- Email: [email protected]
Patent blue-enhanced lymphaticovenular anastomosis
Journal of Plastic, Reconstructive & Aesthetic Surgery (2013) 66, 382e389
Patent blue-enhanced lymphaticovenular anastomosis Benoit Ayestaray a,b,*, Farid Bekara a, Jean-Baptiste Andreoletti b a b
Department of Plastic and Reconstructive Surgery, Nimes University Hospital, pl Pr Robert Debre´, 30000 Nimes, France Department of Plastic and Reconstructive Surgery, Breast Institute, 15 Av. Jean Jaure`s, 90000 Belfort, France
Received 2 July 2012; accepted 21 October 2012
KEYWORDS Lymphedema; Supermicrosurgery; Patent blue; Lymphatic vessel; Lymphaticovenular anastomosis
Summary Background: Lymphoedema supermicrosurgery is known to be difficult to perform. Lymphatic vessels are not easy to individualise, because of their small calibre (inferior to 1 mm) and their translucent appearance. Patent blue is an organic colourant, which is able to enhance the lymphatic network. We have evaluated the morbidity and the efficacy of patent blue lymphatic enhancement, with a view to perform lymphaticovenular anastomosis. Methods: From November 2010 to January 2012, 20 patients with chronic lymphoedema of the upper limb were treated by lymphaticovenular anastomosis. The mean age of the patients was 60.1 years (range, 47e78 years). The mean duration of lymphoedema was 3.2 years (range, 1e9 years). The mean volume of patent blue injected subdermally before surgery was 1.3 ml (range, 1e2 ml). The number and the calibre of enhanced lymphatic vessels at each operative site were noted. The quality of patent blue enhancement was analysed. The efficacy of surgery was assessed by quantitative measures. Results: The mean number of coloured lymphatic vessels per operative site was 2.1 (range, 1e4). The calibre of lymphatic vessels ranged from 0.3 to 0.8 mm (average, 0.57 mm). The quality of enhancement was moderate in two patients (8%), good in nine patients (36%) and excellent in 14 patients (56%). The mean number of lymphaticovenular anastomosis performed per operative site was 2.8 (range, 2e4). The mean operative time was 2.3 h (range, 2e3 h). No allergic (0%) and infectious (0%) reactions secondary to patent blue injection occurred. No secondary lymphangitis (0%) was noted. The delay of skin resorption of the blue stain ranges from 20 to 45 days (average, 30.3 days). Four patients (20%) had a remaining blue staining at the injection site. The average circumferential differential reduction rate was 13.2% (range, 4.2e27.2%) (p < 0.001). The average cross-sectional area differential reduction rate was 24.1% (range, 9.5e46.7%) (p < 0.001). The average volume differential reduction rate was 22.8% (range, 7.2e48.8%) (p < 0.001).
* Corresponding author. Department of Plastic and Reconstructive Surgery, Nimes University Hospital, pl Pr Robert Debre ´, 30000 Nimes, France. E-mail address: [email protected] (B. Ayestaray). 1748-6815/$ - see front matter Crown Copyright ª 2012 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons. All rights reserved. http://dx.doi.org/10.1016/j.bjps.2012.10.019
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Conclusions: Patent blue-enhanced lymphaticovenular anastomosis is a safe and effective technique to treat patients with secondary lymphoedema. Its ease of use, low cost and efficiency should make it used on a priority basis to perform lymphaticovenular anastomosis. Crown Copyright ª 2012 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons. All rights reserved.
EBM level Level IV Despite recent innovations in lymph node selection associated with a breast cancer resection, secondary lymphoedema of the upper limb remains a severely debilitating condition after axillary lymphadenectomy. The treatment of lymphatic system diseases is complex and challenging. Conservative treatment, such as compressive therapy and lymph drainage, is necessary to avoid the worsening of the lymphoedema but is unable to maintain the improvement stable over time. Supermicrosurgical techniques have recently allowed us to improve the outcomes of oedema relief. It is based on lymphaticovenular bypasses between lymphatic vessels and adjacent subdermal venules.1 These vessels usually measure 0.3e0.8 mm in calibre and are translucent. Thus, they are difficult to identify intra-operatively. Recent innovations in vascular fluorescence have made the lymphatic vessel visualisation possible.2e6 The drawback is the high price of the camera device, which is around V 40,000 (US$ 42,000). On the other hand, patent blue is a low-cost organic colourant that is able to enhance lymphatic channels.7 The aim of this study is to evaluate the morbidity and the efficacy of this method, associated with lymphaticovenular anastomosis, for the treatment of chronic lymphoedema resisting conservative treatment.
conservative treatment. The mean age of the patients was 60.1 years (range, 47e78 years). The mean duration of lymphoedema was 3.2 years (range, 1e9 years). The Campisi clinical stage ranged from 2 to 5 (average, 2.8). The mean circumferential excess rate was 17.7% (range, 8e34%). The primary ‘end’ point of this study was to assess the efficacy of enhancement of lymphatic vessels by patent blue. The secondary ‘end’ point was to evaluate the morbidity of the method and its influence on lymphoedema relief after lymphaticovenular anastomosis. Assessment of the efficacy of the procedure was made by counting the number and evaluating intra-operatively the quality of enhancement of lymphatic vessels under microscope. The efficacy of the surgery was assessed by analysing two criteria, before and every month after the surgery, during a period of follow-up of 6 months: e a qualitative analysis of the soft tissue characteristics: softness, thickness (pinch test) and sensibility e a quantitative circumferential analysis, by measuring the circumferences of the arm (superior, middle and inferior parts), the forearm (superior, middle and inferior parts), the wrist and the hand, by calculating the cross-sectional area (CSA Z p.r2 Z C2/4p) at the same levels and the volume of lymphoedema (V Z p.h (C12 þ C32 þ C1.C3)/12).
Surgical procedure Methods From November 2010 to January 2012, 20 patients with a worsening chronic lymphoedema of the upper limb were treated by lymphaticovenular anastomosis (Table 1). This prospective study was approved by the Institutional Ethics Committee of two university-affiliated hospitals. All patients were enrolled in this study at least 12 months after the beginning of their lymphoedema. They were treated by conservative treatment, such as compression therapy with a Level 3 elastic stocking associated with a daily elastic bandage, and lymph drainage for at least 6 months. Their lymphoedema increased and worsened despite the daily
Table 1 Nomenclature of the various configurations of lymphaticovenular anastomosis. LVA configuration
Type of LV anastomosis
p-shaped l-shaped i-shaped
2 end-to-side 1 end-to-side þ 1 end-to-end 1 end-to-end
Before scrubbing, patent blue dye (2 ml; 2.5% Bleu Patente ´ V by Guerbet Laboratory, France) was injected subdermally 15 cm distal to the incision site, using a 0.5 ml syringe and a 24 G needle. A skin massage from distal to proximal was performed for 1 min. This procedure enhances the visualisation of the lymphatic vessels intra-operatively. All patients were operated under local anaesthesia with 1% lidocaine with 1/100,000 epinephrine. The mean volume of local anaesthetic used was 6.5 ml (range, 3e10 ml). The lymphatic vessels were dissected subdermally, through a 2.5 cm (range, 2e3 cm) skin incision. Every lymphaticovenular anastomosis was performed at the medial part of the forearm and arm, where the lymphatic network is usually dense.8 Three different configurations of lymphaticovenular anastomosis (Table 2) were used: p-shaped (double end-to-side), l-shaped (endto-side þ end-to-end) and i-shaped (end-to-end) (Video). The type of configuration was chosen according to the calibre and the anatomy of the vessels (lymphatics and venules). Lymphaticovenular anastomoses were performed with EMI Supermicrosurgery Instruments (EMI Factory Co., Ltd., Nagano, Japan) or Ultrafine Microsurgical Instruments
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Table 2
Summary of patients treated by patent blue-enhanced lymphaticovenular anastomosis.
Patient
Age Sex Duration of Severity Campisi Side Circumferential mC mC Average mC mCSA mCSA Average mV (years) lymphedema stage excess (cm) reduction reduction (cm2) reduction mCSA (cm3) 2 (years) rate ( % ) (cm) rate (%) reduction (cm ) rate (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Average
62 51 74 48 63 59 61 52 48 57 69 52 65 47 66 78 54 75 53 68 60.1
F F F F F F F F F F F F F F F F F F F F
3 1 4 8 5 1 1 2 6 2 5 1 2 9 3 1 7 4 1 2 3.2
þ þ þþ þþþ þþ þ þþ þþ þþþ þ þþþ þþ þ þþþ þþ þ þþþ þþ þþ þ
II II III IV II II III III III II V III II IV II II IV III III II 2.8
R L L R L R R L R L L L R R L R R R L R
16 8 19 27 12 9 25 21 28 8 34 14 11 27 10 9 28 14 25 9 17.7
30.5 27.4 34.8 31.5 28.6 33.2 32.2 29.5 33.2 27.2 35.5 27.6 30 29.8 26.4 37 35 27.8 36.4 29.8 31.1
3 1.4 6 5.7 1.4 2.2 7.2 6.2 6.8 1.6 9.5 1.6 2.2 4.6 1.2 2.6 9.4 2.8 8.4 2.2 4.3
10.1 4.9 17.4 19.4 4.2 6.6 21.1 19.9 20 5.9 27.2 6 7.6 15.2 4.7 7.5 27.2 8.8 23.4 7.6 13.2
77.4 62.3 101.5 82.1 69.3 93.8 89.6 71.8 93.6 60.7 100.3 63 77.7 73.1 57.8 113.3 101.9 65.3 110.1 72.9 81.8
14.3 6.4 31.6 25.5 7.4 11.9 36.8 27.5 34.9 6.9 46.5 6.9 10.7 20.8 4.7 14.5 46.7 13 44.1 10 21
18.5 10.2 31.2 34.4 10.7 12.7 41 35.5 37.3 11.3 46.7 10.9 13.7 28.4 9.5 12.8 45.8 17.9 40 13.7 24.1
45656.9 33460.6 54630.7 46413.1 37475.9 47506.9 50356.4 37015.3 48758.9 30927.7 61524.3 34554.4 44427 37231.2 33259.1 52975.7 63265.7 37475.9 52975.7 38382.5 44413.7
Average mV reduction mV reduction (cm3) rate (%) 8966 2532.9 17154.8 12952.5 2705.7 5756.7 19227.3 11786.7 16363.3 3425.3 29128.7 3626.7 5555.1 8548.6 3367.6 8548.7 30870.1 8793.3 20580.1 4921.9 11240.6
18.5 7.5 31.4 27.9 7.2 12.1 38.2 26.4 33.5 11 47.3 10.5 12.5 22.9 10.1 16.1 48.8 23.4 38.8 12.8 22.8
M: male , F : female; Severity : moderate (þ) , severe (þþ) , fibrosis (þþþ); R: right , L: left.
B. Ayestaray et al.
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Medicon and Co., Tuttlingen, Germany), and 11/0 nylon monofilament on a 50 mm needle (Ethilon, Ethicon, Johnson & Johnson Co., USA). After dissection of subdermal lymphatic vessels and adjacent venules, their calibres were measured with a professional scaled ruler (Shinwa Sokutei Co., Ltd., Sapporo Eigyosho, Japan).
Statistical analysis Quantitative data were analysed by an independent biostatistician from the department of biostatistics of Montpellier University Hospital. The paired t-test was used to compare the mean of postoperative measures to the preoperative value, overall and for each patient, with a follow-up of 6 months. Values of p < 0.05 were considered statistically significant.
Results The mean volume of patent blue injected per patient was 1.3 ml (range, 1e2 ml). The skin incision length ranged from 2 to 3 cm (average, 2.5 cm). The mean number of patent blue-enhanced lymphatic vessels per operative site was 2 (range, 1e4). The calibre of lymphatic vessels used for anastomosis from ranged 0.3e0.8 mm (average, 0.57 mm). The quality of enhancement (Figure 1) was moderate in five cases (25%), good in eight cases (40%) and excellent in seven cases (35%). The average operative time was 2.3 h (range, 2e3 h). The number of lymphaticovenular anastomoses performed during the same operative time ranged from 2 to 4 (average, 1.6). The patients were operated 1e3 times successively (average, 2). The mean number of lymphaticovenular anastomoses per limb was 7.2 (range, 4e8). The total number of end-to-side anastomoses for each patient ranged from 2 to 4 (average, 2.9). The total number of lymphaticovenular anastomoses performed in this study was 57 p-shaped (73%), nine l-shaped (11.6%) and 12 ishaped (15.4%). A venous back-flow (Figure 2) was found in 91 lymphaticovenular anastomoses (63.2%). Sixteen patients (80%) had a complete blue staining resorption at the operative site (Figure 3). The mean delay of blue staining resorption was 30.3 days (range, 20e45 days). Four patients (20%) had a remaining blue staining at the injection site (Figure 4). The size of the remaining skin colouration ranges from 1 to 5 cm (average, 2.2 cm). No patient (0%) experienced a postoperative worsening of their lymphoedema after surgery. No patient (0%) developed an allergy to Patent Blue, or a postoperative infection, including lymphangitis (Table 3). One patient (5%) had a superficial skin ulceration, inferior than 1 cm,2 at the operative site. This ulceration was spontaneously healed in 20 days. No patient (0%) experienced postoperative haematomas. No patient (0%) developed hypertrophic scars. Nineteen patients (95%) had a qualitative improvement of soft tissues after surgery. The soft tissues were softer, the pinch test was thicker and the subjective skin sensibility was improved. The reduction of the pinch test at the forearm ranged from 2 to 8 mm (average, 5.4 mm). Seventeen patients (85%) had a clinically significant circumferential reduction after surgery. The weight of their limb was also felt
Figure 1 Classification of the variations of patent blue enhancement for lymphatic vessels. Intraoperative views of patent blue-enhanced lymphatic vessels, adjacent to subdermal venules. The colouration is lighter than the purple aspect of the venules, and has 3 degrees of variation: a) moderate: very light blue, secondary to a fast diffusion of patent blue into the lymphatic network. b) good: pale turquoise blue, easily distinguishable from the colour of the adjacent venules. c) excellent: bright turquoise blue, secondary to a high impregnation of the lymphatic vessels.
to be lighter. They had to change their elastic stocking for a smaller one 2 months after surgery. The average circumferential differential reduction rate was 13.2% (range, 4.2e27.2%) (p < 0.001). The average cross-sectional area differential reduction rate was 24.1% (range, 9.5e46.7%) (p < 0.001). The average volume differential reduction rate was 22.8% (range, 7.2e48.8%) (p < 0.001). Fifteen patients (75%) definitively stopped lymph drainage 4 months after
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B. Ayestaray et al. surgery. Six patients (30%) stopped wearing their elastic stocking and bandage definitively 6 months after surgery. Eighteen patients (90%) moved to a better quality of life 6 months after surgery (Figure 5).
Discussion
Figure 2 Intraoperative view of one p-shaped lymphaticovenular anastomosis (yellow star) and two i-shaped lymphaticovenular anastomosis (yellow arrow). A venous back-flow (blue arrow) is noted at the left end-to-side lymphaticovenular anastomosis. A third lymphatic channel, which has not been used for microsurgical bypass, can be seen at the superior part of the picture.
Chronic lymphoedema is a public health issue, leading to severe functional troubles in everyday life. Nowadays, medical treatments are not efficient enough to have a stable reduction of lymphoedema in time. Recurrence is usual when compressive therapy and lymph drainage are stopped. Conservative treatment can also be inefficient regarding the oedema, which will progressively increase and worsen despite garments and physiotherapy. That is the reason why lymphaticovenular anastomosis was introduced with a view to overcome these issues. Lymphaticovenular anastomosis derives from lymphaticovenous bypasses described by Yamada in 1969.9 The technique was refined by O’Brien,10e12 and then by Koshima who introduced the concept of supermicrosurgery.1,13 Indeed, the differential pressure between the subdermal lymphatic vessels and the subdermal venules is lower, compared to larger veins.14 Then, the rate of thrombosis at the anastomosis site is decreased with supermicrosurgical techniques, comparing to classical lymphaticovenous bypasses.15
Figure 3 Case 6: Complete blue staining resorption 59 year old female having a postoperative lymphedema of the right upper limb, secondary to an axillary lymphadenectomy 1 year ago. 1.5 ml of patent blue was injected subdemally at the anterior part of the forearm. 4 lymphaticovenular anastomosis were performed (1 p þ 1 l) through 1 skin incision. The circumferential reduction rate was 6.6%, the cross-sectional area reduction rate was 12.7%, and the average volume reduction rate was 12.1% after a followup of 6 months. The blue staining resorption was complete, 20 days after surgery. a) Postperative view, immediately after surgery: typical aspect of the blue staining of the skin at the operative site the day of surgery. b) Postoperative view, 20 days after surgery : the blue staining has completely disappeared.
Figure 4 Case 9: Not completed blue staining resorption 48 year old female having a postoperative lymphedema of the right upper limb, secondary to an axillary lymphadenectomy 6 years ago. 1.5 ml of patent blue was injected subdermally at the anterior part of the forearm. 6 lymphaticovenular anastomosis were performed (1 p þ 1 l þ 2 i) through 3 skin incisions. The circumferential reduction rate was 20%, the cross-sectional area reduction rate was 37.3%, and the average volume reduction rate was 33.5% after a follow-up of 6 months. The blue staining resorption was not completed. a) Preoperative view: campisi stage III lymphedema of the right upper limb. The oedema is located at the arm, the forearm and the hand. A depression of the right shoulder is visible, due to the weight of the lymphedema. b) Postoperative view, 3 months after surgery: a light blue coloured area is still visible at the distal part of the forearm. A relief of the oedema at the arm, the forearm and the hand is visible.
Table 3
Summary of patients treated by patent blue-enhanced lymphaticovenular anastomosis.
Patient Patent Number of Number of Calibre of Quality of LVA Complication Blue (ml) blue skin enhanced LV (mm) enhancement configurations Allergy Infection Lymphangitis staining volume incisions LV skin resorption 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Average
1 1 1.5 1 2 1.5 1 2 1.5 1 2 1 1.5 1 1 1 1.5 1 2 1.5 1.3
4 2 4 3 4 1 4 2 3 4 3 3 4 4 4 3 4 4 4 3 3.4
7 5 6 6 8 4 7 2 4 6 5 5 6 8 7 3 5 6 4 6 5.5
0.5e0.8 0.4e0.6 0.3e0.6 0.5e0.7 0.3e0.8 0.4e0.7 0.5e0.6 0.4e0.8 0.6e0.8 0.3e0.7 0.3e0.5 0.6e0.8 0.5e0.7 0.4e0.7 0.3e0.8 0.5e0.6 0.4e0.7 0.5e0.7 0.6e0.8 0.4e0.7 0.57
þþ þþ þþþ þ þþþ þþ þþ þþþ þ þþþ þþþ þþ þþþ þ þþ þþ þþþ þ þþþ þþþ
4p None 2pþ2i None 3pþl None 4p None 4p None pþl None 3pþ2i None pþ2i None pþlþ2i None 4p None 4p None 2pþl None 2pþ2l None 4p None 2 p þ l þ 2 i None 3p None 2pþ2l None 4p None 3pþ2i None 4p None
Quality of enhancement:þ : moderate; þþ : good; þþþ : excellent, NC : Not Completed. a Calculated for the 16 patients having a complete blue staining resorption.
None None None None None None None None None None None None None None None None None None None None
None None None None None None None None None None None None None None None None None None None None
20 30 NC 35 25 20 45 40 NC 45 NC 20 25 20 40 30 NC 20 40 30 30.3a
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B. Ayestaray et al. enhancement in lymphatic vessels was also elaborated. This simple, affordable and reliable method should be used as a first-line standard in lymphatic supermicrosurgery.
Disclosure None.
Conflict of interest None.
Acknowledgements The author thanks very much Claire Duflos, M.D. from the department of biostatistics of Montpellier University Hospital for the statistical analysis of the data. Figure 5 Variation of the average volume of the operated upper limb in patients treated by lymphaticovenular anastomosis.
Supermicrosurgical techniques for lymphoedema remain difficult to perform because of the small calibre and the translucent appearance of lymphatic vessels. Different methods of lymphatic enhancement have been described. The most common is the indocyanine green dye, permitting us to locate lymphatic vessels by near-infrared fluorescence.2e6 The high price of the PhotoDynamic Eye (PDE), necessary to visualise the fluorescence, is the main disadvantage of this method. Lipodiol can also be used for lymphangiography. It is coupled with magnetic resonance imaging16e18 or computed tomography.19,20 Thus, it cannot be used intra-operatively. A radionuclide, such as 99mTc, is used for lymphoscintigraphy.21e25 The main disadvantage of this method is the morbidity related to the radioactivity. It cannot be used also intra-operatively. In this prospective study, Patent Blue appears as a safe and reliable dye marker to enhance lymphatic vessels. It does not need associated sophisticated devices to be used, such as the PDE or computed tomography. Its low price (V 1.85) makes the procedure very affordable. The technique is also very simple to learn and reproducible. Its low morbidity makes it a very safe method to use. Indeed, no severe complication occurred in this clinical series. Except for one case of partial skin ulceration, which spontaneously healed in 20 days, no postoperative infection, lymphangitis or allergic reaction occurred. Considering the lymphoedema reduction rates of this series, which are very close to those published with indocyanine green dye,2e6 patent blue does not affect the patency of lymphaticovenular anastomosis. In this way, patent blue-enhanced lymphaticovenular anastomosis is a safe and reliable method to treat chronic lymphoedema of the upper limb. It should be a widespread method to perform supermicrosurgical lymphaticovenular anastomosis more easily. The results of this clinical series demonstrate the safety and the efficacy of patent blue-enhanced lymphaticovenular anastomosis to treat postoperative lymphoedema of the upper limb, resistant to conservative treatment. A classification of the various degrees of patent blue
Appendix A. Supplementary data Supplementary video associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.bjps.2012.10.019.
References 1. Koshima I, Inagawa K, Urushibara K, et al. Supermicrosurgical lymphaticovenular anastomosis for the treatment of lymphoedema in the upper extremities. J Reconstr Microsurg 2000;16:432e7. 2. Unno N, Inuzuka K, Suzuki M, et al. Preliminary experience with a novel fluorescence lymphography using indocyanine green in patients with secondary lymphoedema. J Vasc Surg 2007;45: 1016e21. 3. Ogata F, Narushima M, Mihara M, et al. Intraoperative lymphography using indocyanine green dye for near-infrared fluorescence labeling in lymphoedema. Ann Plast Surg 2007; 59:180e4. 4. Unno N, Nishiyama M, Suzuki M, et al. Quantitative lymph imaging for assessment of lymph function using indocyanine green fluorescence lymphography. Eur J Vasc Endovasc 2008; 36:230e6. 5. Rassmussen JC, Tan IC, Marshall MV, et al. Lymphatic imaging in humans with near-infrared fluorescence. Curr Opin Biotechnol 2009;20:74e82. 6. Narushima M, Mihara M, Yamamoto Y, et al. The intravascular stenting method for treatment of extremity lymphoedema with multiconfiguration lymphaticovenous anastomoses. Plast Reconstr Surg 2010;125:935e43. 7. Yap YL, Lim J, Shim TWH, Naidu S, Ong WC, Lim TC. Patent blue dye in lymphaticovenular anastomosis. Ann Ac Med 2009; 38(8):704e6. 8. Zuther JE. Anatomy. In: Zuther JE, editor. Lymphoedema management. 2nd ed. Stuttgart: Thieme Verlag; 2009. p. 1e28. 9. Yamada Y. Studies on lymphatic venous anastomosis in lymphedema. Nagoya J Med Sci 1969;32:1e21. 10. O’Brien BM, Sykes P, Threlfall GN, Browning FS. Microlymphaticovenous anastomoses for obstructive lymphedema. Plast Reconstr Surg 1977;60:197e211. 11. O’Brien BM, Shafiroff BB. Microlymphaticovenous and resectional surgery in obstructive lymphedema. World J Surg 1979; 3:3e15.
Patent blue-enhanced lymphaticovenular anastomosis 12. O’Brien BM, Mellow CG, Khazanchi RK, Dvir E, Kumar V, Pederson WC. Long-term results after microlymphaticovenous anastomoses for the treatment of obstructive lymphedema. Plast Reconstr Surg 1990;85:562e72. 13. Koshima I, Nanba Y, Tsutsui T, et al. Long-term follow-up after lymphaticovenular anastomosis for lymphedema in the leg. J Reconstr Microsurg 2003;19:209e15. 14. Baumeister RG, Siuda S. Treatment of lymphedemas by microsurgical lymphatic grafting: what is proved? Plast Reconstr Surg 1990;85:64e74. Discussion 75e76. 15. Nagase T, Gonda K, Inoue K, et al. Treatment of lymphedema with lymphaticovenular anastomoses. Int J Clin Oncol 2005;10: 304e10. 16. Havard AC, Collins DJ, Guy RL, Husband JE. Magnetic resonance behaviour of lipiodol. Clin Radiol 1992;45:198e200. 17. Dimakakos E, Koureas A, Koutoulidis V, et al. Interstitial magnetic resonance lymphography: is it a new method for the diagnosis of lymphedema? Int Angiol 2007;26:367e71. 18. Dimakakos E, Koureas A, Koutoulidis V, et al. Interstitial magnetic resonance lymphography: the clinical effectiveness of a new method. Lymphology 2008;41:116e25. 19. Kos S, Haueisen H, Lachmund U, Roeren T. Lymphangiography: forgotten tool or rising star in the diagnosis and therapy of
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postoperative lymphatic vessel leakage. Cardiovasc Intervent Radiol 2007;30:968e73. Safar K, Aouaifia A, Oudjit A, Le Pimpec-Barthes F, Riquet M, Legmann P. Value of CT lymphangiography in the detection of lymphatic leakage: a report of nine cases. J Radiol 2011;92: 25e31 [French]. Yuan Z, Chen L, Luo Q, Zhu J, Lu H, Zhu R. The role of radionuclide lymphoscintigraphy in extremity lymphedema. Ann Nucl Med 2006;20:341e4. Baulieu F, Lorette G, Baulieu JL, Vaillant L. Lymphoscintigraphic exploration in the limbs lymphatic disease. Presse Med 2010;39:1292e304 [French]. Maegawa J, Mikami T, Yamamoto Y, Satake T, Kobayashi S. Types of lymphoscintigraphy and indications for lymphaticovenous anastomosis. Microsurgery 2010;30:437e42. Liu NF, Lu Q, Liu PA, Yan ZX, Wu XF. Comparison study of radionuclide lymphoscintigraphy and dynamic magnetic resonance lymphangiography for the diagnosis of extremity lymphedema. Zhonghua Zheng Xing Wai Ke Za Zhi. 2011;27:241e5. Mikami T, Hosono M, Yakubi Y, et al. Classification of lymphoscintigraphy and relevance to surgical indication for lymphaticovenous anastomosis in upper limb lymphedema. Lymphology 2011;44:155e67.
Patent blue-enhanced lymphaticovenular anastomosis Benoit Ayestaray a,b,*, Farid Bekara a, Jean-Baptiste Andreoletti b a b
Department of Plastic and Reconstructive Surgery, Nimes University Hospital, pl Pr Robert Debre´, 30000 Nimes, France Department of Plastic and Reconstructive Surgery, Breast Institute, 15 Av. Jean Jaure`s, 90000 Belfort, France
Received 2 July 2012; accepted 21 October 2012
KEYWORDS Lymphedema; Supermicrosurgery; Patent blue; Lymphatic vessel; Lymphaticovenular anastomosis
Summary Background: Lymphoedema supermicrosurgery is known to be difficult to perform. Lymphatic vessels are not easy to individualise, because of their small calibre (inferior to 1 mm) and their translucent appearance. Patent blue is an organic colourant, which is able to enhance the lymphatic network. We have evaluated the morbidity and the efficacy of patent blue lymphatic enhancement, with a view to perform lymphaticovenular anastomosis. Methods: From November 2010 to January 2012, 20 patients with chronic lymphoedema of the upper limb were treated by lymphaticovenular anastomosis. The mean age of the patients was 60.1 years (range, 47e78 years). The mean duration of lymphoedema was 3.2 years (range, 1e9 years). The mean volume of patent blue injected subdermally before surgery was 1.3 ml (range, 1e2 ml). The number and the calibre of enhanced lymphatic vessels at each operative site were noted. The quality of patent blue enhancement was analysed. The efficacy of surgery was assessed by quantitative measures. Results: The mean number of coloured lymphatic vessels per operative site was 2.1 (range, 1e4). The calibre of lymphatic vessels ranged from 0.3 to 0.8 mm (average, 0.57 mm). The quality of enhancement was moderate in two patients (8%), good in nine patients (36%) and excellent in 14 patients (56%). The mean number of lymphaticovenular anastomosis performed per operative site was 2.8 (range, 2e4). The mean operative time was 2.3 h (range, 2e3 h). No allergic (0%) and infectious (0%) reactions secondary to patent blue injection occurred. No secondary lymphangitis (0%) was noted. The delay of skin resorption of the blue stain ranges from 20 to 45 days (average, 30.3 days). Four patients (20%) had a remaining blue staining at the injection site. The average circumferential differential reduction rate was 13.2% (range, 4.2e27.2%) (p < 0.001). The average cross-sectional area differential reduction rate was 24.1% (range, 9.5e46.7%) (p < 0.001). The average volume differential reduction rate was 22.8% (range, 7.2e48.8%) (p < 0.001).
* Corresponding author. Department of Plastic and Reconstructive Surgery, Nimes University Hospital, pl Pr Robert Debre ´, 30000 Nimes, France. E-mail address: [email protected] (B. Ayestaray). 1748-6815/$ - see front matter Crown Copyright ª 2012 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons. All rights reserved. http://dx.doi.org/10.1016/j.bjps.2012.10.019
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Conclusions: Patent blue-enhanced lymphaticovenular anastomosis is a safe and effective technique to treat patients with secondary lymphoedema. Its ease of use, low cost and efficiency should make it used on a priority basis to perform lymphaticovenular anastomosis. Crown Copyright ª 2012 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons. All rights reserved.
EBM level Level IV Despite recent innovations in lymph node selection associated with a breast cancer resection, secondary lymphoedema of the upper limb remains a severely debilitating condition after axillary lymphadenectomy. The treatment of lymphatic system diseases is complex and challenging. Conservative treatment, such as compressive therapy and lymph drainage, is necessary to avoid the worsening of the lymphoedema but is unable to maintain the improvement stable over time. Supermicrosurgical techniques have recently allowed us to improve the outcomes of oedema relief. It is based on lymphaticovenular bypasses between lymphatic vessels and adjacent subdermal venules.1 These vessels usually measure 0.3e0.8 mm in calibre and are translucent. Thus, they are difficult to identify intra-operatively. Recent innovations in vascular fluorescence have made the lymphatic vessel visualisation possible.2e6 The drawback is the high price of the camera device, which is around V 40,000 (US$ 42,000). On the other hand, patent blue is a low-cost organic colourant that is able to enhance lymphatic channels.7 The aim of this study is to evaluate the morbidity and the efficacy of this method, associated with lymphaticovenular anastomosis, for the treatment of chronic lymphoedema resisting conservative treatment.
conservative treatment. The mean age of the patients was 60.1 years (range, 47e78 years). The mean duration of lymphoedema was 3.2 years (range, 1e9 years). The Campisi clinical stage ranged from 2 to 5 (average, 2.8). The mean circumferential excess rate was 17.7% (range, 8e34%). The primary ‘end’ point of this study was to assess the efficacy of enhancement of lymphatic vessels by patent blue. The secondary ‘end’ point was to evaluate the morbidity of the method and its influence on lymphoedema relief after lymphaticovenular anastomosis. Assessment of the efficacy of the procedure was made by counting the number and evaluating intra-operatively the quality of enhancement of lymphatic vessels under microscope. The efficacy of the surgery was assessed by analysing two criteria, before and every month after the surgery, during a period of follow-up of 6 months: e a qualitative analysis of the soft tissue characteristics: softness, thickness (pinch test) and sensibility e a quantitative circumferential analysis, by measuring the circumferences of the arm (superior, middle and inferior parts), the forearm (superior, middle and inferior parts), the wrist and the hand, by calculating the cross-sectional area (CSA Z p.r2 Z C2/4p) at the same levels and the volume of lymphoedema (V Z p.h (C12 þ C32 þ C1.C3)/12).
Surgical procedure Methods From November 2010 to January 2012, 20 patients with a worsening chronic lymphoedema of the upper limb were treated by lymphaticovenular anastomosis (Table 1). This prospective study was approved by the Institutional Ethics Committee of two university-affiliated hospitals. All patients were enrolled in this study at least 12 months after the beginning of their lymphoedema. They were treated by conservative treatment, such as compression therapy with a Level 3 elastic stocking associated with a daily elastic bandage, and lymph drainage for at least 6 months. Their lymphoedema increased and worsened despite the daily
Table 1 Nomenclature of the various configurations of lymphaticovenular anastomosis. LVA configuration
Type of LV anastomosis
p-shaped l-shaped i-shaped
2 end-to-side 1 end-to-side þ 1 end-to-end 1 end-to-end
Before scrubbing, patent blue dye (2 ml; 2.5% Bleu Patente ´ V by Guerbet Laboratory, France) was injected subdermally 15 cm distal to the incision site, using a 0.5 ml syringe and a 24 G needle. A skin massage from distal to proximal was performed for 1 min. This procedure enhances the visualisation of the lymphatic vessels intra-operatively. All patients were operated under local anaesthesia with 1% lidocaine with 1/100,000 epinephrine. The mean volume of local anaesthetic used was 6.5 ml (range, 3e10 ml). The lymphatic vessels were dissected subdermally, through a 2.5 cm (range, 2e3 cm) skin incision. Every lymphaticovenular anastomosis was performed at the medial part of the forearm and arm, where the lymphatic network is usually dense.8 Three different configurations of lymphaticovenular anastomosis (Table 2) were used: p-shaped (double end-to-side), l-shaped (endto-side þ end-to-end) and i-shaped (end-to-end) (Video). The type of configuration was chosen according to the calibre and the anatomy of the vessels (lymphatics and venules). Lymphaticovenular anastomoses were performed with EMI Supermicrosurgery Instruments (EMI Factory Co., Ltd., Nagano, Japan) or Ultrafine Microsurgical Instruments
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Table 2
Summary of patients treated by patent blue-enhanced lymphaticovenular anastomosis.
Patient
Age Sex Duration of Severity Campisi Side Circumferential mC mC Average mC mCSA mCSA Average mV (years) lymphedema stage excess (cm) reduction reduction (cm2) reduction mCSA (cm3) 2 (years) rate ( % ) (cm) rate (%) reduction (cm ) rate (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Average
62 51 74 48 63 59 61 52 48 57 69 52 65 47 66 78 54 75 53 68 60.1
F F F F F F F F F F F F F F F F F F F F
3 1 4 8 5 1 1 2 6 2 5 1 2 9 3 1 7 4 1 2 3.2
þ þ þþ þþþ þþ þ þþ þþ þþþ þ þþþ þþ þ þþþ þþ þ þþþ þþ þþ þ
II II III IV II II III III III II V III II IV II II IV III III II 2.8
R L L R L R R L R L L L R R L R R R L R
16 8 19 27 12 9 25 21 28 8 34 14 11 27 10 9 28 14 25 9 17.7
30.5 27.4 34.8 31.5 28.6 33.2 32.2 29.5 33.2 27.2 35.5 27.6 30 29.8 26.4 37 35 27.8 36.4 29.8 31.1
3 1.4 6 5.7 1.4 2.2 7.2 6.2 6.8 1.6 9.5 1.6 2.2 4.6 1.2 2.6 9.4 2.8 8.4 2.2 4.3
10.1 4.9 17.4 19.4 4.2 6.6 21.1 19.9 20 5.9 27.2 6 7.6 15.2 4.7 7.5 27.2 8.8 23.4 7.6 13.2
77.4 62.3 101.5 82.1 69.3 93.8 89.6 71.8 93.6 60.7 100.3 63 77.7 73.1 57.8 113.3 101.9 65.3 110.1 72.9 81.8
14.3 6.4 31.6 25.5 7.4 11.9 36.8 27.5 34.9 6.9 46.5 6.9 10.7 20.8 4.7 14.5 46.7 13 44.1 10 21
18.5 10.2 31.2 34.4 10.7 12.7 41 35.5 37.3 11.3 46.7 10.9 13.7 28.4 9.5 12.8 45.8 17.9 40 13.7 24.1
45656.9 33460.6 54630.7 46413.1 37475.9 47506.9 50356.4 37015.3 48758.9 30927.7 61524.3 34554.4 44427 37231.2 33259.1 52975.7 63265.7 37475.9 52975.7 38382.5 44413.7
Average mV reduction mV reduction (cm3) rate (%) 8966 2532.9 17154.8 12952.5 2705.7 5756.7 19227.3 11786.7 16363.3 3425.3 29128.7 3626.7 5555.1 8548.6 3367.6 8548.7 30870.1 8793.3 20580.1 4921.9 11240.6
18.5 7.5 31.4 27.9 7.2 12.1 38.2 26.4 33.5 11 47.3 10.5 12.5 22.9 10.1 16.1 48.8 23.4 38.8 12.8 22.8
M: male , F : female; Severity : moderate (þ) , severe (þþ) , fibrosis (þþþ); R: right , L: left.
B. Ayestaray et al.
(-
Patent blue-enhanced lymphaticovenular anastomosis
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Medicon and Co., Tuttlingen, Germany), and 11/0 nylon monofilament on a 50 mm needle (Ethilon, Ethicon, Johnson & Johnson Co., USA). After dissection of subdermal lymphatic vessels and adjacent venules, their calibres were measured with a professional scaled ruler (Shinwa Sokutei Co., Ltd., Sapporo Eigyosho, Japan).
Statistical analysis Quantitative data were analysed by an independent biostatistician from the department of biostatistics of Montpellier University Hospital. The paired t-test was used to compare the mean of postoperative measures to the preoperative value, overall and for each patient, with a follow-up of 6 months. Values of p < 0.05 were considered statistically significant.
Results The mean volume of patent blue injected per patient was 1.3 ml (range, 1e2 ml). The skin incision length ranged from 2 to 3 cm (average, 2.5 cm). The mean number of patent blue-enhanced lymphatic vessels per operative site was 2 (range, 1e4). The calibre of lymphatic vessels used for anastomosis from ranged 0.3e0.8 mm (average, 0.57 mm). The quality of enhancement (Figure 1) was moderate in five cases (25%), good in eight cases (40%) and excellent in seven cases (35%). The average operative time was 2.3 h (range, 2e3 h). The number of lymphaticovenular anastomoses performed during the same operative time ranged from 2 to 4 (average, 1.6). The patients were operated 1e3 times successively (average, 2). The mean number of lymphaticovenular anastomoses per limb was 7.2 (range, 4e8). The total number of end-to-side anastomoses for each patient ranged from 2 to 4 (average, 2.9). The total number of lymphaticovenular anastomoses performed in this study was 57 p-shaped (73%), nine l-shaped (11.6%) and 12 ishaped (15.4%). A venous back-flow (Figure 2) was found in 91 lymphaticovenular anastomoses (63.2%). Sixteen patients (80%) had a complete blue staining resorption at the operative site (Figure 3). The mean delay of blue staining resorption was 30.3 days (range, 20e45 days). Four patients (20%) had a remaining blue staining at the injection site (Figure 4). The size of the remaining skin colouration ranges from 1 to 5 cm (average, 2.2 cm). No patient (0%) experienced a postoperative worsening of their lymphoedema after surgery. No patient (0%) developed an allergy to Patent Blue, or a postoperative infection, including lymphangitis (Table 3). One patient (5%) had a superficial skin ulceration, inferior than 1 cm,2 at the operative site. This ulceration was spontaneously healed in 20 days. No patient (0%) experienced postoperative haematomas. No patient (0%) developed hypertrophic scars. Nineteen patients (95%) had a qualitative improvement of soft tissues after surgery. The soft tissues were softer, the pinch test was thicker and the subjective skin sensibility was improved. The reduction of the pinch test at the forearm ranged from 2 to 8 mm (average, 5.4 mm). Seventeen patients (85%) had a clinically significant circumferential reduction after surgery. The weight of their limb was also felt
Figure 1 Classification of the variations of patent blue enhancement for lymphatic vessels. Intraoperative views of patent blue-enhanced lymphatic vessels, adjacent to subdermal venules. The colouration is lighter than the purple aspect of the venules, and has 3 degrees of variation: a) moderate: very light blue, secondary to a fast diffusion of patent blue into the lymphatic network. b) good: pale turquoise blue, easily distinguishable from the colour of the adjacent venules. c) excellent: bright turquoise blue, secondary to a high impregnation of the lymphatic vessels.
to be lighter. They had to change their elastic stocking for a smaller one 2 months after surgery. The average circumferential differential reduction rate was 13.2% (range, 4.2e27.2%) (p < 0.001). The average cross-sectional area differential reduction rate was 24.1% (range, 9.5e46.7%) (p < 0.001). The average volume differential reduction rate was 22.8% (range, 7.2e48.8%) (p < 0.001). Fifteen patients (75%) definitively stopped lymph drainage 4 months after
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B. Ayestaray et al. surgery. Six patients (30%) stopped wearing their elastic stocking and bandage definitively 6 months after surgery. Eighteen patients (90%) moved to a better quality of life 6 months after surgery (Figure 5).
Discussion
Figure 2 Intraoperative view of one p-shaped lymphaticovenular anastomosis (yellow star) and two i-shaped lymphaticovenular anastomosis (yellow arrow). A venous back-flow (blue arrow) is noted at the left end-to-side lymphaticovenular anastomosis. A third lymphatic channel, which has not been used for microsurgical bypass, can be seen at the superior part of the picture.
Chronic lymphoedema is a public health issue, leading to severe functional troubles in everyday life. Nowadays, medical treatments are not efficient enough to have a stable reduction of lymphoedema in time. Recurrence is usual when compressive therapy and lymph drainage are stopped. Conservative treatment can also be inefficient regarding the oedema, which will progressively increase and worsen despite garments and physiotherapy. That is the reason why lymphaticovenular anastomosis was introduced with a view to overcome these issues. Lymphaticovenular anastomosis derives from lymphaticovenous bypasses described by Yamada in 1969.9 The technique was refined by O’Brien,10e12 and then by Koshima who introduced the concept of supermicrosurgery.1,13 Indeed, the differential pressure between the subdermal lymphatic vessels and the subdermal venules is lower, compared to larger veins.14 Then, the rate of thrombosis at the anastomosis site is decreased with supermicrosurgical techniques, comparing to classical lymphaticovenous bypasses.15
Figure 3 Case 6: Complete blue staining resorption 59 year old female having a postoperative lymphedema of the right upper limb, secondary to an axillary lymphadenectomy 1 year ago. 1.5 ml of patent blue was injected subdemally at the anterior part of the forearm. 4 lymphaticovenular anastomosis were performed (1 p þ 1 l) through 1 skin incision. The circumferential reduction rate was 6.6%, the cross-sectional area reduction rate was 12.7%, and the average volume reduction rate was 12.1% after a followup of 6 months. The blue staining resorption was complete, 20 days after surgery. a) Postperative view, immediately after surgery: typical aspect of the blue staining of the skin at the operative site the day of surgery. b) Postoperative view, 20 days after surgery : the blue staining has completely disappeared.
Figure 4 Case 9: Not completed blue staining resorption 48 year old female having a postoperative lymphedema of the right upper limb, secondary to an axillary lymphadenectomy 6 years ago. 1.5 ml of patent blue was injected subdermally at the anterior part of the forearm. 6 lymphaticovenular anastomosis were performed (1 p þ 1 l þ 2 i) through 3 skin incisions. The circumferential reduction rate was 20%, the cross-sectional area reduction rate was 37.3%, and the average volume reduction rate was 33.5% after a follow-up of 6 months. The blue staining resorption was not completed. a) Preoperative view: campisi stage III lymphedema of the right upper limb. The oedema is located at the arm, the forearm and the hand. A depression of the right shoulder is visible, due to the weight of the lymphedema. b) Postoperative view, 3 months after surgery: a light blue coloured area is still visible at the distal part of the forearm. A relief of the oedema at the arm, the forearm and the hand is visible.
Table 3
Summary of patients treated by patent blue-enhanced lymphaticovenular anastomosis.
Patient Patent Number of Number of Calibre of Quality of LVA Complication Blue (ml) blue skin enhanced LV (mm) enhancement configurations Allergy Infection Lymphangitis staining volume incisions LV skin resorption 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Average
1 1 1.5 1 2 1.5 1 2 1.5 1 2 1 1.5 1 1 1 1.5 1 2 1.5 1.3
4 2 4 3 4 1 4 2 3 4 3 3 4 4 4 3 4 4 4 3 3.4
7 5 6 6 8 4 7 2 4 6 5 5 6 8 7 3 5 6 4 6 5.5
0.5e0.8 0.4e0.6 0.3e0.6 0.5e0.7 0.3e0.8 0.4e0.7 0.5e0.6 0.4e0.8 0.6e0.8 0.3e0.7 0.3e0.5 0.6e0.8 0.5e0.7 0.4e0.7 0.3e0.8 0.5e0.6 0.4e0.7 0.5e0.7 0.6e0.8 0.4e0.7 0.57
þþ þþ þþþ þ þþþ þþ þþ þþþ þ þþþ þþþ þþ þþþ þ þþ þþ þþþ þ þþþ þþþ
4p None 2pþ2i None 3pþl None 4p None 4p None pþl None 3pþ2i None pþ2i None pþlþ2i None 4p None 4p None 2pþl None 2pþ2l None 4p None 2 p þ l þ 2 i None 3p None 2pþ2l None 4p None 3pþ2i None 4p None
Quality of enhancement:þ : moderate; þþ : good; þþþ : excellent, NC : Not Completed. a Calculated for the 16 patients having a complete blue staining resorption.
None None None None None None None None None None None None None None None None None None None None
None None None None None None None None None None None None None None None None None None None None
20 30 NC 35 25 20 45 40 NC 45 NC 20 25 20 40 30 NC 20 40 30 30.3a
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B. Ayestaray et al. enhancement in lymphatic vessels was also elaborated. This simple, affordable and reliable method should be used as a first-line standard in lymphatic supermicrosurgery.
Disclosure None.
Conflict of interest None.
Acknowledgements The author thanks very much Claire Duflos, M.D. from the department of biostatistics of Montpellier University Hospital for the statistical analysis of the data. Figure 5 Variation of the average volume of the operated upper limb in patients treated by lymphaticovenular anastomosis.
Supermicrosurgical techniques for lymphoedema remain difficult to perform because of the small calibre and the translucent appearance of lymphatic vessels. Different methods of lymphatic enhancement have been described. The most common is the indocyanine green dye, permitting us to locate lymphatic vessels by near-infrared fluorescence.2e6 The high price of the PhotoDynamic Eye (PDE), necessary to visualise the fluorescence, is the main disadvantage of this method. Lipodiol can also be used for lymphangiography. It is coupled with magnetic resonance imaging16e18 or computed tomography.19,20 Thus, it cannot be used intra-operatively. A radionuclide, such as 99mTc, is used for lymphoscintigraphy.21e25 The main disadvantage of this method is the morbidity related to the radioactivity. It cannot be used also intra-operatively. In this prospective study, Patent Blue appears as a safe and reliable dye marker to enhance lymphatic vessels. It does not need associated sophisticated devices to be used, such as the PDE or computed tomography. Its low price (V 1.85) makes the procedure very affordable. The technique is also very simple to learn and reproducible. Its low morbidity makes it a very safe method to use. Indeed, no severe complication occurred in this clinical series. Except for one case of partial skin ulceration, which spontaneously healed in 20 days, no postoperative infection, lymphangitis or allergic reaction occurred. Considering the lymphoedema reduction rates of this series, which are very close to those published with indocyanine green dye,2e6 patent blue does not affect the patency of lymphaticovenular anastomosis. In this way, patent blue-enhanced lymphaticovenular anastomosis is a safe and reliable method to treat chronic lymphoedema of the upper limb. It should be a widespread method to perform supermicrosurgical lymphaticovenular anastomosis more easily. The results of this clinical series demonstrate the safety and the efficacy of patent blue-enhanced lymphaticovenular anastomosis to treat postoperative lymphoedema of the upper limb, resistant to conservative treatment. A classification of the various degrees of patent blue
Appendix A. Supplementary data Supplementary video associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.bjps.2012.10.019.
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