A systematic review and meta-analysis of technical aspects and clinical outcomes of botulinum toxin prior to abdominal wall reconstruction

This systematic review and meta-analyses are conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [11]. A concise description of the study protocol was registered to the International Prospective Register of Systematic Reviews (PROSPERO registration number CRD42020198246).

Studies that describe the injection of BTA into the lateral abdominal wall muscles in ≥ 5 patients were eligible for inclusion. Eligibility was regardless of clinical scenario. Studies reporting in any other than European language, non-human studies, and conference abstracts were excluded.

For the second objective, we selected only those studies that describe the intramuscular injection of BTA in patients with a ventral incisional hernia and report computed tomography (CT) measures obtained both before- and after BTA treatment. Studies that describe patients with an abdominal wall defect other than a ventral hernia were analyzed only for other endpoints (BTA techniques and regimens). Studies that use concomitant progressive pneumoperitoneum (PPP) besides BTA were analyzed separately.

The PubMed (Medline), EMBASE (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), and CINAHL (EBSCO) databases were searched without date or language restrictions. The search was finalized on March 23, 2021. The search strategy includes the free text and index terms: abdominal hernia, ventral hernia, midline hernia, incisional hernia, botox, and botulinum toxin (see Supplementary Information 1, which demonstrates the full PubMed search strategy).

Two reviewers (AST and JJMC) independently considered the studies—that were identified by the search strategy—for eligibility. If title and abstract showed potential eligibility or eligibility was in doubt, the full text was assessed for final decision. If studies showed ineligibility during full-text assessment, the reasons were documented. Groups that published more than one eligible study were contacted to ensure that only the most recent study describing the same (subgroup of) patients was included. Discrepancies were resolved through discussion.

Data were collected in duplicate by two reviewers (AST and JJMC) using a predefined data extraction form. Only aggregate data from the original manuscripts were collected. After independent data collection, data were compared, checked for, and discrepancies were resolved through discussion.

Study characteristics: year of publication, study design, sample size, and participant specification.

BTA characteristics: indication, type of BTA, dosage, injected volume, number of injections, injected muscles, radiological guidance, assessment of intramuscular distribution, direct complications, use of concomitant PPP, and timing prior to surgery. CT measures: transverse hernia width, lateral abdominal wall muscle length (measured along the inner surface from the quadratus lumborum to the rectus abdominis) and thickness (measured from the inner side of the transversus abdominis to the outer side of the external oblique), intra-abdominal width, intra-abdominal volume, hernia volume, and loss of domain. Surgical outcomes: type of surgical repair, CST, use of mesh, fascial closure rate, postoperative pain medication, follow-up, and hernia recurrence.

The risk of bias in the RCT was assessed using the revised Cochrane risk of bias tool (RoB 2) [12]. The body of evidence was assessed using the Newcastle–Ottawa Quality Assessment Form [13].

The primary search yielded 714 results. After removal of duplicates, titles and abstracts of 584 studies were screened. Following full-text assessment of 63 studies, 23 studies were included (Fig. 1).

Study- and patient characteristics are presented in Table 1. We identified one RCT [14], two prospective comparative studies [15, 16], three retrospective comparative studies [17‐19], six prospective cohort studies [7, 20‐24], and eleven retrospective cohort studies [25‐35], all published between 2009 and 2021. Eighteen studies describe the injection of BTA to optimize patients prior to ventral hernia repair and one study [19] performs intraoperative BTA injections during open hernia repair. Two studies [14, 32] describe the use of BTA in patients with an open abdomen following damage-control laparotomy (DCL), one study [24] describes patients with giant inguinoscrotal hernia, and one study [34] describes a combination of ventral, flank and inguinal hernia. Combined, the 23 studies include 995 patients of which 664 have been treated with BTA. The median defect width from 15 studies [7, 16‐23, 25‐30] that exclusively describe patients with a midline ventral hernia is 13.9 cm (IQR 11.4–14.7). Seven [15, 18, 24‐26, 30, 31] of 20 studies that inject BTA prior to a hernia repair report a specific indication for the use of BTA. These indications vary between expected difficulty obtaining midline closure to a specific hernia width with or without loss of domain.

Botulinum injection techniques and treatment regimens are presented in Table 2. Sixteen studies [14, 16‐21, 24, 26‐32, 34] use onabotulinumtoxin A (Botox^®, Allergan, Dublin, Ireland) with a dose varying between 100 and 300 units. Five studies [7, 15, 22, 25, 35] use 500 units of abobotulinumtoxin A (Dysport^®, IPSEN, Boulogne-Billancourt, France), one study [23] uses 100 units of incobotulinumtoxinA (Xeomin^® Merz Pharmaceuticals GmbH, Frankfurt, Germany), and one study uses 400 units of BTA but does not specify the brand [33]. The median volume in which BTA is diluted for injection is 150 mL (IQR 52.5–150). Thirteen studies [14, 16‐18, 20, 21, 23, 24, 26, 31, 32, 34, 35] perform three injections bilaterally, located on the anterior axillary line, between the costal border and iliac spine. Four studies [7, 15, 22, 28] perform five injections bilaterally, two on the anterior axillary line and three over the external oblique muscle. One study [30] uses three-to-five injection bilaterally. Fifteen studies [14, 15, 17, 18, 20, 21, 24‐26, 30‐35] inject all three muscles (external oblique, internal oblique and transversus abdominis), whereas two studies [22, 27] spare the transversus abdominis from injection. One study [16] specifically investigates the standard three-layer against the selective two-layer muscle injection. In the elective setting, BTA is generally injected about 4 weeks preoperatively (range 0–6 weeks). In patients with an open abdomen, BTA is injected within 2 days following the DCL. Injections are predominantly performed under ultrasonographic (US) guidance. Two studies [15, 25] use additional electromyographic guidance (EMG), two studies [7, 28] exclusively use EMG, one study [18] describes guidance with low dose CT, and one study [19] injects BTA intraoperative under direct visualization. None of the studies report procedural visualization of intramuscular spread. Sixteen studies [14‐17, 20‐22, 24‐27, 29‐32, 34] report to have observed no direct major complications following the injections. Four studies [16, 20, 21, 30] do however describe that patients commonly report pain immediately after the injection, a feeling of abdominal distension or bloating, weaker cough or sneeze, and back pain. Not one of these side effects required intervention. Additional PPP is performed in five studies [24, 25, 31, 33, 35].

The body of evidence was rated good in three studies [15, 17, 18], fair in one study [14], and poor in nineteen studies [7, 16, 19‐35], ranging from three to seven stars using the Newcastle–Ottawa ranking scale (see Supplementary Information 2, which demonstrates the full body of evidence assessment). Most studies lack a control group for comparison. A follow-up time shorter than 1 year was deemed inadequate in studies that describe patients with ventral hernia. Additional risk of bias assessment of the RCT showed ‘some risk of bias’ in the selection of reported results, and low risk of bias in all other domains.

Two studies on ventral hernia patients [31, 35] investigate the combined effect of BTA and PPP. They find a mean increase in length of the lateral abdominal wall of 3.1 cm per side for ventral hernia patients also undergoing PPP. Two studies report contradicting outcomes regarding transverse hernia width. One study [25] finds a non-significant reduction of 1.0 cm (p = 0.455), while another study [35] reports a significant increase in hernia width of 5.0 cm (p = 0.015). Two studies find a significant reduction of loss of domain after the combined treatment of BTA and PPP. Expressing loss of domain as described by Tanaka et al. [36], one study [25] reports a reduction from 29.1 to 14.1% (p = 0.001), and another study [24] a reduction from 28.1 to 22.8% (p < 0.01).

Surgical data and clinical outcomes of the 19 studies that investigate BTA in ventral hernia patients are presented in Table 3. Described surgical techniques are open repair [7, 15, 17, 22, 23, 25, 26, 28‐31, 35], laparoscopic or laparoscopic-assisted repair [16, 20, 21], and totally extracorporeal minimally invasive repair [27]. Thirteen of nineteen studies [15‐17, 19‐21, 23, 25, 27‐31] describe the use of mesh in all repairs, whereas in three studies [18, 22, 35], meshes are used in selected patients only. Sixteen studies describe performed CST. In these studies, 48% (IQR 25.3–69.5) of patients underwent a CST (specific types and percentages are presented in Table 3).

Meta-analysis of three studies [15, 17, 18], which directly compare ventral hernia patients with and without BTA pretreatment, shows that BTA (without PPP) significantly increases fascial closure rate [RR 1.08 (95% CI 1.02–1.16, I² = 0%, p = 0.02)] (Fig. 4).

In 14 studies [7, 16‐18, 20‐23, 25‐30], which describe 420 BTA pretreated ventral hernia patients (without PPP), the median preoperative defect width is 13.9 cm (IQR 11.4–14.6), and fascial closure is achieved in 100% (IQR 88.5–100). During a median follow-up of 19.0 months (IQR 11.6–24.0), their median hernia recurrence rate is 0% (IQR 0–9).

In a prospective study, Bueno-Lledo et al. [15] include 80 patients with a large midline incisional hernia (11–17 cm). Forty patients were pretreated with BTA followed by retrorectus repair, without CST, 4 weeks later. The other 40 patients did not receive BTA and underwent modified anterior CST followed by onlay mesh repair. Baseline demographics do not differ between both groups. Fascial closure is achieved in all 40 patients treated with BTA and in 38 patients of the control group (p = 0.372). The only significantly different outcome between both groups is the number of patients with wound dehiscence requiring reoperation, being lower in the BTA group (0 vs 4, p = 0.031).

In a propensity-score matched study, Deerenberg et al. [18] retrospectively investigate the fascial closure rate in patients with large ventral hernia with (n = 75) and without (n = 145) BTA. Patients from both groups were matched according to BMI, hernia width, and loss of domain. Fascial closure is achieved significantly more often in patients treated with BTA (92% vs 81%, p = 0.036).

In the retrospective case-controlled study by Zendejas et al. [17], 22 patients with ventral incisional hernia that had received preoperative BTA are matched with 66 controls, based on age, sex, BMI, history of hernia recurrence, and type of repair (open vs. laparoscopic). Patients treated with BTA required significantly less opioid analgesia on postoperative day 2 and 5, and reported significantly less pain on day 2 and 4. No differences in postoperative wound complications and hernia recurrence are observed.

Blaha et al. [19] specifically investigate the analgesic effect of BTA in patients undergoing open ventral hernia repair. Retrospectively, 19 patients in which BTA is injected bilateral into the oblique- and rectus muscles under direct visualization during surgery are compared to 22 controls. No significant difference is observed in postoperative pain scores nor use of morphine equivalent up to 5 days.

The double-blinded RCT by Zielinski et al. [14] describes 46 patients with an open abdomen following damage-control laparotomy (DCL). On average 1.8 days after DCL, the lateral abdominal wall muscles are injected with either BTA or normal saline. No differences in cumulative 10-day fascial closure rate nor length of hospital stay were observed. Also, throughout the first 5 days following DCL, there was no difference in morphine equivalent use.