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

doi:10.21203/rs.3.rs-5166504/v1

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

https://doi.org/10.21203/rs.3.rs-5166504/v1

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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 (R-NOS).

Methods: FIRST is a single-center, prospective observational 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 R-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 (QoL), upper limb function, and anxiety-depressive symptoms, which are measured using various validated scales and questionnaires.

Discussion: The novelty of this study lies in its ability to provide information on the impact of free perforator fat flaps in R-NTOS treatment using validated, standardized and recommended methods of assessment for neuropathic pain, particularly considering the psychosocial impact.

Recurrent Neurogenic Thoracic Outlet Syndrome

Pain

Brachial plexus

Free perforator flap

Neurolysis

Microsurgery.

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 (1–3 per 100,000) that is classified according to the structure constricted: neurogenic (NTOS), arterial (ATOS), or venous (VTOS).

NTOS accounts for approximately 90% of all forms of TOS [4] 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 (PCS) and Mental Component Scores (MCS) below the population norm [5].

The most common surgical treatment is compression release with anterior scalenectomy, which may be combined with a first rib resection [6]. However, symptoms recur in 5–30% of operated patients [7]. 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 [8].

Fat perforator flaps, on the other hand, offer an alternative approach that minimizes donor site sequelae by eliminating the need for muscle harvesting [9]. 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. Furthermore, the free transfer of the perforator flap prevents the formation of new scars in an already painful anatomical region.

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 neurogenic thoracic outlet syndrome (R-NTOS). By utilizing validated and recommended questionnaires, our investigation seeks to assess the impact of wrapping the brachial plexus with a free perforator fat flap after neurolysis in the context of R-NTOS on pain and QoL outcomes.

Study design

The FIRST (Free fat flap In Recurrent neurogenic thoracic outlet Syndrome pain Treatment) clinical trial is a prospective observational single-center 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.

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 R-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 quality of life (QoL). Firstly, the patient must indicate the location of their pain. Patients will then rate the intensity of their pain on three numerical scales (NS): 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).

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.

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 R-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 the Questionnaire Douleur de Saint-Antoine (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 Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire.

8. Improvement in anxiety-depressive symptoms measured with the Hospital Anxiety and Depression Scale (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[10] of the McGill Pain Questionnaire (MPQ) developed by Melzack and Wall [11].

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) [12] validated in French [13]. 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. in 2001 [14].

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 [15], 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 [16].

Statistical methods

All pre- and post-operative 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.

A non-parametric Wilcoxon test will be utilized to conduct univariate analysis of the primary and secondary quantitative endpoints between pre- and post-operative data. The significance threshold for p-values will be set at 0.05. Statistical analyses will be performed using RStudio software.

Patients size

The number of patients is challenging to determine due to the rarity of the surgical indication. However, we estimate that approximately 20 patients will be needed for this study. This estimation is based on expecting a mean difference of -3 for our primary endpoint, with a standard deviation of 2. We have set the beta risk at 20% and the alpha risk at 5%.

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, materiovigilance, etc.). 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 (CRF).

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 (GNEDS - Groupement Nantais d’Ethique dans le Domaine de la Santé) on October 2, 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 M.D., M.Sc. and François Thuau, includes Nantes experts in this pathology: Dr. Guillaume Gadbled M.D. and Prof. Pierre Perrot M.D., Ph.D., 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 (ICMJE) when sharing the entirety of the final trial dataset.

Our innovative study focuses on the use of free perforator fat flaps to wrap the brachial plexus following neurolysis in cases of recurrent neurogenic thoracic outlet syndrome (R-NTOS). We emphasize the importance of preserving donor site integrity while minimizing local dissection to prevent exacerbating fibrosis. Moreover, our wrapping technique has demonstrated effectiveness in reducing the recurrence of postoperative fibrosis [17]. The study employs validated, standardized, and recommended methods for evaluating neuropathic pain, taking into account its psychosocial impact.

However, it is crucial to note that 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 primary objective is to assess the impact on pain of wrapping the brachial plexus with a free perforator fat flap after neurolysis in the context of neurogenic thoracic outlet syndrome (NTOS), from baseline (Day − 1) to six months post-surgery. This six-month period is essential for evaluating postoperative outcomes thoroughly. We would like to highlight that alternative interventions using pedicled flaps (e.g., latissimus dorsi, omentum[18] or deltopectoral flaps [19]) pose significant drawbacks such as functional impairment, abdominal incision, or concerns regarding thoracic aesthetics.

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 R-NTOS. Additionally, we aim to assess the medical-economic impact of this longer surgical procedure involving two surgical teams in the operating room, which we believe will result in fewer recurrences and associated consequences, such as work stoppage.

Trial status

This trial is still ongoing; patient inclusion is not yet complete. The updated protocol is at version 1 on 17 September 2023. The first patient was included on 18 December 2023. Recruitment by the investigating center will continue until 24 months and the study period will end on 18 May 2026.

Adverse event

ATOS

Arterial thoracic outlet syndrome

CNIL

Commission nationale de l'informatique et des libertés

DASH

Disabilities of the Arm, Shoulder, and Hand

FIRST

Free fat flap In Recurrent neurogenic thoracic outlet Syndrome pain Treatment

GNEDS

Groupement Nantais d’Ethique dans le Domaine de la Santé

HADS

Hospital Anxiety and Depression Scale

ICMJE

International Committee for Medical Journal Editors

MCS

Mental component status

MPQ

McGill pain questionnaire

Numerical scales

NTOS

Neurogenic thoracic outlet syndrome

PCS

Physical component status

QDSA

Questionnaire de douleur de Saint-Antoine

QoL

Quality of Life

RNTOS

Recurrent neurogenic thoracic outlet syndrome

SF-12

Short-Form 12

SF-36

Short-Form 36

TOS

Thoracic outlet syndrome

VTOS

Veinous thoracic outlet syndrome

Ethics approval and consent to participate

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

Clinical trial number: Trial registration: NCT06172101 first registration 12/07/2023

Consent for publication Not applicable — no identifying images or other personal or clinical details of participants are presented here

Consent to Participate declaration : All the patients have provided their consent.

Availability of data and materials: 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

Competing interests: There are no financial or competing interests to be declared for the investigators.

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

Authors' contributions: UL and FT designed the trial, FT, GG, UL wrote the protocol, AP, UL, FT wrote the manuscript. GG, TG and PP assisted with the drafting of the manuscript. TG wrote the methodological/statistical analyses in the protocol. All authors read and approved the final manuscript

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No competing interests reported.

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Editorial decision: Revision requested
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You are reading this latest preprint version

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

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