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Peer Review

Peer Reviewed

Review

All Edema Is Lymphedema: Progressing Lymphedema and Wound Management to an Integrated Model of Care

January 2022
Wound Manag Prev. 2022;68(1):8–15

Abstract

BACKGROUND: Chronic edema affects millions of people in the United States and worldwide. Edema can result from a variety of diseases, trauma, medications, and other contributing factors; however, all edema is related to lymphatic fluid dysregulation. Additionally, lymphatic impairment and integumentary dysfunction are interrelated, leading to complex clinical presentations that require an integrated medical model of care to maximize outcomes. PURPOSE: This narrative review article will highlight the current evidence that details lymphatic physiology, fluid regulation by the endothelial glycocalyx layer, and the interconnectedness of the vascular and integumentary systems leading to a paradigm shift in our understanding of edema, lymphedema, and chronic wounds. Traditional pedagogy remains siloed with respect to the body systems, whereas current evidence indicates a certain interdependence, particularly between and among the venous, lymphatic, and integumentary systems. METHODS: Comprehensive narrative review of the current and past literature (2010–2021 through PubMed, Google Scholar, MEDLINE Complete, UpToDate) focusing on lymphatic physiology, fluid regulation, the endothelial glycocalyx layer, lymphedema, and venous insufficiency. Review focuses on new evidence supporting the interconnectedness of the systems to support a unified medical management approach. RESULTS: All edema is related to lymphatic dysfunction, whether transient or permanent, thereby creating a lymphedema continuum. Further, lymphatic impairment creates cutaneous regions of skin barrier failure, rendering the skin more susceptible to breakdown and chronic wounds. CONCLUSION: A synthesis of the current evidence suggests an interconnected relationship of the lymphatic, venous, and integumentary systems, highlighting the need for a more integrated medical model of care to provide efficient and comprehensive care and improve patient outcomes.

Introduction

All edema is a result of lymphatic dysfunction (either acute or chronic, either temporary or permanent) and recognized clinically as lymphedema; all edema is lymphedema. It is a simple statement, yet controversial in many circles. This fundamental scientific principle of modern lymphatic medicine is a pivotal key to moving lymphedema therapy and wound management forward to an integrated model of care. Yet, in many respects, this principle challenges historically ingrained beliefs thought to be true about lymphedema.

Paradigm shifts are infrequent and often initially controversial, as adoption of the revised Starling Principle was upon recognition of the endothelial glycocalyx. Dogma dies hard. As such, questions and confusion thwart the progression of understanding and interventions. When education remains rooted in “teaching to the test,” new revelations that can advance clinical care remain embedded at the benchtop position rather than at the patient’s bedside where medical care can be improved.

To be specific, all edema is a result of a lymphatic involvement, and its clinical manifestation is determined by its dysfunction or damage to this important system. This narrative review brings to light the scientific evidence demonstrating why all edema is lymphedema and provides insight into how to integrate this new paradigm shift into modern medical practice.

Methods

A narrative review of the literature from 2010 to 2021 was performed by searching PubMed, Google Scholar, MEDLINE Complete, and UpToDate, focusing on articles related to lymphatic physiology, fluid regulation, endothelial glycocalyx layer, lymphedema, and venous insufficiency. The authors sought to provide a comprehensive background for understanding current knowledge related to lymphedema and to highlight the gaps and emerging evidence that supports a more integrated approach to care and management of lymphatic, venous, and integumentary dysfunction.

Results

Endothelial glycocalyx layer redefines Starling’s principle. Ernest Starling’s principle of interstitial and luminal microvascular equilibrium between hydrostatic and osmotic pressures emanated from his work at Guy’s Hospital in London, resulting in his classic publication in 1896. In this model of the microcirculation, higher hydrostatic fluid pressure on the arterial side of the blood capillaries was thought to push fluid into the interstitium. In contrast, lower capillary hydrostatic pressure, coupled with higher capillary oncotic pressure of blood proteins, was thought to pull fluid back into the venous end of the blood capillaries. This became the basis of education in lymphedema certification programs as the model of the microcirculation. Under this model, it was thought that 90% of interstitial fluid was reabsorbed back into venous end of the blood capillaries, and the lymphatic capillaries were only responsible for about 10% of reabsorption of interstitial fluid.

This construct of the microcirculation began to be questioned as the body of scientific evidence and understanding of the endothelial glycocalyx layer (EGL) grew. The concept of an EGL was first proposed in 19401 and first visualized by Luft in 1966 via electron microscopy.2 The EGL is made up of two continuous layers: a gel-like base layer coating vascular endothelial cells, and a hair-like layer projecting into the vessel lumen.3,4 The EGL creates a barrier between the blood and vascular endothelial cells, interstitium, and the vessels.3-7 Healthy EGL is 0.5 µm thick in the blood capillaries and thicker in larger vessels, measuring up to 4.5 µm in the carotid artery.3,4

Curvy clefts, or channels, with tight junctions control fluid and protein movement through the EGL.4 The EGL acts as a molecular sieve, regulating the movement of fluid and macromolecules, such as white blood cells and proteins, out of the blood capillaries.3-5,8 In essence, the EGL is the gatekeeper of the microcirculation and has led to a new formulation of the century-old Starling Principle, now referred to as the Michel–Weinbaum Glycocalyx Model or the revised Starling Hypothesis for Microvascular Fluid Exchange.9-12

The base layer of the EGL is composed of a matrix of chains of glycoproteins and proteoglycans, creating “backbones” that attach directly into the membranes of the vascular endothelial cells of the vessel wall.3,4,7 These backbones are linked by glycosaminoglycans that can absorb 10 000 times their weight in water,5 forming the gel layer. The luminal layer is made up of hair-like projections attached to these “backbone” proteins. The hair-like projections are organized like bushes, in a hexagonal configuration, with roots communicating with the gel base layer. Blood flow shear forces bend the hair-like projections of the EGL, exerting a mechanical force (mechanotransduction) on the “backbones” embedded in the vascular endothelial cell wall. In turn, vascular endothelial cells respond to these mechanical signals by producing and releasing nitric oxide which dilates the vessel.4,5,13

Under normal conditions, the EGL is negatively charged and repels red blood cells from the vessel wall, creating an “exclusion zone.”3-5 However, the EGL is dynamic and can “shed” in response to stimuli, such as inflammation, ischemia, sepsis, trauma, atherosclerosis, diabetes, tobacco, intravenous fluid mismanagement, and other causes.3,5,14,15 During inflammation, this shedding allows more fluid to escape through the EGL4,5 and exposes adhesion molecules to which platelets or white blood cells (WBCs) attach.3 WBCs are squeezed tightest in the blood capillary where they enter the venule and are known to alter the thickness of the EGL temporarily by 20%.4 When the glycocalyx is shed, WBCs tether to exposed adhesion molecules and remain tethered as they roll across the venule wall to exit into the interstitium, known as diapedesis. Demarginated WBCs contribute to inflammation as they degranulate, increasing oxidative stress components.

Gradually gathering evidence to replacing Starling’s Principle as the new model of the microcirculation, Levick and Michel made another important discovery in 2010.16 They mathematically demonstrated that there is only diminishing net filtration across the blood capillary beds and no net reabsorption of fluid back into the venous side. Realizing this concept challenged over 100 years of dogma surrounding Starling’s Principle, Levick and Michel wrote “In making these forceful statements, we are mindful of William Harvey’s remark in his classic, De Motu Cordis (1628): ‘I tremble lest I have mankind as my enemies, so much has wont and custom become second nature. Doctrine once sown strikes deep its root, and respect for antiquity influences all men.’”16

Through this new body of evidence, it was realized that nearly 100% of all fluid and proteins moving from the blood capillaries into the interstitial space is subsequently absorbed by the lymphatic capillaries alone. Soon, the EGL was recognized as the new paradigm of the microcirculation, replacing Starling’s Principle. In a 2014 review, Mortimer and Rockson stated “arguably, it may be better to consider the presence of chronic edema as synonymous with the presence of lymphedema, inasmuch as all edema represents relative lymph drainage failure.”12 Following this train of thought, in 2018, Bjork and Hettrick explained that all edema is on a lymphedema continuum, and the integumentary and lymphatic systems are interdependent.17 In 2019, Bjork and Ehmann introduced a system of soft tissue assessment to match tissue textures with appropriate compression textiles, expounded on the theory that all edema is lymphedema albeit from various underlying etiologies.18

Initial lymph. All components of lymph are collectively called the lymphatic load.19 The lymphatic load is defined as everything that must be managed by the lymphatic system via lymphatic absorption, transport, and filtration.19 This includes fluid, proteins, lipids, dead and senescent cells, cancer cells, enzymes, WBCs, bacteria, endotoxins, perfumes, dyes, and pollutants. The lymphatic protesome is now recognized to vary from organ to organ and may prove to be a therapeutic target for organ dysfunction.20,21 Based on Starling’s Principle of the microcirculation versus the EGL, earlier descriptions of this lymphatic load labeled it as “lymph” only after it entered the lumen of the lymphatic capillaries. However, the EGL and other new evidence changes the way that is now viewed.

According to Wiig, the “interstitium” is defined as lymph plus the extracellular matrix (ECM), and “interstitial fluid” is synonymous with “initial lymph” or “afferent lymph.”22 All fluid, proteins, and other components of the lymphatic load are managed solely by the lymphatic capillaries, thus lymph outside the lymphatic capillary lumen is the same as that which enters it. Further, the ECM and dermal lymphatic capillary plexus is one continuous functional structure, which the authors call the “lymphintegument.”

Lymphintegument. The lymphatic capillaries of the skin and elastic fibers form an integral morphofunctional structure.23 Microfibrils, also known as anchoring filaments, connect elastic fibers of the ECM to overlapping flaps that act as valves to blind-tipped lymphatic capillaries and connect to the wall of the lymphatic capillaries themselves. When initial lymph fills the interstitial space, elastic fibers are stretched, thereby expanding the lumen of the lymphatic capillary and opening the overlapping flaps to allow lymph to enter the capillary plexus.23-25 Thus, lymphatics must act as a mechanical extension of the interstitium to be functional.26

In addition, microfibrils of the ECM directly interface with the endothelial cells of the lymphatic capillaries. Microfibrils of anchoring filaments are known to be expressed by lymph endothelial cells in culture, and mechanical stimulation of anchoring filaments may result in a biochemical response in the cell that mediates lymphangiogenesis.26,27 The three-dimensional architecture of the ECM is not only congruent with the lymphatic capillaries; the alignment and expression of the fibers within it are reflective of the stressors applied to it. Microdeformation of the ECM drives cellular responses.

The cellular effects of microdeformation are not new concepts. For many years, negative pressure wound therapy (NPWT) has been utilized to accelerate blood capillary formation, or granulation, for wound healing of the skin. Although studies have been focused on angiogenesis, the concurrent effect on lymphangiogenesis cannot be understated. Wiegand and White explained how microdeformation causes a deformation of the cellular cytoskeleton, which initiates signaling cascades that lead to the release of growth factors.28 This, in turn, promotes cell proliferation and migration in addition to increasing the expression of ECM components and contractile elements that are necessary for wound healing.28 Because the continuous inflow of nutrient-rich lymph to the integument via blood capillaries must be matched with removal of wastes via lymphatic capillary reabsorption, it makes perfect sense that angiogenesis and lymphangiogenesis occur simultaneously and are interdependent. This theory is further supported by the knowledge that the same cells that are critical mediators in wound healing are also key cells in lymphatic capillary regeneration. Macrophages have been found to be key to signaling in both angiogenesis and lymphangiogenesis.29 Additional evidence suggests that macrophages can transdifferentiate into lymphatic endothelial cells as well.29

The three-dimensional matrix of the lymphintegument acts as a tissue pump.30,31 Microdeformations drive the formation of channels in the ECM, funneling lymph toward the lymph capillary tips for reabsorption. Many modalities activate this tissue pump and facilitate lymph flow through lymphatic vessels in the ECM, including active and passive phases of manual lymphatic drainage (MLD), intermittent NPWT, intermittent pneumatic compression (designed for lymphedema), and lymphatic alternating pressure profiles (LAPP) of textured textiles in bandaging and compression garments.18 This resultant lymph flow itself helps to direct the growth of new lymph capillaries.

Macrophages secrete both vascular endothelial growth factor C (VEGF-C) and chemotactants along a VEGF-C gradient that is influenced by lymph flow.32 In a mousetail model of skin regeneration, fluid flow through the interstitial space preceded the development of new lymph capillaries. Single lymphatic endothelial cells migrated in the direction of flow. Cells aligned and subsequently joined to form a new vessel at day 25; by day 60, that vessel had matured into a configuration resembling normal lymphatic capillary plexuses.33

The integumentary and lymphatic systems are interdependent.17 Imaging of the dermal lymphatic capillaries using indocyanine green fluoroscopy has shown lymph capillary derangement and dermal backflow in areas of hemosiderin staining.34 In fact, Wandolo et al35 showed in a bovine model that heme-containing proteins (specifically, oxymyoglobin, hemoglobin, and myoglobin, which lyse in the interstitial tissues creating hemosiderin) suppress lymphatic pumping. The authors theorized hemoglobin/myoglobin-induced changes that hinder the pumping ability of the lymphatics may contribute to edema formation of venous origin.

More recently, it was shown that lymphatic anatomy and contractile function degrade with the progression of venous insufficiency,36 potentially leading to the development of venous ulceration. Histological studies from 1994 showed that collapse of the lymphatic capillary lumen results in the subsequent derangement of the anchoring filaments secondary to chronic venous insufficiency and stasis dermatitis.37 Carlson38 explained how localized lymphatic failure produces a cutaneous region susceptible to infection, inflammation, and carcinogenesis, which is failure of the skin as an immune organ. Carlson38 described this as lymphatic dermopathy, highlighting the interconnectedness of the “lymphintegument.”

Lymph stasis. The emerging evidence points to a need to redefine interstitial fluid as initial lymph, the interstitial spaces as dilated lymphatic channels/vacuoles with intact lymphatic vessels, the ECM of the skin as the lymphintegument, the lymphintegument as a tissue pump, and all edema as lymphedema. Yet, the historical definition of lymphedema as “high-protein edema” apparently conflicts with these new definitions. Lymphedema can be “high-protein” or “low-protein” edema. Many of components of the lymphatic load are known to elicit chronic inflammation, not just proteins. Essentially, all the pathogens and waste products typically removed by the lymphatics can pool and stagnate in the tissues and elicit a cascade of deleterious soft tissue effects. The degree of soft tissue dysfunction is related to the degree of lymph stasis and the individual’s inflammatory reaction to it.

Pooling and stagnation of lymph in the interstitium results in a pathohistological state of chronic inflammation and oxidative stress. According to Földi et al, “…oxidation and degradation of interstitial proteins attracts monocytes that change into macrophages. Macrophages ingest the proteins and activate fibroblasts that, in turn, form collagen resulting in fibrotic changes, thickening, and connective tissue proliferation.”19 Considering the vast body of evidence related to wound healing, one can appreciate that other components of the lymphatic load, such as bioburden or matrix metalloproteinases (MMPs), are now thought to contribute to inflammation and trophic tissue changes, not just the degradation of blood plasma proteins. Further, fibrotic tissue changes can be palpated in localized areas, such as in peri-wound tissues or in retromalleolar pockets where lymphedema tends to pool.

Staging and diagnosis. The prominent role of the lymphatics in tissue fluid homeostasis in all forms of chronic edema was recognized in the LIMPRINT international epidemiology study.39 “Chronic edema” was defined as edema that had been present for more than 3 months and was considered synonymous with “lymphedema.”40 This was further supported by Mortimer and Rockson in 2014 when they stated, “All chronic edema indicates an inadequacy or failure of lymph drainage … Arguably, it may be better to consider the presence of chronic edema as synonymous with the presence of lymphedema, inasmuch as all edema represents relative lymph drainage failure.”12 This updated definition was a formidable step in elevating the recognition and diagnosis of chronic lymphedema.

According to the new microcirculation paradigm, all patients presenting with swelling do in fact have lymphedema to some degree. The lymphatic system may be overwhelmed (ie, ankle sprain, congestive heart failure), resulting in transient lymphedema or lymphatic insufficiency, or the system may be damaged, leading to the disease of lymphedema due to permanent lymphatic impairment.17 The impairment may be due to congenital abnormalities, trauma, lymphatic bacterial infections, and or venous hypertension.41 For a comprehensive listing of lymphedema risk factors, see Table 1.

However, identifying risk factors and diagnosing lymphedema before overt clinical changes are evident is optimal for a preventative and early intervention model of treatment versus a reactive model.

Staging for lymphedema has been defined by the Executive Committee of the International Society of Lymphology (2016) (Table 2).43 According to the Society, stage 0 lymphedema is a latent or subclinical condition in which swelling is not yet evident despite impaired lymph transport. It is not until stage 2 or stage 3 when soft tissue changes secondary to lymph stasis are evident. Stage 0 encompasses risk factors that predispose a person to lymphedema as described in Table 1.

It is important to identify all comorbidities that place a patient at risk for or contribute to their lymphedema so that the complexity of clinical management can be reflected and an individualized plan of care developed. Since all edema resides on a lymphedema continuum17,18 and can result in deleterious effects in soft tissues, functional mobility, and quality of life, the early diagnosis of lymphedema and intervention is advantageous. This is corroborated by current research that shows complete decongestive therapy (CDT) is effective when integrated into rehabilitation for edema not previously recognized as lymphedema.44-59

Treatment. Complete decongestive therapy has emerged as the gold standard for lymphedema management.60 CDT is delivered in 2 phases, both of which involve skin and nail care, MLD, compression bandaging, exercise, and patient education. Phase 1 is carried out by a certified lymphedema therapist until a plateau in fluid reduction has been achieved. Phase 2 is the maintenance phase carried out by the patient for life-long management of lymphedema.

MLD, a core component of CDT, is recognized as a therapeutic intervention that is specifically used for lymphedema treatment. Lymphatic and integumentary rehabilitation17 is a new approach in which treatment modalities for the lymphatic and integumentary systems are integrated into a variety of rehabilitation applications. Because all edema is lymphedema, the benefits of adding MLD to surgical protocols has been shown to improve outcomes. This has been demonstrated for total knee replacements45-47 and orthopedic injuries.48 MLD has also been found effective in managing chronic venous insufficiency,49-52,61 venous leg ulcers,53,54 neurological diseases,55 autoimmune diseases,56 and autism.57,58 MLD has also been shown to be effective when combined with proprioceptive neuromuscular facilitation.59

 

Conclusion

The body of knowledge about the lymphatic system is continuously expanding. As noted in this article, patients with unrecognized or improperly treated lymphedema will progress through stages leading to integumentary changes and challenging wounds. Conversely, edematous conditions that are not swiftly addressed may progress to lymphatic dysfunction, integumentary dysfunction, ulcerations, and ultimately lymphedema. As more becomes known about the interdependence of the systems, a more holistic medical model is needed to integrate care and understanding of this interdependence. The siloed approach to care, particularly lymphedema and wound management, is a disservice to patients. Emerging evidence about obesity-induced lymphedema, fat disorders, chronic integumentary dysfunction, and the complexities associated with prolonged lymphedema give rise to an opportunity to provide an integrative approach to care for these patients. Not only would this improve outcomes and quality of life,  but it would also save significant financial resources if the proper treatment or referrals are implemented early.62,63

Acknowledgments

This article is dedicated to Robyn Bjork for her tireless work in promoting awareness about lymphedema and her vision for advancing the practice of lymphatic medicine and treatment. We wish you joy and happiness in your retirement. We also thank Mark Melin, MD, FACS, RPVI, FACCWS, for his review of the original manuscript.

Potential Conflicts of Interest

Dr Hettrick is on the faculty and is the Director of Wound Education, International Lymphedema & Wound Care Institute, Tifton, GA. Mr Aviles is a wound care and lymphedema instructor and advisor for the Academy of Lymphatic Studies, Sebastian, FL.

Affiliations

Dr Hettrick is a professor, Department of Physical Therapy, Nova Southeastern University, Fort Lauderdale, FL. Mr Aviles is the wound care clinical coordinator, Natchitoches Regional Medical Center, Natchitoches, LA.

Address for Correspondence

Address all correspondence to: Frank Aviles, Jr, PT, CWS, FACCWS, CLT-LANA, ALM, AWCC, DAPWCA, 501 Keyser Avenue, Natchitoches, LA 71457; tel: 318-214-4822; fax: 1-888-467-9563; email: Frank.Aviles@nrmchospital.org.

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