Scientific Evidence for Nutritional and Pharmacologic Treatment in VLU

Nutrition

Published January 2023, a systematic review on nutrition stated that VLU patients tend to have a deficit of nutrients such as vit A, D, or zinc and an excess of lipids and carbohydrates. A clinical trial with an oral nutritional supplement found that high calorie, high protein, enriched oral supplementation had a positive effect on ulcer healing. Another systematic review concluded that omega-3 fatty acids, Mg, zinc, vit A, C, D and resveratrol with probiotics improved VLU healing.

Pharmacologic compounds

As for pharmacologic treatment, the scientific evidence available for MPFF is a meta-analysis including 5 RCTs. This meta-analysis demonstrated a significantly better healing rate in the MPFF group and shorter median time to healing: 16 weeks for MPFF vs 21 in the control group.

The cost-effectiveness analysis showed that MPFF adjuvant therapy improved the cost-effectiveness ratio by 45%. For Pentoxifylline the Cochrane systematic review concluded that it is an effective adjunct to compression bandaging for treating VLUs and may be effective in the absence of compression. The whole group of flavonoids was also an object of the Cochrane review for VLUs treatment. It included MPFF and hydroxyethylrutosides and was inconclusive in despite of significant ulcer healing improvement documented, as some trials were considered to be poorly reported. The sulodexide’s Cochrane review concluded that it may increase the healing of VLUs, however the evidence was judged to be of low quality.

In conclusion, nutritional supplements are indicated for patients with vitamin/ mineral deficiencies. For venous leg ulcers, in addition to standard wound care and compression therapy, an adjunctive treatment with MPFF, pentoxifylline, hydroxyethylrutosides and sulodexide was established in several RCTs, metaanalysis and Cochrane’s systematic reviews.

See all Wound Masterclass MasterSeries on demand: bigmarker.com/wound-masterclass

References

1. Gloviczki ML, Kalsi H, Gloviczki P, Gibson M, Cha S, Heit JA. Validity of International Classification of Diseases, Ninth Revision, Clinical Modification codes for estimating the prevalence of venous ulcer. J Vasc Surg Venous Lymphat Disord. 2014 Oct;2(4):362-7. doi: 10.1016/j.jvsv.2014.03.002. Epub 2014 May 10. PMID: 26993538.

2. Nagoba BS et al. Acidic environment and wound healing: a review, Wounds 2015;27(1):5-11

3. Hidalgo E et al. Cytotoxicity mechanisms of sodium hypochlorite in cultured human dermal fibroblasts and its bactericidal effectiveness. Chem Biol Interact. 2002 Mar 20;139(3):265-82.

4. C. Winterbourn et al. Modeling the Reactions of Superoxide and Myeloperoxidase in the Neutrophil Phagosome. Implications for Microbial Killing. J Biol Chem Volume 281. No. 52. Dec. 29, 2006. 39860 - 39869;

5. Robson MC. Treating chronic wounds with hypochlorous acid disrupts biofilm. Wound Prevention and Management 2020;66 (5):9-10

6. Swanson, T., Ousey, K., Haesler, E., Bjarnsholt, T., Carville, K., Idensohn, P., Kalan, L., Keast, D. H., Larsen, D., Percival, S., Schultz, G., Sussman, G., Waters, N., & Weir, D. (2022). IWII Wound Infection in Clinical Practice Consensus Document: 2022 Update. Journal of wound care, 31(S12), S10-S21. https://doi.org/10.12968/jowc.2022.31.Sup12.S10 doi: 10.1111/wrr.12994. Epub 2022 Feb 7. Erratum in: Wound Repair Regen. 2022 Jul;30(4):536. PMID: 35130362; PMCID: PMC9305950.

7. Eriksson E, Liu PY, Schultz GS, Martins-Green MM, Tanaka R, Weir D, Gould LJ, Armstrong DG, Gibbons GW, Wolcott R, Olutoye OO, Kirsner RS, Gurtner GC. Chronic wounds: Treatment consensus. Wound Repair Regen. 2022 Mar;30(2):156-171.

8. Wound Repair and Regeneration – the international journal of tissue repair and regeneration. Available from: https://onlinelibrary.wiley.com/journal/1524475x

9. Melphine M. Harriott, Nayan Bhindi, Salam Kassis, Blair Summitt, Galen Perdikis, Blair A. Wormer, Timothy M. Rankin, Christodoulos Kaoutzanis, Mario Samaha, Charles Stratton, Jonathan E. Schmitz. Comparative Antimicrobial Activity of Commercial Wound-Care Solutions on Bacterial and Fungal Biofilms, Ann Plast Surg. 83(4): 404-410, 2019.

10. Optical Microscopy and the Extracellular Matrix Structure: A review, Cells 2021, 10(7),1760; https://doi.org/10.3390/cells10071760

11. Sandi G. Dempsey, Christopher H. Miller, Ryan C. Hill, Kirk C. Hansen, and Barnaby C. H. May, Journal of Proteome Research 2019 18 (4), 1657-1668, DOI: 10.1021/acs.jproteome.8b00908

12. Topps J, Kay et al (1968). Digestion of concentrate and of hay diets in the stomach and intestines of ruminants. Br J Nutr 22, 261-280, 2. Engelhardt W and Hales J (1977). Partition of capillary blood flow in rumen, reticulum, and omasum of sheep. American Journal of Physiology- Endocrinology and Metabolism 232(1 ): E53. 3. Baldwin, R. L; McLeod, K. R; Klotz, J. L.; Heitmann, R. N.Rumen development,

Day DJ, May BCH. A novel chemotactic factor derived from the extracellular matrix protein decorin recruits mesenchymal stromal cells in vitro and in vivo. PLoS One. 2020 Jul 13;15(7):e0235784. doi: 10.1371/journal.pone.0235784. Erratum in: PLoS One. 2020 Sep 3;15(9):e0238964. PMID: 32658899; PMCID: PMC7357784.

15. Suami H, Scaglioni MF. Anatomy of the Lymphatic System and the Lymphosome Concept with Reference to Lymphedema. Semin Plast Surg. 2018 Feb;32(1):5-11. doi: 10.1055/s-0038-1635118. Epub 2018 Apr 9. PMID: 29636647; PMCID: PMC5891651.

16. Kubik S, Manestar M. Topographic relationship of the ventromedial lymphatic bundle and the superficial inguinal nodes to the subcutaneous veins. Clin Anat. 1995;8(1):25-8. doi: 10.1002/ca.980080104. PMID: 7535176.

17. Kirk C. Hansen, Angelo D’Alessandro, Cristina C. Clement, Laura Santambrogio, Lymph formation, composition and circulation: a proteomics perspective, International Immunology, Volume 27, Issue 5, May 2015, Pages 219–227, https://doi. org/10.1093/intimm/dxv012

18. Zwart SR, Laurie SS, Chen JJ, Macias BR, Lee SMC, Stenger M, Grantham B, Carey K, Young M, Smith SM. Association of Genetics and B Vitamin Status With the Magnitude of Optic Disc Edema During 30-Day Strict Head-Down Tilt Bed Rest. JAMA Ophthalmol. 2019 Oct 1;137(10):11951200. doi: 10.1001/jamaophthalmol.2019.3124. PMID: 31415055; PMCID: PMC6696878.

19. Broekhuizen LN, Mooij HL, Kastelein JJ, Stroes ES, Vink H, Nieuwdorp M. Endothelial glycocalyx as potential diagnostic and therapeutic target in cardiovascular disease. Curr Opin Lipidol. 2009 Feb;20(1):57-62. doi: 10.1097/ MOL.0b013e328321b587. PMID: 19106708.

20. Castro-Ferreira R, Cardoso R, Leite-Moreira A, Mansilha A. The Role of Endothelial Dysfunction and Inflammation in Chronic Venous Disease. Ann Vasc Surg. 2018 Jan;46:380-393. doi: 10.1016/j.avsg.2017.06.131. Epub 2017 Jul 6. PMID: 28688874.

21. Weinbaum, S., Cancel, L.M., Fu, B.M. et al. The Glycocalyx and Its Role in Vascular Physiology and Vascular Related Diseases. Cardiovasc Eng Tech 12, 37–71 (2021). https://doi.org/10.1007/s13239-020-00485-9

H, Takemura G, Suzuki K, Takada C, Tomita H, Zaikokuji R, Hotta Y, Miyazaki N, Yano H, Muraki I, Kuroda A, Fukuda H, Kawasaki Y, Okamoto H, Kawaguchi T, Watanabe T, Doi T, Yoshida T, Ushikoshi H, Yoshida S, Ogura S. BrainSpecific Ultrastructure of Capillary Endothelial Glycocalyx and Its Possible

22. Ando Y,

Contribution for Blood Brain Barrier. Sci Rep. 2018 Nov 30;8(1):17523. doi: 10.1038/ s41598-018-35976-2. PMID: 30504908; PMCID: PMC6269538.

23. Potje SR, Paula TD, Paulo M, Bendhack LM. The Role of Glycocalyx and Caveolae in Vascular Homeostasis and Diseases. Front Physiol. 2021 Jan 13;11:620840. doi: 10.3389/fphys.2020.620840. PMID: 33519523; PMCID: PMC7838704.

24. Suzuki, Akio et al. Form Follows Function: The Endothelial Glycocalyx. Translational Research, Volume 247, 158 – 167. DOI: https://doi.org/10.1016/j. trsl.2022.03.014

25. 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 Dec;36(12):e22630. doi: 10.1096/fj.202200053RR. PMID: 36315163.

26. Kolluri R, Lugli M, Villalba L, Varcoe R, Maleti O, Gallardo F, Black S, Forgues F, Lichtenberg M, Hinahara J, Ramakrishnan S, Beckman JA. An estimate of the economic burden of venous leg ulcers associated with deep venous disease. Vasc Med. 2022 Feb;27(1):63-72. doi: 10.1177/1358863X211028298. Epub 2021 Aug 16. Erratum in: Vasc Med. 2021 Sep 22;:1358863X211048020. PMID: 34392750; PMCID: PMC8808361.

27. O’Donnell TF Jr, Passman MA, Marston WA, Ennis WJ, Dalsing M, Kistner RL, Lurie F, Henke PK, Gloviczki ML, Eklöf BG, Stoughton J, Raju S, Shortell CK, Raffetto JD, Partsch H, Pounds LC, Cummings ME, Gillespie DL, McLafferty RB, Murad MH, Wakefield TW, Gloviczki P; Society for Vascular Surgery; American Venous Forum. Management of venous leg ulcers: clinical practice guidelines of the Society for Vascular Surgery ® and the American Venous Forum. J Vasc Surg. 2014 Aug;60(2 Suppl):3S-59S. doi: 10.1016/j.jvs.2014.04.049. Epub 2014 Jun 25. PMID: 24974070.

28. Gloviczki P, Comerota AJ, Dalsing MC, Eklof BG, Gillespie DL, Gloviczki ML, Lohr JM, McLafferty RB, Meissner MH, Murad MH, Padberg FT, Pappas PJ, Passman MA, Raffetto JD, Vasquez MA, Wakefield TW; Society for Vascular Surgery; American Venous Forum. The care of patients with varicose veins and associated chronic venous diseases: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg. 2011 May;53(5 Suppl):2S-48S. doi: 10.1016/j.jvs.2011.01.079. PMID: 21536172.

29. Gloviczki P, Lawrence PF, Wasan SM, Meissner MH, Almeida J, Brown KR, Bush RL, Di Iorio M, Fish J, Fukaya E, Gloviczki ML, Hingorani A, Jayaraj A, Kolluri R, Murad MH, Obi AT, Ozsvath KJ, Singh MJ, Vayuvegula S, Welch HJ. 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. 2022 Oct 12:S2213-333X(22)00417-6. doi: 10.1016/j. jvsv.2022.09.004. Epub ahead of print. PMID: 36326210.

30. Raffetto JD, Ligi D, Maniscalco R, Khalil RA, Mannello F. Why Venous Leg Ulcers

Have Difficulty Healing: Overview on Pathophysiology, Clinical Consequences, and Treatment. J Clin Med. 2020 Dec 24;10(1):29. doi: 10.3390/jcm10010029. PMID: 33374372; PMCID: PMC7795034.

31. Goldschmidt E, Schafer K, Lurie F. A systematic review on the treatment of nonhealing venous ulcers following successful elimination of superficial venous reflux. J Vasc Surg Venous Lymphat Disord. 2021 Jul;9(4):1071-1076.e1. doi: 10.1016/j. jvsv.2020.12.085. Epub 2021 Feb 26. PMID: 33647527.

32. Gohel MS, Heatly F, Liu X et al. A randomized trial of early endovenous ablation in venous ulceration. N Engl J Med 2018; 378:2105-114 DOI: 10.1056/NEJMoa1801214

33. Gloviczki P, Bergan JJ, Rhodes JM, Canton LG, Harmsen S, Ilstrup DM. Mid-term results of endoscopic perforator vein interruption for chronic venous insufficiency: lessons learned from the North American subfascial endoscopic perforator surgery registry. The North American Study Group. J Vasc Surg. 1999 Mar;29(3):489-502. doi: 10.1016/s0741-5214(99)70278-8. PMID: 10069914.

34. Köksoy C, Bahçecioğlu İB, Çetinkaya ÖA, Akkoca M. Iliocaval outflow obstruction in patients with venous ulcers in a small comparison study between patients with primary varicose veins and chronic deep vein disease. J Vasc Surg Venous Lymphat Disord. 2021 May;9(3):703-711. doi: 10.1016/j.jvsv.2020.08.019. Epub 2020 Aug 19.

PMID: 32827736.

35. Lawrence PF, Hager ES, Harlander-Locke MP, Pace N, Jayaraj A, Yohann A, Kalbaugh C, Marston W, Kabnick L, Saqib N, Pouliot S, Piccolo C, Kiguchi M, Peralta S, Motaganahalli R. Treatment of superficial and perforator reflux and deep venous stenosis improves healing of chronic venous leg ulcers. J Vasc Surg Venous Lymphat Disord. 2020 Jul;8(4):601-609. doi: 10.1016/j.jvsv.2019.09.016. Epub 2020 Feb 21.

PMID: 32089497.

36. Marston W, Ta ng J, Kirsner RS, Ennis W. Wound Healing Society 2015 update on guidelines for venous ulcers. Wound Repair Regen. 2016 Jan- Feb;24(1):136-44. doi:

10.1111/wrr.12394. PMID: 26663616.

37. De Maeseneer MG, Kakkos SK, Aherne T, Baekgaard N, Black S, Blomgren

L, Giannoukas A, Gohel M, de Graaf R, Hamel-Desnos C, Jawien A, JaworuckaKaczorowska A, Lattimer CR, Mosti G, Noppeney T, van Rijn MJ, Stansby G, Esvs Guidelines Committee, Kolh P, Bastos Goncalves F, Chakfé N, Coscas R, de Borst

GJ, Dias NV, Hinchliffe RJ, Koncar IB, Lindholt JS, Trimarchi S, Tulamo R, Twine CP, Vermassen F, Wanhainen A, Document Reviewers, Björck M, Labropoulos N, Lurie F, Mansilha A, Nyamekye IK, Ramirez Ortega M, Ulloa JH, Urbanek T, van Rij AM, Vuylsteke ME. Editor’s Choice - European Society for Vascular Surgery (ESVS) 2022

Clinical Practice Guidelines on the Management of Chronic Venous Disease of the Lower Limbs. Eur J Vasc Endovasc Surg. 2022 Feb;63(2):184-267. doi: 10.1016/j. ejvs.2021.12.024. Epub 2022 Jan 11. Erratum in: Eur J Vasc Endovasc Surg. 2022 AugSep;64(2-3):284-285. PMID: 35027279.

38. García-Rodríguez MT, Rodríguez-Parrado M, Seijo-Bestilleiro R, González-Martín

C. Influence of Nutrition Status and Compression Therapy on Venous Ulcer Healing: A Systematic Review. Adv Skin Wound Care. 2023 Jan 1;36(1):45-53. doi: 10.1097/01.

ASW.0000902492.97059.f2. PMID: 36537775.

39. Melo PG, Mota JF, Nunes CAB, Malaquias SG, Coelho ASG, Soriano JV, Bachion

MM. Effects of Oral Nutritional Supplementation on Patients with Venous Ulcers: A Clinical Trial. J Clin Med. 2022 Sep 26;11(19):5683. doi: 10.3390/jcm11195683. PMID: 36233551; PMCID: PMC9570985.

40. de Souza T, Monteiro JDC, Curioni CC, Cople-Rodrigues C, Citelli M. Nutrients with Antioxidant Properties and Their Effects on Lower-Limb Ulcers: A Systematic Review. Int J Low Extrem Wounds. 2022 Jan 24:15347346221074861. doi: 10.1177/15347346221074861. Epub ahead of print. PMID: 35072533.

41. Coleridge-Smith P, Lok C, Ramelet AA. Venous leg ulcer: a metaanalysis of adjunctive therapy with micronized purified flavonoid fraction. Eur J Vasc Endovasc Surg. 2005 Aug;30(2):198-208. doi: 10.1016/j.ejvs.2005.04.017. PMID: 15936227.

42. Simka, M., Majewski, E. The Social and Economic Burden of Venous Leg Ulcers. Am J Clin Dermatol 4, 573–581 (2003). https://doi.org/10.2165/00128071-20030408000007 pub2. PMID: 27251175;

43. Jull AB, Arroll B, Parag V, Waters J. Pentoxifylline for treating venous leg ulcers. Cochrane Database Syst Rev. 2012 Dec 12;12(12):CD001733. doi: 10.1002/14651858. CD001733.pub3. PMID: 23235582; PMCID: PMC7061323.

44. Wu B, Lu J, Yang M, Xu T. Sulodexide for treating venous leg ulcers. Cochrane Database Syst Rev. 2016 Jun 2;2016(6):CD010694. doi: 10.1002/14651858.CD010694.