The use of botulinum toxin A in chemical component separation: a review of techniques and outcomes

Introduction

Ventral hernias are a frequent complication after open abdominal surgery and up to 30% develop incisional hernias^[1-3]. Repair of incisional hernias is difficult due to scarring and the distortion of tissue planes innate to a reoperative field. In complex cases, such as massive hernias, those with loss of domain, recurrent hernias, or hernias with infection or contamination, patient morbidity can be greatly increased. Despite advances in mesh technology, refinement of surgical techniques, and the advent of myofascial reconstruction techniques, abdominal wall reconstruction (AWR) in these patients is still associated with high rates of recurrence^[4-6]. In addition, each failed attempt at hernia repair results in higher morbidity, costs, and risk of recurrence for each subsequent repair^[7,8].

An especially challenging patient population for hernia specialists is those with loss of domain. This occurs when an abdominal wall defect progresses to a size at which it may no longer accommodate the abdominal viscera, leading to irreducible protrusion into the hernia sac. Chronic muscle retraction reduces the volume of the peritoneal cavity and precludes tension-free fascial closure during AWR, with potential problems such as abdominal compartment syndrome, ventilatory restriction, and an elevated risk of hernia recurrence. In hernia defects over 8.3 cm in width, component separation is often needed to achieve primary, tension-free fascial closure^[9]. Other techniques that have been utilized to increase the abdominal domain in large hernias with loss of domain include progressive pneumoperitoneum and soft tissue expanders. These are not without risk of morbidity however^[10,11].

More recently, preoperative injection of botulinum toxin A (BTA) has been added to the surgeon’s armamentarium for AWR as an off-label use. BTA is a neurotoxin produced by the bacterium Clostridium botulinum, which has been shown to have a variety of therapeutic uses through its inhibitory effect on presynaptic cholinergic nerve terminals^[12]. Treatment of a muscle with BTA results in functional denervation within 2 days and with peak effect after 4-6 weeks, leading to flaccid paralysis. This has been successfully used for several ocular and facial nerve disorders, as well as a range of other neuromuscular disorders including laryngeal, cervical and hand dystonia^[12]. The first experimental study reporting the benefits of BT and its application in abdominal wall repair was published by Cakmak et al.^[13] In a rat study, they demonstrated increased abdominal wall laxity after BTA injection in the lateral abdominal wall. The amount of intraperitoneal saline required to reach a fixed intraabdominal pressure after BTA administration was significantly higher than before treatment with BTA. The neurotoxin BTA results in a form of chemical component separation, causing relaxation of the lateral muscles of the abdominal wall. The first report of preoperative injection of BTA for AWR was by Ibarra-Hurtado et al.^[14]in 2009, where BTA was used to facilitate fascial closure in 12 patients. The lateral muscle paralysis achieved, and transverse hernia defect reduction in size, allowed for closure with minimal tension. BTA might also decrease pain after AWR and the need for narcotic analgesia. Besides blocking the release of acetylcholine, BTA also prevents release of the pain-modulating molecules calcitonin gene-related peptide and substance P from the presynaptic motor nerve terminal^[15].

The following review aims to summarize the literature regarding the clinical use of BTA in AWR, and assess the varying regimens, published effects, outcomes, and complications reported.

Methods

A literature review was performed using the PubMed Medline database. The following search and keyword techniques were used: [(“botulinum”) AND (“hernia”) NOT (“paraesophageal” OR “esophageal” OR “hiatal” OR “diaphragmatic” OR “disk”)]. We limited our review to studies written in English.

Our search yielded 47 articles, and 10 met our inclusion criteria for review^[14,16-24]. Two independent reviewers assessed the articles for inclusion. Studies that did not report outcomes of preoperative BTA use in AWR for ventral hernia were excluded. We also excluded review articles, case reports, cadaveric studies, and studies on groin hernias.

Two BTA products were utilized in the 10 studies included for analysis - onabotulinum toxin A (Botox®, Allergan, Dublin, Ireland) and abobotulinum toxin A (Dysport®, Ipsen, Boulogne-Billancourt, France). These two BTA products have varying potency and conversion to onabotulinum toxin A (Botox®, Allergan) dosing was performed based on the most commonly published conversion ratio of 1:3 onabotulinum toxin A:abobotulinum toxin A to report the total BTA units used in each study^[25].

Results

Discussion

Improving outcomes of AWR in large hernias starts with optimization of modifiable patient factors, such as weight loss, smoking cessation and controlling diabetes. Furthermore, to reduce complication and recurrence rates, the goal of AWR should be achievement of primary fascial closure with mesh reinforcement, instead of bridging the hernia defect with mesh^[26]. Both increased intrabdominal pressure, as well as morbid obesity which is associated with increased intrabdominal pressure, may play a role in the development of hernias and hernia recurrences^[27]. Different component separation techniques can be used to increase abdominal cavity volume and decrease intrabdominal pressure, but this necessitates destruction of the anatomical tissue planes of the abdominal wall^[28,29]. The use of BTA as a chemical rather than surgical technique for components separation achieves abdominal wall compliance by elongation and thinning of the musculature, although such application is currently off-label^[16].

While there are relatively few studies evaluating the efficacy of BTA in AWR, and no randomized controlled trials, the existing evidence remains promising. Studies evaluating abdominal wall muscle thickness and length were able to show significant differences after administration of BTA^{[16,18-22,24]}. As would be expected with these effects on the musculature, many studies then showed a decrease in the mean transverse defect size. In studies reporting fascial closure, all but one achieved very high success rates after pre-operative BTA. Zendejas et al.^[17] reported a low fascial closure rate in their BTA patients (40.9%), but this was not dissimilar from their propensity matched control group (36.4%). This raises the question of whether this lower fascial closure rate reflects surgeon preference and surgical technique as opposed to BTA treatment effect. Three studies, including the largest review to date by Bueno-Lledó et al.^[20,21], used PPP as an adjunct to BTA in AWR, which makes extrapolation of results to patients receiving BTA only difficult^[19]. Further limitations of this review include the significant amount of heterogeneity in regard to hernia characteristics, surgical techniques, and the type of mesh used. While BTA appears to be an effective adjunct therapy in AWR, none of the studies in this review detailed the selection criteria and hernia characteristics that may define patients who would benefit most from BTA injection.

There is significant variation in technique, number of sites and timing of injection in the reviewed articles. Functional denervation starts after 2 days and the effect peaks at approximately 2 weeks after BTA injection and lasts beyond 30 days^[12,30]. Injection at least 2 weeks prior to surgery seems most beneficial for AWR. Ultrasound guidance appears sufficient for targeted BTA injection and was used in all but one study. Guidance techniques should be based on the comfort of the provider however^[16-24]. All studies injected at least the EO and IO, with most injecting the TA as well. Theoretically, paralysis of all 3 layers of the lateral abdominal wall could interfere with the stabilizing function of the core abdominal muscles, potentially contributing to back pain and predisposing to injury, as hypothesized by Elstner et al.^[22] However, in large ventral hernias, this stabilizing function is likely already impaired due to disruption of the midline. If this is a concern in patients with pre-existing conditions, application of an abdominal binder or selective injection of the EO and IO can be performed, sparing the TA and its truncal stabilizing function. Elstner et al.^[22] found comparable results of two and three layer BTA injection in laparoscopic hernia repair. A total of at least 200 BTA units at a concentration of 2 U/mL or more was used in all studies. Since there is great heterogeneity in timing, sites and total BTA units injected in the studies, no conclusion on the optimal dose, concentration, sites, or target muscle layer(s) can be formulated. Furthermore, one study which assessed abdominal wall effects of BTA with both functional CT and EMG at 1-4 weeks after injection showed non-uniform distribution and duration of the induced paralysis^[31].

BTA has also been shown to prevent release of the pain-modulating molecules calcitonin gene-related peptide and substance P from the presynaptic motor nerve terminal and could have a positive effect on postoperative pain control^[15]. One study reported on post-operative pain and found promising results with decreased morphine use and pain reported in the short-term postoperative period. Nevertheless, the analgesic effects of BTA would benefit from further research^[17].

With the introduction of new medications for clinical use, patient safety is of utmost importance. The majority of studies did not report complications with the use of BTA and of those that did, they were minor in nature. Complaints after BTA injection included a mild cough or sneeze, bloating, and back pain, and nearly all resolved after application of an abdominal binder. However, serious adverse effects of BTA injection can occur and have been described after administration at other sites of the body. These adverse effects are often related to the specific injection site, non-sterile injection technique, or injection into infected tissue^[32]. Four cases of life-threatening botulism have occurred after injection of highly concentrated, unlicensed preparation of BTA for cosmetic purposes^[33]. Although the precise human lethal dose of crystalline BTA is not known, extrapolation from primate studies suggest an approximate intravenous or intramuscular lethal dose of 40 U/kg of BTA in humans^[34,35]. Therefore, for an average 70 kg human, the lethal dose would be 2800 units in total; in AWR, the maximum reported total dose used is 300 units of BTA, which is drastically lower than the described lethal dose. Proper storage of the product, selection of the correct dose, and proper administration techniques are necessary to prevent these adverse events when injecting BTA into the abdominal wall. Patients with neuromuscular junction disorders such as myasthenia gravis, Lambert-Eaton syndrome, and anterior horn disorders are particularly susceptible to the adverse events of botulinum toxin and should not be injected with BTA^[32].

Conclusion

The initial results of BTA use in AWR are promising and safe, with beneficial alterations to the abdominal wall and high rates of fascial closure, and only minor side effects reported. There remains much variance in BTA treatment regimens and at this time, a consensus on the dosage, technique, and timing of injection has yet to be reached. There remains a lack of high-level evidence and the existing literature is limited by studies with small sample sizes, unclear patient selection criteria, and treatment regimen heterogeneity.