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Botulinum Toxin inAbdominal Wall
Hernia Repair
TalarTejirian andLouiseYeung
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 andPharmacology
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
disulde bridge [2].
Botulinum binds with high afnity to cholinergic nerve terminals, specically 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
307

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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 2–3days, with maximal effect at
around 2weeks. 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
(<12weeks) or higher doses without as much fear of inducing treatment failure
[4, 5].
The safety prole for botulinum toxin is fairly good, as the toxin binds with high
afnity 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 inuenza-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 inAbdominal Wall Hernia Repair
309
Applications inHernia Surgery
Hernia surgery is a rapidly developing subeld 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 difcult 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 denition or precise measurement method for this, a generally accepted denition 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 ofInjection
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 100units 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 7cm 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 200–300units of BTA.Three hundred units are chosen unless the patient is small and frail with thinned muscle layers.
Data andOutcomes
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 signicant differences in the pressure and volume between the control and
BTA groups [20]. In 2009, Ibarra etal. 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 4weeks. The next ten patients underwent a CT scan
4weeks after BTA injection and were noted to have a mean decrease of >5cm 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 inAbdominal Wall Hernia Repair
311
Studies Involving Ventral/Incisional Hernia Repair andBTA
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 2.5cm per side. Other studies showed an
increase of 4cm per side [11, 21–23]. 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 specic 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 200units of BTA versus 300units 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, 21–23]. 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 difcult 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 ofInjection
As BTA does not work immediately, the timing of the injection in relation to the
hernia repair needs to be considered. It takes 2weeks to get the maximal clinical
effectiveness of BTA; however Ibarra etal. found that the changes in the abdominal
wall could take place up to 4weeks. Therefore their recommendation was to perform the operation 1month after BTA injection, which was their practice in both
studies [18, 24]. The studies authored by Ibrahim reported injection 1–4weeks prior
to the planned repair except for one that reports injections were done between 7 and
14days preoperatively [11, 21–23]. In contrast, Zendejas etal. 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
1–19days beforehand. As it is unlikely that the benets 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 specically in patients with an
acute open abdomen. Zielinski etal. 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 150units of onabotulinumtoxin A (Botox®) divided into three
locations, for a total of 300units over the entire abdomen. The authors reported half
the patients underwent BTA injection within 24h 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 benets as well. One benet may result from the fact that BTA paralysis lasts 3–6months, working not only preoperatively but extending benets 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 benet 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 inammation 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 [29–32]. A case report of a patient who received 300units
of onabotulinumtoxin A (Botox
signicant 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 ofInjection andFormulations
The original description of the injection by Ibarra etal. 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 inAbdominal Wall Hernia Repair
313
abobotulinumtoxin A (Dysport®) with 50units at each site. Total amount of bilateral
abobotulinumtoxin A (Dysport®) was 500units diluted in 5ml 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 150units of onabotulinumtoxin A (Botox
) diluted in
saline to a concentration of 2units/ml into each lateral abdominal wall muscular
complex at three points, totaling 300units 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 200units versus 300units of onabotulinumtoxin A (Botox®). Average gain in the lateral muscle length via CT measurement was 3.6cm in the 200-unit group and 4.4 cm in the 300-unit group, a
statistically signicant difference [23]. There are no reports of use of incobotu-
®
linumtoxin A (Xeomin
) for the abdominal wall.
Specific Safety Considerations inAbdominal 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 prole, 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 difculty breathing. There is the highly unlikely but possible risk of death. There are several contraindications for the use of BTA.Specically for onabotulinumtoxin A (Botox
label recommends that adult patients receive no more than 400units 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 signicant 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 efcacy 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 prole, and there are both subjective and
objective benets 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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