Edema: What Tools Do We Have?

Lower extremity edema is a common comorbidity in wound patients with varying associated etiologies and contributing factors. Regardless of the etiology, edema is associated with delayed wound healing. The increased interstitial fluid volume that defines edema can contribute to the following depending on its extent^1-4:

• Poor oxygenation
• Pro-inflammatory metabolic waste products
• Infection risk
• Pain
• Reduced mobility

While compression is the gold standard for managing edema, optimizing treatment for patients with phlebolymphedema often involves more than just compression.⁵ Furthermore, other interventions are of additional utility in managing patients who cannot tolerate therapeutic compression due to peripheral arterial disease, claustrophobia, heat intolerance, and skin reactions. These interventions can include⁵:

• Dietary modifications
• Supplements
• Prescription medications
• Weight reduction
• Exercise therapies
• Positional recommendations
• Intermittent pneumatic compression devices

What is Micronized Purified Flavonoid Fraction (MPFF)?

Micronized purified flavonoid fraction (MPFF) is a venoactive drug (VAD) that is typically classified as a nutritional supplement in the US.^5,6 It is a ratio, or fraction, of different flavonoids. Flavonoids are natural plant secondary metabolites that are known to exert anti-inflammatory and additional favorable effects.⁷ The flavonoids present in MPFF include⁷:

• Diosmin
• Hesperidin
• Diosmetin
• Linarin
• Isorhoifolin

These flavonoids are naturally present in the rind of a certain orange type and undergo minimal processing (micronized, purified) before oral consumption.⁷

How MPFF Can Be Used to Treat Certain Vascular Diseases

There has been significant research on the efficacy and effectiveness of MPFF, leading to its inclusion in many societal recommendations and guidelines.^5,6 Its use is common in the treatment and management of many vascular diseases⁶:

• Venous insufficiency
• Venous leg ulcers
• Lymphedema
• Post-phlebitic syndrome
• Hemorrhoids

In phlebolymphedema, vascular leakage and stasis are often present. MPFF decreases red blood cell viscosity and exerts an anti-inflammatory effect. Contents within blood vessels normally flow in a laminar fashion, meaning the contents stay in the center of the vessel. Conditions that increase contact between vascular contents and the vessel lining contribute to inflammation of the blood vessel wall. The associated increased blood viscosity of stasis irritates the vascular endothelium, creating a positive feedback loop of inflammation that can ultimately lead to ulceration.⁸ MPFF reduces the effects of stasis by decreasing bradykinin-induced microvascular leakage and inappropriate leucocyte activation. A systematic review and meta-analysis of 7 randomized double-blind placebo-controlled trials including 1,692 patients identified MPFF significantly improved 9 leg symptoms including⁹:

• Pain
• Heaviness
• Feeling of swelling
• Cramps
• Paresthesia
• Burning sensation
• Pruritus

In addition, the researchers also found decreased functional discomfort, ankle circumference, leg redness, and skin changes, as well as increased quality of life.⁹ MPFF’s use in microcirculatory disorders includes the adjunctive treatment of venous leg ulcers, where its use is strongly associated with both the ability to heal and accelerated healing. A meta-analysis has shown a 32% raised chance of ulcer healing and a 5-week shorter healing process.¹⁰

Conclusion

MPFF has a favorable safety profile and a wealth of evidence supporting its use in phlebolymphedema and venous leg ulcer healing. The product is available as a pharmaceutical in Europe, and usually as an over-the-counter supplement in the United States.

References

1. Venous Ulcers. Eds. Bergan JJ, Shortell CK. Amsterdam: Elsevier Academic; 2007.
2. Mayrovitz HN and Larsen PB. Effects of compression bandaging on leg pulsatile blood flow. Clin Physiol. 1997;17(1):105-117.
3. Top S, Arveschoug AK, Fogh K. Do Short-Stretch Bandages Affect Distal Blood Pressure in Patients with Mixed Aetiology Leg Ulcers? J Wound Care. 2009;18(10):439-442.
4. Raff AB, Kroshinsky D. Cellulitis: A Review. JAMA. 2016;316(3):325-337.
5. Gloviczki P, Lawrence PF, Wasan SM, et al. The 2023 Society for Vascular Surgery, American Venous Forum, and American Vein and Lymphatic Society clinical practice guidelines for the management of varicose veins of the lower extremities. Part II. J Vasc Surg Venous Lymphat Disord. 2023;101670. doi:https://doi.org/10.1016/j.jvsv.2023.08.011
6. Farah MH, Nayfeh T, Urtecho M, et al. A systematic review supporting the Society for Vascular Surgery, the American Venous Forum, and the American Vein and Lymphatic Society guidelines on the management of varicose veins. J Vasc Surg Venous Lymphat Disord. 2022;10(5):1155-1171. doi:10.1016/j.jvsv.2021.08.011
7. Panche AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci. 2016;5:e47. doi:10.1017/jns.2016.41
8. Mitra R, Nersesyan A, Pentland K, Melin MM, Levy RM, Ebong EE. Diosmin and its glycocalyx restorative and anti-inflammatory effects on injured blood vessels. FASEB J. 2022;36(12):e22630. doi:10.1096/fj.202200053RR
9. Kakkos SK, Nicolaides AN. Efficacy of micronized purified flavonoid fraction (Daflon®) on improving individual symptoms, signs and quality of life in patients with chronic venous disease: a systematic review and meta-analysis of randomized double-blind placebo-controlled trials. Int Angiol. 2018;37(2):143-154. doi:10.23736/S0392-9590.18.03975-5
10. Coleridge-Smith P, Lok C, Ramelet AA. Venous leg ulcer: a meta-analysis of adjunctive therapy with micronized purified flavonoid fraction. Eur J Vasc Endovasc Surg. 2005;30(2):198-208. doi:10.1016/j.ejvs.2005.04.017

Further Reading 

1. Akhmetzianov RV, Bredikhin RA. Clinical Efficacy of Conservative Treatment with Micronized Purified Flavonoid Fraction in Female Patients with Pelvic Congestion Syndrome. Pain Ther. 2021;10(2):1567-1578. doi:10.1007/s40122-021-00312-6
2. Sheikh P, Lohsiriwat V, Shelygin Y. Micronized Purified Flavonoid Fraction in Hemorrhoid Disease: A Systematic Review and Meta-Analysis. Adv Ther. 2020;37(6):2792-2812. doi:10.1007/s12325-020-01353-7
3. Mansilha A, Sousa J. Benefits of venoactive drug therapy in surgical or endovenous treatment for varicose veins: a systematic review. Int Angiol. 2019;38(4):291-298. doi:10.23736/S0392-9590.19.04216-0
4. Gloviczki P, Lawrence PF, Wasan SM, et al. The 2022 Society for Vascular Surgery, American Venous Forum, and American Vein and Lymphatic Society clinical practice guidelines for the management of varicose veins of the lower extremities. Part I. Duplex Scanning and Treatment of Superficial Truncal Reflux: Endorsed by the Society for Vascular Medicine and the International Union of Phlebology. J Vasc Surg Venous Lymphat Disord. 2023;11(2):231-261.e6. doi:10.1016/j.jvsv.2022.09.004

About the Author

Dr. Laura Swoboda, DNP, APNP, FNP-BC, CWOCN-AP, is a Professor of Health Sciences, Family Nurse Practitioner, and certified wound specialist in Milwaukee Metro, Wisconsin. Dr. Swoboda is on the NPIAP’s Prophylactic Dressing Standards Initiative Task Force, a member of the editorial board for the Wound Care Learning Network and Wound Management and Prevention, and on the board of directors for the WOCNCB and the AAWC.