High Pressure 3 × 30 Minute Compression Methods for Advanced Lower Limb Lymphedema Patients.

Introduction: In advanced lymphedema of lower limbs, stage III bandaging under the routinely applied pressure of 40-60 mmHg remains largely ineffective. This is caused by skin and subcutaneous tissue stiffness due to fibrosis. Edema fluid accumulates deep in the subcutaneous tissue. Evacuating this fluid requires a high external compression force to overcome the resistance of fibrous tissue. We aimed to investigate the effectiveness of the compression method, with high pressure lasting for 3 days. Methods and Results: Twenty-one patients with lower limb lymphedema, stage III, of the postinflammatory type were included. Patients with acute inflammatory symptoms, venous thrombosis, profuse varicose veins, diabetes, and cardiac insufficiency with edema were excluded. A 10-cm-wide rubber bandage was applied to the foot and calf. The interface pressure measured using PicoPress ranged from 58 to 120 mmHg. Skin and deep tissue tonometry, skin water concentration, leg circumference, and drop of interface pressure were measured. Ultrasound examination was done before and after each compression session. The calf circumference decreased by 15.9 ± 5.4%, deep tissue stiffness by 58.9 ± 18.9%, skin stiffness by 69.6 ± 13.5%, and skin water concentration by 43.8 ± 11.5%. Interface pressure dropped to 66.3 mmHg (28-110 mmHg); ultrasonography images showed less fluid in the tissue. Conclusions: High-pressure 30-minute leg compression can remove excess edema fluid within 3 days and enable adjustment of nonstretch compression stockings. This method is more effective in advanced lymphedema at the beginning of therapy than the standard 30-50-mmHg bandaging as it provides an immediate effect.

Lymphatic Vascular Insufficiency and Focal Edema in Early Stages of Noncancer-Related Lymphedema.

Introduction: Lymph flows along the lymphatics due to spontaneous contraction. However, injury and inflammation may deteriorate lymphatic' s endothelial and muscle cells and valves. In consequence, lymphatic vessels (LVs) become insufficient. Their contraction strength and rate slow down, and then lymph flow stops. Our study aimed to investigate the changes in lymph flow in early lymphedema cases. Methods and Results: In 36 patients with unilateral lymphedema stages 0 and I, we performed indocyanine green (ICG) lymphography, lymphoscintigraphy, skin water concentration, and stiffness measurement. We compared lymph flow velocity, LVs' appearance, contraction pattern, and rate between swollen and healthy limbs. ICG lymphography revealed (1) slower lymph flow after 3 minutes of foot movement; in lower calf level, lymphatics are seen in 22 (61.1%) swollen limbs compared with 36 (100%) healthy limbs (p < 0.0001); (2) dye spots in the foot (47.1%) and calves (13.9%) in swollen limbs; (3) dilated foot (41.7%) and calves' lymphatics (52.8%); (4) different patterns of lymphatics contractility with slower contractions rate and (5) higher fluorescent intensity in edema limbs. There was higher skin water concentration at foot and ankle level and higher skin stiffness in the foot. Conclusions: Our studies have shown the distortion in lymphatic function as dilatation, slower lymph flow, slower contraction rate, presence of areas with occluded lymphatics (dermal backflow in foot and calves-focal edema), and higher skin water concentration in these regions in limbs with early lymphedema. ICG lymphography can be used for the early detection of LV insufficiency, which allows early prophylactic implementation.

Lower Limb Lipedema-Superficial Lymph Flow, Skin Water Concentration, Skin and Subcutaneous Tissue Elasticity.

Background: Lipedema of lower limbs is characterized by bilateral accumulations of excess adipose tissue starting from the ankle to the hips and buttocks. The studies with lymphoscintigraphy (LSC) and magnetic resonance (MR) lymphography show altered transport index and enlarged lymphatic vessels (LVs). Our studies aimed to investigate the superficial lymph flow, water accumulation, skin and subcutaneous tissue elasticity, and the possibility of using this information to diagnose lipedema. Methods and Results: Fifty patients with lipedema and 50 control subjects (women) were included. The Indocyanine Green (ICG) lymphography, LSC, skin water measurement, skin durometry, and deep tissue tonometry were done in all participants. ICG lymphography revealed: (1) Slower lymph flow in lipedema patients; after 3 minutes of feet movement in a horizontal position, the ICG-dyed lymph reached the upper calf level in 8% of lipedema patients compared with 56% in the control group (p ˂ 0.0001). (2) More than three LVs were noticed more often in lipedema patients. (3) The higher number of abnormal LV images at all limb levels and during each observation stage with a statistically significant number of foggy and dilated. (4) Statistically significant higher fluorescent intensity in all limb levels. Skin water concentration was higher in the feet in lipedema (p = 0.000189). Conclusion: Our studies have shown the differences in superficial lymph flow and water concentration between lipedema and normal limbs. Data proove the usefulness of ICG lymphography, skin water concentration and skin and subcutaneous tissue elasticity measurements in diagnosing lipedema.

Long-Term Benzathine Penicillin Prophylaxis Lasting for Years Effectively Prevents Recurrence of Dermato-Lymphangio-Adenitis (Cellulitis) in Limb Lymphedema.

Background: The lymphedema-affected limbs are predisposed to acute and, subsequently, chronic dermato-lymphangio-adenitis (DLA) episodes in around 40%-50% of cases, irrespective of what the primary etiological factor is for the development of this condition. DLA is of bacterial etiology, and it needs antibiotic control and prevention of recurrence. Our aim was to follow the effects of years-long continuous no-break administration of benzathine penicillin on the recurrence of acute DLA episodes. Methods and Results: Two hundred thirty-one patients were affected with lymphedema of lower and upper limbs. The mean duration of lymphedema was 10.2 ± 7.3 (range 2-30) years, and the number of DLA attacks/patient was 3.3 ± 3.2 (range 1-10). The total number of DLA episodes was 805. Benzathine penicillin injections 1,200,000 units were given i.m. at 14-21 days intervals (mean 18 ± 9 days) with short accidental breaks only. The period of therapy was 39.2 ± 38.7 (median 32) months. Recurrence occurred in 23 out of 231 (10%) (p < 0.01). There were 42 DLA incidents compared with 805 before introduction of therapy (5.2%) patients (hazard ratio 0.05, 95% confidence interval 0.034-0.079) (p < 0.01). Among patients with recurrence, there was a decrease of DLA episodes from 6.2% ± 3.6% to 1.7% ± 1.0%/patient. There were no differences in effectiveness of penicillin prophylaxis between etiological groups, depending on stages of lymphedema. Conclusions: Long-term years-long benzathine penicillin prophylaxis is extremely effective in prevention of DLA recurrence. It can be applied for years with no breaks, without clinical side-effects, and raising resistance to antibiotics. Microbial colonization and evoked inflammatory reaction of hosts should be controlled from the first symptoms of lymph stasis, irrespective of the etiology of lymphedema.

Tissue Structure and Edema Fluid Events During Treatment of Lymphedema of Limbs with a Manual Pressure-Calibrated Device, Linforoll.

Background: Linforoll is a device composed of handpiece with roller and pressure sensor connected wireless to the computer displaying the pressure curve of the applied force. In a previous study, we proved it to regulate the applied force according to the hydromechanic conditions of the massaged tissues. Standardization of massage based on applied force was repeatable in the same patient; it decreased limb volume and provided evident increase in tissue elasticity. Methods and Results: In this study, we measured additional parameters useful for the understanding of tissue and fluid events and approval of the device for general practice. These were skin stiffness, subcutaneous tissue stiffness independent of skin, skin water concentration, changes in skin temperature, skin capillary blood flow, subcutaneous tissue fluid pressure, volume of the moved edema fluid, and visualization of movement on indocyanine green (ICG) lymphography. Measurements were done before and during the massage. The data were obtained from a group of 20 patients with obstructive lymphedema of lower limbs during the Linforoll massage. There was a lack of significant changes in skin stiffness, skin water concentration, skin surface temperature, and capillary blood flow, but evident increase in the subcutaneous tissue elasticity (tonometry) and lymphography-shown flow of the edema fluid. Conclusions: The skin tissue hydromechanic parameters remained normal proving lack of destructive changes under high massaging pressures. The obtained data evidently show that not the skin but the subcutis accumulated edema fluid that can successfully be moved proximally under pressures of 80-120 mmHg.

The Neglected Leg Lymphatic Vascular Changes in the Pathomechanism of Delayed Onset Muscle Soreness in Runners.

Background: Delayed onset muscle soreness (DOMS) in runners is classified as a leg muscle strain injury and presents with tenderness or stiffness to palpation and movement limitation. Most attention is directed at muscles but not at the mass of other limb soft tissues, including their lymphatic vasculature, although they undergo mechanical stress and bruises, edema, nail destruction, and pains contributing to symptoms. Methods and Results: The study was done on lower limbs of long-distance runners suffering from DOMS complaints. There were 16 runners, 11 males and 5 females, age 22-28, practicing long-distance running over the last 5 years, with body mass index (BMI) 23 ± 4. Inclusion criteria: three to five marathon runs per year and daily 3-5 km slow runs. Last long distance run 3 to 7 days before the investigation. Controls were six subjects initiating running, of the same age group and BMI. Testing of blood and lymph flow was done before and after standard ergometer 300 W 30 minutes cycling. The measurement methods were leg and big toe venous plethysmography, big toe capillary Doppler, tonometry of skin and deep tissues, lymphoscintigraphy, and indocyanine green (ICG) fluorescent lymphography. (a) Strain gauge plethysmography of the calf and big toe revealed a two- to three-times higher venous capacity in runners than in controls, (b) the increased toe venous capacity was confirmed by point Doppler recordings showing two- to three-times higher blood capillary flow compared to controls, (c) lymphoscintigraphy revealed retention of tracer in feet, dilated superficial and deep lymphatics, and enlarged popliteal and inguinal lymph nodes, and (d) ICG lymphograms showed confluents of accumulated fluid in foot and calf subcutaneous tissue with fluorescence level reaching 40%-50% compared to 20% in controls. Conclusion: Our results show that, 3-5 days after run, not only muscles but also skin and subcutaneous tissue reveal major tissue fluid accumulation, an overload bringing about functional lymphatic transport insufficiency. This may be an additional factor responsible for DOMS symptoms.

The long-term arterial assist intermittent pneumatic compression generating venous flow obstruction is responsible for improvement of arterial flow in ischemic legs.

BACKGROUND: There is a large group of patients with ischemia of lower limbs not suitable for surgical reconstruction of arteries treated with the help of external assist by intermittent pneumatic compression devices (IPC). Until recently the generally accepted notion was that by compressing tissues below the knee, veins become emptied, venous pressure drops to zero and the increased arterial-venous pressure gradient enables greater arterial flow. We used a pump that, in contradiction to the "empty veins" devices, limited the limb venous outflow by venous obstructions and in a long period therapy expanded the perfusion vessels and brought about persistent reactive hyperemia. AIM: To check the toe and calf arterial inflow measured by venous stasis plethysmography and capillary flow velocity during arterial assist IPC in a long-term therapy of ischemic legs. MATERIAL AND METHODS: Eighteen patients (12M, 6F) age 62 to 75 with leg peripheral arterial disease (PAD, Fontaine stage II) were studied. Pneumatic device with two 10cm wide cuffs (foot, calf) (Bio Compression Systems, Moonachie, NJ, USA) inflated to 120 mmHg for 5-6 sec to obstruct the venous flow, deflation time 16 sec, applied for 45-60 min daily for a period of 2 years. RESULTS: At pump inflation increase in toe arterial pressure, volume, capillary blood flow velocity and one-minute arterial inflow test was observed. Increased toe volume appeared concomitantly with the inflated chamber venous obstruction. Resting pressure in the great saphenous vein increased. The two years therapy showed persistence of the resting limb increased toe capillary flow. Intermittent claudication distance increased by 20-120%. After two years arterial assist TBI increased from 0.2 to 0.6 (range 0.3 to 0.8) (p<0.05 vs pre-therapy). The toe arterial inflow dominated over that in calf skin and muscles, nevertheless, there was prolongation of the claudication distance presumably due to dilatation of exchange vessels also in muscles. CONCLUSIONS: Our arterial assist IPC brought about increase in the toe capillary flow, long lasting dilatation of toe capillaries and extension of painless walking distance. The crucial factor of rhythmic repeated venous outflow obstructions should be taken into account in designing effective assist devices.

Edema Fluid Can Be Successfully Evacuated from the Lymphedematous Limbs by Implantation of Silicone Tubings Bypassing the Site of Flow Obstruction Long-Term Observations.

Background: Lymphedema of limbs is caused by partial or total obstruction of lymphatic collectors. In advanced cases all main lymphatics are obstructed and tissue fluid accumulates in the interstitial spaces. The microsurgical lympho-venous shunts cannot be performed. We propose in such cases drainage of fluid accumulations by creating artificial flow pathways to the nonobstructed regions by implantation of silicone tubes. Aim: To present the 3 to over 6 year follow-up results of therapy by subcutaneous implantation of silicone tubes. Methods: In 150 patients with obstructive limb lymphedema after pelvic or axillary lymphadenectomy and irradiation in uterine or breast cancer or following soft tissue inflammation silicone tubes were implanted subcutaneously. Results: There was (1) immediate decrease of limb circumference within days after implantation; (2) in lower limbs in a 3-year follow-up a decrease in mid-calf circumference by a mean -8.7% (p < 0.05) with range of -3.2% to -31.0% corresponding to 90-900 mL volume and in the mid-thigh a mean -1.8% (p < 0.05) with range of -9.3% to +3% equal to 0-900 mL. In the upper limb in the 2-year follow-up the decrease in the mid-forearm was -8.5% (p < 0.01) with a range of -3.0% to -22.0% and in the mid-arm a mean -12% (p < 0.05) with a range of -7% to -22%. That corresponded to 180-700 mL volume for the limb; (3) decreased tissue stiffness; (4) maintenance of tubes patency on control lymphoscintigraphy, contrast opacification, and ultrasonography; and (5) lack of reaction to foreign body and effective control of inflammation at the site of implantation using low doses of benzathine penicillin. Conclusions: The technical simplicity of the surgical procedure, fast decrease of limb edema, and lack of tissue reaction to the implant make the method worth applying in advanced stages of lymphedema.

The Effectiveness of Intermittent Pneumatic Compression in Therapy of Lymphedema of Lower Limbs: Methods of Evaluation and Results.

BACKGROUND: Evaluation of intermittent pneumatic compression (IPC) in lymphedema is classically based on measurements of circumferences and volume of the edematous limb. However, although important, it provides only a general information without insight into what proceeds under the skin with respect to hydromechanical and structural changes. AIM AND METHODS: We present the multimodal evaluation of the effectiveness of IPC device in limb edema by measuring tissue stiffness, fluid pressure, and flow volume, and lymphoscintigraphic and near-infrared fluorescence (NIRF) indocyanine green (ICG) lymphography imaging of edema fluid movement, before and after one 45-60 minute compression cycle in over 50 patients with lymphedema stage II and III. RESULTS: (1) Tissue fluid pressures were lower than those applied by IPC device. (2) The higher the applied compression force, the larger the flow volume. (3) Skin stiffness (superficial tonometry) decreased mainly in the calf, whereas, subcutaneous tissue (deep tonometry) was observed at all limb levels. (4) Skin water concentration (dielectric constant) was only insignificantly decreased, but subcutaneous extracellular water (bioimpedance Ldex index, fluid movement force test) was effectively moved away to limb proximal regions. (5) Imaging tissue (edema) fluid flow pathways on lymphoscintigram and real-time flow on NIRF ICG video could be observed and were evaluated semiquantitatively. CONCLUSIONS: Adjustment of compression parameters to tissue stiffness, fluid accumulation volumes, and fluid movement ability (hydraulic conductivity of tissues) at various limb levels is indispensable for effective therapy. Redesigning of compression devices will be needed to enable applying differentiated compression pressures and prolonged timings at various limb levels.

Imaging lymphatics in human normal and lymphedema limbs-Usefulness of various modalities for evaluation of lymph and edema fluid flow pathways and dynamics.

The human lymphatic system morphology and function still remain largely unknown to clinicians and biologists. How does the lymphatic vascular system look like in comparison to the blood transport system, how does lymph flow, where does capillary filtrate accumulate in cases with lymphatic obstruction caused by inflammation, trauma, and cancer therapy, remain as basic questions. Visualization of the lymphatic pathways and dynamics of lymph flow, and in cases of obstruction, the localization of the capillary filtrate/edema fluid accumulation becomes indispensable. The contemporary methods only partly meet these requirements. Since the early 1950s of the 20th century only few specific clinical methods of imaging of limb lymphatics are being used in human clinic. Each of the applied modalities provides different images due to different physical chemistry and distribution of tracer, methods used for its detection in tissues, their sensitivity and specificity and clinical type of lymph vessel pathology. Here, the advantages and disadvantages of the most commonly used 3 methods of imaging: the iodinated oil X-ray, isotopic, and fluorescent lympangiographies are presented. The study is based on retrospective and recent collections of lymphangiograms from large cohorts of patients. Imaging of lymph nodes has not been included as it is requiring different interpretation compared with vessels. Composite evaluation of X-ray, isotopic, and fluorescent lymphographic images or, as it is practiced now the isotope and indocyanine green near infrared lymphographies, provide most clinically important information. Special attention was directed at methods enabling early diagnosis of imminent lymphedema especially in cases with cancer therapy-related lymphedema. Groups of typical images obtained with the 3 methods are presented.

Tonometry of Deep Tissues for Setting Effective Compression Pressures in Lymphedema of Limbs.

BACKGROUND: The therapeutic intermittent pneumatic compression (IPC) pressures are usually set arbitrarily at levels between 40 and 60 mmHg. However, it is not known how much force has been transferred to edema fluid. There is a need to know how high edema fluid pressures should be generated to evacuate the stagnant fluid. The externally applied compression force dissipates in hard tissues and only a portion of it is conveyed to tissue fluid. Simultaneous measuring of compression force using deep tissue tonometry and recording edema fluid pressures under a tonometer would give hints of how high should therapist or patient set IPC pressures to mobilize fluid. AIM: (1) To simultaneously measure the applied tonometer force and the generated edema fluid pressures under the tonometer, (2) to plot tonometer force against fluid pressure data to create a correlation curve for setting pressure of IPC at levels initiating fluid flow, (3) to work out a formula for setting pressures in the pneumatic device for individual patient, based on tonometry, (4) to prove the value of formula on a cohort of patients treated with IPC. METHODS: Deep tissue tonometry force and tissue fluid pressures under the tonometer indentor were measured in lower limbs in a group of 20 patients with lymphedema stages I-III. RESULTS: (1) Deep tissue tonometry penetrating to a depth of 10 mm provided data on pressure generated in tissue fluid under the tonometer indentor. (2) Plotting the applied tonometer force against the tonometer-generated tissue fluid pressures revealed that force to reach the threshold of 30 mmHg fluid pressure necessary for initiation of flow should be >1000 g/sq. cm. (3) A formula, based on tonometry values, for setting ICP pressures at levels generating pressures for initiating edema fluid flow was worked out. (4) Usefulness of the formula for setting IPC at effective levels was proved on a cohort of patients. CONCLUSIONS: Deep tissue tonometry of limbs is useful for setting IPC devices at compression pressures for mobilizing edema fluid.

Indocyanine green near-infrared lymphangiography for evaluation of effectiveness of edema fluid flow under therapeutic compression.

The commonly used modalities for therapy of limb lymphedema are manual lymphatic drainage, manual devices moving edema fluid and intermittent pneumatic compression (IPC). What seems to be necessary for validation of the effect of the compression procedure is imaging of the mobilized moving edema fluid. Picture of edema fluid flow would allow the therapist to use force adjusted to the tissue volume and stiffness differing in various limb regions as well as identify sites of abundant accumulation of fluid requiring more compression. The purpose of the present study was to visualize tissue edema fluid flow during manual drainage, Linforoll massage, IPC and bandaging. To obtain data how high compression pressures should be used to mobilize indocyanine green (ICG)-stained fluid, concomitantly tissue fluid pressure measurements were performed. The following observations were obtained: (1) the possibility of real-time observation of edema fluid movement using various compression modalities, (2) the threshold pressures necessary to move edema fluid to be over 80 mm Hg in the compression device and over 40 mm Hg in the tissue fluid and (3) inefficacy of compression in some cases despite applying high compression force. These observations point to the need of ICG lymphangiography before compression therapy in each patient. The images observed during the compression procedure give an insight into the distribution of edema fluid, sites of its accumulation and efficacy of applied external force on fluid mobilization.

Predilection to Dermato-Lymphangio-Adenitis in Obstructive Lymphedema of Lower Limbs Depending on Genetic Polymorphisms at TNFα-308G>A, CCR2-190G>A, CD14-159C>T, TLR2 2029C>T, TLR4 1063A>G, TLR4 1363C>T, TGFß 74G>C, and TGFß 29T>C.

BACKGROUND: Infection is the most common type of complication observed in lymphedema and is promoted by lymphatic system dysfunction, which causes locoregional immune disorders. Infectious complications are primarily bacterial and most commonly cellulitis (dermato-lymphangio-adenitis, DLA) caused by patients' own skin Staphylococci epidermidis and aureus. The clinical course and outcomes in the immune response to infection have been shown to be associated with genetic polymorphisms. AIM: To investigate polymorphism of TNFα-308G>A, CCR2-190G>A, CD14-159C>T, TLR2 2029C>T, TLR4 1063A>G, TLR4 1363C>T, TGFß 74G>C, and TGFß 29T>C. The second part of study was the correlation of levels of TNFα and TGFß with their genes polymorphism in one hundred patients with lower limb postdermatitis lymphedema. RESULTS: (a) High percentage of TNFα homozygotes, no differences in genotypes of CD14-159C>T, CCR2-190G>A, TGFß 74G>C, TGFß 29T>C, and TLR4 1063A>G, low percentage of TLR2 2029C>T heterozygotes and homozygotes TT, and a high percentage of TLR4 1363C>T homozygotes TT, (b) low serum levels of TGFß and TNFα in 19% and 43% of patients, respectively, however, lack of correlation between low levels of these cytokines and frequency of homozygotes CC and AA, respectively. CONCLUSIONS: The practical implications of finding high frequency of genotype TT of TLR4 1363C>T are indications for testing this gene in patients with obstructive lymphedema of lower limbs and early antibiotic prophylaxis of recurrent attacks of DLA, and during elective surgery of lymphedema. The obtained data are also important as a contribution to mapping of genetic variations in acquired lymphedema of lower limbs.

Serum Immune Proteins in Limb Lymphedema Reflecting Tissue Processes Caused by Lymph Stasis and Chronic Dermato-lymphangio-adenitis (Cellulitis).

BACKGROUND: Lymphedema of limbs affects a large mass of tissues. Pathological changes develop in skin and subcutaneous tissue. Bacterial retention in edema fluid is followed by chronic inflammatory reaction. The question arises whether the chronic processes affecting a large mass of limb tissues are reflected in the serum by appearance of specific proteins accumulating and subsequently absorbed from the lymphedematous tissues Aim: To measure the concentration of serum proteins (1) participating in cellular disintegration such as caspase 1, sFas, high-mobility group box 1 (HMGB1), and serpin, (2) cell growth regulating factors such as cortisol, human growth hormone, keratinocyte growth factor, and insulin-like growth factor (IGF), and (3) angiogenic and growth factors such as angiopoetins 1 and 2, adiponectin, leptin, and transforming growth factor beta. RESULTS: We found (1) increased concentration of serum caspase 1, sFas, serpin, and HMGB1 accounting for cellular destruction, (2) raised levels of cortisol and IGF, confirming active cellular processes, and (3) elevated concentrations of angiopoetin 1, adiponectin, and leptin, indicating proliferation of adipose tissue. CONCLUSIONS: Proteins appearing in serum in high concentrations in patients with lymphedema without systemic clinical and biochemical signs of inflammation indicate that multiple processes of destruction and rebuilding proceed in the lymphedematous tissues. Measuring concentration of caspase 1, sFas, serpin, HMGB1 protein, adiponectin, and leptin give insight into these processes. Lymphedema should be considered as tissue process characterized not only by increase in mobile tissue fluid volume but also tissue restructuring. Compression and drainage therapy should be complemented by anti-inflammatory medication.