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Prevention of venous reflux with full utilization of venoplasty in lymphaticovenular anastomosis
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Prevention of venous reflux with full utilization of venoplasty in lymphaticovenular anastomosis Shinsuke Akita , Yoshihisa Yamaji , Hideki Tokumoto , Haruka Maei , Takafumi Tezuka , Hideyuki Ogata , Kentaro Kosaka , Yoshitaka Kubota , Motone Kuriyama , Nobuyuki Mitsukawa PII: DOI: Reference:
S1748-6815(19)30488-7 https://doi.org/10.1016/j.bjps.2019.10.020 PRAS 6304
To appear in:
Journal of Plastic, Reconstructive & Aesthetic Surgery
Received date: Accepted date:
16 June 2019 9 October 2019
Please cite this article as: Shinsuke Akita , Yoshihisa Yamaji , Hideki Tokumoto , Haruka Maei , Takafumi Tezuka , Hideyuki Ogata , Kentaro Kosaka , Yoshitaka Kubota , Motone Kuriyama , Nobuyuki Mitsukawa , Prevention of venous reflux with full utilization of venoplasty in lymphaticovenular anastomosis, Journal of Plastic, Reconstructive & Aesthetic Surgery (2019), doi: https://doi.org/10.1016/j.bjps.2019.10.020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons.
Prevention of venous reflux with full utilization of venoplasty in lymphaticovenular anastomosis
Shinsuke Akita, MD, PhD.1, Yoshihisa Yamaji MD, PhD.2, Hideki Tokumoto, MD, PhD.3, Haruka Maei, MD.1, Takafumi Tezuka, MD.1, Hideyuki Ogata MD.1, Kentaro Kosaka, MD, PhD.1, Yoshitaka Kubota, MD, PhD.1; Motone Kuriyama, MD, PhD.1, 4, Nobuyuki Mitsukawa MD, PhD.1
1. Department of Plastic, Reconstructive, and Aesthetic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan 2. Department of Plastic, Reconstructive, and Aesthetic Surgery, Japan Red Cross Maebashi Hospital. Maebashi, Japan 3. Department of Plastic and Reconstructive Surgery, Chiba Cancer Center Hospital, Chiba, Japan 4. Department of Plastic and Reconstructive Surgery, Shinyurigaoka General Hospital, Kawasaki, Japan
Corresponding Author
Shinsuke Akita Department of Plastic, Reconstructive, and Aesthetic Surgery, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba City, Chiba-city, Chiba, 260-8670, Japan Tel: +81-43-222-7171, Fax: +81-43-226-2316
Financial support: None
Funding: The author does not have a financial interest in any of the products, devices, or drugs mentioned in this manuscript.
Conflict of Interest:
None
Short running ahead: Prevention of venous reflux in lymphaticovenular anastomosis
Abstract Background: Intraoperative retrograde blood flow from the vein to the lymphatic vessels in a lymphaticovenular anastomosis (LVA) for lower extremity lymphedema (LEL) leads to poor results. This study aimed to establish a treatment strategy to control venous reflux in LVA. Methods: A unified strategy to prevent venous reflux was used in 95 limbs (study group). Dilated perforating veins were ligated, and LVA at the small branch of the ligated vein was considered. External valvuloplasty in the small vein was performed to eliminate venous reflux pre- and post-LVA. A Y-shaped venoplasty for the relatively large vein was considered in cases without adequate-sized vein stump with functional valve. The results were compared with the 34 limbs undergoing conventional multiple LVAs (control group). Results: Intraoperative venous reflux and postoperative ecchymosis significantly decreased in study group (0/462 anastomosis vs 15/148 anastomosis, p < 0.0001 and 0/81 patients vs 3/25 patients, p = 0.01, respectively). The average frequency of cellulitis during a year following LVA was significantly smaller in study group than in control group (0.05 ± 0.03 vs 0.20 ± 0.06, p = 0.04).The amount of improvement in LEL index a year after LVA was significantly larger in study group than in control group
(22.2 ± 9.6 vs 18.3 ± 9.8, p = 0.04) Conclusion: Using the new strategy developed in this study, venous reflux could be completely prevented, and stable clinical results were obtained in patients with LEL. Prevention of venous reflux with full utilization of venoplasty might improve the LVA result.
Key words: lower extremity lymphedema; lymphaticovenular anastomosis; venoplasty; venous reflux.
Introduction Lymphaticovenular anastomosis (LVA) using a super-microsurgery is less invasive than conventional surgical treatments and has become the choice of treatments for lower extremity lymphedema (LEL).1-3 Both lymphatic and venous functions should be considered in planning LVA.4-7 As the flow from high-pressure lymphatic system into the low-pressure venous system should be created to achieve stable results, those with lymphedema who have complicated venous stasis disease should not be indicated for LVA.8 It has been reported that intraoperative retrograde blood flow from the vein to the lymphatic vessels at the anastomosed portion leads to poor results.7,9 Therefore, the vein should be appropriately selected to prevent venous reflux. Techniques of extended vein dissection and external valvuloplasty have been proposed for the small vein to prevent venous reflux previously.9 We hypothesized that a more thorough strategy in controlling venous reflux was necessary to achieve more stable results in LVA for LEL. In this study, some novel surgical ideas and techniques have been developed to prevent venous reflux and contact between lymphatic vessel and blood with full utilization of venoplasty in LVA. This study aimed to establish a treatment strategy to control venous reflux in LVA.
Patients and Methods This was a retrospective comparative review of the clinical data in a case series. The study protocol was approved by the hospital’s institutional review board (No. 3000). As a study group, consecutive patients who underwent LVA for lower extremity lymphedema from August 2016 to February 2018 in Chiba University Hospital (Chiba, Japan) and Katsutadai Hospital (Yachiyo, Japan) were enrolled. The surgical results of the patients who underwent LVA from May 2011 to March 2012 in Chiba University hospital using the conventional surgical method were used as a control group. Additionally, the patients in control group were enrolled in another study we previously published. Written informed consent to participate in this study was obtained from all patients. Patients who underwent combined surgical treatments for lymphedema (LVA, vascularized lymph node transfer, and/or liposuction) were excluded from the study. Patients who underwent LVA for subclinical lymphedema and early stage LEL were excluded from the study. Patients with post-thrombotic syndrome after deep venous thrombosis treatment and those aged less than 18 years were excluded from the study. Results of 95 limbs of 81 patients in study group and 34 limbs of 25 patients in control
group were analyzed. All patients included in both groups received conservative treatments supervised by specialists and ware compression garment at pressures of at least 30 mm Hg for over 6 months before surgery.
Preoperative Examinations Preoperatively, Indocyanine green (ICG) lymphography and ultrasonography were performed for mapping both the lymphatic and venous flows. One of the purposes of these examinations was to evaluate the lymphatic function and chronic venous insufficiency; second purpose was to determine the portion of skin incision. ICG lymphography was performed to evaluate the lymphatic function of the patients and map the running pattern of the lymphatic vessels.10-11 Lymphatic function was categorized into 0–V stages according to the dermal backflow (DBF) stage classified by Yamamoto et al.12 Although we have indicated LVA for the patients in ICG DBF stage I and II, they were excluded from the analysis because their leg volume did not increase under conservative treatments. All the patients who underwent LVA for ICG DBF stage III and V were included in the study. To observe multiple lines of collecting lymphatic for performing multiple LVAs, multiple injection of ICG was performed.13 The patients underwent ultrasonography to confirm the location of the great saphenous
vein and its associated branches in standing position.9 The patients with failed valve in the main trunk of the great saphenous vein were excluded from surgical indication for LVA, and a vascular surgeon was consulted for the treatment plan of chronic venous disease. Otherwise, when dilation and/or reflux of blood toward the surface was observed at the communication veins that connect the superficial and deep systems, or the vein accompanied with skin perforator artery, these veins were marked to be ligated at the portion of penetration of the deep fascia because blood inflow from the deep to superficial vein might increase the venous pressure, and the risk of venous reflux at LVA might be increased if they were left unattended. Subcutaneous and accompanying veins of the skin perforator artery with anterograde flow around the lymphatic vessels detected in ICG lymphography were assessed by ultrasonography to determine skin incision site in LVA. The location of groin lymph nodes and the feeding blood vessels to the lymph nodes were also detected in order to perform LVA at the efferent or afferent lymphatics.9
Surgical Methods At the site of dilated communication veins or veins accompanying the skin perforator artery detected on preoperative ultrasonography, skin incisions were made with or
without collecting lymphatic vessel identification on preoperative examination. Venous dissection was carefully performed to preserve the collecting lymphatic vessels and the narrow venous branches that might be present. Ligation of the dilated vein located beneath the fascia was performed first to reduce the blood inflow into superficial system. When sizable lymphatic above the deep fascia and non-reflux vein were found in this skin incision, LVA was also performed. The ligated vein that branched an adequately sized small vein with functional valve could be used for LVA (Fig. 1). In our review, we used lymphatic collectors in superficial system including the lymphatics running along with great saphenous vein in majority of the cases, except for the popliteal fossa and groin. Then, skin incisions were made at the sites for LVAs. To include adequately sized vein for anastomosis with the functional venous valve, the veins were dissected beyond the venous bifurcation. Anastomosis between the lymphatic and side wall of the veins was never planned because the venous valve could not be used to prevent blood reflux at LVA. In all anastomoses, the vein stump was used for LVA. Multiple LVAs via multiple skin incisions were performed. During the vein dissection, venous reflux was examined using a retrograde milking test to confirm the valve function before cutting the vein.9 Use of a vein with smaller diameter instead of the
collecting lymphatic vessel was avoided to maximize the flow volume at the anastomotic site. If venous reflux was observed in all venous bifurcations with adequate sizable diameter, external valvuloplasty in the vein was performed to eliminate venous reflux before performing anastomosis.9 In cases without adequate-sized vein stump with functional valve, a novel venoplasty technique was developed (Fig. 2). This technique could be performed in a vein with functional valve that was thicker than the lymphatic vessel. The vein was cut longitudinally at two portions, and the cut ends were sutured to make Y-shaped branches. The two created non-refluxing veins could be used for both two end-to-end anastomoses with proximal and distal ends of a severed collecting lymphatic vessel, or two side-to-end anastomoses with two collecting lymphatic vessels running in parallel. (See Video, Supplemental Digital Content 1, demonstrating the Y-shaped venoplasty procedure. The two venous branches made from one large vein were used for side-to-end anastomoses with two collecting lymphatics running in parallel. The patency of anastomoses was confirmed by patent blue dye.) To minimize the risk of thrombosis associated with venoplasty, the technique was indicated only when non-reflux vein was obtained or after venous reflux was completely prevented by valvuloplasty.
When skin retractor was used during anastomosis, venous reflux was often observed only after releasing the skin traction. External valvuloplasty was performed after anastomosis (See Video, Supplemental Digital Content 2, which demonstrates the external valvuloplasty procedure after completing the side-to-end anastomosis of the LVA and detecting venous reflux. Through-and-through transluminal suture was placed traversing the valve cusps. After an external valvuloplasty, the venous reflux was stopped.) In cases with a high lymphatic flow rate, the presence of an anterograde lymphatic flow and the absence of venous blood reflux could be confirmed by a patency test, and confirmation with a blue dye or ICG was unnecessary. When lymph flow was not high, a patency test using blue dye or ICG was required to confirm the patency at the site of valvuloplasty. When the site of valvuloplasty was very close to the junction to the larger vein, patency test was difficult to perform; thus, the patency at the site of valvuloplasty was confirmed using ICG lymphography. [See Video, Supplemental Digital Content 3, which demonstrates two different cases of ICG lymphography after completion of LVA (white arrow) and valvuloplasty (yellow arrow). In the first case, patency test using ICG was performed to confirm patency at the site of valvuloplasty. In the second case, patency at the site of valvuloplasty was confirmed by ICG lymphography under
squeezing of the surrounding skin because the site of valvuloplasty was very close to the junction.]
Evaluation Prior to wound closure, the final venous reflux of each anastomosis was evaluated and recorded. The occurrence of postoperative ecchymosis, the total number of cellulitis episodes during the 1-year follow-up after LVA, and perioperative changes in lymphedematous volume at 1 year after LVA were recorded using the LEL index. LEL index is calculated according to the five-point circumferences of the limb (i.e., superior edge of the patella, 10 cm above and below the patella, lateral malleolus, and foot dorsum) and body mass index (BMI) to quantitatively assess the severity of lymphedema.14, 15 In our preliminary data analysis, we compared perioperative change in BMI using a paired t-test and found a significant difference in BMI before and after LVA. Therefore, we used the LEL index, an index of lymphedematous volume that considered changes in BMI, to analyze volume changes in this study.
Statistical Analysis
The JMP statistical software (version 13; SAS Institute Inc.; Cary, NC) was used for all statistical analyzes. A chi-square test and unpaired t-test were used to compare each parameter between the groups. A paired t-test was used to compare the perioperative changes in each group. A value of p < 0.05 was considered statistically significant.
Results The basic characteristics of the patients are listed in Table 1. No significant difference was observed between the groups in basic characteristics and the number of anastomosis. The results of the both groups are listed in Table 2. In study group, reflux of blood at the communication veins were observed in 20 limbs of 17 cases and ligation of the dilated veins were performed all of them. Venous reflux was observed in 28 veins out of 462 anastomoses and valvuloplasty was performed for all those veins. Y-shaped venoplasty was performed in eight veins in the cases in which only two parallel collecting lymphatics and a vein that was too thick to anastomose were obtained in the operative field. It was possible to create two anterograde lymphatic flows from the collecting lymphatic to the vein in all of them. During the intraoperative evaluation immediately before skin closure, no venous reflux at anastomosis was observed in all
462 anastomoses in the study group. In the control group, venous reflux was observed in 15 out of 148 anastomoses and there was a significant difference in the ratio of venous reflux between the groups (p < 0.0001). There was also a significant difference between the groups in the ratio of the case in which postoperative ecchymosis was observed (zero out of 81 patients in the study group vs three out of 25 patients in the control group, p = 0.01). In all three patients with extensive subcutaneous hemorrhage, the area of ecchymosis was equal to the area of dermal backflow recognized with ICG lymphography. The average frequency of cellulitis during a year following LVA was significantly smaller in the study group than in the control group (0.05 ± 0.03 vs 0.20 ± 0.06, p = 0.04). The amount of improvement in LEL index was significantly larger in the study group than in the control group (22.2 ± 9.6 vs 18.3 ± 9.8, p = 0.04).
Discussion This study developed a novel strategy to prevent venous reflux at LVA including venoplasty techniques and showed that it was effective in reducing immediate postoperative complications and improving long-term results. Our novel strategy was developed based on the following criteria:
Patients with venous reflux in the main trunk of the saphenous vein were not
indicated for LVA. However, when only reflux of the communicating veins and/or the veins accompanying the perforating artery were noted, LVA could be indicated for the patients after these veins were ligated at the level of deep fascia to minimize the superficial venous pressure at standing position. LVA was also indicated at small branches of these veins just after ligation when venous reflux was not observed.
The vein stump with functional valve was absolutely used for LVA. When adequately sized vein with functional valve could not be found even after complete dissection of the branches, venoplasty techniques (external valvuloplasty and Y-shaped venoplasty) were indicated.
Venous reflux might become apparent after releasing the skin traction. The necessity of external valvuloplasty should be reexamined immediately before skin closure to prevent venous reflux.
In a normal human body condition, blood does not flow into the lymphatic system. Podoplanin is expressed on the surface of lymphatic endothelial cells (LECs), but not on the surface of the vascular endothelial cells.16-19 C-type lectin-like receptor 2 (CLEC-2) is a platelet-activating receptor, and podoplanin is an endogenous ligand for CLEC-2.20, 21
Activated platelets can induce thrombus formation in lymphatic vessels or inhibit the
proliferation of human LEC and suppress lymphangiogenesis.22-24 Because LVA is a surgical procedure that creates a non-physiologically present bypass between lymphatic and blood vessels, contact between blood and LECs should be carefully monitored. Not only in cases of venous reflux but also in existing LVA methods in which LECs are constantly exposed to the bloodstream such as peripheral venous angle plasty method, end-to-side LVA, and side-to-side LVA, the risk of platelet activation and thrombosis should be taken into considerations.25-29 These concerns may become apparent when blood tests for platelet activation are conducted in future clinical studies. Because the risk of venous reflux is theoretically clear, care should be taken to prevent venous reflux. Microsurgical techniques of venoplasty have already been reported as an option for adjusting the size of large vein.30 The risk of thrombosis may be associated with venoplasty techniques. In particular, because Y-shaped venoplasty creates narrow pathway of the fluid, venous reflux should be prevented at proximal portion and narrow pathway should be certainly filled with lymphatic fluid. The study included many patients with relatively advanced-stage lymphedema. It was difficult to observe lymphatic channels in the dermal back flow pattern region in advanced-stage lymphedema. In recent years, new techniques, such as ultra-high
frequency ultrasonographic imaging and photoacoustic lymphangiography, have improved the visualization of lymphatic vessels.31,
32
In both preoperative and
postoperative evaluations, we expect that the development of these new technologies will further improve the surgical treatment of lymphedema. However, this study has some limitations. Although it was possible to compare the results between two equalized groups for basic characteristics, the severity of LEL, and perioperative conservative treatments, there was a remarkable difference in sample size between the two groups. Because significant differences were obtained even in different sample sizes, there was no statistical problem; however, this study was a retrospective comparative study. Moreover, in the study group, several treatment procedures were simultaneously intervened to prevent venous reflux into the lymphatics; thus, only some procedures might be effective for improving the clinical results and the others might not be attributable to the improved outcomes. The sample size included in the study was small, and the study was not designed to validate procedures that were effective. A prospective comparative trial of each single technique with sufficient numbers of the patients will verify the treatment effectiveness. Another limitation of this study was that the postoperative patency rate of the anastomosis in valvuloplasty and venoplasty were not evaluated using ICG lymphography because branches of communicating and
saphenous veins often existed at relatively deep layer in the subcutaneous fat, and some of the collecting lymphatic vessels used in this study were not enhanced by ICG lymphography. We hope that the advances in ultrasound and other techniques to evaluate the lymphatic flow in deep layer would further clarify the effectiveness of this treatment. Another limitation of our study was that we used LEL index in assessing the volume change because BMI of the patients also changed significantly during the study period. Although LEL index has been proven as a useful tool to evaluate the severity and therapeutic effects of lymphedema, considering changes in BMI, factors affecting the changes in values should be carefully considered when evaluating the volume changes of lymphedema.4,6,14, 15
Conclusion As a result of various efforts to prevent venous reflux in LVA, complete prevention of postoperative ecchymosis, stable volume reduction, and reduction of the cellulitis frequency were achieved. Prevention of venous reflux with full utilization of venoplasty might contribute to improved surgical treatment outcomes of LEL.
Acknowledgements
The authors gratefully acknowledge the assistance of Y, Kawashima and K. Hara for data collection.
Financial support: None
Funding: The author does not have a financial interest in any of the products, devices, or drugs mentioned in this manuscript.
Conflict of Interest: None
Ethical Approval: The institutional ethical committee approved this study (approval number; 3000).
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Figure legends
Fig 1. An example of lymphaticovenular anastomosis (LVA) at a small venous branch of the ligated communicating vein. LVA with anterograde flow can be successfully established. The valve function of the small branch of the vein to be anastomosed was essential for the anterograde flow at the LVA portion.
Fig 2.
An illustration to explain the Y-shaped venoplasty technique to make two appropriate-sized veins with functional valve. During the LVA procedure, surgeons occasionally meet two parallel lymphatic vessels with a diameter adequate for anastomosis. Using the Y-shaped venoplasty, two vein stumps with functional valve can be made to perform LVA from one relatively large vein. See also the video, supplemental digital content 1.
Video, Supplemental Digital Content 1 demonstrating the operation of Y-shaped venoplasty.
Video, Supplemental Digital Content 2 demonstrating the operation of external valvuloplasty after completing a side-to-end anastomosis of LVA.
Video, Supplemental Digital Content 3 demonstrating two different cases of ICG lymphography after the completion of LVA (white arrow) and valvuloplasty (yellow arrow).
Table 1. Basic characteristics of the patients in control group and study group.
Total number of limbs (patients)
Age (years)
Control Group
Study Group
34 (25)
95 (81)
51.5 ± 16.2
54.3
± 17.7
P Value
0.49
Sex; Male / Female
3 / 22
7 /74
0.70
Preoperative BMI
23.2 ± 0.7
23.5 ± 0.4
0.64
Preoperative LEL Index
291.3 ± 49.7
281.7 ± 22.3
0.13
Number of Anastomosis
4.4. ± 0.2
4.9 ± 0.1
0.054
BMI, body mass index; LEL Index lower extremity lymphedema index
Table 2. Clinical results following LVA
Control Group
Study Group
34 (25)
95 (81)
Total Number of Anastomosis
148
462
Venous Reflux before Wound Closure
15
0
< 0.0001
Postoperative Ecchymosis
3
0
0.01
Number of cellulitis episodes per year
0.20 ± 0.06
0.05 ± 0.03
0.04
Improvement in LEL Index
18.3 ± 9.8
22.2 ± 9.6
0.04
Number of the Limbs (Patients)
LEL Index lower extremity lymphedema index
P Value
Prevention of venous reflux with full utilization of venoplasty in lymphaticovenular anastomosis Shinsuke Akita , Yoshihisa Yamaji , Hideki Tokumoto , Haruka Maei , Takafumi Tezuka , Hideyuki Ogata , Kentaro Kosaka , Yoshitaka Kubota , Motone Kuriyama , Nobuyuki Mitsukawa PII: DOI: Reference:
S1748-6815(19)30488-7 https://doi.org/10.1016/j.bjps.2019.10.020 PRAS 6304
To appear in:
Journal of Plastic, Reconstructive & Aesthetic Surgery
Received date: Accepted date:
16 June 2019 9 October 2019
Please cite this article as: Shinsuke Akita , Yoshihisa Yamaji , Hideki Tokumoto , Haruka Maei , Takafumi Tezuka , Hideyuki Ogata , Kentaro Kosaka , Yoshitaka Kubota , Motone Kuriyama , Nobuyuki Mitsukawa , Prevention of venous reflux with full utilization of venoplasty in lymphaticovenular anastomosis, Journal of Plastic, Reconstructive & Aesthetic Surgery (2019), doi: https://doi.org/10.1016/j.bjps.2019.10.020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons.
Prevention of venous reflux with full utilization of venoplasty in lymphaticovenular anastomosis
Shinsuke Akita, MD, PhD.1, Yoshihisa Yamaji MD, PhD.2, Hideki Tokumoto, MD, PhD.3, Haruka Maei, MD.1, Takafumi Tezuka, MD.1, Hideyuki Ogata MD.1, Kentaro Kosaka, MD, PhD.1, Yoshitaka Kubota, MD, PhD.1; Motone Kuriyama, MD, PhD.1, 4, Nobuyuki Mitsukawa MD, PhD.1
1. Department of Plastic, Reconstructive, and Aesthetic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan 2. Department of Plastic, Reconstructive, and Aesthetic Surgery, Japan Red Cross Maebashi Hospital. Maebashi, Japan 3. Department of Plastic and Reconstructive Surgery, Chiba Cancer Center Hospital, Chiba, Japan 4. Department of Plastic and Reconstructive Surgery, Shinyurigaoka General Hospital, Kawasaki, Japan
Corresponding Author
Shinsuke Akita Department of Plastic, Reconstructive, and Aesthetic Surgery, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba City, Chiba-city, Chiba, 260-8670, Japan Tel: +81-43-222-7171, Fax: +81-43-226-2316
Financial support: None
Funding: The author does not have a financial interest in any of the products, devices, or drugs mentioned in this manuscript.
Conflict of Interest:
None
Short running ahead: Prevention of venous reflux in lymphaticovenular anastomosis
Abstract Background: Intraoperative retrograde blood flow from the vein to the lymphatic vessels in a lymphaticovenular anastomosis (LVA) for lower extremity lymphedema (LEL) leads to poor results. This study aimed to establish a treatment strategy to control venous reflux in LVA. Methods: A unified strategy to prevent venous reflux was used in 95 limbs (study group). Dilated perforating veins were ligated, and LVA at the small branch of the ligated vein was considered. External valvuloplasty in the small vein was performed to eliminate venous reflux pre- and post-LVA. A Y-shaped venoplasty for the relatively large vein was considered in cases without adequate-sized vein stump with functional valve. The results were compared with the 34 limbs undergoing conventional multiple LVAs (control group). Results: Intraoperative venous reflux and postoperative ecchymosis significantly decreased in study group (0/462 anastomosis vs 15/148 anastomosis, p < 0.0001 and 0/81 patients vs 3/25 patients, p = 0.01, respectively). The average frequency of cellulitis during a year following LVA was significantly smaller in study group than in control group (0.05 ± 0.03 vs 0.20 ± 0.06, p = 0.04).The amount of improvement in LEL index a year after LVA was significantly larger in study group than in control group
(22.2 ± 9.6 vs 18.3 ± 9.8, p = 0.04) Conclusion: Using the new strategy developed in this study, venous reflux could be completely prevented, and stable clinical results were obtained in patients with LEL. Prevention of venous reflux with full utilization of venoplasty might improve the LVA result.
Key words: lower extremity lymphedema; lymphaticovenular anastomosis; venoplasty; venous reflux.
Introduction Lymphaticovenular anastomosis (LVA) using a super-microsurgery is less invasive than conventional surgical treatments and has become the choice of treatments for lower extremity lymphedema (LEL).1-3 Both lymphatic and venous functions should be considered in planning LVA.4-7 As the flow from high-pressure lymphatic system into the low-pressure venous system should be created to achieve stable results, those with lymphedema who have complicated venous stasis disease should not be indicated for LVA.8 It has been reported that intraoperative retrograde blood flow from the vein to the lymphatic vessels at the anastomosed portion leads to poor results.7,9 Therefore, the vein should be appropriately selected to prevent venous reflux. Techniques of extended vein dissection and external valvuloplasty have been proposed for the small vein to prevent venous reflux previously.9 We hypothesized that a more thorough strategy in controlling venous reflux was necessary to achieve more stable results in LVA for LEL. In this study, some novel surgical ideas and techniques have been developed to prevent venous reflux and contact between lymphatic vessel and blood with full utilization of venoplasty in LVA. This study aimed to establish a treatment strategy to control venous reflux in LVA.
Patients and Methods This was a retrospective comparative review of the clinical data in a case series. The study protocol was approved by the hospital’s institutional review board (No. 3000). As a study group, consecutive patients who underwent LVA for lower extremity lymphedema from August 2016 to February 2018 in Chiba University Hospital (Chiba, Japan) and Katsutadai Hospital (Yachiyo, Japan) were enrolled. The surgical results of the patients who underwent LVA from May 2011 to March 2012 in Chiba University hospital using the conventional surgical method were used as a control group. Additionally, the patients in control group were enrolled in another study we previously published. Written informed consent to participate in this study was obtained from all patients. Patients who underwent combined surgical treatments for lymphedema (LVA, vascularized lymph node transfer, and/or liposuction) were excluded from the study. Patients who underwent LVA for subclinical lymphedema and early stage LEL were excluded from the study. Patients with post-thrombotic syndrome after deep venous thrombosis treatment and those aged less than 18 years were excluded from the study. Results of 95 limbs of 81 patients in study group and 34 limbs of 25 patients in control
group were analyzed. All patients included in both groups received conservative treatments supervised by specialists and ware compression garment at pressures of at least 30 mm Hg for over 6 months before surgery.
Preoperative Examinations Preoperatively, Indocyanine green (ICG) lymphography and ultrasonography were performed for mapping both the lymphatic and venous flows. One of the purposes of these examinations was to evaluate the lymphatic function and chronic venous insufficiency; second purpose was to determine the portion of skin incision. ICG lymphography was performed to evaluate the lymphatic function of the patients and map the running pattern of the lymphatic vessels.10-11 Lymphatic function was categorized into 0–V stages according to the dermal backflow (DBF) stage classified by Yamamoto et al.12 Although we have indicated LVA for the patients in ICG DBF stage I and II, they were excluded from the analysis because their leg volume did not increase under conservative treatments. All the patients who underwent LVA for ICG DBF stage III and V were included in the study. To observe multiple lines of collecting lymphatic for performing multiple LVAs, multiple injection of ICG was performed.13 The patients underwent ultrasonography to confirm the location of the great saphenous
vein and its associated branches in standing position.9 The patients with failed valve in the main trunk of the great saphenous vein were excluded from surgical indication for LVA, and a vascular surgeon was consulted for the treatment plan of chronic venous disease. Otherwise, when dilation and/or reflux of blood toward the surface was observed at the communication veins that connect the superficial and deep systems, or the vein accompanied with skin perforator artery, these veins were marked to be ligated at the portion of penetration of the deep fascia because blood inflow from the deep to superficial vein might increase the venous pressure, and the risk of venous reflux at LVA might be increased if they were left unattended. Subcutaneous and accompanying veins of the skin perforator artery with anterograde flow around the lymphatic vessels detected in ICG lymphography were assessed by ultrasonography to determine skin incision site in LVA. The location of groin lymph nodes and the feeding blood vessels to the lymph nodes were also detected in order to perform LVA at the efferent or afferent lymphatics.9
Surgical Methods At the site of dilated communication veins or veins accompanying the skin perforator artery detected on preoperative ultrasonography, skin incisions were made with or
without collecting lymphatic vessel identification on preoperative examination. Venous dissection was carefully performed to preserve the collecting lymphatic vessels and the narrow venous branches that might be present. Ligation of the dilated vein located beneath the fascia was performed first to reduce the blood inflow into superficial system. When sizable lymphatic above the deep fascia and non-reflux vein were found in this skin incision, LVA was also performed. The ligated vein that branched an adequately sized small vein with functional valve could be used for LVA (Fig. 1). In our review, we used lymphatic collectors in superficial system including the lymphatics running along with great saphenous vein in majority of the cases, except for the popliteal fossa and groin. Then, skin incisions were made at the sites for LVAs. To include adequately sized vein for anastomosis with the functional venous valve, the veins were dissected beyond the venous bifurcation. Anastomosis between the lymphatic and side wall of the veins was never planned because the venous valve could not be used to prevent blood reflux at LVA. In all anastomoses, the vein stump was used for LVA. Multiple LVAs via multiple skin incisions were performed. During the vein dissection, venous reflux was examined using a retrograde milking test to confirm the valve function before cutting the vein.9 Use of a vein with smaller diameter instead of the
collecting lymphatic vessel was avoided to maximize the flow volume at the anastomotic site. If venous reflux was observed in all venous bifurcations with adequate sizable diameter, external valvuloplasty in the vein was performed to eliminate venous reflux before performing anastomosis.9 In cases without adequate-sized vein stump with functional valve, a novel venoplasty technique was developed (Fig. 2). This technique could be performed in a vein with functional valve that was thicker than the lymphatic vessel. The vein was cut longitudinally at two portions, and the cut ends were sutured to make Y-shaped branches. The two created non-refluxing veins could be used for both two end-to-end anastomoses with proximal and distal ends of a severed collecting lymphatic vessel, or two side-to-end anastomoses with two collecting lymphatic vessels running in parallel. (See Video, Supplemental Digital Content 1, demonstrating the Y-shaped venoplasty procedure. The two venous branches made from one large vein were used for side-to-end anastomoses with two collecting lymphatics running in parallel. The patency of anastomoses was confirmed by patent blue dye.) To minimize the risk of thrombosis associated with venoplasty, the technique was indicated only when non-reflux vein was obtained or after venous reflux was completely prevented by valvuloplasty.
When skin retractor was used during anastomosis, venous reflux was often observed only after releasing the skin traction. External valvuloplasty was performed after anastomosis (See Video, Supplemental Digital Content 2, which demonstrates the external valvuloplasty procedure after completing the side-to-end anastomosis of the LVA and detecting venous reflux. Through-and-through transluminal suture was placed traversing the valve cusps. After an external valvuloplasty, the venous reflux was stopped.) In cases with a high lymphatic flow rate, the presence of an anterograde lymphatic flow and the absence of venous blood reflux could be confirmed by a patency test, and confirmation with a blue dye or ICG was unnecessary. When lymph flow was not high, a patency test using blue dye or ICG was required to confirm the patency at the site of valvuloplasty. When the site of valvuloplasty was very close to the junction to the larger vein, patency test was difficult to perform; thus, the patency at the site of valvuloplasty was confirmed using ICG lymphography. [See Video, Supplemental Digital Content 3, which demonstrates two different cases of ICG lymphography after completion of LVA (white arrow) and valvuloplasty (yellow arrow). In the first case, patency test using ICG was performed to confirm patency at the site of valvuloplasty. In the second case, patency at the site of valvuloplasty was confirmed by ICG lymphography under
squeezing of the surrounding skin because the site of valvuloplasty was very close to the junction.]
Evaluation Prior to wound closure, the final venous reflux of each anastomosis was evaluated and recorded. The occurrence of postoperative ecchymosis, the total number of cellulitis episodes during the 1-year follow-up after LVA, and perioperative changes in lymphedematous volume at 1 year after LVA were recorded using the LEL index. LEL index is calculated according to the five-point circumferences of the limb (i.e., superior edge of the patella, 10 cm above and below the patella, lateral malleolus, and foot dorsum) and body mass index (BMI) to quantitatively assess the severity of lymphedema.14, 15 In our preliminary data analysis, we compared perioperative change in BMI using a paired t-test and found a significant difference in BMI before and after LVA. Therefore, we used the LEL index, an index of lymphedematous volume that considered changes in BMI, to analyze volume changes in this study.
Statistical Analysis
The JMP statistical software (version 13; SAS Institute Inc.; Cary, NC) was used for all statistical analyzes. A chi-square test and unpaired t-test were used to compare each parameter between the groups. A paired t-test was used to compare the perioperative changes in each group. A value of p < 0.05 was considered statistically significant.
Results The basic characteristics of the patients are listed in Table 1. No significant difference was observed between the groups in basic characteristics and the number of anastomosis. The results of the both groups are listed in Table 2. In study group, reflux of blood at the communication veins were observed in 20 limbs of 17 cases and ligation of the dilated veins were performed all of them. Venous reflux was observed in 28 veins out of 462 anastomoses and valvuloplasty was performed for all those veins. Y-shaped venoplasty was performed in eight veins in the cases in which only two parallel collecting lymphatics and a vein that was too thick to anastomose were obtained in the operative field. It was possible to create two anterograde lymphatic flows from the collecting lymphatic to the vein in all of them. During the intraoperative evaluation immediately before skin closure, no venous reflux at anastomosis was observed in all
462 anastomoses in the study group. In the control group, venous reflux was observed in 15 out of 148 anastomoses and there was a significant difference in the ratio of venous reflux between the groups (p < 0.0001). There was also a significant difference between the groups in the ratio of the case in which postoperative ecchymosis was observed (zero out of 81 patients in the study group vs three out of 25 patients in the control group, p = 0.01). In all three patients with extensive subcutaneous hemorrhage, the area of ecchymosis was equal to the area of dermal backflow recognized with ICG lymphography. The average frequency of cellulitis during a year following LVA was significantly smaller in the study group than in the control group (0.05 ± 0.03 vs 0.20 ± 0.06, p = 0.04). The amount of improvement in LEL index was significantly larger in the study group than in the control group (22.2 ± 9.6 vs 18.3 ± 9.8, p = 0.04).
Discussion This study developed a novel strategy to prevent venous reflux at LVA including venoplasty techniques and showed that it was effective in reducing immediate postoperative complications and improving long-term results. Our novel strategy was developed based on the following criteria:
Patients with venous reflux in the main trunk of the saphenous vein were not
indicated for LVA. However, when only reflux of the communicating veins and/or the veins accompanying the perforating artery were noted, LVA could be indicated for the patients after these veins were ligated at the level of deep fascia to minimize the superficial venous pressure at standing position. LVA was also indicated at small branches of these veins just after ligation when venous reflux was not observed.
The vein stump with functional valve was absolutely used for LVA. When adequately sized vein with functional valve could not be found even after complete dissection of the branches, venoplasty techniques (external valvuloplasty and Y-shaped venoplasty) were indicated.
Venous reflux might become apparent after releasing the skin traction. The necessity of external valvuloplasty should be reexamined immediately before skin closure to prevent venous reflux.
In a normal human body condition, blood does not flow into the lymphatic system. Podoplanin is expressed on the surface of lymphatic endothelial cells (LECs), but not on the surface of the vascular endothelial cells.16-19 C-type lectin-like receptor 2 (CLEC-2) is a platelet-activating receptor, and podoplanin is an endogenous ligand for CLEC-2.20, 21
Activated platelets can induce thrombus formation in lymphatic vessels or inhibit the
proliferation of human LEC and suppress lymphangiogenesis.22-24 Because LVA is a surgical procedure that creates a non-physiologically present bypass between lymphatic and blood vessels, contact between blood and LECs should be carefully monitored. Not only in cases of venous reflux but also in existing LVA methods in which LECs are constantly exposed to the bloodstream such as peripheral venous angle plasty method, end-to-side LVA, and side-to-side LVA, the risk of platelet activation and thrombosis should be taken into considerations.25-29 These concerns may become apparent when blood tests for platelet activation are conducted in future clinical studies. Because the risk of venous reflux is theoretically clear, care should be taken to prevent venous reflux. Microsurgical techniques of venoplasty have already been reported as an option for adjusting the size of large vein.30 The risk of thrombosis may be associated with venoplasty techniques. In particular, because Y-shaped venoplasty creates narrow pathway of the fluid, venous reflux should be prevented at proximal portion and narrow pathway should be certainly filled with lymphatic fluid. The study included many patients with relatively advanced-stage lymphedema. It was difficult to observe lymphatic channels in the dermal back flow pattern region in advanced-stage lymphedema. In recent years, new techniques, such as ultra-high
frequency ultrasonographic imaging and photoacoustic lymphangiography, have improved the visualization of lymphatic vessels.31,
32
In both preoperative and
postoperative evaluations, we expect that the development of these new technologies will further improve the surgical treatment of lymphedema. However, this study has some limitations. Although it was possible to compare the results between two equalized groups for basic characteristics, the severity of LEL, and perioperative conservative treatments, there was a remarkable difference in sample size between the two groups. Because significant differences were obtained even in different sample sizes, there was no statistical problem; however, this study was a retrospective comparative study. Moreover, in the study group, several treatment procedures were simultaneously intervened to prevent venous reflux into the lymphatics; thus, only some procedures might be effective for improving the clinical results and the others might not be attributable to the improved outcomes. The sample size included in the study was small, and the study was not designed to validate procedures that were effective. A prospective comparative trial of each single technique with sufficient numbers of the patients will verify the treatment effectiveness. Another limitation of this study was that the postoperative patency rate of the anastomosis in valvuloplasty and venoplasty were not evaluated using ICG lymphography because branches of communicating and
saphenous veins often existed at relatively deep layer in the subcutaneous fat, and some of the collecting lymphatic vessels used in this study were not enhanced by ICG lymphography. We hope that the advances in ultrasound and other techniques to evaluate the lymphatic flow in deep layer would further clarify the effectiveness of this treatment. Another limitation of our study was that we used LEL index in assessing the volume change because BMI of the patients also changed significantly during the study period. Although LEL index has been proven as a useful tool to evaluate the severity and therapeutic effects of lymphedema, considering changes in BMI, factors affecting the changes in values should be carefully considered when evaluating the volume changes of lymphedema.4,6,14, 15
Conclusion As a result of various efforts to prevent venous reflux in LVA, complete prevention of postoperative ecchymosis, stable volume reduction, and reduction of the cellulitis frequency were achieved. Prevention of venous reflux with full utilization of venoplasty might contribute to improved surgical treatment outcomes of LEL.
Acknowledgements
The authors gratefully acknowledge the assistance of Y, Kawashima and K. Hara for data collection.
Financial support: None
Funding: The author does not have a financial interest in any of the products, devices, or drugs mentioned in this manuscript.
Conflict of Interest: None
Ethical Approval: The institutional ethical committee approved this study (approval number; 3000).
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Figure legends
Fig 1. An example of lymphaticovenular anastomosis (LVA) at a small venous branch of the ligated communicating vein. LVA with anterograde flow can be successfully established. The valve function of the small branch of the vein to be anastomosed was essential for the anterograde flow at the LVA portion.
Fig 2.
An illustration to explain the Y-shaped venoplasty technique to make two appropriate-sized veins with functional valve. During the LVA procedure, surgeons occasionally meet two parallel lymphatic vessels with a diameter adequate for anastomosis. Using the Y-shaped venoplasty, two vein stumps with functional valve can be made to perform LVA from one relatively large vein. See also the video, supplemental digital content 1.
Video, Supplemental Digital Content 1 demonstrating the operation of Y-shaped venoplasty.
Video, Supplemental Digital Content 2 demonstrating the operation of external valvuloplasty after completing a side-to-end anastomosis of LVA.
Video, Supplemental Digital Content 3 demonstrating two different cases of ICG lymphography after the completion of LVA (white arrow) and valvuloplasty (yellow arrow).
Table 1. Basic characteristics of the patients in control group and study group.
Total number of limbs (patients)
Age (years)
Control Group
Study Group
34 (25)
95 (81)
51.5 ± 16.2
54.3
± 17.7
P Value
0.49
Sex; Male / Female
3 / 22
7 /74
0.70
Preoperative BMI
23.2 ± 0.7
23.5 ± 0.4
0.64
Preoperative LEL Index
291.3 ± 49.7
281.7 ± 22.3
0.13
Number of Anastomosis
4.4. ± 0.2
4.9 ± 0.1
0.054
BMI, body mass index; LEL Index lower extremity lymphedema index
Table 2. Clinical results following LVA
Control Group
Study Group
34 (25)
95 (81)
Total Number of Anastomosis
148
462
Venous Reflux before Wound Closure
15
0
< 0.0001
Postoperative Ecchymosis
3
0
0.01
Number of cellulitis episodes per year
0.20 ± 0.06
0.05 ± 0.03
0.04
Improvement in LEL Index
18.3 ± 9.8
22.2 ± 9.6
0.04
Number of the Limbs (Patients)
LEL Index lower extremity lymphedema index
P Value