Free fat flap transfer in recurrent neurogenic thoracic outlet syndrome pain treatment: FIRST observational pilot study

Abstract

Background:

Neurogenic thoracic outlet syndrome (NTOS), characterized by brachial plexus compression, causes chronic pain and numbness in the upper extremities. Recurrences are common after surgical treatment, which typically includes an anterior scalenectomy and rib resection. Brachial plexus neurolysis and flap coverage can reduce scar fibrosis and prevent further recurrence. The latissimus dorsi flap is a common choice for this purpose. However, perforator fat flaps minimize donor site complications by avoiding muscle harvesting. Furthermore, a free flap transfer prevents new scars from developing in an already painful anatomical region. Given the lack of literature on this subject, we plan to use validated and recommended questionnaires to investigate the impact on pain and quality of life of brachial plexus wrapping with a free fat flap following neurolysis in cases of recurrent NTOS.

Methods:

FIRST is a single-center, prospective observational pilot study recruiting participants over 24 months. Eligible patients over the age of 18 are treated with brachial plexus neurolysis and a free perforator fat flap for recurrent NTOS. The study aims to enroll 20 patients and involves preoperative and postoperative assessments at a six-month follow-up. The primary outcome, measured using numerical scales, is pain reduction. Secondary outcomes include decreased painful body surface area, maximum and average pain levels, changes in quality of life, upper limb function, and anxiety-depressive symptoms, which are measured using various validated scales and questionnaires.

Discussion:

This study will provide insight into the efficacy of free perforator fat flaps in recurrent NTOS using standardized, validated assessments for neuropathic pain, including psychosocial aspects. By providing vascularization around the brachial plexus, fat flaps may reduce inflammation, fibrosis, and perineural scar adhesions, thereby alleviating pain. This technique also avoids extensive local dissection required for regional flaps and reduces donor site morbidity. Potential limitations include the technical complexity of free flap surgery.

Introduction

Thoracic outlet syndrome (TOS) was first described in 1956^[1] by Peet et al as a heterogeneous characterization of symptoms associated with thoracic outlet neurovascular compression. This can cause chronic pain, numbness, and paresthesia in the neck, upper back, and upper extremities^[2,3]. TOS is a relatively rare syndrome (incidence of approximately 3 per 100 000 people per year^[4]) that is classified according to the structure constricted: neurogenic, arterial, or venous.

Neurogenic thoracic outlet syndrome (NTOS) accounts for approximately 90% of all forms of TOS^[5] and leads to significant debilitation. Patients with NTOS experience a level of impairment similar to those with chronic heart failure, with mean Short-Form 12 (SF-12), physical component scores, and mental component scores below the population norm^[6].

The most common surgical treatment is compression release with anterior scalenectomy, which may be combined with a first rib resection^[7]. However, symptoms recur in 5–30% of operated patients^[8]. These recurrences are frequently associated with scar fibrosis surrounding the brachial plexus nerves responsible for their compression. Recurrences are primarily treated with conservative therapies, and if those fail, with another surgery, most notably brachial plexus neurolysis. It is advisable to employ a flap to cover the neurolyzed brachial plexus to prevent further recurrences. This approach enhances local vascularization, provides protection against external compression of nerves, and restricts scar fibrosis. The classic choice for this indication is the pedicled latissimus dorsi muscle flap^[9].

Fat perforator flaps, on the other hand, offer an alternative approach that minimizes donor site sequelae by eliminating the need for muscle harvesting^[10]. Since their description in the 90s, perforator flaps have become the gold standard for soft tissue reconstruction, as their harvesting spares important soft tissues (i.e., muscles, nerves) and typically includes skin and subcutaneous fat tissue. Local strategies for brachial plexus wrapping using perforator flaps, such as the adipofascial deltopectoral flap described by Dolan et al^[11], have been developed. However, the dissection required for these local flaps can contribute to scar formation. In contrast, free perforator flap transfer avoids creating new scars in an already painful anatomical region and allows precise placement of the flap around the brachial plexus without tension.

The literature lacks studies on wrapping the brachial plexus using perforator flaps, creating a gap in our understanding of this surgical procedure. Additionally, there is limited knowledge about the long-term function and quality of life (QoL) in patients undergoing surgery for recurrent NTOS. We hypothesize that free perforator fat flap transfer will reduce pain and improve QoL in recurrent NTOS patients compared to standard treatments. Using validated and recommended questionnaires, we will assess the impact of this technique on pain reduction and QoL outcomes.

Methods/design

Study design

The FIRST (Free fat flap In Recurrent neurogenic thoracic outlet Syndrome pain Treatment) clinical trial is a prospective observational single-center pilot study conducted at Nantes University Hospital, France. The protocol has been written in compliance with SPIRIT recommendations. This study is being conducted in two departments, one of plastic surgery and one of orthopedic surgery, both of which are familiar with NTOS surgery and the challenges of recurrent symptoms. The collaboration between these departments is essential for managing this condition, as the procedure requires the expertise of two surgeons in the operating room. To ensure consistency, all surgical procedures will be performed by the same team of experienced surgeons, thereby minimizing variability in surgical technique and decision-making. The study is registered on ClinicalTrials.gov under the identifier NCT06172101, with the first registration dated 7 December 2023.

Study population

Description of the population and recruitment for the trial

Recruitment is planned over 24 months. Patients of both sexes, aged over 18 years undergoing brachial plexus neurolysis and wrapping with a free perforator fat flap for recurrent NTOS will be offered the FIRST protocol. Patients whose first language is not French, who cannot read or write, and who are under guardianship or trusteeship are excluded.

Study schedule

The study plan described in this section is presented in (Fig. 1). During the routine preoperative consultation with the surgeon (between 180 and 30 days before surgery), the surgeon introduces the study to the patient and obtains informed consent. The day before the operation (D-1), patients will complete inpatient questionnaires on pain and QoL. Firstly, the patient must indicate the location of their pain. Patients will then rate the intensity of their pain on three numerical scales: current pain, usual pain over the last eight days, and most intense pain in the previous eight days (from 0, no pain, to 10, maximum pain imaginable). The patient will also complete the short form of the “Questionnaire Douleur de Saint-Antoine” (QDSA). Following the pain assessment, the patient will fill out the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire to evaluate the functional status of their upper limb. Finally, the patient will complete QoL questionnaires, including the SF-36 and the Hospital Anxiety and Depression Scale (HADS).

Figure 1.

Study diagram.

During the routine postoperative consultation with the surgeon six months after surgery, the following information will be collected:

• Surgery area complications (e.g., hematoma, infection, wound dehiscence, partial or total flap loss, necrosis, need for surgical revision)

• Flap donor site complications (e.g., wound dehiscence, hematoma, lymphocele)

• Responses to the same D-1 questionnaires (pain levels, QDSA, DASH, SF-36, HADS)

The flowchart for the study is shown in (Fig. 2).

Figure 2.

Flow chart of FIRST protocol.

Objectives and outcomes

Objectives

The main objective of this study is to assess the impact of wrapping the brachial plexus with a free perforator fat flap after neurolysis in the context of recurrent NTOS on pain, measured between baseline (D-1) and six months post-surgery.

The secondary objectives include evaluating the impact of the surgical procedure on:

1. Pain localization.

2. Maximum pain experienced in the last eight days.

3. Average pain felt over the last eight days.

4. Symptoms of neuropathic pain.

5. Use of analgesic treatment.

6. Quality of life.

7. Upper limb function.

8. Anxiety-depressive symptoms.

9. Safety of the free fat flaps (adverse effects).

Outcomes

The primary outcome is the reduction in pain, measured before and six months after surgery using a numerical scale ranging from 0 to 10.

Similarly, the secondary outcomes, also measured before and six months after surgery, are:

1. Reduction in painful body surface area assessed using a pain area diagram.

2. Decrease in maximum pain experienced in the previous eight days on a numerical scale of 0 to 10.

3. Reduction in average pain experienced over the last eight days on a numerical scale of 0 to 10.

4. Decrease in the intensity of items on the short version of QDSA.

5. Reduction in analgesic consumption (number of drugs, dose, frequency, dose/day ratio) as reported in the patient’s diary.

6. Improvement in quality of life using the SF-36 self-questionnaire.

7. Improvement in upper limb function assessed with the DASH questionnaire.

8. Improvement in anxiety-depressive symptoms measured with HADS.

9. Resolution of adverse events between baseline (D-1) and 6 months after surgery.

Measures used to determine the outcomes

The QDSA (short form) assesses pain description using a multidimensional verbal scale comprising 16 adjectives rated from 0 (absent) to 4 (extremely strong). It also evaluates pain intensity and the experience of anxiety and depression. The questionnaire is an adaptation in French^[12] of the McGill Pain Questionnaire developed by Melzack and Wall^[13].

The SF-36 questionnaire consists of 36 items and evaluates eight dimensions of health, with scores ranging from 0 to 100. It is widely used in clinical research and public health to assess quality of life (QoL)^[14] validated in French^[15]. A QoL score below 66 indicates impairment.

The DASH questionnaire includes 30 items rated from 0 (best score) to 100 (worst score), assessing upper limb function and discomfort in leisure and work activities. Developed in North America in 1994, it was translated and validated in French by Dubert et al^[16].

The HADS is used to assess levels of anxiety and depression with 14 items rated from 0 to 3. Developed by Zigmond and Snaith in 1983^[17], it provides separate scores for anxiety (A) and depression (D). Scores of 7 or less indicate no symptoms, 8 to 10 suggest doubtful symptomatology, and 11 or more indicate definite symptomatology^[18].

Statistical methods

All pre- and postoperative data will be analyzed descriptively. The 95% confidence intervals for qualitative variables will be reported as numbers and percentages. Depending on the distribution of variables, quantitative data will be presented as mean with standard deviation or median with interquartile range.

In case of normal distribution, confirmed by a Shapiro–Wilk test, a paired samples t-test will be used to conduct univariate analysis of the primary and secondary quantitative endpoints between pre- and postoperative data. If the distribution is non-normal, a non-parametric Wilcoxon test will be employed. The significance threshold for P values will be set at 0.05. Statistical analyses will be performed using RStudio software.

Interim analyses and sample size adjustments

Recruitment will occur over 24 months, with interim analyses at the 12-month midpoint to assess progress, preliminary data, and any major adverse events. Based on these analyses, adjustments to the recruitment strategy and sample size may be made if necessary. If the interim analysis reveals significant deviations from expected results or adverse events, the sample size will be recalculated to ensure the study’s statistical power and validity, using appropriate statistical methods.

Sample size

Determining the number of patients required for this study was challenging due to the rarity of the surgical indication^[19]. However, the sample size was calculated as 20 patients using G*Power 3.1 software (Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany)^[20]. A paired t-test was used for sample size determination. The calculation was based on a two-tailed test with an alpha risk (α) of 0.05 and a power (1-β) of 0.8, with β set at 0.2. The effect size was determined to be 0.667, assuming a mean pain improvement of 2 points on the Visual Analog Scale (VAS). This effect size was derived from previous studies on neuropathic pain improvement, where a 2-point change on the VAS was found^[21-23] and considered clinically significant in chronic pain^[24]. The standard deviation was set at 3, as reported in similar studies^[25].

Adverse event (AE) management

No additional procedures beyond standard care will be performed during the study. In case of an adverse event related to the patient’s care occurring under the current protocol, it will be promptly reported to the appropriate vigilance system (such as pharmacovigilance, biovigilance, hemovigilance, and materiovigilance). Ensuring the safety of the procedure is a secondary objective. All adverse events observed by the investigator or reported by the subjects during the study will be documented in the adverse event section of the Case Report Form. AEs are classified as minor or major based on their severity and clinical impact. Minor AEs are transient complications manageable with conservative measures, not requiring surgical revision or prolonged hospitalization (e.g., mild hematoma, superficial wound dehiscence). They are generally not expected to affect long-term recovery. Major AEs are severe complications requiring surgical intervention, prolonged hospitalization, or resulting in lasting impairment (e.g., flap loss, deep infection).

Ethical, regulatory, and dissemination aspects

The clinical study will be conducted in accordance with the relevant versions of the French Public Health Code, national and international Good Clinical Practice guidelines, and the Declaration of Helsinki, as applicable. Approval for this clinical study was obtained from the local Ethical Board of Nantes (Groupement Nantais d’Ethique dans le Domaine de la Santé) under the reference number 23-125-10-24 on 2 October 2023 (refer to Additional file for the French informed consent).

Data collected during the study will be electronically processed in compliance with the requirements of the CNIL, the French Data Protection Authority (in accordance with the French Reference Methodology MR004).

The amended protocol should be a dated, updated version. If necessary, the information form and consent form should be amended. The updated protocol is at version 1 on 17 September 2023

The protocol and trial have been made possible by an Executive Committee, which includes a Scientific Committee and a Steering Committee. The Scientific Committee, led by Dr Ugo Lancien, MD, MSc, and François Thuau, includes Nantes experts in this pathology: Dr Guillaume Gadbled, MD, and Prof. Pierre Perrot, MD, PhD, along with a biostatistician, a methodologist, and the project manager. The Steering Committee comprises members of the Scientific Committee, as well as the data management team and the nurse study coordinator from the Plastic Surgery Department.

Trial results will be published in international surgical, medical, and scientific journals, and presented at national and international conferences. The investigators will adhere to the rules and guidelines of the International Committee for Medical Journal Editors when sharing the entirety of the final trial dataset.

Discussion

Our innovative study focuses on the use of free perforator fat flaps to wrap the brachial plexus following neurolysis in cases of recurrent NTOS. This approach employs validated, standardized, and recommended methods for evaluating neuropathic pain, with particular attention to its psychosocial impact.

We emphasize the importance of preserving donor site integrity while minimizing local dissection to prevent exacerbating fibrosis. Our wrapping technique has demonstrated effectiveness in reducing the recurrence of postoperative fibrosis^[26]. The underlying mechanism for fibrosis prevention involves addressing tissue hypoxia caused by repeated surgical interventions, which increases oxidative stress and tissue apoptosis, thereby exacerbating inflammatory and proliferative processes that lead to scar formation^[27]. The transfer of vascularized tissue aims to counteract this hypoxia by providing a mechanical barrier to prevent adhesion of the plexus to surrounding tissues. Additionally, adipose tissue has anti-inflammatory properties mediated by the secretion of anti-inflammatory cytokines from adipose stromal cells. These cells may also contribute to reducing nociceptive hypersensitivity and promoting peripheral nerve regeneration^[28-30].

Compared to regional muscle flaps, such as the latissimus dorsi flap, free perforator fat flaps offer reduced donor site morbidity. The latissimus dorsi flap, while effective, is associated with functional donor site complications, including muscle weakness^[10]. Similarly, the free omental flap, which has shown excellent outcomes in radiation-induced plexopathy^[31], carries significant risks, such as abdominal hernia or eventration^[32].

Local adipofascial flaps, such as the deltopectoral flap described by Dolan et al^[11], provide a viable alternative. This technique involves harvesting a local flap based on perforators from the internal mammary artery within the second and third intercostal spaces. While this approach offers a promising means of revascularizing nerves and limiting fibrosis, its application is more suitable for small, low-positioned areas of the plexus. Even though the flap can measure up to 10 × 10 cm, only a limited portion can adequately cover and wrap the plexus, particularly in the supraclavicular region where adhesions with anterior scalene remnants are commonly found. In contrast, free perforator fat flaps, such as the anterolateral thigh, superficial circumflex iliac artery perforator, or deep inferior epigastric perforator flaps, offer a larger surface area (typically 10 × 20 cm) and greater flexibility for customized wrapping^[33-35]. Furthermore, Dolan et al’s study is retrospective, without comparison of pre- and postoperative pain, and only evaluates pain through VAS, which does not fully capture all the dimensions of the pain.

Another local alternative, the scalene fat pad wrap described by Teijink et al^[36], involves dividing the fat pad for wrapping. However, this technique is only technically described without clinical outcome assessment. Furthermore, the flap is not suitable when scarred^[37], which is frequent in recurrent NTOS after previous scalenectomy. Its small size and limited maneuverability restrict its use, especially for infraclavicular coverage.

It is crucial to acknowledge that recurrences may occur beyond the six-month follow-up period, with some cases reported up to 80 months postoperatively^[38]. To address this limitation, systematic annual follow-ups will be conducted by the referring surgeon for at least seven years, and a subsequent study will be conducted if late recurrences arise.

Furthermore, our study is single-center, which inherently introduces selection bias and limits the generalizability of our findings. The diversity of surgical practices and experiences across different teams may impact the external validity of our results. For instance, the success rates of free flaps are directly correlated with the surgical team’s experience^[39,40]. These factors should be considered when interpreting our results and planning future multicenter studies.

However, this approach necessitates extended operative time and the expertise of a double surgical team with precise microsurgical skills. Furthermore, the availability of suitable recipient vessels becomes critical following certain decompression procedures, such as resection of the thyrocervical trunk or cervical transverse.

Our study does not include a control arm due to the rarity of the surgical indication. Therefore, we have chosen to compare our results with those from other studies in the literature. Additionally, we aim to evaluate the medical-economic impact of this extended surgical procedure involving two surgical teams in the operating room, which we anticipate will reduce recurrence rates and associated consequences, such as work absenteeism. Therefore, we will compare the total hospitalization costs (e.g., operative times, hospital stay duration, ICU stays) with data from patients who underwent brachial plexus neurolysis for recurrent NTOS prior to the study period. These comparisons will be correlated with recurrence rates, the number of reoperations required, and the reduction in analgesic consumption to provide a comprehensive analysis of the procedure’s cost-effectiveness.

In conclusion, this study serves as a pilot phase intended to pave the way for a larger randomized trial to validate our findings and provide more robust recommendations for managing recurrent NTOS.

Ethical approval

This clinical study was submitted to and approved by the local Ethical Board of Nantes (Groupement Nantais d’Ethique dans le Domaine de la Santé) on 2 October 2023.

Consent

None.

Sources of funding

This study is an academic study with no funder and sponsored by the CHU Nantes.

Author contributions

U.L. and F.T. designed the trial. F.T., G.G., and U.L. wrote the protocol. A.P., U.L., and F.T. wrote the manuscript. G.G., T.G., and P.P. assisted with the drafting of the manuscript. T.G. wrote the methodological/statistical analyses in the protocol. All authors read and approved the final manuscript.

Conflicts of interest disclosure

None.

Research registration unique identifying number (UIN)

None.

Guarantor

None.

Provenance and peer review

None.

Data availability statement

Data collected during the test may be processed electronically, following the requirements of CNIL (compliance with reference methodology MR004). The investigators will share the entirety of the final trial dataset.