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Botulinum Toxin inAbdominal Wall Hernia Repair
TalarTejirian andLouiseYeung
Introduction
Despite being one of the most potent biologic toxins, botulinum neurotoxin has been found to have a broad degree of versatility in clinical applications. Initial ideas for therapeutic use emerged as early as 1817, when the toxin was rst extracted from infected sausage and found to cause paralysis of skeletal muscle. The caus­ative agent, Clostridium botulinum, was not elucidated until 1895 and was given its name due to its association with sausage (botulus, sausage in Latin) [1]. From these humble beginnings, botulinum toxin now has a vast array of clinical uses in the elds of neurology, ophthalmology, gastroenterology, urology, orthopedics, derma­tology, pain management, plastic surgery, and, increasingly, general and hernia surgery.
22
Background andPharmacology
Botulinum toxin products are made up of a botulinum neurotoxin component in addition to various nontoxic complexing proteins. The pharmacological structure of botulinum is made up of an interconnected heavy and light amino chain acid with a disulde bridge [2].
Botulinum binds with high afnity to cholinergic nerve terminals, specically to
the glycoprotein structures, temporarily interrupting the transmission through the
T. Tejirian, M.D., F.A.C.S. (*) · L. Yeung, M.D., F.A.C.S. Department of Surgery, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA, USA e-mail: talar.x.tejirian@kp.org; louise.yeung@kp.org
© Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) 2019 S. S. Davis Jr. et al. (eds.), The SAGES Manual of Hernia Surgery,
https://doi.org/10.1007/978-3-319-78411-3_22
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T. Tejirian and L. Yeung
synapse and inhibiting the release of acetylcholine from the presynaptic terminal. Botulinum toxin also has the ability to block the cholinergic autonomic innervation of various glands and smooth muscles. Studies have also shown the effect of botuli­num toxin on pain transmitters. Effects of botulinum blockade have been described for substance P, glutamate, calcitonin gene-related peptide, and noradrenaline [2].
The toxin rst starts taking effect within 2–3days, with maximal effect at around 2weeks. The overall effect will start declining at around the 2.5-month mark, with fair consistency. Despite repeat or prolonged usage, no habituation effects are usually seen. However, antigens may be formed against botulinum toxin given that they consist of foreign protein. These antibodies may induce therapy failure by blocking the effects of the toxin. Only antibodies against the botulinum toxin itself (rather than those against the complexing proteins) will block the biologic activity and so are referred to as neutralizing antibodies. Risk factors for antibody-induced therapy failure include single dose and interjection interval, but do not include cumulative dose, treatment time, and patient age. Current studies show a frequency of immunogenicity of only 1–5% [3], less than previously thought; thus studies are emerging that support more frequent (<12weeks) or higher doses without as much fear of inducing treatment failure [4, 5].
The safety prole for botulinum toxin is fairly good, as the toxin binds with high afnity to the cholinergic nerve terminal. Local effects and unintended diffusion into adjacent sites may cause weakness in and around the target area [6]. It is pos­sible for small amounts to be distributed throughout the body via systemic circula­tion. This is usually only clinically apparent when extremely large amounts of botulinum toxin are used and is detected as increased jitter in muscles distant from the injection site [2]. Other systemic adverse effects are rare but include allergic reactions, generalized weakness, and inuenza-like symptoms. Caution should be exercised in patients with existing pareses such as myasthenia gravis, Lambert­Eaton syndrome, amyotrophic lateral sclerosis, or other myopathies or motor neu­ropathies [
7].
While there are seven serotypes of botulinum toxin, only types A and B are approved for medical uses. Four commercial botulinum toxin preparations are approved and available in the United States and European countries.
®
Onabotulinumtoxin A (trade name Botox
, Allergan Inc., Irvine, CA), abobotu­linumtoxin A (trade name Dysport®, Ipsen Ltd., Slough, UK), incobotulinumtoxin A (trade name Xeomin®, Merz Pharmaceuticals, Frankfurt, Germany), and rimabotulinumtoxin B (trade name Myobloc® or NeuroBloc®, US World Meds, Louisville, KY) have varying shelf lives between 24 and 36 months. Botox®, Dysport®, and Xeomin® act by cleaving synaptosomal-associated protein 25 on the A serotype, whereas Myobloc® or NeuroBloc® cleaves the vesicle-associated mem­brane protein on the B serotype. Additional preparations available elsewhere inter­nationally include Prosigne (Lanzhou Biological Products, China, Lanzhou, Gansu, China), Meditoxin or Neuronox (Medy-Tox, Seoul, Korea), and Botulax (letibotu­linumtoxin A; Hugel Inc., Chuncheon, Korea).
22 Botulinum Toxin inAbdominal Wall Hernia Repair
309
Applications inHernia Surgery
Hernia surgery is a rapidly developing subeld within the specialties of general and plastic surgery. With the advent of laparoscopic and robotic technologies, as well as advances made in biomedical technology and mesh development, evolving tech­niques are allowing surgeons to tackle more challenging and larger, more complex hernias than ever before, while still striving for excellent long-term outcomes.
Large hernias, whether primary or incisional in origin, pose a difcult challenge for repair. Up to 20% of patients undergoing laparotomy may develop an incisional hernia [8], with rates as high as 35% for those patients needing emergency procedures [9]. Additionally, factors such as obesity, diabetes, wound infection, immunosuppression, malignancy, smoking, and previous laparotomy will increase the risk of hernia devel­opment [10]. Simply performing a bridging repair, or closing an abdominal defect under too much tension, has a high rate of failure. Each previous failed hernia repair places a patient at increasingly higher risk of recurrence as the quality of the tissue declines from repeated dissection, mesh explantation, and fascial debridement and retraction [11]. The recurrence rate of incisional hernia was reported as 24% after rst repair, increasing to 35% after second and 39% after third attempted repair [12]. Hernia repair can be further complicated if the patient has “loss of domain.” While there is no explicit denition or precise measurement method for this, a generally accepted deni­tion is where 50% of the abdominal viscera reside outside the abdominal cavity [13]. The upper size limit of hernias that can be repaired takes many factors into consider­ation apart from absolute size, including the location of the hernia, orientation and number of defects, amount and compressibility of intra-abdominal contents, and the quality and compliance of the abdominal wall. If closure of the abdominal fascia is successfully accomplished, additional risks remain. These include abdominal compart­ment syndrome if intra- abdominal pressures are too high after closure, or ap necrosis and donor site morbidity in the case of myofascial cutaneous ap closure [14].
With these considerations in mind, there has been interest in increasing abdominal wall compliance or expanding the amount of tissue within the abdominal wall. Lengthening the abdominal wall musculature may allow for primary fascial closure and thus, the best chance for successful hernia repair. This is currently describing in the lit­erature by using one of three methods—progressive preoperative pneumoperitoneum (PPP) [15, 16], tissue expanders [15, 17], and botulinum toxin A (BTA) [18, 19]. The remainder of this chapter will focus on the role of botulinum toxin A in hernia repair.
Technique ofInjection
Anatomy
The abdominal wall musculature is divided into the medial and lateral components. Medially the rectus abdominis muscle is surrounded by the anterior and posterior fascia. At the lateral edge of the rectus abdominis muscle, the fascial layers fuse to
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T. Tejirian and L. Yeung
form the linea semilunaris and then split to surround the muscles of the lateral com­partment. Three muscle layers comprise the lateral abdominal wall, which is the focus of the area of the BTA injection. Anterior to posterior the muscular layers are as follows: external oblique, internal oblique, and transversus abdominis.
Our Technique
One month before planned incisional hernia repair, BTA injection is performed under sterile technique using ultrasound guidance in the interventional radiology suite. The entire abdomen and bilateral anks are prepped and draped after mid­azolam and fentanyl are administered. The planned tract is anesthetized with 1% lidocaine. BTA solution is prepared by diluting 100–150 units of onabotulinum­toxin A (Botox®) into 100units of preservative-free sterile saline. Three locations are chosen along the lateral abdominal wall utilizing ultrasound guidance to identify all three muscle layers. Using a 21 gauze 7cm needle attached to the BTA/saline solution, the three layers of the abdominal wall are traversed at an angle while visu­alized under ultrasound. Care is taken not to violate the peritoneum. Injection is started in the transversus muscle, visualizing the solution bathing the muscle bers. The injection is continuous as the needle is slowly pulled back into the internal oblique then external oblique muscles, with uninterrupted ultrasound visualization of the injection. This is repeated for the two other locations on the unilateral side. The identical procedure is performed on the contralateral lateral abdominal wall, totaling six injection sites and 200–300units of BTA.Three hundred units are cho­sen unless the patient is small and frail with thinned muscle layers.
Data andOutcomes
The rst trial experimenting with the use of botulinum toxin for the abdominal wall was performed in 2006. In this study, BTA was injected into the abdominal wall of rats to evaluate if muscle paralysis could decrease intra-abdominal pressure and increase intra-abdominal volume. Despite only a 3-day study period, the authors found signicant differences in the pressure and volume between the control and BTA groups [20]. In 2009, Ibarra etal. published the landmark paper describing BTA injection before abdominal wall reconstruction for hernia repair. Twelve patients had bilateral BTA injection under electromyographic guidance. The rst two patients underwent weekly transverse hernia measurements, and the authors noted no further reduction after 4weeks. The next ten patients underwent a CT scan 4weeks after BTA injection and were noted to have a mean decrease of >5cm for the transverse hernia defect. There were no complications related to the BTA injec­tion [18]. Since this publication, the literature for the use of BTA on the abdominal wall is increasing; however the research is very heterogeneous.
22 Botulinum Toxin inAbdominal Wall Hernia Repair
311
Studies Involving Ventral/Incisional Hernia Repair andBTA
In addition to the landmark study above, additional studies showed the abdominal wall changes that occur after BTA injection. Pre- and post-BTA injection CT scans have shown an increase in the length of the abdominal wall. Ibarra-Hurtado showed a mean increase in muscle length of about 2.5cm per side. Other studies showed an increase of 4cm per side [11, 2123]. Ibarra-Hurtado also showed a reduction of the lateral abdominal muscle thickness by 1 cm [24]. This translates into both an increase in the abdominal wall volume and improved compliance. Both Ibarra stud­ies reported they were able to close the abdominal wall defect either by open simple closure or Rives-Stoppa; however some patients required abdominal wall compo­nents separation. Four studies from the same group, published in 2016 and 2017, include up to 56 patients with each subsequent study examining updated outcomes from a cumulative patient population. While some of the specic methodology details are unclear in the individual papers, the largest cohort of 56 patients allows for a more detailed breakdown of the several arms of treatment. The study included patients who received 200units of BTA versus 300units of BTA and another group that received BTA and PPP.CT scan measurements were done for all participants before and after BTA to check the amount of muscle lengthening and the size of the defect. In all of this group’s studies, the patients underwent laparoscopic or hybrid laparoscopic-open-laparoscopic repair of the hernia with intraperitoneal onlay mesh. If the defect was not able to be closed primarily, then an endoscopic compo­nent release was performed [11, 2123]. In one of these studies, Elstner et al. reported up to a 58% decrease in the hernia defect size on CT scan [11].
Studies have been published where BTA injection was coupled with PPP when repairing larger hernias. The data in these papers is difcult to interpret as it is unclear how much each of the two adjuncts individually contributed to reestablish­ing enough domain to repair the complex hernias [11, 25].
Timing ofInjection
As BTA does not work immediately, the timing of the injection in relation to the hernia repair needs to be considered. It takes 2weeks to get the maximal clinical effectiveness of BTA; however Ibarra etal. found that the changes in the abdominal wall could take place up to 4weeks. Therefore their recommendation was to per­form the operation 1month after BTA injection, which was their practice in both studies [18, 24]. The studies authored by Ibrahim reported injection 1–4weeks prior to the planned repair except for one that reports injections were done between 7 and 14days preoperatively [11, 2123]. In contrast, Zendejas etal. published results of 22 patients who underwent BTA injection, where 13 patients had the injection the same day as the operation [26]. Only nine patients underwent preoperative injection 1–19days beforehand. As it is unlikely that the benets of the BTA injection were
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T. Tejirian and L. Yeung
present during the operation for most of these patients, the authors could not com­ment on hernia defect or abdominal wall musculature changes. Their focus was on evaluating postoperative pain and nding decreases in pain on hospital days #2 and #5 compared to controls.
Other Uses
One additional area of interest is the use of BTA specically in patients with an acute open abdomen. Zielinski etal. performed BTA injection in 18 patients with open abdomens resulting from acute surgical diseases. After patients underwent initial laparotomy, a negative-pressure dressing or Wittman patch was placed and resuscitation completed for at least 12–24 h. BTA injection was performed after resuscitation was complete. The lateral abdominal muscle complex on each side was injected with 150units of onabotulinumtoxin A (Botox®) divided into three locations, for a total of 300units over the entire abdomen. The authors reported half the patients underwent BTA injection within 24h of the rst laparotomy, and overall they achieved an 83% fascial closure rate with one to eight serial abdominal explo­rations [27].
In addition to aiding in the closure of the abdominal wall, BTA injection has other potential benets as well. One benet may result from the fact that BTA paral­ysis lasts 3–6months, working not only preoperatively but extending benets post­operatively as well. Normally, the lateral abdominal wall muscle complex, when active, leads to forces of lateral retraction which is opposed by the linea alba [28]. When the linea alba is reapproximated with the hernia repair, it needs time to remodel and scar together. With the lateral paralysis in place, it allows the linea alba to heal for several months without the constant lateral forces. This can theoretically decrease hernia recurrence or separation of the reapproximated linea alba.
A second potential benet is in the ability of BTA to modulate pain. BTA is known to inhibit substance P and calcitonin gene-related peptide. These molecules are factors involved in inammation and pain sensation. BTA has already been shown to help in other myofascial and muscular pain syndromes; therefore it is very possible that the BTA injection can decrease postoperative pain and potentially lower opioid requirements [2932]. A case report of a patient who received 300units of onabotulinumtoxin A (Botox signicant and durable decrease in pain [33]. Additionally, BTA injection has been described for abdominal cutaneous nerve entrapment syndrome; however the effects of BTA in this syndrome were not evaluated [34].
®
) after laparoscopic ventral hernia repair reported a
Reported Techniques ofInjection andFormulations
The original description of the injection by Ibarra etal. involved using electromy­ography to identify ve points of maximum activity on each side of the lateral abdominal muscle complexes. Each side was injected with 250 units of
22 Botulinum Toxin inAbdominal Wall Hernia Repair
313
abobotulinumtoxin A (Dysport®) with 50units at each site. Total amount of bilateral abobotulinumtoxin A (Dysport®) was 500units diluted in 5ml of saline for a con­centration of 100 units/ml. The second study by Ibarra et al. describes the same technique except with ultrasound-guided injection at ve points placing the injec­tion between the external and internal oblique muscles. Other authors all describe a
®
similar technique of injecting 150units of onabotulinumtoxin A (Botox
) diluted in saline to a concentration of 2units/ml into each lateral abdominal wall muscular complex at three points, totaling 300units injected into six points. At each point, ultrasound guidance is used to insure injection into all three muscle layers [11, 21
23, 26, 27, 33]. Ibrahim does report some use of an equivalent use of abobotulinum-
®
toxin A (Dysport
) instead of onabotulinumtoxin A (Botox®). There is one paper with CT comparisons of patients who received 200units versus 300units of ona­botulinumtoxin A (Botox®). Average gain in the lateral muscle length via CT mea­surement was 3.6cm in the 200-unit group and 4.4 cm in the 300-unit group, a statistically signicant difference [23]. There are no reports of use of incobotu-
®
linumtoxin A (Xeomin
) for the abdominal wall.
Specific Safety Considerations inAbdominal Hernia Use
None of the authors have described any complications from the use of BTA injec­tions. There are potential risks that should be disclosed to all patients. As with any procedure, there are always risks of infection, bleeding, and pain. There is also a low but possible risk of peritoneal violation and damage to intra-abdominal struc­tures such as intestine. Overall BTA has a very good safety prole, but it should be noted that injection of the abdominal wall for hernia repair is an off-label use. There is also the theoretical risk of the spread of BTA from the injection site leading to symptoms of botulism such as asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and difculty breath­ing. There is the highly unlikely but possible risk of death. There are several contra­indications for the use of BTA.Specically for onabotulinumtoxin A (Botox label recommends that adult patients receive no more than 400units in a 3-month period. There are also patients who have hypersensitivity reactions such as anaphy­laxis or urticaria. Caution is necessary for patients with pre-existing neuromuscular disorders as they are at risk of increased clinically signicant effects similar to botu­lism. A careful history to rule out peripheral motor neuropathic diseases, amyo­trophic lateral sclerosis, or neuromuscular junction disorders such as myasthenia gravis or Lambert-Eaton syndrome is important. BTA should not be used in women
®
that are pregnant or breastfeeding. Onabotulinumtoxin A (Botox
), incobotulinum­toxin A (Xeomin®), and abobotulinumtoxin A (Dysport®) contain albumin, which is a derivative of human blood so there are very unlikely but theoretical risks of trans­mission of illnesses. Additionally, there is the potential of developing antibodies against onabotulinumtoxin A (Botox
®
) and abobotulinumtoxin A (Dysport®) that may reduce the efcacy of future use. While incobotulinumtoxin A (Xeomin®) has a much lower reported rate of antibody formation, it has been observed [35].
®
), the
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T. Tejirian and L. Yeung
Antibody formation increases when higher doses are given at shorter intervals. Administering BTA and aminoglycosides such as gentamicin can potentiate the toxin effects. As abobotulinumtoxin A (Dysport®) may contain trace amounts of cow’s milk protein, it has the unique contraindication of requiring caution in those who are allergic. The units of abobotulinumtoxin A (Dysport®) and incobotulinum­toxin A (Xeomin®) are unique to its preparation and therefore are not interchange­able with other BTA medications such as onabotulinumtoxin A (Botox®). Additionally, abobotulinumtoxin A (Dysport®) warnings include potential immune reaction with intradermal use only.
Conclusion
BTA holds a promising role in complex hernia repair. Although data is limited, all evidence points to a good safety prole, and there are both subjective and objective benets to its use. Future directions for investigation would need to elucidate optimum dosage, timing of administration and further clarify patient selection guidelines.
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