Factors affecting outcomes after supermicrosurgical lymphovenous anastomosis in a defined patient population

Abstract

BACKGROUND:

The optimal surgical treatment for lymphedema is still subject of intensive research. Therefore, it is vital to investigate what significance lymphovenous anastomosis (LVA) has in this context.

OBJECTIVE:

This study aims to determine the short- and long-term results as well as the most important factors that can improve outcomes after LVA.

METHODS:

This study includes a complete data set of 26 patients who received LVA for a therapy-resistant lymphedema. Patients were followed up for an average of 23 months.

RESULTS:

50% of the patients reported a subjective improvement. Without conservative treatment after the operation the patients showed significant better results (100% vs. 40.9%, p = 0.030). The localization of lymphedema as well as the region of LVA had a significant influence. In patients with lymphedema affecting the entire leg, symptom improvement was significantly lower (35.3% vs. 77.8%, p = 0.039). Patients who received LVA in an upper limb show a significantly higher improvement in symptoms than patients who received LVA in a lower limb (100% vs. 30%, p = 0.021).

CONCLUSIONS:

We identified factors with a significant influence on the outcome of patients after receiving LVA. Patients with early-stage upper extremity lymphedema seem to benefit most from this procedure.

Keywords

Lymphedema surgery lymphovenous anastomosis microsurgery results postoperative care

1 Introduction

According to Földi and Földi in 2006 [1], lymphedema affect 140 to 250 million people worldwide. Despite the fact that surgical therapy has become a promising possibility in the treatment of this disease, as of today, the optimal therapeutic procedure is still the subject of intensive research. To date, there is no consensus on the ideal surgical procedure which should be recommended for each type and stage of lymphedema.

Therefore, it is vital to investigate what significance minimally invasive supermicrosurgical lymphovenous anastomosis (LVA) has in this context. There is a consensus that local improvements in patients with no improvement to conservative treatment in detail described by Casley-Smith [2] can be achieved by LVA, particularly in the region of the performed lymphovenous anastomosis. This has been proven by numerous studies in recent years [6 –16]. In addition, the surgical treatment of LVA is less invasive and thus has fewer risks and complications. However, there are still no generally valid recommendations for the ideal postoperative treatment of patients after LVA.

The aim of this study is to determine the short- and long-term results as well as the most important factors that can improve outcomes after LVA by analyzing all relevant pre-, intra- and postoperative factors in a defined patient population. With the help of these findings, current intra- and especially postoperative treatment options can be evaluated.

2 Methods and materials

The responsible ethics committee has approved this clinical trial.

2.1 Patients - general procedure

This study includes patients who received LVA during the period of 2011–2017 at the Department of Trauma Surgery, Orthopaedics and Plastic Surgery at the University Medical Centre Goettingen in Germany for an existing therapy-resistant lymphedema after exhausting conservative therapy measures. In total, 49 patients received LVA at the University Medical Centre Goettingen in this time period.

All pre-, intra- and postoperative factors with a possible impact on the outcome after LVA were analyzed. This made it possible to consider basic diseases, risk factors (obesity, nicotine abuse) and particularly the genesis of lymphedema as well as previous conservative therapy treatments. Data was collected via data collection forms and from the hospital’s own documentation (patient records and digital medical records). Furthermore, a prospective data collection was carried out through follow-up contact with referring physicians in telephone conversations and correspondence. In addition, a questionnaire was developed in order to collect all important data on the postoperative development of lymphedema and especially the complaints of the patients during the follow-up examinations.

We included only those patients from whom all necessary pre-, intra- and postoperative factors as well as complete aftercare information could be determined. Out of the 49 patients originally included, 23 were excluded due to missing data, a lack of willingness to complete the survey or death during the follow-up period. Therefore, we performed calculations using the complete data set of 26 patients.

We classified the severity of lymphedema into the following stages according to the current International Society of Lymphology (ISL) consensus document [3]:

Stage 0: Latent or sub-clinical condition without detectable swelling

Stage I: Edema with high protein content; elevation of the affected limb reduces swelling

Stage II: Edema with secondary tissue changes; elevation of the affected limb does not eliminate swelling

Stage III: Deforming hard swelling, lymphatic elephantiasis, typical trophic skin changes

All operations were performed by a specialist in plastic surgery or a senior trainee under the guidance of a specialist. The analysis includes the influence of preoperative medication in case the patient received therapy for at least seven days prior to surgery. Postoperative medication was defined to be the medication prescribed at discharge.

The follow-up period lasted until 09/15/2018. Contact was maintained for an average of 23 months (range: 4–54 months) with all of the 26 patients (100%) with a complete possible evaluation of all pre-, intra- and postoperative factors.

2.2 Surgical approach

During the medical briefing the day before the operation, the most severely affected areas of the limb are marked in order to achieve improvement in these areas through LVA. Performing the operation under general anaesthesia is optimal for patient and surgeon. After local disinfection, the colouring agent “patentblue” is injected between the toes or fingers. This makes it possible to colour the lymph vessels in order to detect a large lymph vessel and connect it with a corresponding vein. It is also possible to use Indocyanine Green (ICG) lymphography [4, 5] to visualize the lymph vessels and to determine the ideal incision based on the different ICG lymphography patterns. Even in cases with stardust or other signs of dermal backflow (except regions with a diffuse pattern in ICG-imaging), the most affected areas are still chosen for preparation; in most cases, suitable lymph vessels and veins can be detected. (Annotation: Indocyanine Green (ICG) has been approved for use in intravenous applications. Injection of ICG into skin or subcutaneous tissue is an off-label use.)

Afterwards, the operation area is sterilized and covered. Only a small incision (3–5 cm) is necessary in the previously planned area. Once an intact and adequately large lumen lymph vessel is found in the subcutaneous tissue, a sufficiently large vein nearby is dissected. If the lymphatic vessel and the corresponding vein are free for a sufficient length, preparations for anastomosis begin. The lymph vessel and the vein are cut at the previously defined point in order to perform a tension-free anastomosis. Depending on the lumen, either an end to end or an end to side anastomosis is performed (in case there is a mismatch that is too large). Then, the patency and flow are checked using ICG lymphography. Finally, irrigation and haemostasis as well as a check for the cessation of bleeding are performed. Subsequently, the skin is closed with precisely placed single button sutures. All patients received a wound dressing with Steri-Strips™, sterile plaster and finally a loose elastocompressive wrapping of the affected limb.

2.3 Statistics

Statistical analyses were performed using the SPSS statistical software (IBM SPSS Statistics version 24). Univariate analyses were performed using the Pearson chi-square test or Fisher’s exact chi-square test. The continuous variables were compared using t-test statistics. Correlation analyses were performed with the Pearson rank correlation coefficient (r-value). The correlation was considered “weak” if the r-value was <0.3, “moderate” if 0.3–0.5 or “high” if >0.5. A p-value of less than 0.05 was considered to indicate statistical significance.

3 Results

3.1 Patient-specific data

Patient characteristics are shown in Table 1. Out of the 26 included patients, 21 were female (80.8%) and five were male (19.2%). The patients were between 26–78 years old with a mean age of 54.9 years.

Table 1
The recorded preoperative patient characteristics of 26 patients receiving LVA for an existing therapy-resistant lymphedema

Patient characteristics Proportion of patients [% ]

Female gender (n = 21) 80.8%

Hypertension (n = 5) 19.2%

Nicotine abuse (n = 13) 50%

Diabetes mellitus (n = 2) 7.7%

Positive family history (n = 14) 53.8%

Cancer-related secondary lymphedema (n = 23) 88.5%

Lymphedema of lower extremity (n = 21) 80.8%

Patient characteristics	Proportion of patients [% ]
Female gender (n = 21)	80.8%
Hypertension (n = 5)	19.2%
Nicotine abuse (n = 13)	50%
Diabetes mellitus (n = 2)	7.7%
Positive family history (n = 14)	53.8%
Cancer-related secondary lymphedema (n = 23)	88.5%
Lymphedema of lower extremity (n = 21)	80.8%

BMI, body mass index.

The mean lymphedema duration was 8.4 years (range: 2 to 35 years). 23 patients (88.5%) suffered from cancer-related secondary lymphedema; lymphadenectomy was performed in all of these patients. In addition, 53.8% of patients had a family history of cancer. Three patients (11.5%) had a traumatic genesis of the lymphedema. In 21 patients (80.8%), the lower limb was affected, while five patients (19.2%) suffered from lymphedema of the upper extremity.

According to the current classification of lymphedema of the International Society of Lymphology (ISL), most patients in our study had stage II lymphedema (65.4%), followed by patients with stage I (26.9%) and stage III lymphedema (7.7%) (Fig. 1).

Fig. 1

Lymphedema stages of the investigated patients of our cohort according to the ISL classification.

The most common cardiovascular risk factors were nicotine abuse (50%), arterial hypertension (19.2%) and type 2 diabetes (7.7%). On average, smokers showed a nicotine abuse of 3.7 pack years. The mean body mass index was 27; the majority of the patients (69.2%) thus had pre-obesity (BMI 25–29.9).

All patients received conservative treatment preoperatively (Fig. 2). The mean duration of conservative pre-therapy was 6.8 years (range: 1 to 25 years). 21 patients (80.8%) had two manual lymphatic drainage treatments per week, three patients (11.5%) had three and one patient (3.8%) had four. Half of the patients received 45 minutes of manual lymphatic drainage per session, 11 patients (42.3%) received 60-minute treatments and two patients (7.7%) received 30-minute treatments.

Fig. 2

Frequency of use of manual lymphatic drainage (MLD) preoperative versus postoperative.

In addition to manual lymphatic drainage, 92.3% of the patients had compression therapy preoperatively (Fig. 3). Approximately half of the patient cohort (46.2%) used compression garments in compression class II. The remaining patients used compression garments in compression class III. Most patients (76.4%) used flat-knitted garments; four patients (15.4%) used circular knitted garments. In addition, one patient (3.8%) also made use of intermittent pneumatic compression and six patients (23.1%) received additional physical therapy.

Fig. 3

Frequency of use of compression therapy preoperative versus postoperative.

3.2 Intra- and postoperative findings

The average number of LVAs performed per affected area was 1.85 (range: 1 to 4). A significant correlation between the number of LVAs and the improvement of symptoms could not be determined (1 to 4 LVA: 33.3% vs. 69.2% vs. 33.3% vs. 0%, p = 0.235). Three of the nine patients with one anastomosis (33.3%) mentioned an improvement of symptoms directly after surgery and during follow-up. The highest range of symptom improvement was seen in patients with two anastomoses; 69.2% of these patients reported symptom improvement. In three patients, three LVAs were created during the first operation. Only one of them mentioned symptom improvement and was satisfied with the result. The patient who received four anastomoses did not experience any symptom improvement and was subsequently not pleased.

In four patients (15.4%), atropine had to be given intraoperatively by the anesthesiologists to stabilize bradycardia. These patients experienced worse outcomes and a significantly reduced improvement of symptoms in aftercare (0% vs. 57.1%, p = 0.036) (Fig. 4). Intraoperative application of catecholamines did not result in a significantly worse outcome after LVA.

Following surgery, the patients received a wound dressing with Steri-Strips™, sterile plaster and finally a loose elastocompressive wrapping of the affected limb which was elevated on a pillow. All patients were prescribed routine postoperative antibiotic prophylaxis for three weeks. The patients were encouraged to massage the limb distally of the anastomoses.

Generally, the use of compression garments or manual lymphatic drainage postoperatively was not recommended; it was only recommended on an as-needed basis. 21 patients (80.8%) reported stopping conservative treatment after surgery. In ten cases, conservative treatment was continued within one month and in seven cases within two to six months. In total, 84.6% of the patients used compression garments postoperatively (Fig. 3). As prior to surgery, most patients (69.2%) used flat-knitted garments and 15.4% used circular knitted garments. Furthermore, most patients (46.2%) used compression garments in compression class II postoperatively, while 10 patients (38.5%) had to use class III out of necessity. Manual lymphatic drainage was performed postoperatively in 17 patients (65.4%) (Fig. 2). Eleven patients (42.3%) had two manual lymphatic drainage treatments per week postoperatively, four patients (15.4%) had one and two patients (7.7%) had three. In addition, four patients (15.4%) used intermittent pneumatic compression and five patients (19.2%) received additional physical therapy.

With regard to these different postoperative approaches, we observed that patients who continued compression therapy or manual lymphatic drainage after surgery had a significantly worse outcome. Patients who received manual lymphatic drainage again during aftercare showed significantly reduced improvement in symptoms (29.4% vs. 88.9%, p = 0.004). Ultimately, this shows us not only that manual lymphatic drainage should be avoided postoperatively in order to avoid endangering the newly created lymphovenous anastomosis, but also that patients simply do not need manual lymphatic drainage postoperatively. This also occurred in the patients who used compression garments again in aftercare (40.9% vs. 100%, p = 0.030).

There was also a correlation between the frequency of manual lymphatic drainage per week and an improvement in symptoms after lymphovenous bypass procedures. Patients who did not use manual lymphatic drainage postoperatively showed significantly more improvement in symptoms than patients who underwent manual lymphatic drainage once, twice or three times a week (88.9% vs. 50% vs. 27.3% vs. 0%, p = 0.021).

3.3 Long term outcomes

At the end of the follow-up, 50% of the patients reported a subjective improvement of their symptoms. In four patients (15.4%), no conservative therapy measures were needed after LVA. These patients also showed a significantly higher level of symptom improvement in aftercare (100% vs. 40.9%, p = 0.030).

In order to evaluate the local improvement of lymphedema in the area of LVA, we also performed local circumferential measurements in the area of the applied LVA. In total, only 36.4% of the patients showed a reduction of the circumferential measurement in the area of LVA during follow-up. Therefore, we investigated possible causes and evaluated patients with the highest and lowest circumferential reduction after LVA. It was noted that the worst results were achieved in patients with lymphedema at the distal lower extremity and the lower leg. Patients with LVA at the proximal lower limb (thigh and/or groin) or at the upper limbs were the patients with the best results.

Half of the patients were treated with further lymphatic surgical procedures. More specifically, two patients (7.7%) underwent lymph node transfer and four patients (15.4%) lymph vessel transplantation. In six patients (23.1%), additional LVAs were performed later. One patient underwent lymph node transplantation in addition to another LVA.

3.4 Findings with a significant influence on outcomes after LVA

The use of atropine to stabilize bradycardia during the operation was correlated with a worse outcome after LVA and a significantly reduced improvement of symptoms in aftercare (0% vs. 57.1%, p = 0.036) (Fig. 4).

Fig. 4

Kaplan-Meier estimates for improvement of symptoms in aftercare according to the use of atropine to stabilize bradycardia during the operation.

Furthermore, we observed that localization of lymphedema as well as the region of LVA had a significant influence on the improvement of the patient’s symptoms. In patients with lymphedema affecting the entire leg, symptom improvement was significantly lower after LVA (35.3% vs. 77.8%, p = 0.039) (Figs. 5 and 6).

Fig. 5

Frequency of subjective improvement of symptoms depending on whether lymphedema affects the entire leg.

Fig. 6

Kaplan-Meier estimates for improvement of symptoms in aftercare according to lymphedema affects the entire leg.

Particularly outstanding are the results obtained on the upper extremities. If patients with a lymphedema of the entire arm or leg are removed from calculations, then patients who received LVA in an upper limb show a significantly higher improvement in symptoms than patients who received LVA in a lower limb (100% vs. 30%, p = 0.021).

4 Discussion

We found a significant negative influence on the outcome after performing LVA if lymphedema affects the entire leg or arm as well as generally if lymphedema affects a lower limb. Due to the particularly outstanding results obtained on the upper extremities, we conclude that the best results with LVAs could be achieved in patients with early stage lymphedema involving an upper extremity. This accords with the results of Chang et al. in 2013 [6]: they showed symptom improvement in 96% of the patients with arm lymphedema compared to 57% of patients with lower extremity lymphedema. This is also supported by the findings of Pereira et al. in 2018, who demonstrated an improvement in symptoms in all patients with lymphedema of the upper extremity; the mean volume reduction was 64.97% versus 39.8% in patients with leg lymphedema [7].

Scaglioni et al. proposed that there is still no international consent about the number of anastomoses necessary for satisfactory results [8]. In our analysis, we could not demonstrate significant correlation between the amount of anastomoses and outcome, which is comparable to the observations of Tourani in 2016 [9].

The role of conservative treatment subsequent to lymphatic surgery and the applied methods is a topic in numerous past and present studies. Eliska et al. indicate that manual lymphatic drainage encourages lymphatic flow, but it can also cause focal damage to subcutaneous lymphatics [10]. In our study, 15.4% of the patients received no conservative treatment after the operation. All of them mentioned an improvement after surgery, and 75% of these patients were satisfied with the results. In comparison, only 40.9% of patients with conservative treatment after LVA reported fewer complaints. Moreover, just six of these patients (27.3%) experienced subjective satisfactory outcomes. Therefore, to support significant improvement after LVA we recommend discontinuing conservative therapy measures.

There are several studies discussing stagnation of symptom improvement over time. A reduced shunt patency seems to be the main reason for this phenomenon. Even our results display a difference between the patients’ satisfaction directly after the operation and during the follow-up survey. Half of the participants (50%) experienced an improvement over time while six patients (23.1%) mentioned a decreasing effect. It could be possible that the LVA suffers from a loss of function over time. A systematic review of different studies about the long-term patency of LVA by Tourani et al. fortified this theory. In experimental animal trials, patency rates fell from 90.9% after one week to 44.4% after six months [9]. This was supported by Maegawa et al. in 2012 who showed decreasing patency rates from 75% at 12 months to 36% at 24 months [11]. Continuous destruction and decompensation of the affected limb’s lymphatic system could be a possible explanation. Olszweski indicated that patients with chronic inflammations or post-inflammatory edema presented a reduced shunt function over time [12]. Our study showed that patients who underwent the surgery in the year 2016 or later were more likely to experience an improvement than those who received LVA prior to that. Further randomized multicenter trials with a larger cohort of patients will be needed to identify factors with a significant influence on the long-term patency and effectiveness of LVA.

4.1 Summary

LVA can be effective in reducing lymphedema severity but cannot provide a restitutio ad integrum. We demonstrated that at the end of the follow-up (average follow-up time 23 months) as a long-term outcome 50% of our patient cohort showed a notable relief in lymphedema symptoms. In addition, based on our results, we recommend discontinuing conservative therapy measures after the surgery to achieve significant symptom improvement with LVA. Furthermore, we were able to identify factors with a significant influence on the outcome of patients after receiving LVA. As a synopsis of our results, patients with early-stage upper extremity lymphedema seem to benefit most from this procedure. Comparing results of different studies shows that LVA or general lymphatic microsurgery should be included in further research in general. Randomized multicenter trials with larger cohorts of patients are necessary to identify more influencing factors. The unclear long-term shunt patency especially remains a challenging issue. The general aim should be an acceptable quality of life for lymphedema patients as well as qualitative and quantitative edema improvement.

Financial disclosure

None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript. All authors have nothing to disclose. No funding was received for this article.

Conflict of interest

None.

Clinical Trial Registry Number

DRKS00017413 (German Clinical Trials Register)

Ethic Committee Approval Number

10/10/14

University Medical Centre Goettingen, Germany

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