrose/amino acid admixtures, and lipid infusions in adults was 20.6%, 7.2%, and 15.1%, respectively.10

History of Parenteral Nutrition Filtration Recommendations
Prior to the 1990s, there was extensive debate on whether in-line filters should be used for PN administration. Some literature suggested the use of in-line filters for all PN products while other authors recommended against the use of in-line filters in favor of other infection control measures.11,12 In 1994, the Food and Drug Administration (FDA) issued a safety alert after 2 deaths and at least 2 cases of respiratory distress related to calcium phosphate precipitation in unfiltered TNA.4 After reviewing these incidents and consulting with ASPEN, the FDA suggested the use of a 1.2 micron air-eliminating filter for lipid-containing products and a 0.22 micron air-eliminating filter for lipid-free products. In 1998, ASPEN published a PN guideline, which included the option to either use a 1.2 micron filter for all PN products or a 0.2 or 1.2 micron filter for dextrose/amino acid admixtures and a 1.2 to 5 micron filter for TNA.13 In contrast to the aforementioned guidelines, the 2002 guideline on preventing bloodstream infections from the Centers for Disease Control and Prevention recommended against the routine use of in-line filters in favor of the more cost-effective approach of filtering PN solutions in the pharmacy.4

The ASPEN guidelines were further modified in 2014 to recommend 1.2 micron air-eliminating filters for lipid-containing PN solutions and 0.22 micron air-eliminating filters for lipid-free PN solutions.4 The 2016 INS Standards of Practice provided filtration recommendations that were consistent with the 2014 ASPEN guidelines but also instructed providers to follow the manufacturer’s directions on filtration requirements for each product.3,4

Filtering recommendations are also available from ISMP. In 2016, ISMP issued a safety alert that discussed the new labeling for ILE (intravenous lipid emulsion) infusions administered alone or in admixtures.4 The safety alert emphasized that 1.2 micron filters should be used for ILE infusions and that 0.22 micron filters should not be used for ILE. At the time of the alert there were inconsistent filtration recommendations across manufacturers, but all ILE package inserts in the United States have been revised to now recommend a 1.2 micron in-line filter when ILE is administered on its own or as a component of an admixture.4,14-17

Current Recommendations for Parenteral Nutrition Filtration
The 2020 ASPEN guidance recommends a 1.2 micron filter for all PN solutions to avoid the confusion of using filters with different pore sizes under different circumstances.4 The 2021 INS standards recommend a 0.2 micron filter for lipid-free PN and a 1.2 micron filter for lipid-containing PN.3 The 2021 INS Guidelines also recommend changing all PN filters according to the manufacturer’s instructions, which typically is every 24 hours, and that filters for dedicated ILE infusions should be changed every 12 hours. There is significant overlap between the 2021 INS guidelines and the 2020 ASPEN recommendations, but there are several key differences, which are depicted in more detail in Table 1 below.

Table 1. Recommendations provided by INS and ASPEN for PN filtration.3,4
GuidelineFilter Size
Filter Change
ASPEN 20204All PN solutions:
1.2 micron filter (including TNA, dextrose/amino acid admixtures, and dedicated ILE infusions)a		Change in-line filters at the same time as the start of a new PN admixture and administration set.b
INS 20213Lipid-free PN:
0.2 micron filterc

Lipid-containing PN:
1.2 micron filterc		Follow the manufacturer’s instructions for filter changes. Typically, filters should be changed every 24 hours as a part of the administration set or with each new PN container. Filters used for dedicated ILE infusions should be changed every 12 hours.
 
Schedule filter changes at the same time as administration set changes. A primary administration set with an integrated in-line filter is preferred when possible.
a The previous recommendation included a 0.22 micron filter for dextrose/amino acid admixtures and a 1.2 micron filter for TNA.4
b Previous guidelines recommended changing the administration tubing and filters with each new PN container.4
c The previous recommendation was to follow the manufacturer’s directions and the filtration requirements.3
Abbreviations: ASPEN = American Society for Parenteral and Enteral Nutrition, ILE = intravenous lipid emulsion, INS = Infusion Nurses Society, PN = parenteral nutrition, TNA = total nutrient admixture

Additional Recommendations for Parenteral Nutrition Administration
Both ASPEN and INS provide additional recommendations for maximizing safety of PN solutions, including proper procedures for filter priming, placement, and changes, and guidance for certain clinical circumstances (see Table 2).

Table 2. Additional PN administration recommendations.3,4
  • Prime and position filters according to the manufacturer’s directions.3
    • Avoid inverting the filter while priming so the vented side fills before the infusion flows to the patient’s side.4
    • Prime dextrose/amino acid admixtures by completely filling the tubing and the filter on the distal end of the tubing.4
    • A separate 1.2 micron filter should be used for dedicated ILE infusions.3 The ILE should be infused separately using a VAD or lumen, or together with a 1.2 micron filter attached below the Y-site and below the 0.2 micron filter that is used for the dextrose/amino acid admixture.3,4
  • Position the in-line filter near the level of the VAD insertion site (as close to the VAD hub as possible) to prevent changes in flow rate.3 Close a downstream clamp if the filter position needs to be temporarily switched to avoid accidental bolusing or back-siphoning.
  • Connect the filter to the hub of the patient’s VAD.4
  • If a filter becomes occluded/clogged, replace the filter with a new one.4
    • Do not allow unfiltered PN to infuse.4
  • Change PN filters according to the manufacturer’s directions and/or guideline recommendations.3
  • Change PN administration sets for PN solutions with each new PN container (usually every 24 hours).3
    • Replace dedicated infusion ILE administration sets with each new infusion.3 DEHP-free administration sets should be used to deliver lipid-based admixtures, such as ILE or lipid-containing PN, to avoid the toxicity associated with the presence of DEHP in lipid solutions.
  • Do not exceed a hang time of 12 hours for dedicated ILE infusions.3
  • Air-eliminating filters are recommended in patients with left-to-right cardiac or pulmonary shunting to prevent air and particulate matter from reaching the arterial circulation.3
  • Avoid co-administering medications with PN.4 If coadministration cannot be avoided, attach the medication tubing at a Y-site above the PN filter and flush the line before and after the medication is administered.
Abbreviations: DEHP = di(2-ethylhexyl) phthalate, ILE = intravenous lipid emulsion, PN = parenteral nutrition, VAD = vascular access device.

Additional Considerations in Pediatric Patients
Critically ill neonates and older children frequently receive PN but the 2017 ASPEN guideline on nutrition in critically ill children does not mention PN filtration.18 In the absence of pediatric-specific guidance on filtering PN solutions, some clinicians may apply the global recommendations for filtration to this population. Other clinicians may choose to follow European recommendations, which include using a 1.2 to 1.5 micron filter with lipid-containing PN infusions and a 0.22 micron filter with lipid-free PN solutions.19 However, many clinicians do not use filters in children; a survey conducted in 2017 reported that TNA, dextrose/amino acid admixtures, and lipid infusions were not filtered in 18.6%, 1.7%, and 9.7% of children, respectively.10 If a filter is used in children, some experts recommend keeping the filter below the level of the patient’s heart to prevent inadvertent bolus dosing and hemodynamic alterations that can occur when the filter is raised and lowered.20

Numerous factors related to PN use in children support the potential benefit of filtering. Neonates and other children are thought to be at higher risk of PN-associated adverse events, partly due to their narrower blood vessels and smaller blood volume in which to dilute potentially incompatible nutritional components and/or medications.3,21 Evidence supporting the benefit of filtration in children is mixed. Some studies have shown decreased rates of systemic inflammatory response syndrome, respiratory function, renal dysfunction, and overall complications with in-line filter use, but another study did not find a benefit in preventing sepsis.3,19,22,23 None of these studies were focused on PN and most are older which may limit their relevance to current practice.

Conclusion
Using an in-line filter during parenteral solution administration is a widely used strategy to minimize harm from particulate and pathogen exposure, but evolving and conflicting recommendations for PN solutions have prevented a standard approach in practice. Recent recommendations from ASPEN and INS support using a 1.2 micron filter for all PN solutions (particularly those that contain lipids), and INS endorses using a 0.2 micron filter for solutions that do not contain lipids. Clinicians are urged to follow current best practices for sterile solution administration, including PN solutions.

References

  1. Ayers P, Adams S, Boullata J, et al. A.S.P.E.N. parenteral nutrition safety consensus recommendations. JPEN J Parenter Enteral Nutr. 2014;38(3):296-333. doi:10.1177/0148607113511992
  2. High alert medications in acute care settings. Institute for Safe Medication Practices. August 23, 2018. Accessed July 9, 2021. https://www.ismp.org/recommendations/high-alert-medications-acute-list
  3. Gorski LA, Hadaway L, Hagle ME, et al. Infusion therapy standards of practice, 8th edition. J Infus Nurs. 2021;44(1S Suppl 1):S1-S224. doi:10.1097/NAN.0000000000000396
  4. Worthington P, Gura KM, Kraft MD, et al. Update on the use of filters for parenteral nutrition: an ASPEN position paper. Nutr Clin Pract. 2021;36(1):29-39. doi:10.1002/ncp.10587
  5. Bethune K, Allwood M, Grainger C, Wormleighton C; British Pharmaceutical Nutrition Group Working Party. Use of filters during the preparation and administration of parenteral nutrition: position paper and guidelines prepared by a British pharmaceutical nutrition group working party. Nutrition. 2001;17(5):403-408. doi:10.1016/s0899-9007(01)00536-6
  6. Benlabed M, Perez M, Gaudy R, et al. Clinical implications of intravenous drug incompatibilities in critically ill patients. Anaesth Crit Care Pain Med. 2019;38(2):173-180. doi:10.1016/j.accpm.2018.04.003
  7. Tran T, Kupiec TC, Trissel LA. Particulate matter in injections: what is it and what are the concerns? Int J Pharm Compound. 2006;10(3):202-204.
  8. Ball PA. Intravenous in-line filters: filtering the evidence. Curr Opin Clin Nutr Metab Care. 2003;6(3):319-325. doi:10.1097/01.mco.0000068969.34812.5d
  9. Shay DK, Fann LM, Jarvis WR. Respiratory distress and sudden death associated with receipt of a peripheral parenteral nutrition admixture. Infect Control Hosp Epidemiol. 1997;18(12):814-817.
  10. Christensen ML, Ayers P, Boullata JI, et al. Lipid injectable emulsion survey with gap analysis. Nutr Clin Pract. 2017;32(5):694-702. doi:10.1177/0884533617719671
  11. Jump WG, Poremba A. Filtering TPN solutions containing trace elements or insulin. Am J Hosp Pharm. 1980;37(12):1615.
  12. Blevins R, Garibaldi RA. Filter use for hyperalimentation therapy. Infect Control. 1982;3(3):208.
  13. Hirsch A. Considerations for injectable lipid emulsion administration: in-line filters and DEHP-free tubing. Georgia Society for Parenteral and Enteral Nutrition Newsletter. 2019;5(winter):1-13.
  14. Smoflipid. Package insert. Fresenius Kabi USA, LLC; 2020.
  15. Omegaven. Package insert. Fresenius Kabi USA, LLC; 2020.
  16. Nutrilipid. Package insert. B. Braum Medical Inc.; 2020.
  17. Clinolipid. Package insert. Baxter Healthcare Corporation; 2021.
  18. Mehta NM, Skillman HE, Irving SY, et al. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Pediatric Critically Ill Patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition. JPEN J Parenter Enteral Nutr. 2017;41(5):706-742. doi:10.1177/0148607117711387
  19. Puntis J, Hojsak I, Ksiazyk J; ESPGHAN/ESPEN/ESPR/CSPEN working group on pediatric parenteral nutrition. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Organisational aspects. Clin Nutr. 2018;37(6 Pt B):2392-2400. doi:10.1016/j.clnu.2018.06.953
  20. Chau D, Gish B, Tzanetos D, Zhang C. A dangerous side of in-line IV filters when used for vasoactive infusions in infants. Anesthesia Patient Safety Foundation Newsletter. 2013;28(2):29-48.
  21. Martindale RG, Berlana D, Boullata JI, et al. Summary of proceedings and expert consensus statements from the international summit “Lipids in Parenteral Nutrition”. JPEN J Parenter Enteral Nutr. 2020;44 Suppl 1:S7-S20. doi:10.1002/jpen.1746
  22. van den Hoogen A, Krediet TG, Uiterwaal CS, Bolenius JF, Gerards LJ, Fleer A. In-line filters in central venous catheters in a neonatal intensive care unit. J Perinat Med. 2006;34(1):71-74. doi:10.1515/JPM.2006.009
  23. Jack T, Boehne M, Brent BE, et al. In-line filtration reduces severe complications and length of stay on pediatric intensive care unit: a prospective, randomized, controlled trial. Intensive Care Med. 2012;38(6):1008-1016. doi:10.1007/s00134-012-2539-7

Prepared by:
Nicole Szydlowski
PharmD Candidate, Class of 2023
Heather Ipema, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

August 2021

The information presented is current as June 21, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.